Evaluation of vascular effects after photodynamic and photothermal therapies using benzoporphyrin derivative monoacid ring A on a rodent dorsal skinfold model

NASA Astrophysics Data System (ADS)

Smith, Tia K.; Choi, Bernard; Ramirez-San-Juan, Julio C.; Nelson, John S.; Kelly, Kristen M.

2005-04-01

Background and Objectives: Pulsed dye laser (PDL) irradiation is the standard clinical treatment for vascular lesions. However, PDL treatment of port wine stain birthmarks (PWS) is variable and unpredictable. Photodynamic therapy (PDT) using benzoporphyrin derivative monoacid ring A (BPD) and yellow light may induce substantial vascular effects and potentially offer a more effective treatment. In this study, we utilize a rodent dorsal skinfold model to evaluate the vascular effects of BPD-PDT at 576 nm as compared to PDL. Study Design/Materials and Methods: A dorsal skinfold window was created on the backs of female Sprague-Dawley rats, allowing epidermal and subdermal irradiation and subdermal imaging. One mg/kg BPD was administered intravenously via a jugular venous catheter. Study groups were: control (no BPD, no light), PDL (585 nm, τp 1.5 ms, 10 J/cm2), and PDT (BPD + continuous wave irradiation (CW) at 576nm, τp 16 min, 96 J/cm2). Vessels were imaged and assessed for damage using laser speckle imaging (LSI) before, immediately after, and 18 hours post-intervention. Results: Epidermal irradiation was accomplished without blistering, scabbing or ulceration. PDL and PDT resulted in similar reductions in vascular perfusion 18 hours post-intervention (34.6% and 33.4%, respectively). Conclusions: BPD-PDT can achieve safe and selective vascular effects and may offer an alternative therapeutic option for treatment of hypervascular skin lesions including PWS birthmarks.

Extended use up to 5 years of the etonogestrel-releasing subdermal contraceptive implant: comparison to levonorgestrel-releasing subdermal implant.

PubMed

Ali, Moazzam; Akin, Ayse; Bahamondes, Luis; Brache, Vivian; Habib, Ndema; Landoulsi, Sihem; Hubacher, David

2016-11-01

Is it possible to extend the use of the 3-year one-rod etonogestrel (ENG)-releasing subdermal contraceptive implant to 5 years? The extended use of the one-rod ENG-releasing subdermal contraceptive implant showed 100% efficacy in years 4 and 5. The initial regulated trials on the ENG-releasing subdermal contraceptive implant conducted in the 1990 s were designed to measure cumulative 3-year efficacy. The ENG-implant has both well established safety and efficacy for up to 3 years. Pharmacokinetic data on ENG show high levels at 3 years and some previous clinical research confirms efficacy beyond the current approved duration of 3 years. Today, many women, because the labeled duration has been reached, have the ENG implant removed at 3 years, increasing costs, inconvenience and risks. For the first 3 years, this study was an open-label, multi-centre randomized trial comparing the 3-year ENG implant to the 5-year levonorgestrel (LNG)-releasing implant. After 3 years, a subset of 390 ENG participants, consented to extended use. We compared efficacy, side effects and removal procedures of both implants. We used Kaplan-Meier (K-M) analysis. We included an observational cohort of copper intrauterine device (IUD) users as non-users of hormonal contraceptive method for comparative purposes. The study took place in family planning clinics in seven countries worldwide. Women were enlisted after an eligibility check and informed consent, and 1328 women were enrolled: 390, 522 and 416 in the ENG-implant, LNG-implant and IUD groups, respectively. Over 200 women used the ENG implant for at least 5 years. No pregnancies occurred during the additional 2 years of follow up in the ENG or LNG implant group. The overall 5-year K-M cumulative pregnancy rates for ENG- and LNG- implants were 0.6 per 100 women-years (W-Y) [95% confidence interval (CI): 0.2-1.8] and 0.8 per 100 W-Y [95% CI: 0.2-2.3], respectively. Complaints of bleeding changes were similar; however, ENG-users were more likely than LNG-users to experience heavy bleeding (p < 0.05). The median duration of the implant removal procedure was 64 seconds shorter for the one-rod ENG-implant (inter-quartile range (IQR) = 30.5, 117.5) compared to the two-rod LNG product (IQR = 77.0, 180.0). The 2-year rate for pregnancy in the IUD group compared with the two implant groups combined was 4.1 per 100 W-Y [95% CI: 2.5-6.5]. Few women were ≤19 years old or nulligravida. Although there was no weight limit for enrolment in the study, the number of women ≥70 kg were few. The results from this study corroborate previous evidence showing high contraceptive efficacy through 4 years for the ENG-implant. Data through 5 years are a novel contribution and further proof of the product's capability to provide safe and effective contraception that rivals the current 5-year LNG-subdermal implant. The findings provide valuable information for policy makers, family planning programmers and clinicians that the ENG-releasing subdermal implant is still highly effective up to 5 years after insertion. Compared to previous efforts, our study population was geographically diverse and our study had the highest number of participants completing at least 5 years of use. The trial was registered as ISRCTN33378571. The contraceptive devices and funds for conduct of the study were provided by the United Nations Development Programme/United Nations Population Fund/World Health Organization (WHO)/UNICEF/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR), WHO. This report contains the collective views of an international group of experts, and does not necessarily represent the decisions or the stated policy of the WHO. All stated authors have no conflict of interest, except Dr Hubacher who reported grants from United States Agency for International Development, during the conduct of the study; other from Advisory Boards (Teva, Bayer, OCON), outside the submitted work. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Comparing the Tolerability of a Novel Wound Closure Device Using a Porcine Wound Model

PubMed Central

Townsend, Katy L.; Akeroyd, Jen; Russell, Duncan S.; Kruzic, Jamie J.; Robertson, Bria L.; Lear, William

2018-01-01

Objective: To compare the tolerability and mechanical tensile strength of acute skin wounds closed with nylon suture plus a novel suture bridge device (SBD) with acute skin wounds closed with nylon suture in a porcine model. Approach: Four Yucatan pigs each received 12 4.5 cm full-thickness incisions that were closed with 1 of 4 options: Suture bridge with nylon, suture bridge with nylon and subdermal polyglactin, nylon simple interrupted, and nylon simple interrupted with subdermal polyglactin. Epithelial reaction, inflammation, and scarring were examined histologically at days 10 and 42. Wound strength was examined mechanically at days 10 and 42 on ex vivo wounds from euthanized pigs. Results: Histopathology in the suture entry/exit planes showed greater dermal inflammation with a simple interrupted nylon suture retained for 42 days compared with the SBD retained for 42 days (p < 0.03). While tensile wound strength in the device and suture groups were similar at day 10, wounds closed with the devices were nearly 8 times stronger at day 42 compared with day 10 (p < 0.001). Innovation: A novel SBD optimized for cutaneous wound closure that protects the skin surface from suture strands, forms a protective bridge over the healing wound edges, and knotlessly clamps sutures. Conclusion: This study suggests that the use of a SBD increases the tolerability of nylon sutures in porcine acute skin wound closures allowing for prolonged mechanical support of the wound. For slow healing wounds, this may prevent skin wound disruption, such as edge necrosis and dehiscence. PMID:29892494

Development, validation and utilization of a highly sensitive LC-MS/MS method for quantification of levonorgestrel released from a subdermal implant in human plasma.

PubMed

Cirrincione, Lauren R; Penchala, Sujan Dilly; Scarsi, Kimberly K; Podany, Anthony T; Winchester, Lee C; Back, David J; Khoo, Saye H; Fletcher, Courtney V; Siccardi, Marco; Else, Laura J

2018-05-01

Levonorgestrel (LNG) is a synthetic progestin that is available in oral contraceptive tablets, a subdermal implant, and an intrauterine system for contraception. LNG pharmacokinetics are a pivotal determinant of contraceptive efficacy and essential in assessing drug-drug interactions influencing LNG exposure following different routes of LNG administration. A highly sensitive LC-MS/MS method was developed and validated to quantify levonorgestrel in human plasma. Liquid-liquid extraction was utilized with a sample volume of 500 μL to extract levonorgestrel from plasma. Chromatographic separation of LNG was achieved with a Fortis™ C18 (3 μm: 100 mm × 2.1 mm) reverse phase analytical column. The mobile phases consisted of de-ionized water plus 0.1% NH 4 OH (100:0.1%, v/v) (A), and methanol plus 0.1% NH 4 OH (100:0.1%, v/v) (B) delivered as a gradient at a flow rate of 400 μL/min. Detection of LNG and internal standard (D-(-)-norgestrel-d7) was achieved using positive polarity mode monitoring at 313.2-245.2 amu and 320.1-251.2 amu, respectively. The assay was linear over the calibration range of 49.6 to 1500 pg/mL. This method was used to quantify plasma LNG released by subdermal implant in support of a drug interaction study among women with HIV receiving efavirenz- or nevirapine-based antiretroviral therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

Ultrasound appearances of Implanon implanted contraceptive devices.

PubMed

McNeill, G; Ward, E; Halpenny, D; Snow, A; Torreggiani, W

2009-01-01

Subdermal contraceptive devices represent a popular choice of contraception. Whilst often removed without the use of imaging, circumstances exist where imaging is required. Ultrasound is the modality of choice. The optimal technique and typical sonographic appearances are detailed in this article.

Extended use up to 5 years of the etonogestrel-releasing subdermal contraceptive implant: comparison to levonorgestrel-releasing subdermal implant

PubMed Central

Ali, Moazzam; Akin, Ayse; Bahamondes, Luis; Brache, Vivian; Habib, Ndema; Landoulsi, Sihem; Hubacher, David

2016-01-01

STUDY QUESTION Is it possible to extend the use of the 3-year one-rod etonogestrel (ENG)-releasing subdermal contraceptive implant to 5 years? SUMMARY ANSWER The extended use of the one-rod ENG-releasing subdermal contraceptive implant showed 100% efficacy in years 4 and 5. WHAT IS KNOWN ALREADY The initial regulated trials on the ENG-releasing subdermal contraceptive implant conducted in the 1990 s were designed to measure cumulative 3-year efficacy. The ENG-implant has both well established safety and efficacy for up to 3 years. Pharmacokinetic data on ENG show high levels at 3 years and some previous clinical research confirms efficacy beyond the current approved duration of 3 years. Today, many women, because the labeled duration has been reached, have the ENG implant removed at 3 years, increasing costs, inconvenience and risks. STUDY DESIGN SIZE, DURATION For the first 3 years, this study was an open-label, multi-centre randomized trial comparing the 3-year ENG implant to the 5-year levonorgestrel (LNG)-releasing implant. After 3 years, a subset of 390 ENG participants, consented to extended use. We compared efficacy, side effects and removal procedures of both implants. We used Kaplan–Meier (K–M) analysis. We included an observational cohort of copper intrauterine device (IUD) users as non-users of hormonal contraceptive method for comparative purposes. PARTICIPANTS/MATERIALS, SETTING, METHODS The study took place in family planning clinics in seven countries worldwide. Women were enlisted after an eligibility check and informed consent, and 1328 women were enrolled: 390, 522 and 416 in the ENG-implant, LNG-implant and IUD groups, respectively. MAIN RESULTS AND THE ROLE OF CHANCE Over 200 women used the ENG implant for at least 5 years. No pregnancies occurred during the additional 2 years of follow up in the ENG or LNG implant group. The overall 5-year K–M cumulative pregnancy rates for ENG- and LNG- implants were 0.6 per 100 women-years (W-Y) [95% confidence interval (CI): 0.2–1.8] and 0.8 per 100 W-Y [95% CI: 0.2–2.3], respectively. Complaints of bleeding changes were similar; however, ENG-users were more likely than LNG-users to experience heavy bleeding (p < 0.05). The median duration of the implant removal procedure was 64 seconds shorter for the one-rod ENG-implant (inter-quartile range (IQR) = 30.5, 117.5) compared to the two-rod LNG product (IQR = 77.0, 180.0). The 2-year rate for pregnancy in the IUD group compared with the two implant groups combined was 4.1 per 100 W-Y [95% CI: 2.5–6.5]. LIMITATIONS, REASONS FOR CAUTION Few women were ≤19 years old or nulligravida. Although there was no weight limit for enrolment in the study, the number of women ≥70 kg were few. WIDER IMPLICATIONS OF THE FINDINGS The results from this study corroborate previous evidence showing high contraceptive efficacy through 4 years for the ENG-implant. Data through 5 years are a novel contribution and further proof of the product's capability to provide safe and effective contraception that rivals the current 5-year LNG-subdermal implant. The findings provide valuable information for policy makers, family planning programmers and clinicians that the ENG-releasing subdermal implant is still highly effective up to 5 years after insertion. Compared to previous efforts, our study population was geographically diverse and our study had the highest number of participants completing at least 5 years of use. TRIAL REGISTRATION The trial was registered as ISRCTN33378571. STUDY FUNDING/COMPETING INTEREST(S) The contraceptive devices and funds for conduct of the study were provided by the United Nations Development Programme/United Nations Population Fund/World Health Organization (WHO)/UNICEF/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR), WHO. This report contains the collective views of an international group of experts, and does not necessarily represent the decisions or the stated policy of the WHO. All stated authors have no conflict of interest, except Dr Hubacher who reported grants from United States Agency for International Development, during the conduct of the study; other from Advisory Boards (Teva, Bayer, OCON), outside the submitted work. PMID:27671673

Increased negatively of interstitial fluid pressure in rat skin contributes to the edema formation induced by Zymosan.

PubMed

Ostgaard, G; Reed, R K

1993-11-01

Increased negatively of interstitial fluid pressure (Pif) contributes to rapid edema formation in several acute inflammatory reactions attesting to an "active" role for the loose connective tissues in the transcapillary fluid exchange and edema formation under these circumstances. The present study reports the effect of the complement activator Zymosan on Pif, transcapillary fluid, and albumin flux. Micropipettes (tip diameter 5 to 7 microns) connected to a servo-controlled counterpressure system were used to measure Pif in rat dermis. When compared to saline injection, subdermal injection of 1 mg Zymosan in 10 microliters 0.15 M NaCl increased total tissue water by 1.6 ml/g dry weight in 5 min, corresponding to about 150% increase in interstitial fluid volume. Pif increased from +0.4 to +3.7 mm Hg. Increased negativity of Pif can be masked by the edema formation which will increase Pif. Measurements were therefore also performed after circulatory arrest, when transcapillary fluid flux and edema formation are abolished. Using this experimental protocol Pif fell from +0.3 mm Hg to -2.5 mm Hg 5 min after subdermal injection of Zymosan and remained at this level throughout the observation period of 90 min. Injection of saline alone after circulatory arrest increased Pif transiently by about 1 mm Hg. Thus, subdermal injection of Zymosan causes increased negativity of Pif by about 4 mm Hg. Although the lowering of Pif itself will explain a minor part of the increased fluid filtration, the results attest to the role of loose connective tissues being active in the edema-generating process also in the inflammatory reaction induced by Zymosan.

Flexible Near-Field Wireless Optoelectronics as Subdermal Implants for Broad Applications in Optogenetics.

PubMed

Shin, Gunchul; Gomez, Adrian M; Al-Hasani, Ream; Jeong, Yu Ra; Kim, Jeonghyun; Xie, Zhaoqian; Banks, Anthony; Lee, Seung Min; Han, Sang Youn; Yoo, Chul Jong; Lee, Jong-Lam; Lee, Seung Hee; Kurniawan, Jonas; Tureb, Jacob; Guo, Zhongzhu; Yoon, Jangyeol; Park, Sung-Il; Bang, Sang Yun; Nam, Yoonho; Walicki, Marie C; Samineni, Vijay K; Mickle, Aaron D; Lee, Kunhyuk; Heo, Seung Yun; McCall, Jordan G; Pan, Taisong; Wang, Liang; Feng, Xue; Kim, Tae-Il; Kim, Jong Kyu; Li, Yuhang; Huang, Yonggang; Gereau, Robert W; Ha, Jeong Sook; Bruchas, Michael R; Rogers, John A

2017-02-08

In vivo optogenetics provides unique, powerful capabilities in the dissection of neural circuits implicated in neuropsychiatric disorders. Conventional hardware for such studies, however, physically tethers the experimental animal to an external light source, limiting the range of possible experiments. Emerging wireless options offer important capabilities that avoid some of these limitations, but the current size, bulk, weight, and wireless area of coverage is often disadvantageous. Here, we present a simple but powerful setup based on wireless, near-field power transfer and miniaturized, thin, flexible optoelectronic implants, for complete optical control in a variety of behavioral paradigms. The devices combine subdermal magnetic coil antennas connected to microscale, injectable light-emitting diodes (LEDs), with the ability to operate at wavelengths ranging from UV to blue, green-yellow, and red. An external loop antenna allows robust, straightforward application in a multitude of behavioral apparatuses. The result is a readily mass-producible, user-friendly technology with broad potential for optogenetics applications. Copyright © 2017 Elsevier Inc. All rights reserved.

Flexible near field wireless optoelectronics as subdermal implants for broad applications in optogenetics

PubMed Central

Shin, Gunchul; Gomez, Adrian M.; Al-Hasani, Ream; Jeong, Yu Ra; Kim, Jeonghyun; Xie, Zhaoqian; Banks, Anthony; Lee, Seung Min; Han, Sang Youn; Yoo, Chul Jong; Lee, Jong-Lam; Lee, Seung Hee; Kurniawan, Jonas; Tureb, Jacob; Guo, Zhongzhu; Yoon, Jangyeol; Park, Sung-Il; Bang, Sang Yun; Nam, Yoonho; Walicki, Marie C.; Samineni, Vijay K.; Mickle, Aaron D.; Lee, Kunhyuk; Heo, Seung Yun; McCall, Jordan G.; Pan, Taisong; Wang, Liang; Feng, Xue; Kim, Taeil; Kim, Jong Kyu; Li, Yuhang; Huang, Yonggang; Gereau, Robert W.; Ha, Jeong Sook; Bruchas, Michael R.; Rogers, John A.

2017-01-01

Summary In vivo optogenetics provides unique, powerful capabilities in the dissection of neural circuits implicated in neuropsychiatric disorders. Conventional hardware for such studies, however, physically tethers the experimental animal to an external light source limiting the range of possible experiments. Emerging wireless options offer important capabilities that avoid some of these limitations, but the current size, bulk, weight, and wireless area of coverage is often disadvantageous. Here, we present a simple but powerful setup based on wireless, near-field power transfer and miniaturized, thin flexible optoelectronic implants, for complete optical control in a variety of behavioral paradigms. The devices combine subdermal magnetic coil antennas connected to microscale, injectable LEDs, with the ability to operate at wavelengths ranging from ultraviolet to blue, green/yellow, and red. An external loop antenna allows robust, straightforward application in a multitude of behavioral apparatuses. The result is a readily mass-producible, user-friendly technology with broad potential for optogenetics applications. PMID:28132830

Unsteady jet in designing innovative drug delivery system

NASA Astrophysics Data System (ADS)

Wang, Cong; Mazur, Paul; Cosse, Julia; Rider, Stephanie; Gharib, Morteza

2014-11-01

Micro-needle injections, a promising pain-free drug delivery method, is constrained by its limited penetration depth. This deficiency can be overcome by implementing fast unsteady jet that can penetrate sub-dermally. The development of a faster liquid jet would increase the penetration depth and delivery volume of micro-needles. In this preliminary work, the nonlinear transient behavior of an elastic tube balloon in providing fast discharge is analyzed. A physical model that combines the Mooney Rivlin Material model and Young-Lapalce's Law was developed and used to investigate the fast discharging dynamic phenomenon. A proof of concept prototype was constructed to demonstrate the feasibility of a simple thumb-sized delivery system to generate liquid jet with desired speed in the range of 5-10 m/s. This work is supported by ZCUBE Corporation.

Efficacy and Safety of Long-Acting Reversible Contraception

PubMed Central

Stoddard, Amy; McNicholas, Colleen; Peipert, Jeffrey F.

2013-01-01

Long-acting reversible contraception (LARC) includes intrauterine devices (IUDs) and the subdermal implant. These methods are the most effective reversible methods of contraception, and have the additional advantages of being long-lasting, convenient, well liked by users and cost effective. Compared with other user-dependent methods that increase the risk of noncompliance-related method failure, LARC methods can bring ‘typical use’ failure rates more in line with ‘perfect use’ failure rates. LARC methods are ‘forgettable’; they are not dependent on compliance with a pill-taking regimen, remembering to change a patch or ring, or coming back to the clinician for an injection. LARC method failure rates rival that of tubal sterilization at <1% for IUDs and the subdermal implant. For these reasons, we believe that IUDs and implants should be offered as first-line contraception for most women. This article provides a review of the LARC methods that are currently available in the US, including their effectiveness, advantages, disadvantages and contraindications. Additionally, we dispel myths and misconceptions regarding IUDs, and address the barriers to LARC use. PMID:21668037

Introduction of the levonorgestrel intrauterine system in Kenya through mobile outreach: review of service statistics and provider perspectives.

PubMed

Hubacher, David; Akora, Vitalis; Masaba, Rose; Chen, Mario; Veena, Valentine

2014-02-01

The levonorgestrel intrauterine system (LNG IUS) was developed over 30 years ago, but the product is currently too expensive for widespread use in many developing countries. In Kenya, one organization has received donated commodities for 5 years, providing an opportunity to assess impact and potential future role of the product. We reviewed service statistics on insertions of the LNG IUS, copper intrauterine device (IUD), and subdermal implant from 15 mobile outreach teams during the 2011 calendar year. To determine the impact of the LNG IUS introduction, we analyzed changes in uptake and distribution of the copper IUD and subdermal implant by comparing periods of time when the LNG IUS was available with periods when it was not available. In addition, we interviewed 27 clinicians to assess their views of the product and of its future role. When the LNG IUS was not available, intrauterine contraception accounted for 39% of long-acting method provision. The addition of the LNG IUS created a slight rise in intrauterine contraception uptake (to 44%) at the expense of the subdermal implant, but the change was only marginally significant (P = .08) and was largely attributable to the copper IUD. All interviewed providers felt that the LNG IUS would increase uptake of long-acting methods, and 70% felt that the noncontraceptive benefits of the product are important to clients. The LNG IUS was well-received among providers and family planning clients in this population in Kenya. Although important changes in service statistics were not apparent from this analysis (perhaps due to the small quantity of LNG IUS that was available), provider enthusiasm for the product was high. This finding, above all, suggests that a larger-scale introduction effort would have strong support from providers and thus increase the chances of success. Adding another proven and highly acceptable long-acting contraceptive technology to the method mix could have important reproductive health impact.

Axillary migration of Nexplanon®: Case report.

PubMed

Diego, Daniela; Tappy, Erryn; Carugno, Jose

2017-02-01

A 19-year-old patient presented to the clinic, and we inserted a single rod subdermal etonogestrel implant (Nexplanon ®), which subsequently migrated to the ipsilateral axilla. Distant Nexplanon® migration is a rare serious complication that should be considered when a device is nonpalpable. Management options are discussed. Copyright © 2017 Elsevier Inc. All rights reserved.

Cost-effectiveness of subdermal implantable buprenorphine versus sublingual buprenorphine to treat opioid use disorder.

PubMed

Carter, John A; Dammerman, Ryan; Frost, Michael

2017-08-01

Subdermal implantable buprenorphine (BSI) was recently approved to treat opioid use disorder (OUD) in clinically-stable adults. In the pivotal clinical trial, BSI was associated with a higher proportion of completely-abstinent patients (85.7% vs 71.9%; p = .03) vs sublingual buprenorphine (SL-BPN). Elsewhere, relapse to illicit drug use is associated with diminished treatment outcomes and increased costs. This study evaluated the cost-effectiveness of BSI vs SL-BPN from a US societal perspective. A Markov model simulated BSI and SL-BPN cohorts (clinically-stable adults) transiting through four mutually-exclusive health states for 12 months. Cohorts accumulated direct medical costs from drug acquisition/administration; treatment-diversion/abuse; newly-acquired hepatitis-C; emergency room, hospital, and rehabilitation services; and pediatric poisonings. Non-medical costs of criminality, lost wages/work-productivity, and out-of-pocket expenses were also included. Transition probabilities to a relapsed state were derived from the aforementioned trial. Other transition probabilities, costs, and health-state utilities were derived from observational studies and adjusted for trial characteristics. Outcomes included incremental cost per quality-adjusted-life-year (QALY) gained and incremental net-monetary-benefit (INMB). Uncertainty was assessed by univariate and probabilistic sensitivity analysis (PSA). BSI was associated with lower total costs (-$4,386), more QALYs (+0.031), and favorable INMB at all willingness-to-pay (WTP) thresholds considered. Higher drug acquisition costs for BSI (+$6,492) were outpaced, primarily by reductions in emergency room/hospital utilization (-$8,040) and criminality (-$1,212). BSI was cost-effective in 89% of PSA model replicates, and had a significantly higher NMB at $50,000/QALY ($20,783 vs $15,007; p < .05). BSI was preferred over SL-BPN from a health-economic perspective for treatment of OUD in clinically-stable adults. These findings should be interpreted carefully, due to some relationships having been modeled from inputs derived from multiple sources, and would benefit from comparison with outcomes from studies that employ administrative claims data or a naturalistic comparative design.

Pathophysiology and animal modeling of underactive bladder.

PubMed

Tyagi, Pradeep; Smith, Phillip P; Kuchel, George A; de Groat, William C; Birder, Lori A; Chermansky, Christopher J; Adam, Rosalyn M; Tse, Vincent; Chancellor, Michael B; Yoshimura, Naoki

2014-09-01

While the symptomology of underactive bladder (UAB) may imply a primary dysfunction of the detrusor muscle, insights into pathophysiology indicate that both myogenic and neurogenic mechanisms need to be considered. Due to lack of proper animal models, the current understanding of the UAB pathophysiology is limited, and much of what is known about the clinical etiology of the condition has been derived from epidemiological data. We hereby review current state of the art in the understanding of the pathophysiology of and animal models used to study the UAB.

Physiological Monitoring in Diving Mammals

DTIC Science & Technology

2013-09-30

developed based upon the succesful construction of an oximeter used in Weddel seals [1]. A delivery device will be fabricated to allow...The implantation device containing the tag, muscle oximeter sensor and implantation device. Figure 5. Tag housing with subdermal pins. The... oximeter probe with 3 LEDs and photo sensor to estimate muscle O2 saturation. Figure 6. The oximeter sensor implanted into the muscle with the

76 FR 62419 - General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee; Notice of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-07

... Agency's Web site and call the appropriate advisory committee hot line/phone line to learn about possible... wrinkles in the face. The AQUAMID dermal filler is intended for use in mid-to-deep sub-dermal implantation... before the meeting. If FDA is unable to post the background material on its Web site prior to the meeting...

Elastin Calcification and its Prevention with Aluminum Chloride Pretreatment

PubMed Central

Vyavahare, Narendra; Ogle, Matthew; Schoen, Frederick J.; Levy, Robert J.

1999-01-01

Elastin, an abundant structural protein present in the arterial wall, is prone to calcification in a number of disease processes including porcine bioprosthetic heart valve calcification and atherosclerosis. The mechanisms of elastin calcification are not completely elucidated. In the present work, we demonstrated calcification of purified elastin in rat subdermal implants (Ca2+ = 89.73 ± 9.84 μg/mg after 21 days versus control, unimplanted Ca2+ = 0.16 ± 0.04 μg/mg). X-ray diffraction analysis along with resolution enhanced FTIR spectroscopy demonstrated the mineral phase to be a poorly crystalline hydroxyapatite. We investigated the time course of calcification, the effect of glutaraldehyde crosslinking on calcification, and mechanisms of inhibition of elastin calcification by pretreatment with aluminum chloride (AlCl3). Glutaraldehyde pretreatment did not affect calcification (Ca2+ = 89.06 ± 17.93 μg/mg for glutaraldehyde crosslinked elastin versus Ca2+ = 89.73 ± 9.84 μg/mg for uncrosslinked elastin). This may be explained by radioactive (3H) glutaraldehyde studies showing very low reactivity between glutaraldehyde and elastin. Our results further demonstrated that AlCl3 pretreatment of elastin led to complete inhibition of elastin calcification using 21-day rat subdermal implants, irrespective of glutaraldehyde crosslinking (Ca2+ = 0.73–2.15 μg/mg for AlCl3 pretreated elastin versus 89.73 ± 9.84 for untreated elastin). The AlCl3 pretreatment caused irreversible binding of aluminum ions to elastin, as assessed by atomic emission spectroscopy. Moreover, aluminum ion binding altered the spatial configuration of elastin as shown by circular dichroism (CD), Fourier transform infrared (FTIR), and 13C nuclear magnetic resonance (NMR) spectroscopy studies, suggesting a net structural change including a reduction in the extent of β sheet structures and an increase in coil-turn conformations. Thus, it is concluded that purified elastin calcifies in rat subdermal implants, and that the AlCl3-pretreated elastin completely resists calcification due to irreversible aluminum ion binding and subsequent structural alterations caused by AlCl3. PMID:10487855

Twelve-month discontinuation rates of levonorgestrel intrauterine system 13.5 mg and subdermal etonogestrel implant in women aged 18-44: A retrospective claims database analysis.

PubMed

Law, Amy; Liao, Laura; Lin, Jay; Yaldo, Avin; Lynen, Richard

2018-04-21

To investigate the 12-month discontinuation rates of levonorgestrel intrauterine system 13.5 mg (LNG-IUS 13.5) and subdermal etonogestrel (ENG) implant in the US. We identified women aged 18-44 who had an insertion of LNG-IUS 13.5 or ENG implant from the MarketScan Commercial claims database (7/1/2013-9/30/2014). Women were required to have 12 months of continuous insurance coverage prior to the insertion (baseline) and at least 12-months after (follow-up). Discontinuation was defined as presence of an insurance claim for pregnancy-related services, hysterectomy, female sterilization, a claim for another contraceptive method, or removal of the index contraceptive without re-insertion within 30 days. Using Cox regression we examined the potential impact of ENG implant vs. LNG-IUS 13.5 on the likelihood for discontinuation after controlling for patient characteristics. A total of 3680 (mean age: 25.4 years) LNG-IUS 13.5 and 23,770 (mean age: 24.6 years) ENG implant users met the selection criteria. Prior to insertion, 56.6% of LNG-IUS 13.5 and 42.1% of ENG implant users had used contraceptives, with oral contraceptives being most common (LNG-IUS 13.5: 42.1%; ENG implant: 28.5%). Among users of LNG-IUS 13.5 and ENG implant, rates of discontinuation were similar during the 12-month follow-up (LNG-IUS 13.5: 24.9%; ENG implant: 24.0%). Regression results showed that women using LNG-IUS 13.5 vs. ENG implant had similar likelihood for discontinuation (hazard ratio: 0.97, 95% confidence interval: 0.90-1.05, p=.41). In the real-world US setting, women aged 18-44 using LNG-IUS 13.5 and ENG implant have similar discontinuation rates after 12 months. In the United States, women aged 18-44 using levonorgestrel intrauterine system (13.5 mg) and subdermal etonogestrel implant have similar discontinuation rates after 12 months. Copyright © 2018 Elsevier Inc. All rights reserved.

Pathophysiology and animal modeling of underactive bladder

PubMed Central

Tyagi, Pradeep; Smith, Phillip P.; Kuchel, George A.; de Groat, William C.; Birder, Lori A.; Chermansky, Christopher J.; Adam, Rosalyn M.; Tse, Vincent; Chancellor, Michael B.; Yoshimura, Naoki

2015-01-01

While the symptomology of underactive bladder (UAB) may imply a primary dysfunction of the detrusor muscle, insights into pathophysiology indicate that both myogenic and neurogenic mechanisms need to be considered. Due to lack of proper animal models, the current understanding of the UAB pathophysiology is limited, and much of what is known about the clinical etiology of the condition has been derived from epidemiological data. We hereby review current state of the art in the understanding of the pathophysiology of and animal models used to study the UAB. PMID:25238890

The Pathophysiology of Insomnia

PubMed Central

Levenson, Jessica C.; Kay, Daniel B.

2015-01-01

Insomnia disorder is characterized by chronic dissatisfaction with sleep quantity or quality that is associated with difficulty falling asleep, frequent nighttime awakenings with difficulty returning to sleep, and/or awakening earlier in the morning than desired. Although progress has been made in our understanding of the nature, etiology, and pathophysiology of insomnia, there is still no universally accepted model. Greater understanding of the pathophysiology of insomnia may provide important information regarding how, and under what conditions, the disorder develops and is maintained as well as potential targets for prevention and treatment. The aims of this report are (1) to summarize current knowledge on the pathophysiology of insomnia and (2) to present a model of the pathophysiology of insomnia that considers evidence from various domains of research. Working within several models of insomnia, evidence for the pathophysiology of the disorder is presented across levels of analysis, from genetic to molecular and cellular mechanisms, neural circuitry, physiologic mechanisms, sleep behavior, and self-report. We discuss the role of hyperarousal as an overarching theme that guides our conceptualization of insomnia. Finally, we propose a model of the pathophysiology of insomnia that integrates the various types of evidence presented. PMID:25846534

Necrotizing soft tissue infections (NSTIs): literary review and description of a Fournier syndrome case.

PubMed

Gubitosi, Adelmo; Moccia, Giancarlo; Ruggiero, Roberto; Docimo, Giovanni; Foroni, Fabrizio; Esposito, Emanuela; Villaccio, Giuseppe; Esposito, Alessandro; Agresti, Ettore; Agresti, Massimo

2013-01-01

A 62 y.o. male with tight fimosis, swelling, redness, pain on palpating and necrosis of the penis and scrotum was admitted in our clinic, (FGSI = 6) with periferic vasculopathy; and diabetes mellitus type II and he was in dialysis treatment before the hospitalization. The patient was HCV affected. In 24 hours he underwent radical surgical debridement with excision of all necrotic material from penis and scrotum up to the subdermal layer and tissue of doubtful viability for about 75% of the skin and circumcision. In third, fifth and seventh postoperative days he underwent to local infusion of autologous PLT growth factors. The patient was discharged in 9th postoperative day and FGSI was still 6; the skin and subdermal tissue was barely reskined, with low homogeneous granulation, edema was heavely reduced. In our case, deviation from homeostasis status at admission was the main worrying factor. We found that diabetes mellitus and renal dysfunction at admission was also important risk factor for FG. "E.Coli" was the most common organism isolated from patient wound cultures. The FGSI is an objective and easy to apply score method to quantify the metabolic status and can be used to evaluate therapeutic options and assess results.

A multicenter comparative study on the efficacy, safety, and acceptability of the contraceptive subdermal implants Norplant and Norplant-II.

PubMed

del Carmen Cravioto, M; Alvarado, G; Canto-de-Cetina, T; Bassol, S; Oropeza, G; Santos-Yung, R; Valencia, J; Palma, Y; Fuziwara, J L; Navarrete, T; Garza-Flores, J; Pérez-Palacios, G

1997-06-01

In order to assess efficacy, safety, and acceptability of the contraceptive subdermal implants Norplant and Norplant-II in Mexican women, a comparative phase III clinical trial was undertaken in eight clinics across the country. The study involved 1052 women who were followed-up trimonthly for three years. Cumulative pregnancy rates were 0.29% and 0.34% for Norplant and Norplant-II implants, respectively. Similar overall cumulative discontinuation rates were observed at three years: 50.38% for Norplant capsules, and 50.44% for Norplant-II rods. The main method-related reason for termination was endometrial bleeding irregularity which led to discontinuation rates of 11.94% and 11.62% for Norplant and Norplant-II contraceptive systems, respectively. In 15,279 woman-months of experience accumulated with Norplant implants and 14,092 with Norplant-II implants, there were few adverse events reported. No difference was found between the two groups in either difficulty for implants placement and removal or women's discomfort, even though the time required for insertion and removal of Norplant capsules was longer than for Norplant-II rods. It is concluded that during the first three years of use, both implants systems are equally effective, safe, and acceptable.

Copper retention, calcium release and ultrastructural evidence indicate specific Cuprolinic Blue uptake and peculiar modifications in mineralizing aortic valves.

PubMed

Ortolani, F; Tubaro, F; Petrelli, L; Gandaglia, A; Spina, M; Marchini, M

2002-01-01

Previously, reactions with copper phthalocyanines at 0.05 M critical electrolyte concentration were found to cause demineralization in calcifying porcine aortic valves after subdermal implantation in rat, as well as simultaneous visualization of peculiar phthalocyanine-positive layers around cells and cell-derived matrix vesicles. In the present investigation, an appraisal was made of the mechanism and specificity of reactions with Cuprolinic Blue by comparing quantitatively calcium release and copper retention by calcified aortic valves reacted with this phthalocyanine under different critical electrolyte concentration conditions, and the corresponding ultrastructural patterns. It was found that (i) decalcifying properties are inversely proportional to salt molarity; (ii) reactivity to Cuprolinic Blue is critical electrolyte concentration-dependent, since the greatest copper retention occurred in 0.05 M critical electrolyte concentration Cuprolinic Blue-reacted samples, the only ones that also exhibited phthalocyanine-positive layers; (iii) the appearance of phthalocyanine-positive layers depends on Cuprolinic Blue uptake, revealing pericellular clustering of calcium-binding, anionic molecules; and (iv) minor Cuprolinic Blue uptake occurs by residual proteoglycans which still remain in the extracellular matrix after 6-week-long subdermal implantation. The present results indicate that this method is appropriate for the study of mineralized tissues and illustrate peculiar tissue modifications occurring at least in the experimental conditions used here.

An evaluation of fluorescent elastomer for marking bluegills in experimental studies

USGS Publications Warehouse

Dewey, Michael R.; Zigler, Steven J.

1996-01-01

We evaluated subdermal injection of a fluorescent elastomer for marking bluegills Lepomis macrochirus in laboratory and pond studies. Marking did not affect the growth or survival of adult or juvenile bluegills. Marks were visible for at least 6 months. This technique is a reliable, relatively inexpensive marking method for the identification of individual fish in experimental studies. Costs of application range from US$0.01 to $0.03 per mark.

Microvascular complications associated with injection of cosmetic facelift dermal fillers

NASA Astrophysics Data System (ADS)

Yousefi, Siavash; Prendes, Mark; Chang, Shu-Hong; Wang, Ruikang K.

2015-02-01

Minimally-invasive cosmetic surgeries such as injection of subdermal fillers have become very popular in the past decade. Although rare, some complications may follow injections such as tissue necrosis and even blindness. There exist two hypothesis regarding source of these complications both of which include microvasculature. The first hypothesis is that fillers in between the tissue structures and compress microvasculature that causes blockage of tissue neutrition and oxygen exchange in the tissue. In another theory, it is hypothesized that fillers move inside major arteries and block the arteries/veins. In this paper, we study these hypotheses using optical coherence tomography and optical microangiography technologies with different hyaluronic-acid fillers in a mouse ear model. Based on our observations, the fillers eventually block arteries/veins if injected directly into them that eventually causes tissue necrosis.

Multiple laser pulses in conjunction with an optical clearing agent to improve the curative effect of cutaneous vascular lesions.

PubMed

Ma, Jun; Chen, Bin; Li, Dong; Zhang, Yue; Ying, Zhaoxia

2018-03-14

Port-wine stain (PWS) birthmark is a congenital microvascular malformation of the skin. A 1064-nm Nd:YAG laser can achieve a deeper treatment, but the weak absorption by blood limits its clinical application. Multiple laser pulses (MLPs) are a potential solution to enhance the curative effect of a Nd:YAG laser. To reduce the pulse number (p n ) required for the thermal destruction of the blood vessel, the effect of glucose in conjunction with MLP was investigated. In vivo experiments were performed on a dorsal skin chamber model. Different concentrations (20, 25, 30, and 40%) of glucose were applied to the sub-dermal side of the hamster skin before laser irradiation. Identical vessels with diameters of 200 ± 30 and 110 ± 20 μm were chosen as representatives of typical PWS vessels. Instant thermal responses of the blood vessel were recorded by a high-speed camera. The required p n for blood vessel damage was compared with that without glucose pretreatment. Results showed that the use of glucose with a concentration of 20% combined with MLP Nd:YAG laser to damage blood vessels is more appropriate because severe hemorrhage or carbonization easily appeared in blood vessels at higher glucose concentration of 25, 30, and 40%. When 20% glycerol is pretreated on the sub-dermal hamster skin, the required p n for blood vessel damage can be significantly decreased for different power densities. For example, p n can be reduced by 40% when the power density is 57 J/cm 2 . In addition, generation of cavitation and bubbles in blood vessels is difficult upon pretreatment with glucose. The combination of glucose with MLP Nd:YAG laser could be an effective protocol for reducing the p n required for blood vessel damage. Randomized controlled trial (RCT) and human trials will be conducted in the future.

[Certain immunohistochemical markers of the intravitality of strangulation mechanical asphyxia].

PubMed

Bogomolov, D V; Putintsev, V A; Zbrueva, Yu V; Denisova, O P

Thus article was designed to report the results of the investigations into specific histological features of the skin and soft tissue samples taken from the strangulation areas on the neck and from the lungs of the persons who had committed suicide by hanging. The studies revealed the well apparent expression of fibrinogen in the derma and the subdermal cellolocutaneous layer of the skin subjected to intravital strangulation. Similar changes were absent in lung alveoli.

A three-year comparative study of continuation rates, bleeding patterns and satisfaction in Australian women using a subdermal contraceptive implant or progestogen releasing-intrauterine system.

PubMed

Weisberg, Edith; Bateson, Deborah; McGeechan, Kevin; Mohapatra, Lita

2014-02-01

BACKGROUND Long-acting reversible contraceptive methods (LARCs) are safe, highly effective, readily reversible, and require no action on the part of the user following insertion. Early discontinuation may put women at increased risk of unintended pregnancy. METHODS Following insertion of a progestogen-only subdermal implant or intrauterine system (IUS) at Family Planning NSW, women 18 years and older completed a questionnaire about their choice. At 6 weeks, 6, 12, 24 and 36 months by telephone or online they completed a questionnaire about bleeding patterns, side effects, satisfaction, and reasons for discontinuation. RESULTS Two hundred IUS users and 149 implant users were enrolled. The former were generally older, married or in a de-facto relationship, and had children. Forty-seven percent of implant users discontinued within three years compared to 27% of IUS users (p = 0.002). In the first two years amenorrhoea was more frequent in implant users. Frequent bleeding/spotting was more prevalent in the first year of IUS use but over time was twice as prevalent in implant users. Infrequent bleeding/spotting was more common in IUS users. CONCLUSION Both devices are highly effective and acceptable cost-effective methods. While LARCs should be promoted to women of all ages seeking contraception, early discontinuation due to unacceptable bleeding highlights the need for pre-insertion counselling.

Development of an On-animal Separation-based Sensor for Monitoring Drug Metabolism in Freely Roaming Sheep

PubMed Central

Scott, David E.; Willis, Sean D.; Gabbert, Seth; Johnson, Dave A.; Naylor, Erik; Janle, Elsa M.; Krichevsky, Janice E.; Lunte, Craig E.; Lunte, Susan M.

2015-01-01

The development of an on-animal separation-based sensor that can be employed for monitoring drug metabolism in a freely roaming sheep is described. The system consists of microdialysis sampling coupled directly to microchip electrophoresis with electrochemical detection (MD-ME-EC). Separations were accomplished using an all-glass chip with integrated platinum working and reference electrodes. Discrete samples from the microdialysis flow were introduced into the electrophoresis chip using a flow-gated injection approach. Electrochemical detection was accomplished in-channel using a two-electrode isolated potentiostat. Nitrite was separated by microchip electrophoresis using reverse polarity and a run buffer consisting of 50 mM phosphate at pH 7.4. The entire system was under telemetry control. The system was first tested with rats to monitor the production of nitrite following introduction of nitroglycerin into the subdermal tissue using a linear probe. The data acquired using the on-line MD-ME-EC system was compared to that obtained off-line analysis by liquid chromatography with electrochemical detection (LC-EC), using a second microdialysis probe implanted parallel to the first probe in the same animal. The MD-ME-EC device was then used on-animal to monitor the subdermal metabolism of nitroglycerin in sheep. The ultimate goal is to use this device to simultaneously monitor drug metabolism and behavior in a freely roaming animal. PMID:25697221

Low-Power, 8-Channel EEG Recorder and Seizure Detector ASIC for a Subdermal Implantable System.

PubMed

Do Valle, Bruno G; Cash, Sydney S; Sodini, Charles G

2016-12-01

EEG remains the mainstay test for the diagnosis and treatment of patients with epilepsy. Unfortunately, ambulatory EEG systems are far from ideal for patients who have infrequent seizures. These systems only last up to 3 days and if a seizure is not captured during the recordings, a definite diagnosis of the patient's condition cannot be given. This work aims to address this need by proposing a subdermal implantable, eight-channel EEG recorder and seizure detector that has two modes of operation: diagnosis and seizure counting. In the diagnosis mode, EEG is continuously recorded until a number of seizures are recorded. In the seizure counting mode, the system uses a low-power algorithm to track the number of seizures a patient has, providing doctors with a reliable count to help determine medication efficacy or other clinical endpoint. An ASIC that implements the EEG recording and seizure detection algorithm was designed and fabricated in a 0.18 μm CMOS process. The ASIC includes eight EEG channels and is designed to minimize the system's power and size. The result is a power-efficient analog front end that requires 2.75 μW per channel in diagnosis mode and 0.84 μW per channel in seizure counting mode. Both modes have an input referred noise of approximately 1.1 μVrms.

Immediate versus delayed insertion of an etonogestrel releasing implant at medical abortion-a randomized controlled equivalence trial.

PubMed

Hognert, Helena; Kopp Kallner, Helena; Cameron, Sharon; Nyrelli, Christina; Jawad, Izabella; Heller, Rebecca; Aronsson, Annette; Lindh, Ingela; Benson, Lina; Gemzell-Danielsson, Kristina

2016-11-01

Does a progestin releasing subdermal contraceptive implant affect the efficacy of medical abortion if inserted at the same visit as the progesterone receptor modulator, mifepristone, at medical abortion? A etonogestrel releasing subdermal implant inserted on the day of mifepristone did not impair the efficacy of the medical abortion compared with routine insertion at 2-4 weeks after the abortion. The etonogestrel releasing subdermal implant is one of the most effective long acting reversible contraceptive methods. The effect of timing of placement on the efficacy of mifepristone and impact on prevention of subsequent unintended pregnancy is not known. This multicentre, randomized controlled, equivalence trial with recruitment between 13 October 2013 and 17 October 2015 included a total of 551 women with pregnancies below 64 days gestation opting for the etonogestrel releasing subdermal implant as postabortion contraception. Women were randomized to either insertion at 1 hour after mifepristone intake (immediate) or at follow-up 2-4 weeks later (delayed insertion). An equivalence design was used due to advantages for women such as fewer visits to the clinic with immediate insertion. The primary outcome was the percentage of women with complete abortion not requiring surgical intervention within 1 month. Secondary outcomes included insertion rates, pregnancy and repeat abortion rates during 6 months follow-up. Analysis was per protocol and by intention to treat. Women aged 18 years and older who had requested medical termination of a pregnancy up to 63 days of gestation and opted for an etonogestrel releasing contraceptive implant were recruited in outpatient family planning clinics in six hospitals in Sweden and Scotland. Efficacy of medical abortion was 259/275 (94.2%) in the immediate insertion group and 239/249 (96%) in the routine insertion group with a risk difference of 1.8% (95% CI -0.4 to 4.1%), which was within the ±5% margin of equivalence. The insertion rate was 275/277 (98.9%) in the immediate group compared to 187/261 (71.6%) women in the routine group (P < 0.001). At 6 months of follow-up significantly fewer women in the immediate group had become pregnant again (2/277, 0.8%) compared to the routine group (10/261, 3.8%) P = 0.018. For the main outcome loss to follow-up data was minimized through access to patient records. Efforts were made to reduce loss to follow-up also for secondary outcomes. The results of the sensitivity analysis did not differ from the intention to treat or per protocol analysis. Guidelines on postabortion contraception should be amended to include insertion of the etonogestrel releasing implant at the time of mifepristone intake for medical abortion up to and including a gestation of 63 days. This study was funded by the Swedish Research Council (2012-2844), Stockholm City County and Karolinska Institutet (ALF). The contraceptive implants were provided by Merck and supplied by MSD Sweden. HKK and KGD have received honorariums for giving lectures for MSD/Merck and have participated in the national (HKK and KGD) and international (KGD) medical advisory boards for MSD/Merck. The other authors have nothing to declare. ClinicalTrials number NCT01920022. 06 August 2013. 13 October 2013. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Female adolescents' compliance with contraceptive regimens.

PubMed

Jay, M S; DuRant, R H; Litt, I F

1989-06-01

Although today's adolescents have access to a variety of contraceptive options, they remain inconsistent and suboptimal users of these methods. A particularly frustrating problem for those caring for adolescents is the issue of noncompliance with contraceptives, which is an important antecedent of adolescent pregnancy. In the future, new fertility-related developments such as subdermal hormonal implants may reduce the likelihood of noncompliance. For the present, however, systematic monitoring rather than only when noncompliance is suspected is essential in enhancing adolescents' contraceptive compliance.

Pathophysiological Progression Model for Selected Toxicological Endpoints

EPA Science Inventory

The existing continuum paradigms are effective models to organize toxicological data associated with endpoints used in human health assessments. A compendium of endpoints characterized along a pathophysiological continuum would serve to: weigh the relative importance of effects o...

In situ gelable interpenetrating double network hydrogel formulated from binary components: thiolated chitosan and oxidized dextran.

PubMed

Zhang, Hanwei; Qadeer, Aisha; Chen, Weiliam

2011-05-09

In situ gelable interpenetrating double-network hydrogels composed of thiolated chitosan (Chitosan-NAC) and oxidized dextran (Odex), completely devoid of potentially cytotoxic small molecule cross-linkers and that do not require complex maneuvers or catalysis, have been formulated. The interpenetrating network structure is created by Schiff base formations and disulfide bond inter-cross-linkings through exploiting the disparity of their reaction times. Compared with the autogelable thiolated chitosan hydrogels that typically require a relatively long time span for gelation to occur, the Odex/Chitosan-NAC composition solidifies rapidly and forms a well-developed 3D network in a short time span. Compared with typical hydrogels derived from natural materials, the Odex/Chitosan-NAC hydrogels are mechanically strong and resist degradation. The cytotoxicity potential of the hydrogels was determined by an in vitro viability assay using fibroblast as a model cell, and the results reveal that the hydrogels are noncytotoxic. In parallel, in vivo results from subdermal implantation in mice models demonstrate that this hydrogel is not only highly resistant to degradation but also induces very mild tissue response.

In situ Gelable Interpenetrating Double Network Hydrogel Formulated from Binary Components: Thiolated Chitosan and Oxidized Dextran

PubMed Central

Zhang, Hanwei; Qadeer, Aisha; Chen, Weiliam

2011-01-01

In situ gelable interpenetrating double network hydrogels composed of thiolated chitosan (Chitosan-NAC) and oxidized dextran (Odex), completely devoid of potentially cytotoxic small molecule crosslinkers and do not require complex maneuvers or catalysis, have been formulated. The interpenetrating network structure is created by Schiff base formations and disulfide bond inter-crosslinkings through exploiting the disparity of their reaction times. Compare to the auto-gelable thiolated chitosan hydrogels that typically require a relatively long time span for gelation to occur, the Odex/Chitosan-NAC composition solidifies rapidly and forms a well-developed three-dimensional network in a short time span. Compare to typical hydrogels derived from natural materials, the Odex/Chitosan-NAC hydrogels are mechanically strong and resist degradation. The cytotoxicity potential of the hydrogels was determined by an in vitro viability assay using fibroblast as a model cell and the results reveal that the hydrogels are non-cytotoxic. In parallel, in vivo results from subdermal implantation in mice models demonstrate that this hydrogel is not only highly resistant to degradation but also induces very mild tissue response. PMID:21410248

A Comparison of Pathophysiology in Humans and Rodent Models of Subarachnoid Hemorrhage

PubMed Central

Leclerc, Jenna L.; Garcia, Joshua M.; Diller, Matthew A.; Carpenter, Anne-Marie; Kamat, Pradip K.; Hoh, Brian L.; Doré, Sylvain

2018-01-01

Non-traumatic subarachnoid hemorrhage (SAH) affects an estimated 30,000 people each year in the United States, with an overall mortality of ~30%. Most cases of SAH result from a ruptured intracranial aneurysm, require long hospital stays, and result in significant disability and high fatality. Early brain injury (EBI) and delayed cerebral vasospasm (CV) have been implicated as leading causes of morbidity and mortality in these patients, necessitating intense focus on developing preclinical animal models that replicate clinical SAH complete with delayed CV. Despite the variety of animal models currently available, translation of findings from rodent models to clinical trials has proven especially difficult. While the explanation for this lack of translation is unclear, possibilities include the lack of standardized practices and poor replication of human pathophysiology, such as delayed cerebral vasospasm and ischemia, in rodent models of SAH. In this review, we summarize the different approaches to simulating SAH in rodents, in particular elucidating the key pathophysiology of the various methods and models. Ultimately, we suggest the development of standardized model of rodent SAH that better replicates human pathophysiology for moving forward with translational research. PMID:29623028

Surgical Site Infiltration for Abdominal Surgery: A Novel Neuroanatomical-based Approach

PubMed Central

Janis, Jeffrey E.; Haas, Eric M.; Ramshaw, Bruce J.; Nihira, Mikio A.; Dunkin, Brian J.

2016-01-01

Background: Provision of optimal postoperative analgesia should facilitate postoperative ambulation and rehabilitation. An optimal multimodal analgesia technique would include the use of nonopioid analgesics, including local/regional analgesic techniques such as surgical site local anesthetic infiltration. This article presents a novel approach to surgical site infiltration techniques for abdominal surgery based upon neuroanatomy. Methods: Literature searches were conducted for studies reporting the neuroanatomical sources of pain after abdominal surgery. Also, studies identified by preceding search were reviewed for relevant publications and manually retrieved. Results: Based on neuroanatomy, an optimal surgical site infiltration technique would consist of systematic, extensive, meticulous administration of local anesthetic into the peritoneum (or preperitoneum), subfascial, and subdermal tissue planes. The volume of local anesthetic would depend on the size of the incision such that 1 to 1.5 mL is injected every 1 to 2 cm of surgical incision per layer. It is best to infiltrate with a 22-gauge, 1.5-inch needle. The needle is inserted approximately 0.5 to 1 cm into the tissue plane, and local anesthetic solution is injected while slowly withdrawing the needle, which should reduce the risk of intravascular injection. Conclusions: Meticulous, systematic, and extensive surgical site local anesthetic infiltration in the various tissue planes including the peritoneal, musculofascial, and subdermal tissues, where pain foci originate, provides excellent postoperative pain relief. This approach should be combined with use of other nonopioid analgesics with opioids reserved for rescue. Further well-designed studies are necessary to assess the analgesic efficacy of the proposed infiltration technique. PMID:28293525

Comparison of three acute stress models for simulating the pathophysiology of stress-related mucosal disease.

PubMed

Saxena, Bhagawati; Singh, Sanjay

2017-05-30

Stress-related mucosal disease (SRMD) is highly prevalent in intensive care patients leading to increasing treatment cost and mortality. SRMD is a disease elusive of ideal treatment. Evaluation of drugs is very pertinent for the efficient and safe treatment of SRMD. It relies mainly on in vivo screening models. There are various stress models, and till date, none of them is validated for simulating the SRMD pathophysiology. The present study aims to choose the best model, which reproduce pathophysiology of SRMD, among previously established stress models. This study evaluates ulcer index, hexosamine content, microvascular permeability, and gastric content in three acute stress models (cold-restraint, restraint, and water immersion restraint). Macroscopic pictures of the ulcerogenic stomach explain that in contrast to other models, cold-restraint stress (CRS) exposure produced marked ulcers on the fundic area of the stomach. Results of the present study depicted that each stress model significantly increased ulcer index, microvascular permeability and decreased hexosamine level, however, the maximum in the case of CRS-exposed rats. Total acidity and pH of the gastric content remains unchanged in all the stress models. On the contrary, the gastric volume significantly decreased only in case of CRS, while unchanged in other stress models. The overall results revealed that the CRS resembles the pathophysiology of SRMD closely. It is the best and feasible model among all the models to evaluate drugs for the treatment of SRMD.

New animal models of cystic fibrosis: what are they teaching us?

PubMed Central

Keiser, Nicholas W.; Engelhardt, John F.

2013-01-01

Purpose of review Cystic fibrosis is the first human genetic disease to benefit from the directed engineering of three different species of animal models (mice, pigs, and ferrets). Recent studies on the cystic fibrosis pig and ferret models are providing new information about the pathophysiology of cystic fibrosis in various organ systems. Additionally, new conditional cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice are teaching unexpected lessons about CFTR function in surprising cellular locations. Comparisons between these animal models and the human condition are key to dissecting the complexities of disease pathophysiology in cystic fibrosis. Recent findings Cystic fibrosis pigs and ferrets have provided new models to study the spontaneous development of disease in the lung and pancreas, two organs that are largely spared overt spontaneous disease in cystic fibrosis mice. New cystic fibrosis mouse models are now interrogating CFTR functions involved in growth and inflammation at an organ-based level using conditional knockout technology. Together, these models are providing new insights on the human condition. Summary Basic and clinical cystic fibrosis research will benefit greatly from the comparative pathophysiology of cystic fibrosis mice, pigs, and ferrets. Both similarities and differences between these three cystic fibrosis models will inform pathophysiologically important mechanisms of CFTR function in humans and aid in the development of both organ-specific and general therapies for cystic fibrosis. PMID:21857224

On the horizon: new options for contraception.

PubMed

Reifsnider, E

1997-01-01

Future contraceptives include refinements of existing contraceptives and totally new methods. New formulations of oral contraceptives, subdermal hormonal implants, injectable hormones, vaginal spermicides, and intrauterine devices (IUDs) are being tested around the world. New methods that are not yet available include the use of vaginal preparations containing sperm-immobilizing agents, gonadotrophin releasing hormone agonists and antagonists, vaccines against ova and sperm, and endogenous hormones. Male contraceptive methods use hormones to suppress testosterone and vaccines to immobilize sperm. The availability of all future contraceptives is dependent on ample funds for research, development, and testing, and such funds are in jeopardy.

Use of mouse models to study the mechanisms and consequences of RBC clearance

PubMed Central

Hod, E. A.; Arinsburg, S. A.; Francis, R. O.; Hendrickson, J. E.; Zimring, J. C.; Spitalnik, S. L.

2013-01-01

Mice provide tractable animal models for studying the pathophysiology of various human disorders. This review discusses the use of mouse models for understanding red-blood-cell (RBC) clearance. These models provide important insights into the pathophysiology of various clinically relevant entities, such as autoimmune haemolytic anaemia, haemolytic transfusion reactions, other complications of RBC transfusions and immunomodulation by Rh immune globulin therapy. Mouse models of both antibody- and non-antibody-mediated RBC clearance are reviewed. Approaches for exploring unanswered questions in transfusion medicine using these models are also discussed. PMID:20345515

Sino-implant (II) - a levonorgestrel-releasing two-rod implant: systematic review of the randomized controlled trials

PubMed Central

Steiner, Markus J.; Lopez, Laureen M.; Grimes, David A.; Cheng, Linan; Shelton, Jim; Trussell, James; Farley, Timothy M.M.; Dorflinger, Laneta

2013-01-01

Background Sino-implant (II) is a subdermal contraceptive implant manufactured in China. This two-rod levonorgestrel-releasing implant has the same amount of active ingredient (150 mg levonorgestrel) and mechanism of action as the widely available contraceptive implant Jadelle. We examined randomized controlled trials of Sino-implant (II) for effectiveness and side effects. Study design We searched electronic databases for studies of Sino-implant (II), and then restricted our review to randomized controlled trials. The primary outcome of this review was pregnancy. Results Four randomized trials with a total of 15,943 women assigned to Sino-implant (II) had first-year probabilities of pregnancy ranging from 0.0% to 0.1%. Cumulative probabilities of pregnancy during the four years of the product's approved duration of use were 0.9% and 1.06% in the two trials that presented date for four-year use. Five-year cumulative probabilities of pregnancy ranged from 0.7% to 2.1%. In one trial, the cumulative probability of pregnancy more than doubled during the fifth year (from 0.9% to 2.1%), which may be why the implant is approved for four years of use in China. Five-year cumulative probabilities of discontinuation due to menstrual problems ranged from 12.5% to 15.5% for Sino-implant (II). Conclusions Sino-implant (II) is one of the most effective contraceptives available today. These available clinical data, combined with independent laboratory testing, and the knowledge that 7 million women have used this method since 1994, support the safety and effectiveness of Sino-implant (II). The lower cost of Sino-implant (II) compared with other subdermal implants could improve access to implants in resource-constrained settings. PMID:20159174

Metabolic effects of the contraceptive skin patch and subdermal contraceptive implant in Mexican women: A prospective study

PubMed Central

2014-01-01

Background The contraceptive skin patch (CSP) accepted by the U.S. FDA in 2001 includes ethinylestradiol and norelgestromine, whereas the subdermal contraceptive implant (SCI) has etonogestrel and is also approved by the FDA. In Mexico, both are now widely used for contraception but their effects on Mexican population are unknown. The objective of the study was to evaluate if these treatments induce metabolic changes in a sample of indigenous and mestizo Mexican women. Methods An observational, prospective, longitudinal, non-randomized study of women between 18 and 35 years of age assigned to CSP or SCI. We performed several laboratory tests: clinical chemistry, lipid profile, and liver and thyroid function tests. Also, serum levels of insulin, C-peptide, IGF-1, leptin, adiponectin, and C reactive protein were assayed. Results Sixty-two women were enrolled, 25 used CSP (0 indigenous; 25 mestizos) and 37 used SCI (18 indigenous; 19 mestizos). Clinical symptoms were relatively more frequent in the SCI group. Thirty-four contraceptive users gained weight without other clinical significant changes. After 4 months of treatment, significant changes were found in some biochemical parameters in both treatment groups. Most were clinically irrelevant. Interestingly, the percentage of users with an abnormal atherogenic index diminished from 75% to 41.6% after follow-up. Conclusions The CSP slightly modified the metabolic variables. Most changes were nonsignificant, whereas for SCI users changes were more evident and perhaps beneficial. Results of this attempt to evaluate the effects of contraceptives in mestizo and native-American populations show that clinical symptoms are frequent in Mexican users of CSP and SCI. Although these medications may affect some metabolic variables, these changes seem clinically irrelevant. Induction of abnormalities in other physiological pathways cannot be ruled out. PMID:24767248

Pharmacokinetics of Long-Acting Tenofovir Alafenamide (GS-7340) Subdermal Implant for HIV Prophylaxis

PubMed Central

Gunawardana, Manjula; Remedios-Chan, Mariana; Miller, Christine S.; Fanter, Rob; Yang, Flora; Marzinke, Mark A.; Hendrix, Craig W.; Beliveau, Martin; Moss, John A.; Smith, Thomas J.

2015-01-01

Oral or topical daily administration of antiretroviral (ARV) drugs to HIV-1-negative individuals in vulnerable populations is a promising strategy for HIV-1 prevention. Adherence to the dosing regimen has emerged as a critical factor determining efficacy outcomes of clinical trials. Because adherence to therapy is inversely related to the dosing period, sustained release or long-acting ARV formulations hold significant promise for increasing the effectiveness of HIV-1 preexposure prophylaxis (PrEP) by reducing dosing frequency. A novel, subdermal implant delivering the potent prodrug tenofovir alafenamide (TAF) with controlled, sustained, zero-order (linear) release characteristics is described. A candidate device delivering TAF at 0.92 mg day−1 in vitro was evaluated in beagle dogs over 40 days for pharmacokinetics and preliminary safety. No adverse events related to treatment with the test article were noted during the course of the study, and no significant, unusual abnormalities were observed. The implant maintained a low systemic exposure to TAF (median, 0.85 ng ml−1; interquartile range [IQR], 0.60 to 1.50 ng ml−1) and tenofovir (TFV; median, 15.0 ng ml−1; IQR, 8.8 to 23.3 ng ml−1), the product of in vivo TAF hydrolysis. High concentrations (median, 512 fmol/106 cells over the first 35 days) of the pharmacologically active metabolite, TFV diphosphate, were observed in peripheral blood mononuclear cells at levels over 30 times higher than those associated with HIV-1 PrEP efficacy in humans. Our report on the first sustained-release nucleoside reverse transcriptase inhibitor (NRTI) for systemic delivery demonstrates a successful proof of principle and holds significant promise as a candidate for HIV-1 prophylaxis in vulnerable populations. PMID:25896688

Use of a single implant of elcometrine (ST-1435), a nonorally active progestin, as a long acting contraceptive for postpartum nursing women.

PubMed

Coutinho, E M; Athayde, C; Dantas, C; Hirsch, C; Barbosa, I

1999-02-01

Because of its unique features, the contraceptive effectiveness and tolerance during breast-feeding of 16-methylene-17 alpha-acetoxy-19-nor-4-pregnene-3,20-dione (elcometrine), delivered within a single subdermal capsule of medical grade polydimethylsiloxane, was investigated. Unlike other progestational steroids, elcometrine has no affinity for androgen and estrogen receptors and is inactive by the oral route. A total of 66 breast-feeding women receiving elcometrine by the subdermal route were enrolled in the study, and 69 women who elected to use Copper-T380 intrauterine devices (IUD) served as control subjects. The women and their infants were observed until the end of the first postpartum year. There were no significant differences in growth and development measurements among the infants in the elcometrine and control groups. The percentage of infants continuing to breast-feed at 3 and 6 months was significantly higher in the elcometrine group. There were no significant differences between the concentration of elcometrine in the mother's blood and milk. At 75 days, blood levels of elcometrine in the infants were near the undetectable and were significantly lower than the levels in maternal blood or milk (p < 0.01). In 15 of 25 infants, blood levels of elcometrine were at the limit of assay sensitivity or undetectable. Two pregnancies occurred in women using IUD, whereas none occurred in those using implants. There were menstrual bleeding irregularities in both groups. A single elcometrine capsule placed subcutaneously at 6-monthly intervals appears to be an effective method of contraception for lactating women and results in blood concentrations of nursing infants at or near undetectable levels.

Vascularization and tissue infiltration of a biodegradable polyurethane matrix

PubMed Central

Ganta, Sudhakar R.; Piesco, Nicholas P.; Long, Ping; Gassner, Robert; Motta, Luis F.; Papworth, Glenn D.; Stolz, Donna B.; Watkins, Simon C.; Agarwal, Sudha

2016-01-01

Urethanes are frequently used in biomedical applications because of their excellent biocompatibility. However, their use has been limited to bioresistant polyurethanes. The aim of this study was to develop a nontoxic biodegradable polyurethane and to test its potential for tissue compatibility. A matrix was synthesized with pentane diisocyanate (PDI) as a hard segment and sucrose as a hydroxyl group donor to obtain a microtextured spongy urethane matrix. The matrix was biodegradable in an aqueous solution at 37°C in vitro as well as in vivo. The polymer was mechanically stable at body temperatures and exhibited a glass transition temperature (Tg) of 67°C. The porosity of the polymer network was between 10 and 2000 µm, with the majority of pores between 100 and 300 µm in diameter. This porosity was found to be adequate to support the adherence and proliferation of bone-marrow stromal cells (BMSC) and chondrocytes in vitro. The degradation products of the polymer were nontoxic to cells in vitro. Subdermal implants of the PDI–sucrose matrix did not exhibit toxicity in vivo and did not induce an acute inflammatory response in the host. However, some foreign-body giant cells did accumulate around the polymer and in its pores, suggesting its degradation is facilitated by hydrolysis as well as by giant cells. More important, subdermal implants of the polymer allowed marked infiltration of vascular and connective tissue, suggesting the free flow of fluids and nutrients in the implants. Because of the flexibility of the mechanical strength that can be obtained in urethanes and because of the ease with which a porous microtexture can be achieved, this matrix may be useful in many tissue-engineering applications. PMID:12522810

The component leaching from decellularized pericardial bioscaffolds and its implication in the macrophage response.

PubMed

Mendoza-Novelo, Birzabith; Castellano, Laura E; Padilla-Miranda, Ruth G; Lona-Ramos, María C; Cuéllar-Mata, Patricia; Vega-González, Arturo; Murguía-Pérez, Mario; Mata-Mata, José L; Ávila, Eva E

2016-11-01

The extracellular matrix molecules remaining in bioscaffolds derived from decellularized xenogeneic tissues appear to be important for inducing cell functions conducting tissue regeneration. Here, we studied whether decellularization methods, that is, detergent Triton X-100 (TX) alone and TX combined with reversible alkaline swelling (STX), applied to bovine pericardial tissue, could affect the bioscaffold components. The in vitro macrophage response, subdermal biodegradation, and cell infiltration were also studied. The results indicate a lower leaching of fibronectin, but a higher leaching of laminin and sulfated glycosaminoglycans from tissues decellularized with STX and TX, respectively. The in vitro secretion of interleukin-6 and monocyte chemoattractant protein by RAW264.7 macrophages is promoted by decellularized bioscaffold leachates. A lower polymorphonuclear cell density is observed around decellularized bioscaffolds at 1-day implantation; concurrently showing a higher cell infiltration in STX- than in TX-implant. Cells infiltrated into TX-implant show a fibroblastic morphology at 7-day implantation, concurrently the capillary formation is observed at 14-day. Pericardial bioscaffolds suffer biodegradation more pronounced in STX- than in TX-implant. Both TX and STX decellularization methods favor a high leaching of basal lamina components, which presumably promotes a faster macrophage stimulation compared to nondecellularized tissue, and appear to be associated with an increased host cell infiltration in a rat subdermal implantation. Meanwhile, the connective tissue components leaching from TX decellularized bioscaffolds, unlike the STX ones, appear to be associated with an enhanced angiogenesis accompanied by an early-promoted fibroblastic cell transition. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2810-2822, 2016. © 2016 Wiley Periodicals, Inc.

A theoretical framework informing research about the role of stress in the pathophysiology of bipolar disorder.

PubMed

Brietzke, Elisa; Mansur, Rodrigo Barbachan; Soczynska, Joanna; Powell, Alissa M; McIntyre, Roger S

2012-10-01

The staggering illness burden associated with Bipolar Disorder (BD) invites the need for primary prevention strategies. Before preventative strategies can be considered in individuals during a pre-symptomatic period (i.e., at risk), unraveling the mechanistic steps wherein external stress is transduced and interacts with genetic vulnerability in the early stages of BD will be a critical conceptual necessity. Herein we comprehensively review extant studies reporting on stress and bipolar disorder. The overarching aim is to propose a conceptual framework to inform research about the role of stress in the pathophysiology of BD. Computerized databases i.e. PubMed, PsychInfo, Cochrane Library and Scielo were searched using the following terms: "bipolar disorder" cross-referenced with "stress", "general reaction to stress", "resilience", "resistance", "recovery" "stress-diathesis", "allostasis", and "hormesis". Data from literature indicate the existence of some theoretical models to understand the influence of stress in the pathophysiology of BD, including classical stress-diathesis model and new models such as allostasis and hormesis. In addition, molecular mechanisms involved in stress adaptation (resistance, resilience and recovery) can also be translated in research strategies to investigate the impact of stress in the pathophysiology of BD. Most studies are retrospective and/or cross sectional, do not consider the period of development, assess brain function with only one or few methodologies, and use animal models which are not always similar to human phenotypes. The interaction between stress and brain development is dynamic and complex. In this article we proposed a theoretical model for investigation about the role of stress in the pathophysiology of BD, based on the different kinds of stress adaptation response and their putative neurobiological underpinnings. Copyright © 2012 Elsevier Inc. All rights reserved.

Comparison of effectiveness between cork-screw and peg-screw electrodes for transcranial motor evoked potential monitoring using the finite element method.

PubMed

Tomio, Ryosuke; Akiyama, Takenori; Ohira, Takayuki; Yoshida, Kazunari

2016-01-01

Intraoperative monitoring of motor evoked potentials by transcranial electric stimulation is popular in neurosurgery for monitoring motor function preservation. Some authors have reported that the peg-screw electrodes screwed into the skull can more effectively conduct current to the brain compared to subdermal cork-screw electrodes screwed into the skin. The aim of this study was to investigate the influence of electrode design on transcranial motor evoked potential monitoring. We estimated differences in effectiveness between the cork-screw electrode, peg-screw electrode, and cortical electrode to produce electric fields in the brain. We used the finite element method to visualize electric fields in the brain generated by transcranial electric stimulation using realistic three-dimensional head models developed from T1-weighted images. Surfaces from five layers of the head were separated as accurately as possible. We created the "cork-screws model," "1 peg-screw model," "peg-screws model," and "cortical electrode model". Electric fields in the brain radially diffused from the brain surface at a maximum just below the electrodes in coronal sections. The coronal sections and surface views of the brain showed higher electric field distributions under the peg-screw compared to the cork-screw. An extremely high electric field was observed under cortical electrodes. Our main finding was that the intensity of electric fields in the brain are higher in the peg-screw model than the cork-screw model.

Androgen receptor (AR) pathophysiological roles in androgen-related diseases in skin, bone/muscle, metabolic syndrome and neuron/immune systems: lessons learned from mice lacking AR in specific cells

PubMed Central

Chang, Chawnshang; Yeh, Shuyuan; Lee, Soo Ok; Chang, Ta-min

2013-01-01

The androgen receptor (AR) is expressed ubiquitously and plays a variety of roles in a vast number of physiological and pathophysiological processes. Recent studies of AR knockout (ARKO) mouse models, particularly the cell type- or tissue-specific ARKO models, have uncovered many AR cell type- or tissue-specific pathophysiological roles in mice, which otherwise would not be delineated from conventional castration and androgen insensitivity syndrome studies. Thus, the AR in various specific cell types plays pivotal roles in production and maturation of immune cells, bone mineralization, and muscle growth. In metabolism, the ARs in brain, particularly in the hypothalamus, and the liver appear to participate in regulation of insulin sensitivity and glucose homeostasis. The AR also plays key roles in cutaneous wound healing and cardiovascular diseases, including atherosclerosis and abdominal aortic aneurysm. This article will discuss the results obtained from the total, cell type-, or tissue-specific ARKO models. The understanding of AR cell type- or tissue-specific physiological and pathophysiological roles using these in vivo mouse models will provide useful information in uncovering AR roles in humans and eventually help us to develop better therapies via targeting the AR or its downstream signaling molecules to combat androgen/AR-related diseases. PMID:24653668

Detrusor underactivity: Pathophysiological considerations, models and proposals for future research. ICI-RS 2013.

PubMed

van Koeveringe, Gommert A; Rademakers, Kevin L J; Birder, Lori A; Korstanje, Cees; Daneshgari, Firouz; Ruggieri, Michael R; Igawa, Yasuhiko; Fry, Christopher; Wagg, Adrian

2014-06-01

Detrusor underactivity, resulting in either prolonged or inefficient voiding, is a common clinical problem for which treatment options are currently limited. The aim of this report is to summarize current understanding of the clinical observation and its underlying pathophysiological entities. This report results from presentations and subsequent discussion at the International Consultation on Incontinence Research Society (ICI-RS) in Bristol, 2013. The recommendations made by the ICI-RS panel include: Development of study tools based on a system's pathophysiological approach, correlation of in vitro and in vivo data in experimental animals and humans, and development of more comprehensive translational animal models. In addition, there is a need for longitudinal patient data to define risk groups and for the development of screening tools. In the near-future these recommendations should lead to a better understanding of detrusor underactivity and its pathophysiological background. Neurourol. Urodynam. 33:591-596, 2014. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.

Treatment of corns by injectable silicone.

PubMed

Balkin, S W

1975-09-01

Corns and calluses are the most frequently encountered foot complaints. The choices of care range from self trimming and application of over-the-counter remedies to professional treatment, which may include tendon, skin, and bone surgery. A technique using fluid silicone injected subdermally to cushion corns is described. Twenty-nine patients with 71 digital pressure keratoses were injected between 1965 and 1970. Results of treatment of 77% of the corns were rated good to excellent after an average follow-up period of six years, and no serious reactions have been observed. The procedure offers an effective, nondisabling method of treatment, as opposed to lifelong palliation or surgical intervention.

Requirements for the formal representation of pathophysiology mechanisms by clinicians

PubMed Central

Helvensteijn, M.; Kokash, N.; Martorelli, I.; Sarwar, D.; Islam, S.; Grenon, P.; Hunter, P.

2016-01-01

Knowledge of multiscale mechanisms in pathophysiology is the bedrock of clinical practice. If quantitative methods, predicting patient-specific behaviour of these pathophysiology mechanisms, are to be brought to bear on clinical decision-making, the Human Physiome community and Clinical community must share a common computational blueprint for pathophysiology mechanisms. A number of obstacles stand in the way of this sharing—not least the technical and operational challenges that must be overcome to ensure that (i) the explicit biological meanings of the Physiome's quantitative methods to represent mechanisms are open to articulation, verification and study by clinicians, and that (ii) clinicians are given the tools and training to explicitly express disease manifestations in direct contribution to modelling. To this end, the Physiome and Clinical communities must co-develop a common computational toolkit, based on this blueprint, to bridge the representation of knowledge of pathophysiology mechanisms (a) that is implicitly depicted in electronic health records and the literature, with (b) that found in mathematical models explicitly describing mechanisms. In particular, this paper makes use of a step-wise description of a specific disease mechanism as a means to elicit the requirements of representing pathophysiological meaning explicitly. The computational blueprint developed from these requirements addresses the Clinical community goals to (i) organize and manage healthcare resources in terms of relevant disease-related knowledge of mechanisms and (ii) train the next generation of physicians in the application of quantitative methods relevant to their research and practice. PMID:27051514

Brief Report: Pathophysiology of Autism: Neurochemistry.

ERIC Educational Resources Information Center

Cook, Edwin H., Jr.

1996-01-01

This paper reviews what is known about the role of neurochemicals in controlling the development of the brain and in the pathophysiology of autism. Suggested approaches to further research involve using animal models, examining effects of drugs on neurochemicals, and using such technologies as positron emission tomography and magnetic resonance…

Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques.

PubMed

Safronetz, David; Prescott, Joseph; Feldmann, Friederike; Haddock, Elaine; Rosenke, Rebecca; Okumura, Atsushi; Brining, Douglas; Dahlstrom, Eric; Porcella, Stephen F; Ebihara, Hideki; Scott, Dana P; Hjelle, Brian; Feldmann, Heinz

2014-05-13

The pathophysiology of hantavirus pulmonary syndrome (HPS) remains unclear because of a lack of surrogate disease models with which to perform pathogenesis studies. Nonhuman primates (NHP) are considered the gold standard model for studying the underlying immune activation/suppression associated with immunopathogenic viruses such as hantaviruses; however, to date an NHP model for HPS has not been described. Here we show that rhesus macaques infected with Sin Nombre virus (SNV), the primary etiological agent of HPS in North America, propagated in deer mice develop HPS, which is characterized by thrombocytopenia, leukocytosis, and rapid onset of respiratory distress caused by severe interstitial pneumonia. Despite establishing a systemic infection, SNV differentially activated host responses exclusively in the pulmonary endothelium, potentially the mechanism leading to acute severe respiratory distress. This study presents a unique chronological characterization of SNV infection and provides mechanistic data into the pathophysiology of HPS in a closely related surrogate animal model. We anticipate this model will advance our understanding of HPS pathogenesis and will greatly facilitate research toward the development of effective therapeutics and vaccines against hantaviral diseases.

Near-infrared optical properties of ex-vivo human skin and subcutaneous tissues using reflectance and transmittance measurements

NASA Astrophysics Data System (ADS)

Simpson, Rebecca; Laufer, Jan G.; Kohl-Bareis, Matthias; Essenpreis, Matthias; Cope, Mark

1997-08-01

The vast majority of 'non-invasive' measurements of human tissues using near infrared spectroscopy rely on passing light through the dermis and subdermis of the skin. Accurate knowledge of the optical properties of these tissues is essential to put into models of light transport and predict the effects of skin perfusion on measurements of deep tissue. Additionally, the skin could be a useful accessible organ for non-invasively determining the constituents of blood flowing through it. Samples of abdominal human skin (including subdermal tissue) were obtained from either post mortem examinations or plastic surgery. The samples were separated into a dermal layer (epidermis and dermis, 1.5 to 2 mm tick), and a sub-cutaneous layer comprised largely of fat. They were enclosed between two glass coverslips and placed in an integrating sphere to measure their reflectance and transmittance over a range of wavelengths from 600 to 1000 nm. The reflectance and transmittance values were converted into average absorption and reduced scattering coefficients by comparison with a Monte Carlo model of light transport. Improvements to the Monte Carlo model and measurement technique removed some previous uncertainties. The results show excellent separation of reduced scattering and absorption coefficient, with clear absorption peaks of hemoglobin, water and lipid. The effect of tissue storage upon measured optical properties was investigated.

Laser-assisted skin closure at 1.32 microns: the use of a software-driven medical laser system

NASA Astrophysics Data System (ADS)

Dew, Douglas K.; Hsu, Tung M.; Hsu, Long S.; Halpern, Steven J.; Michaels, Charles E.

1991-06-01

This study investigated the use of a computerized 1 .3 micron Nd:YAG laser to seal approximated wound edges in pig skin. The medical laser system used was the DLS Type 1 , 1 .32 micron Nd:YAG laser (Laser Surgery Software, Inc.). The purpose of this study was to evaluate the effectiveness of laser assisted skin closure using the DLS YAG laser in a large animal model. Effectiveness was judged on the basis of wound dehiscence, infection, unusual healing result and consistency of results. Comparative cosmetic result was also evaluated. In this study, the DLS YAG laser was used to close scalpel-induced, full-thickness wounds. The pig model was chosen for its many integumentary similarities to man. Controls included scalpel-induced wounds closed using suture, staple and some with norepair. After adequate anesthesia was achieved, the dorsum of Yucutan pigs (approximately 75- 100 pounds) each was clipped with animal hair clippers from the shoulder area to the hind legs. The area was then shaved with a razor blade, avoiding any inadvertent cuts or abrasions of the skin. The dorsum was divided into four rows of four parallel incisions made by a #15 scalpel blade. Full-thickness incisions, 9 cm long, were placed over the dorsum of the pigs and then closed either with one loosely approximating Prolene" suture (the "no repair' group), multiple interrupted 6-0 nylon sutures, staples or laser. The experimental tissue sealing group consisted of 1 69 laser assisted closures on 1 3 pigs. Sutured control wounds were closed with 6-0 nylon, full thickness, simple, interrupted sutures. Eight sutures were placed 1 cm apart along the 9 cm incision. Stapled control wounds were approximated using two evenly spaced 3-0 VicryP' sub-dermal sutures and the dermis closed using Proximate' skin staples. Eight staples were placed 1 cm apart along the 9 cm incision. The no-repair incisions were grossly approximated using a single 2-0 Prolene full thickness, simple, interrupted suture located at the center of the 9 cm incision. Experimental wounds were approximated using two evenly spaced subdermal 3.0 Vicryl' sutures and the dermis closed by laser sealing using the DLS YAG laser. Wounds were examined daily for the first seven days and followed for up to 20 months postoperatively. To facilitate wound edge approximation, surgical tape that is relatively transparent to 1.3 micron irradiation was used to hold the wound edges approximated while laser application occurred. Surgical tape was also applied to the "no-repair" suture and staple closures at the end of each procedure.

Animal models in burn research.

PubMed

Abdullahi, A; Amini-Nik, S; Jeschke, M G

2014-09-01

Burn injury is a severe form of trauma affecting more than 2 million people in North America each year. Burn trauma is not a single pathophysiological event but a devastating injury that causes structural and functional deficits in numerous organ systems. Due to its complexity and the involvement of multiple organs, in vitro experiments cannot capture this complexity nor address the pathophysiology. In the past two decades, a number of burn animal models have been developed to replicate the various aspects of burn injury, to elucidate the pathophysiology, and to explore potential treatment interventions. Understanding the advantages and limitations of these animal models is essential for the design and development of treatments that are clinically relevant to humans. This review aims to highlight the common animal models of burn injury in order to provide investigators with a better understanding of the benefits and limitations of these models for translational applications. While many animal models of burn exist, we limit our discussion to the skin healing of mouse, rat, and pig. Additionally, we briefly explain hypermetabolic characteristics of burn injury and the animal model utilized to study this phenomena. Finally, we discuss the economic costs associated with each of these models in order to guide decisions of choosing the appropriate animal model for burn research.

Animal Models in Burn Research

PubMed Central

Abdullahi, A.; Amini-Nik, S.; Jeschke, M.G

2014-01-01

Burn injury is a severe form of trauma affecting more than two million people in North America each year. Burn trauma is not a single pathophysiological event but a devastating injury that causes structural and functional deficits in numerous organ systems. Due to its complexity and the involvement of multiple organs, in vitro experiments cannot capture this complexity nor address the pathophysiology. In the past two decades, a number of burn animal models have been developed to replicate the various aspects of burn injury; to elucidate the pathophysiology and explore potential treatment interventions. Understanding the advantages and limitations of these animal models is essential for the design and development of treatments that are clinically relevant to humans. This review paper aims to highlight the common animal models of burn injury in order to provide investigators with a better understanding of the benefits and limitations of these models for translational applications. While many animal models of burn exist, we limit our discussion to the skin healing of mouse, rat, and pig. Additionally, we briefly explain hypermetabolic characteristics of burn injury and the animal model utilized to study this phenomena. Finally, we discuss the economic costs associated with each of these models in order to guide decisions of choosing the appropriate animal model for burn research. PMID:24714880

Human pluripotent stem cell models of autism spectrum disorder: emerging frontiers, opportunities, and challenges towards neuronal networks in a dish.

PubMed

Aigner, Stefan; Heckel, Tobias; Zhang, Jitao D; Andreae, Laura C; Jagasia, Ravi

2014-03-01

Autism spectrum disorder (ASD) is characterized by deficits in language development and social cognition and the manifestation of repetitive and restrictive behaviors. Despite recent major advances, our understanding of the pathophysiological mechanisms leading to ASD is limited. Although most ASD cases have unknown genetic underpinnings, animal and human cellular models of several rare, genetically defined syndromic forms of ASD have provided evidence for shared pathophysiological mechanisms that may extend to idiopathic cases. Here, we review our current knowledge of the genetic basis and molecular etiology of ASD and highlight how human pluripotent stem cell-based disease models have the potential to advance our understanding of molecular dysfunction. We summarize landmark studies in which neuronal cell populations generated from human embryonic stem cells and patient-derived induced pluripotent stem cells have served to model disease mechanisms, and we discuss recent technological advances that may ultimately allow in vitro modeling of specific human neuronal circuitry dysfunction in ASD. We propose that these advances now offer an unprecedented opportunity to help better understand ASD pathophysiology. This should ultimately enable the development of cellular models for ASD, allowing drug screening and the identification of molecular biomarkers for patient stratification.

Advances in the pathophysiology of pre-eclampsia and related podocyte injury

PubMed Central

Craici, Iasmina M.; Wagner, Steven J.; Weissgerber, Tracey L.; Grande, Joseph P.; Garovic, Vesna D.

2014-01-01

Pre-eclampsia is a pregnancy-specific hypertensive disorder that may lead to serious maternal and fetal complications. It is a multisystem disease that is commonly, but not always, accompanied by proteinuria. Its cause(s) remain unknown, and delivery remains the only definitive treatment. It is increasingly recognized that many pathophysiological processes contribute to this syndrome, with different signaling pathways converging at the point of systemic endothelial dysfunction, hypertension, and proteinuria. Different animal models of pre-eclampsia have proven utility for specific aspects of pre-eclampsia research, and offer insights into pathophysiology and treatment possibilities. Therapeutic interventions that specifically target these pathways may optimize pre-eclampsia management and may improve fetal and maternal outcomes. In addition, recent findings regarding placental, endothelial, and podocyte pathophysiology in pre-eclampsia provide unique and exciting possibilities for improved diagnostic accuracy. Emerging evidence suggests that testing for urinary podocytes or their markers may facilitate the prediction and diagnosis of pre-eclampsia. In this review, we explore recent research regarding placental, endothelial, and podocyte pathophysiology. We further discuss new signaling and genetic pathways that may contribute to pre-eclampsia pathophysiology, emerging screening and diagnostic strategies, and potential targeted interventions. PMID:24573315

On the dynamic behavior of three readily available soft tissue simulants

NASA Astrophysics Data System (ADS)

Appleby-Thomas, G. J.; Hazell, P. J.; Wilgeroth, J. M.; Shepherd, C. J.; Wood, D. C.; Roberts, A.

2011-04-01

Plate-impact experiments have been employed to investigate the dynamic response of three readily available tissue simulants for ballistic purposes: gelatin, ballistic soap (both subdermal tissue simulants), and lard (adipose layers). All three materials exhibited linear Hugoniot equations-of-state in the US-uP plane. While gelatin behaved hydrodynamically under shock, soap and lard appeared to strengthen under increased loading. Interestingly, the simulants under test appeared to strengthen in a material-independent manner on shock arrival (tentatively attributed to a rearrangement of the amorphous molecular chains under loading). However, material-specific behavior was apparent behind the shock. This behavior appeared to correlate with microstructural complexity, suggesting a steric hindrance effect.

Unscheduled vaginal bleeding with progestin-only contraceptive use.

PubMed

Zigler, Rachel E; McNicholas, Colleen

2017-05-01

Nearly 20% of women using contraception are using progestin-only contraception, including progestin-only pills, depot-medroxyprogesterone acetate, subdermal etonogestrel implants, and levonorgestrel intrauterine devices. This number will continue to grow with the increased provision of long-acting reversible contraception. Although overall satisfaction among women using progestin-only contraception is high, dissatisfaction and discontinuation may be associated with unscheduled bleeding and spotting. The exact etiology of irregular bleeding associated with progestin-containing contraceptives is not completely understood, yet several mechanisms have been suggested. Several therapies targeting these mechanisms have been evaluated with mixed results. This paper will review the physiology and management of unscheduled bleeding with progestin-containing contraceptives. Copyright © 2016 Elsevier Inc. All rights reserved.

Experimental Diabetes Mellitus in Different Animal Models

PubMed Central

Al-awar, Amin; Veszelka, Médea; Szűcs, Gergő; Attieh, Zouhair; Murlasits, Zsolt; Török, Szilvia; Pósa, Anikó; Varga, Csaba

2016-01-01

Animal models have historically played a critical role in the exploration and characterization of disease pathophysiology and target identification and in the evaluation of novel therapeutic agents and treatments in vivo. Diabetes mellitus disease, commonly known as diabetes, is a group of metabolic disorders characterized by high blood glucose levels for a prolonged time. To avoid late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic symptoms, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies. We overviewed the pathophysiological features of diabetes in relation to its complications in type 1 and type 2 mice along with rat models, including Zucker Diabetic Fatty (ZDF) rats, BB rats, LEW 1AR1/-iddm rats, Goto-Kakizaki rats, chemically induced diabetic models, and Nonobese Diabetic mouse, and Akita mice model. The advantages and disadvantages that these models comprise were also addressed in this review. This paper briefly reviews the wide pathophysiological and molecular mechanisms associated with type 1 and type 2 diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans. PMID:27595114

Pathophysiological analyses of periventricular nodular heterotopia using gyrencephalic mammals.

PubMed

Matsumoto, Naoyuki; Hoshiba, Yoshio; Morita, Kazuya; Uda, Natsu; Hirota, Miwako; Minamikawa, Maki; Ebisu, Haruka; Shinmyo, Yohei; Kawasaki, Hiroshi

2017-03-15

Although periventricular nodular heterotopia (PNH) is often found in the cerebral cortex of people with thanatophoric dysplasia (TD), the pathophysiology of PNH in TD is largely unknown. This is mainly because of difficulties in obtaining brain samples of TD patients and a lack of appropriate animal models for analyzing the pathophysiology of PNH in TD. Here we investigate the pathophysiological mechanisms of PNH in the cerebral cortex of TD by utilizing a ferret TD model which we recently developed. To make TD ferrets, we electroporated fibroblast growth factor 8 (FGF8) into the cerebral cortex of ferrets. Our immunohistochemical analyses showed that PNH nodules in the cerebral cortex of TD ferrets were mostly composed of cortical neurons, including upper layer neurons and GABAergic neurons. We also found disorganizations of radial glial fibers and of the ventricular lining in the TD ferret cortex, indicating that PNH may result from defects in radial migration of cortical neurons along radial glial fibers during development. Our findings provide novel mechanistic insights into the pathogenesis of PNH in TD. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Graph theory findings in the pathophysiology of temporal lobe epilepsy

PubMed Central

Chiang, Sharon; Haneef, Zulfi

2014-01-01

Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy. Accumulating evidence has shown that TLE is a disorder of abnormal epileptogenic networks, rather than focal sources. Graph theory allows for a network-based representation of TLE brain networks, and has potential to illuminate characteristics of brain topology conducive to TLE pathophysiology, including seizure initiation and spread. We review basic concepts which we believe will prove helpful in interpreting results rapidly emerging from graph theory research in TLE. In addition, we summarize the current state of graph theory findings in TLE as they pertain its pathophysiology. Several common findings have emerged from the many modalities which have been used to study TLE using graph theory, including structural MRI, diffusion tensor imaging, surface EEG, intracranial EEG, magnetoencephalography, functional MRI, cell cultures, simulated models, and mouse models, involving increased regularity of the interictal network configuration, altered local segregation and global integration of the TLE network, and network reorganization of temporal lobe and limbic structures. As different modalities provide different views of the same phenomenon, future studies integrating data from multiple modalities are needed to clarify findings and contribute to the formation of a coherent theory on the pathophysiology of TLE. PMID:24831083

Animal models of ischemic stroke and their application in clinical research.

PubMed

Fluri, Felix; Schuhmann, Michael K; Kleinschnitz, Christoph

2015-01-01

This review outlines the most frequently used rodent stroke models and discusses their strengths and shortcomings. Mimicking all aspects of human stroke in one animal model is not feasible because ischemic stroke in humans is a heterogeneous disorder with a complex pathophysiology. The transient or permanent middle cerebral artery occlusion (MCAo) model is one of the models that most closely simulate human ischemic stroke. Furthermore, this model is characterized by reliable and well-reproducible infarcts. Therefore, the MCAo model has been involved in the majority of studies that address pathophysiological processes or neuroprotective agents. Another model uses thromboembolic clots and thus is more convenient for investigating thrombolytic agents and pathophysiological processes after thrombolysis. However, for many reasons, preclinical stroke research has a low translational success rate. One factor might be the choice of stroke model. Whereas the therapeutic responsiveness of permanent focal stroke in humans declines significantly within 3 hours after stroke onset, the therapeutic window in animal models with prompt reperfusion is up to 12 hours, resulting in a much longer action time of the investigated agent. Another major problem of animal stroke models is that studies are mostly conducted in young animals without any comorbidity. These models differ from human stroke, which particularly affects elderly people who have various cerebrovascular risk factors. Choosing the most appropriate stroke model and optimizing the study design of preclinical trials might increase the translational potential of animal stroke models.

Animal models of ischemic stroke and their application in clinical research

PubMed Central

Fluri, Felix; Schuhmann, Michael K; Kleinschnitz, Christoph

2015-01-01

This review outlines the most frequently used rodent stroke models and discusses their strengths and shortcomings. Mimicking all aspects of human stroke in one animal model is not feasible because ischemic stroke in humans is a heterogeneous disorder with a complex pathophysiology. The transient or permanent middle cerebral artery occlusion (MCAo) model is one of the models that most closely simulate human ischemic stroke. Furthermore, this model is characterized by reliable and well-reproducible infarcts. Therefore, the MCAo model has been involved in the majority of studies that address pathophysiological processes or neuroprotective agents. Another model uses thromboembolic clots and thus is more convenient for investigating thrombolytic agents and pathophysiological processes after thrombolysis. However, for many reasons, preclinical stroke research has a low translational success rate. One factor might be the choice of stroke model. Whereas the therapeutic responsiveness of permanent focal stroke in humans declines significantly within 3 hours after stroke onset, the therapeutic window in animal models with prompt reperfusion is up to 12 hours, resulting in a much longer action time of the investigated agent. Another major problem of animal stroke models is that studies are mostly conducted in young animals without any comorbidity. These models differ from human stroke, which particularly affects elderly people who have various cerebrovascular risk factors. Choosing the most appropriate stroke model and optimizing the study design of preclinical trials might increase the translational potential of animal stroke models. PMID:26170628

A 12-month multicenter, randomized study comparing the levonorgestrel intrauterine system with the etonogestrel subdermal implant.

PubMed

Apter, Dan; Briggs, Paula; Tuppurainen, Marjo; Grunert, Julia; Lukkari-Lax, Eeva; Rybowski, Sarah; Gemzell-Danielsson, Kristina

2016-07-01

To compare the levonorgestrel intrauterine system (LNG-IUS 8), which has an average levonorgestrel release rate of ∼8 μg/24 hours during the first year (total levonorgestrel content 13.5 mg; Jaydess/Skyla), with the etonogestrel (ENG) subdermal implant (total content, 68 mg) with regard to the 12-month discontinuation rate (primary outcome). Randomized, open-label, phase III study. Thirty-eight centers in six European countries. Study population of 766 healthy nulliparous and parous women aged 18-35 years. The LNG-IUS 8 or the ENG implant. Discontinuation rate, by treatment group, at Month 12. The 12-month discontinuation rates were 19.6% and 26.8% in the LNG-IUS 8 and ENG implant groups, respectively. The -7.2% difference was statistically significant (95% confidence interval -13.2%, -1.2%). Fewer women in the LNG-IUS 8 group than in the ENG implant group discontinued because of increased bleeding (3.2% vs. 11.3%) or adverse events (14.3% vs. 21.8%). At 12 months, more women in the LNG-IUS 8 group than in the ENG implant group were "very/somewhat satisfied" with their bleeding pattern (60.9% vs. 33.6%) and reported a preference to use their study treatment after study completion (70.1% vs. 58.5%). The LNG-IUS 8 was associated with a significantly lower 12-month discontinuation rate compared with the ENG implant; mainly because ENG implant users frequently discontinued due to increased bleeding. More LNG-IUS 8 users than ENG implant users reported being "very/somewhat satisfied" with their bleeding pattern, and reported a preference to continue using their study treatment after the study. NCT01397097. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

On caudal prehensility and phylogenetic constraint in lizards: The influence of ancestral anatomy on function in Corucia and Furcifer.

PubMed

Zippel, Kevin C; Glor, Richard E; Bertram, John E A

1999-02-01

We examined caudal anatomy in two species of prehensile-tailed lizards, Furcifer pardalis and Corucia zebrata. Although both species use their tails to grasp, each relies on a strikingly different anatomy to do so. The underlying anatomies appear to reflect phylogenetic constraints on the consequent functional mechanisms. Caudal autotomy is presumably the ancestral condition for lizards and is allowed by a complex system of interdigitating muscle segments. The immediate ancestor of chameleons was nonautotomous and did not possess this specialized anatomy; consequently, the derived arrangement in the chameleon tail is unique among lizards. The limb functions as an articulated linkage system with long tendinous bands originating from longitudinal muscles to directly manipulate vertebrae. Corucia is incapable of autotomy, but it is immediately derived from autotomous ancestors. As such, it has evolved a biomechanical system for prehension quite different from that of chameleons. The caudal anatomy in Corucia is very similar to that of lizards with autotomous tails, yet distinct differences in the ancestral pattern and its relationship to the subdermal tunic are derived. Instead of the functional unit being individual autotomy segments, the interdigitating prongs of muscle have become fused with an emphasis on longitudinal stacks of muscular cones. The muscles originate from the vertebral column and a subdermal collagenous tunic and insert within the adjacent cone. However, there is remarkably little direct connection with the bones. The muscles have origins more associated with the tunic and muscular septa. Like the axial musculature of some fish, the tail of Corucia utilizes a design in which these collagenous elements serve as an integral skeletal component. This arrangement provides Corucia with an elegantly designed system capable of a remarkable variety of bending movements not evident in chameleon tails. J. Morphol. 239:143-155, 1999. © 1999 Wiley-Liss, Inc. Copyright © 1999 Wiley-Liss, Inc.

Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome

PubMed Central

Muscatello, Maria Rosaria A; Bruno, Antonio; Scimeca, Giuseppe; Pandolfo, Gianluca; Zoccali, Rocco A

2014-01-01

Irritable bowel syndrome (IBS) is regarded as a multifactorial disease in which alterations in the brain-gut axis signaling play a major role. The biopsychosocial model applied to the understanding of IBS pathophysiology assumes that psychosocial factors, interacting with peripheral/central neuroendocrine and immune changes, may induce symptoms of IBS, modulate symptom severity, influence illness experience and quality of life, and affect outcome. The present review focuses on the role of negative affects, including depression, anxiety, and anger, on pathogenesis and clinical expression of IBS. The potential role of the autonomic nervous system, stress-hormone system, and immune system in the pathophysiology of both negative affects and IBS are taken into account. Psychiatric comorbidity and subclinical variations in levels of depression, anxiety, and anger are further discussed in relation to the main pathophysiological and symptomatic correlates of IBS, such as sensorimotor functions, gut microbiota, inflammation/immunity, and symptom reporting. PMID:24976697

Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome.

PubMed

Muscatello, Maria Rosaria A; Bruno, Antonio; Scimeca, Giuseppe; Pandolfo, Gianluca; Zoccali, Rocco A

2014-06-28

Irritable bowel syndrome (IBS) is regarded as a multifactorial disease in which alterations in the brain-gut axis signaling play a major role. The biopsychosocial model applied to the understanding of IBS pathophysiology assumes that psychosocial factors, interacting with peripheral/central neuroendocrine and immune changes, may induce symptoms of IBS, modulate symptom severity, influence illness experience and quality of life, and affect outcome. The present review focuses on the role of negative affects, including depression, anxiety, and anger, on pathogenesis and clinical expression of IBS. The potential role of the autonomic nervous system, stress-hormone system, and immune system in the pathophysiology of both negative affects and IBS are taken into account. Psychiatric comorbidity and subclinical variations in levels of depression, anxiety, and anger are further discussed in relation to the main pathophysiological and symptomatic correlates of IBS, such as sensorimotor functions, gut microbiota, inflammation/immunity, and symptom reporting.

Current pathophysiological concepts and management of pulmonary hypertension.

PubMed

Lourenço, André P; Fontoura, Dulce; Henriques-Coelho, Tiago; Leite-Moreira, Adelino F

2012-03-22

Pulmonary hypertension (PH), increasingly recognized as a major health burden, remains underdiagnosed due mainly to the unspecific symptoms. Pulmonary arterial hypertension (PAH) has been extensively investigated. Pathophysiological knowledge derives mostly from experimental models. Paradoxically, common non-PAH PH forms remain largely unexplored. Drugs targeting lung vascular tonus became available during the last two decades, notwithstanding the disease progresses in many patients. The aim of this review is to summarize recent advances in epidemiology, pathophysiology and management with particular focus on associated myocardial and systemic compromise and experimental therapeutic possibilities. PAH, currently viewed as a panvasculopathy, is due to a crosstalk between endothelial and smooth muscle cells, inflammatory activation and altered subcellular pathways. Cardiac cachexia and right ventricular compromise are fundamental determinants of PH prognosis. Combined vasodilator therapy is already mainstay for refractory cases, but drugs directed at these new pathophysiological pathways may constitute a significant advance. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Implications of genetic research on the role of the serotonin in depression: emphasis on the serotonin type 1A receptor and the serotonin transporter.

PubMed

Neumeister, Alexander; Young, Theresa; Stastny, Juergen

2004-08-01

Serotonin systems appear to play a key role in the pathophysiology of major depressive disorder. Consequently, ongoing research determines whether serotonin related genes account for the very robust differential behavioral and neural mechanisms that discriminate patients with depression from healthy controls. Serotonin type 1(A) receptors and the serotonin transporters are reduced in depression, and recent genetic research in animals and humans has implicated both in depression. Preclinical studies have utilized a variety of animal models that have been used to explain pathophysiological mechanisms in humans, although it is not clear at all whether these models constitute relevant models for depression in humans. However, data from preclinical studies can generate hypotheses that are tested in humans by combining genetic data with behavioral and physiological challenge paradigms and neuroimaging. These studies will enhance our understanding about combined influences from multiple interacting genes, as well as from environmental factors on brain circuits and their function, and about how these mechanisms may contribute to the pathophysiology of neuropsychiatric disorders.

A Fully Implanted Drug Delivery System for Peripheral Nerve Blocks in Behaving Animals

PubMed Central

Pohlmeyer, Eric A.; Jordon, Luke R.; Kim, Peter; Miller, Lee E.

2009-01-01

Inhibiting peripheral nerve function can be useful for many studies of the nervous system or motor control. Accomplishing this in a temporary fashion in animal models by using peripheral nerve blocks permits studies of the immediate effects of the loss, and/or any resulting short-term changes and adaptations in behavior or motor control, while avoiding the complications commonly associated with permanent lesions, such as sores or self-mutilation. We have developed a method of quickly and repeatedly inducing temporary, controlled motor deficits in rhesus macaque monkeys via a chronically implanted drug delivery system. This assembly consists of a nerve cuff and a subdermal injection dome, and has proved effective for delivering local anesthetics directly to peripheral nerves for many months. Using this assembly for median and ulnar nerve blocks routinely resulted in over 80% losses in hand and wrist strength for rhesus monkeys. The assembly was also effective for inducing ambulatory motor deficits in rabbits through blocks of the sciatic nerve. Interestingly, while standard anesthetics were sufficient for the rabbit nerve blocks, the inclusion of epinephrine was essential for achieving significant motor blockade in the monkeys. PMID:19524613

Animal models of female pelvic organ prolapse: lessons learned

PubMed Central

Couri, Bruna M; Lenis, Andrew T; Borazjani, Ali; Paraiso, Marie Fidela R; Damaser, Margot S

2012-01-01

Pelvic organ prolapse is a vaginal protrusion of female pelvic organs. It has high prevalence worldwide and represents a great burden to the economy. The pathophysiology of pelvic organ prolapse is multifactorial and includes genetic predisposition, aberrant connective tissue, obesity, advancing age, vaginal delivery and other risk factors. Owing to the long course prior to patients becoming symptomatic and ethical questions surrounding human studies, animal models are necessary and useful. These models can mimic different human characteristics – histological, anatomical or hormonal, but none present all of the characteristics at the same time. Major animal models include knockout mice, rats, sheep, rabbits and nonhuman primates. In this article we discuss different animal models and their utility for investigating the natural progression of pelvic organ prolapse pathophysiology and novel treatment approaches. PMID:22707980

Magnetic resonance imaging and spectroscopy of the murine cardiovascular system.

PubMed

Akki, Ashwin; Gupta, Ashish; Weiss, Robert G

2013-03-01

Magnetic resonance imaging (MRI) has emerged as a powerful and reliable tool to noninvasively study the cardiovascular system in clinical practice. Because transgenic mouse models have assumed a critical role in cardiovascular research, technological advances in MRI have been extended to mice over the last decade. These have provided critical insights into cardiac and vascular morphology, function, and physiology/pathophysiology in many murine models of heart disease. Furthermore, magnetic resonance spectroscopy (MRS) has allowed the nondestructive study of myocardial metabolism in both isolated hearts and in intact mice. This article reviews the current techniques and important pathophysiological insights from the application of MRI/MRS technology to murine models of cardiovascular disease.

Magnetic resonance imaging and spectroscopy of the murine cardiovascular system

PubMed Central

Akki, Ashwin; Gupta, Ashish

2013-01-01

Magnetic resonance imaging (MRI) has emerged as a powerful and reliable tool to noninvasively study the cardiovascular system in clinical practice. Because transgenic mouse models have assumed a critical role in cardiovascular research, technological advances in MRI have been extended to mice over the last decade. These have provided critical insights into cardiac and vascular morphology, function, and physiology/pathophysiology in many murine models of heart disease. Furthermore, magnetic resonance spectroscopy (MRS) has allowed the nondestructive study of myocardial metabolism in both isolated hearts and in intact mice. This article reviews the current techniques and important pathophysiological insights from the application of MRI/MRS technology to murine models of cardiovascular disease. PMID:23292717

Graph theory findings in the pathophysiology of temporal lobe epilepsy.

PubMed

Chiang, Sharon; Haneef, Zulfi

2014-07-01

Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy. Accumulating evidence has shown that TLE is a disorder of abnormal epileptogenic networks, rather than focal sources. Graph theory allows for a network-based representation of TLE brain networks, and has potential to illuminate characteristics of brain topology conducive to TLE pathophysiology, including seizure initiation and spread. We review basic concepts which we believe will prove helpful in interpreting results rapidly emerging from graph theory research in TLE. In addition, we summarize the current state of graph theory findings in TLE as they pertain its pathophysiology. Several common findings have emerged from the many modalities which have been used to study TLE using graph theory, including structural MRI, diffusion tensor imaging, surface EEG, intracranial EEG, magnetoencephalography, functional MRI, cell cultures, simulated models, and mouse models, involving increased regularity of the interictal network configuration, altered local segregation and global integration of the TLE network, and network reorganization of temporal lobe and limbic structures. As different modalities provide different views of the same phenomenon, future studies integrating data from multiple modalities are needed to clarify findings and contribute to the formation of a coherent theory on the pathophysiology of TLE. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Pathophysiology and neuroprotection of global and focal perinatal brain injury: lessons from animal models

PubMed Central

Manganozzi, Lucilla; Moretti, Raffaella; Vexler, Zinaida S.; Gressens, Pierre

2016-01-01

BACKGROUND Arterial ischemic stroke occurs most frequently in term newborns than in the elderly, and brain immaturity affects mechanisms of ischemic injury and recovery. The susceptibility to injury of the brain was assumed to be lower in the perinatal period as compared to childhood. This concept was recently challenged by clinical studies showing marked motor disabilities after stroke in neonates, with the severity of motor and cortical sensory deficits similar in both perinatal and childhood ischemic stroke. The understanding of the triggers and the pathophysiological mechanisms of perinatal stroke has greatly improved in recent years, but many aspects remain still unclear. METHODS In this review, we will focus on the pathophysiology of perinatal stroke and on therapeutic strategies that can protect the immature brain from the consequences of stroke by targeting inflammation and brain microenvironment. RESULTS Studies in neonatal rodent models of cerebral ischemia have shown a potential role for soluble inflammatory molecules as important modulators of injury and recovery. A great effort has been made and is still in act to try neuroprotective molecules based on the new physiopatological acquisition. CONCLUSION In this review we aim to give a comprehensive view of new insights concerning pathophysiological mechanism of focal and global perinatal brain injury and its new therapeutic approaches. PMID:26002050

Distribution, composition and functions of gelatinous tissues in deep-sea fishes.

PubMed

Gerringer, Mackenzie E; Drazen, Jeffrey C; Linley, Thomas D; Summers, Adam P; Jamieson, Alan J; Yancey, Paul H

2017-12-01

Many deep-sea fishes have a gelatinous layer, or subdermal extracellular matrix, below the skin or around the spine. We document the distribution of gelatinous tissues across fish families (approx. 200 species in ten orders), then review and investigate their composition and function. Gelatinous tissues from nine species were analysed for water content (96.53 ± 1.78% s.d.), ionic composition, osmolality, protein (0.39 ± 0.23%), lipid (0.69 ± 0.56%) and carbohydrate (0.61 ± 0.28%). Results suggest that gelatinous tissues are mostly extracellular fluid, which may allow animals to grow inexpensively. Further, almost all gelatinous tissues floated in cold seawater, thus their lower density than seawater may contribute to buoyancy in some species. We also propose a new hypothesis: gelatinous tissues, which are inexpensive to grow, may sometimes be a method to increase swimming efficiency by fairing the transition from trunk to tail. Such a layer is particularly prominent in hadal snailfishes (Liparidae); therefore, a robotic snailfish model was designed and constructed to analyse the influence of gelatinous tissues on locomotory performance. The model swam faster with a watery layer, representing gelatinous tissue, around the tail than without. Results suggest that the tissues may, in addition to providing buoyancy and low-cost growth, aid deep-sea fish locomotion.

Distribution, composition and functions of gelatinous tissues in deep-sea fishes

PubMed Central

Drazen, Jeffrey C.; Linley, Thomas D.; Summers, Adam P.; Jamieson, Alan J.; Yancey, Paul H.

2017-01-01

Many deep-sea fishes have a gelatinous layer, or subdermal extracellular matrix, below the skin or around the spine. We document the distribution of gelatinous tissues across fish families (approx. 200 species in ten orders), then review and investigate their composition and function. Gelatinous tissues from nine species were analysed for water content (96.53 ± 1.78% s.d.), ionic composition, osmolality, protein (0.39 ± 0.23%), lipid (0.69 ± 0.56%) and carbohydrate (0.61 ± 0.28%). Results suggest that gelatinous tissues are mostly extracellular fluid, which may allow animals to grow inexpensively. Further, almost all gelatinous tissues floated in cold seawater, thus their lower density than seawater may contribute to buoyancy in some species. We also propose a new hypothesis: gelatinous tissues, which are inexpensive to grow, may sometimes be a method to increase swimming efficiency by fairing the transition from trunk to tail. Such a layer is particularly prominent in hadal snailfishes (Liparidae); therefore, a robotic snailfish model was designed and constructed to analyse the influence of gelatinous tissues on locomotory performance. The model swam faster with a watery layer, representing gelatinous tissue, around the tail than without. Results suggest that the tissues may, in addition to providing buoyancy and low-cost growth, aid deep-sea fish locomotion. PMID:29308245

The pathophysiology of post-stroke aphasia: A network approach.

PubMed

Thiel, Alexander; Zumbansen, Anna

2016-06-13

Post-stroke aphasia syndromes as a clinical entity arise from the disruption of brain networks specialized in language production and comprehension due to permanent focal ischemia. This approach to post-stroke aphasia is based on two pathophysiological concepts: 1) Understanding language processing in terms of distributed networks rather than language centers and 2) understanding the molecular pathophysiology of ischemic brain injury as a dynamic process beyond the direct destruction of network centers and their connections. While considerable progress has been made in the past 10 years to develop such models on a systems as well as a molecular level, the influence of these approaches on understanding and treating clinical aphasia syndromes has been limited. In this article, we review current pathophysiological concepts of ischemic brain injury, their relationship to altered information processing in language networks after ischemic stroke and how these mechanisms may be influenced therapeutically to improve treatment of post-stroke aphasia. Understanding the pathophysiological mechanism of post-stroke aphasia on a neurophysiological systems level as well as on the molecular level becomes more and more important for aphasia treatment, as the field moves from standardized therapies towards more targeted individualized treatment strategies comprising behavioural therapies as well as non-invasive brain stimulation (NIBS).

Human physiological models of insomnia.

PubMed

Richardson, Gary S

2007-12-01

Despite the wide prevalence and important consequences of insomnia, remarkably little is known about its pathophysiology. Available models exist primarily in the psychological domain and derive from the demonstrated efficacy of behavioral treatment approaches to insomnia management. However, these models offer little specific prediction about the anatomic or physiological foundation of chronic primary insomnia. On the other hand, a growing body of data on the physiology of sleep supports a reasonably circumscribed overview of possible pathophysiological mechanisms, as well as the development of physiological models of insomnia to guide future research. As a pragmatic step, these models focus on primary insomnia, as opposed to comorbid insomnias, because the latter is by its nature a much more heterogeneous presentation, reflecting the effects of the distinct comorbid condition. Current understanding of the regulation of sleep and wakefulness in mammalian brain supports four broad candidate areas: 1) disruption of the sleep homeostat; 2) disruption of the circadian clock; 3) disruption of intrinsic systems responsible for the expression of sleep states; or 4) disruption (hyperactivity) of extrinsic systems capable of over-riding normal sleep-wake regulation. This review examines each of the four candidate pathophysiological mechanisms and the available data in support of each. While studies that directly test the viability of each model are not yet available, descriptive data on primary insomnia favor the involvement of dysfunctional extrinsic stress-response systems in the pathology of primary chronic insomnia.

A novel small animal extracorporeal circulation model for studying pathophysiology of cardiopulmonary bypass.

PubMed

Fujii, Yutaka; Shirai, Mikiyasu; Inamori, Shuji; Takewa, Yoshiaki; Tatsumi, Eisuke

2015-03-01

Extracorporeal circulation (ECC) is indispensable for cardiac surgery. Despite the fact that ECCcauses damage to blood components and is non-physiologic, its pathophysiology has not been fully elucidated. This is because difficulty in clinical research and animal experiments keeps the knowledge insufficient. Therefore, it is desirable to have a miniature ECC model for small animals, which enables repetitive experiments, to study the mechanism of pathophysiological changes during ECC. We developed a miniature ECC system and applied it to the rat. We measured changes in hemodynamics, blood gases and hemoglobin (Hb) concentration, serum cytokines (TNF-α, IL-6, IL-10), biochemical markers (LDH, AST, ALT), and the wet-to-dry weight (W/D) ratio of the lung for assessing whether the rat ECC model is comparable to the human ECC. The ECC system consisted of a membranous oxygenator (polypropylene, 0.03 m(2)), tubing line (polyvinyl chloride), and roller pump. Priming volume of this system is only 8 ml. Rats (400-450 g) were divided into the SHAM group (n = 7) and the ECC group (n = 7). Blood samples were collected before, 60 and 120 min after initiation of ECC. During ECC, blood pressure and Hb were maintained around 80 mmHg and 10 g/dL, respectively. The levels of the inflammatory and biochemical markers and the W/D ratio were significantly elevated in the ECC group, indicating some organ damages and systemic inflammatory responses during ECC. We successfully established the ECC for the rat. This miniature ECC model could be a useful approach for studying the mechanism of pathophysiology during ECC and basic assessment of the ECC devices.

The Role of Interleukin-10 in the Pathophysiology of Preeclampsia.

PubMed

Cubro, Hajrunisa; Kashyap, Sonu; Nath, Meryl C; Ackerman, Allan W; Garovic, Vesna D

2018-04-30

The pathophysiology of preeclampsia is complex and not entirely understood. A key feature in preeclampsia development is an immunological imbalance that shifts the maternal immune response from one of tolerance towards one promoting chronic inflammation and endothelial dysfunction. As a key regulator of immunity, IL-10 not only has immunomodulatory activity, but also directly benefits vasculature and promotes successful cellular interactions at the maternal-fetal interface. Here we focus on the mechanisms by which the dysregulation of IL-10 may contribute to the pathophysiology of preeclampsia. Dysregulation of IL-10 has been demonstrated in various animal models of preeclampsia. Decreased IL-10 production in both placenta and peripheral blood mononuclear cells has been reported in human studies, but with inconsistent results. The significance of IL-10 in preeclampsia has shifted from a key biomarker to one with therapeutic potential. As such, a better understanding of the role of this cytokine in the pathophysiology of preeclampsia is of paramount importance.

Lower vertebrate and invertebrate models of Alzheimer's disease - A review.

PubMed

Sharma, Neha; Khurana, Navneet; Muthuraman, Arunachalam

2017-11-15

Alzheimer's disease is a common neurodegenerative disorder which is characterized by the presence of beta- amyloid protein and neurofibrillary tangles (NFTs) in the brain. Till now, various higher vertebrate models have been in use to study the pathophysiology of this disease. But, these models possess some limitations like ethical restrictions, high cost, difficult maintenance of large quantity and lesser reproducibility. Besides, various lower chordate animals like Danio rerio, Drosophila melanogaster, Caenorhabditis elegans and Ciona intestinalis have been proved to be an important model for the in vivo determination of targets of drugs with least limitations. In this article, we reviewed different studies conducted on theses models for the better understanding of the pathophysiology of AD and their subsequent application as a potential tool in the preclinical evaluation of new drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Obsessive Compulsive Disorder: Beyond Segregated Cortico-striatal Pathways

PubMed Central

Milad, Mohammed R.; Rauch, Scott L.

2016-01-01

Obsessive-compulsive disorder (OCD) affects ∼2-3% of the population and is characterized by recurrent intrusive thoughts (obsessions) and repetitive behaviors or mental acts (compulsions), typically performed in response to obsessions or related anxiety. In the past few decades, the prevailing models of OCD pathophysiology have focused on cortico-striatal circuitry. More recent neuroimaging evidence, however, points to critical involvement of the lateral and medial orbitofrontal cortices, the dorsal anterior cingulate cortex and amygdalo-cortical circuitry, in addition to cortico-striatal circuitry, in the pathophysiology of the disorder. In this review, we elaborate proposed features of OCD pathophysiology beyond the classic parallel cortico-striatal pathways and argue that this evidence suggests that fear extinction, in addition to behavioral inhibition, may be impaired in OCD. PMID:22138231

Systems modeling and simulation applications for critical care medicine

PubMed Central

2012-01-01

Critical care delivery is a complex, expensive, error prone, medical specialty and remains the focal point of major improvement efforts in healthcare delivery. Various modeling and simulation techniques offer unique opportunities to better understand the interactions between clinical physiology and care delivery. The novel insights gained from the systems perspective can then be used to develop and test new treatment strategies and make critical care delivery more efficient and effective. However, modeling and simulation applications in critical care remain underutilized. This article provides an overview of major computer-based simulation techniques as applied to critical care medicine. We provide three application examples of different simulation techniques, including a) pathophysiological model of acute lung injury, b) process modeling of critical care delivery, and c) an agent-based model to study interaction between pathophysiology and healthcare delivery. Finally, we identify certain challenges to, and opportunities for, future research in the area. PMID:22703718

Bioengineered vascular constructs as living models for in vitro cardiovascular research.

PubMed

Wolf, Frederic; Vogt, Felix; Schmitz-Rode, Thomas; Jockenhoevel, Stefan; Mela, Petra

2016-09-01

Cardiovascular diseases represent the most common cause of morbidity and mortality worldwide. In this review, we explore the potential of bioengineered vascular constructs as living models for in vitro cardiovascular research to advance the current knowledge of pathophysiological processes and support the development of clinical therapies. Bioengineered vascular constructs capable of recapitulating the cellular and mechanical environment of native vessels represent a valuable platform to study cellular interactions and signaling cascades, test drugs and medical devices under (patho)physiological conditions, with the additional potential benefit of reducing the number of animals required for preclinical testing. Copyright © 2016 Elsevier Ltd. All rights reserved.

Benefits and limitations of animal models in partial bladder outlet obstruction for translational research.

PubMed

Kitta, Takeya; Kanno, Yukiko; Chiba, Hiroki; Higuchi, Madoka; Ouchi, Mifuka; Togo, Mio; Moriya, Kimihiko; Shinohara, Nobuo

2018-01-01

The functions of the lower urinary tract have been investigated for more than a century. Lower urinary tract symptoms, such as incomplete bladder emptying, weak urine stream, daytime urinary frequency, urgency, urge incontinence and nocturia after partial bladder outlet obstruction, is a frequent cause of benign prostatic hyperplasia in aging men. However, the pathophysiological mechanisms have not been fully elucidated. The use of animal models is absolutely imperative for understanding the pathophysiological processes involved in bladder dysfunction. Surgical induction has been used to study lower urinary tract functions of numerous animal species, such as pig, dog, rabbit, guinea pig, rat and mouse, of both sexes. Several morphological and functional modifications under partial bladder outlet obstruction have not only been observed in the bladder, but also in the central nervous system. Understanding the changes of the lower urinary tract functions induced by partial bladder outlet obstruction would also contribute to appropriate drug development for treating these pathophysiological conditions. In the present review, we discuss techniques for creating partial bladder outlet obstruction, the characteristics of several species, as well as issues of each model, and their translational value. © 2017 The Japanese Urological Association.

Cutaneous heat flow during heating and cooling in Alligator mississipiensis.

PubMed

Smith, E N

1976-05-01

Direct in vivo measurement of heat flow across the skin of the American alligator (Alligator mississipiensis) showed increased heat flow during warming. Mean values at 25 degrees C during warming (15-35 degrees C) in air (airspeed 300 cm/s) were 17.9 +/- 92 SE cal/cm2 per h (mean alligator wt 3.27 kg). Cooling heat flow at the same temperature was 13.6 +/- 0.57 cal/cm2 per h. Subdermal heat flow was reduced during warming and was not significantly different from cutaneous heat flow during cooling. This indicated that the alligator was able to control its rate of heat exchange with the environment by altering cutaneous perfusion. Atropine, phenoxybenzamine, nitroglycerin, and Xylocaine did not affect cutaneous heat flow or heating and cooling rates. Atropine blocked bradycardia during cooling.

Facial rejuvenation starts in the midface: three-dimensional volumetric facial rejuvenation has beneficial effects on nontreated neighboring esthetic units.

PubMed

Wollina, Uwe

2016-03-01

Facial aging is a major indication for minimal invasive esthetic procedures. Dermal fillers are a cornerstone in the approach for facial sculpturing. But where to start? Our concept is midfacial volume restoration in first place. This will result in a healthy and youthful appearance creating a facial V-shape. But midfacial filler injection does not only improve the malar area. It has also beneficial effects on neighboring esthetic units. We report on such improvements in periocular and nasolabial region, upper lips and perioral tissue, and the jaw line and discuss anatomical background. We hypothesize that midfacial deep filler injections also may activate subdermal white adipose tissue stem cells contributing to longer lasting rejuvenation. © 2015 Wiley Periodicals, Inc.

WHEN FUE GOES WRONG!

PubMed Central

Poswal, Arvind; Bhutia, Sangay; Mehta, Ruby

2011-01-01

Follicular unit extraction (FUE) is an accepted method of extracting individual follicular unit grafts for hair transplant surgery. Since follicles are harvested from the back of the scalp using tiny punches resulting in minimal scarring, it has gained rapid acceptance among the patients. However, due care needs to be exercised while performing FUE. FUE should not be confused with the older plug graft extraction methods of coring out hair-bearing skin plugs. Lack of due diligence while performing such extractions can lead to subluxation of the grafts into the subdermal layer of scalp. Overtumescence of the scalp donor area, use of blunt punches and trying to “core” out the full thickness grafts can all contribute to this. The following cases illustrate some pitfalls to be avoided while performing FUE and the adverse consequences if they occur. PMID:22121268

The Emergence of Zoonotic Onchocerca lupi Infection in the United States – A Case-Series

PubMed Central

Cantey, Paul T.; Weeks, Jessica; Edwards, Morven; Rao, Suchitra; Ostovar, G. Amin; Dehority, Walter; Alzona, Maria; Swoboda, Sara; Christiaens, Brooke; Ballan, Wassim; Hartley, John; Terranella, Andrew; Weatherhead, Jill; Dunn, James J.; Marx, Douglas P.; Hicks, M. John; Rauch, Ronald A.; Smith, Christiana; Dishop, Megan K.; Handler, Michael H.; Dudley, Roy W. R.; Chundu, Kote; Hobohm, Dan; Feiz-Erfan, Iman; Hakes, Joseph; Berry, Ryan S.; Stepensaski, Shelly; Greenfield, Benjamin; Shroeder, Laura; Bishop, Henry; de Almeida, Marcos; Mathison, Blaine; Eberhard, Mark

2016-01-01

This case-series describes the 6 human infections with Onchocerca lupi, a parasite known to infect cats and dogs, that have been identified in the United States since 2013. Unlike cases reported outside the country, the American patients have not had subconjunctival nodules but have manifested more invasive disease (eg, spinal, orbital, and subdermal nodules). Diagnosis remains challenging in the absence of a serologic test. Treatment should be guided by what is done for Onchocerca volvulus as there are no data for O. lupi. Available evidence suggests that there may be transmission in southwestern United States, but the risk of transmission to humans is not known. Research is needed to better define the burden of disease in the United States and develop appropriately-targeted prevention strategies. PMID:26611778

Modeling mania in preclinical settings: a comprehensive review

PubMed Central

Sharma, Ajaykumar N.; Fries, Gabriel R.; Galvez, Juan F.; Valvassori, Samira S.; Soares, Jair C.; Carvalho, André F.; Quevedo, Joao

2015-01-01

The current pathophysiological understanding of mechanisms leading to onset and progression of bipolar manic episodes remains limited. At the same time, available animal models for mania have limited face, construct, and predictive validities. Additionally, these models fail to encompass recent pathophysiological frameworks of bipolar disorder (BD), e.g. neuroprogression. Therefore, there is a need to search for novel preclinical models for mania that could comprehensively address these limitations. Herein we review the history, validity, and caveats of currently available animal models for mania. We also review new genetic models for mania, namely knockout mice for genes involved in neurotransmission, synapse formation, and intracellular signaling pathways. Furthermore, we review recent trends in preclinical models for mania that may aid in the comprehension of mechanisms underlying the neuroprogressive and recurring nature of BD. In conclusion, the validity of animal models for mania remains limited. Nevertheless, novel (e.g. genetic) animal models as well as adaptation of existing paradigms hold promise. PMID:26545487

Animal Models of Hemophilia and Related Bleeding Disorders

PubMed Central

Lozier, Jay N.; Nichols, Timothy C.

2013-01-01

Animal models of hemophilia and related diseases are important for development of novel treatments and to understand the pathophysiology of bleeding disorders in humans. Testing in animals with the equivalent human disorder provides informed estimates of doses and measures of efficacy, which aids in design of human trials. Many models of hemophilia A, hemophilia B, and von Willebrand disease have been developed from animals with spontaneous mutations (hemophilia A dogs, rats, sheep; hemophilia B dogs; and von Willebrand disease pigs and dogs), or by targeted gene disruption in mice to create hemophilia A, B, or VWD models. Animal models have been used to generate new insights into the pathophysiology of each bleeding disorder and also to perform pre-clinical assessments of standard protein replacement therapies as well as novel gene transfer technology. Both the differences between species and differences in underlying causative mutations must be considered in choosing the best animal for a specific scientific study PMID:23956467

Predictive validity of behavioural animal models for chronic pain

PubMed Central

Berge, Odd-Geir

2011-01-01

Rodent models of chronic pain may elucidate pathophysiological mechanisms and identify potential drug targets, but whether they predict clinical efficacy of novel compounds is controversial. Several potential analgesics have failed in clinical trials, in spite of strong animal modelling support for efficacy, but there are also examples of successful modelling. Significant differences in how methods are implemented and results are reported means that a literature-based comparison between preclinical data and clinical trials will not reveal whether a particular model is generally predictive. Limited reports on negative outcomes prevents reliable estimate of specificity of any model. Animal models tend to be validated with standard analgesics and may be biased towards tractable pain mechanisms. But preclinical publications rarely contain drug exposure data, and drugs are usually given in high doses and as a single administration, which may lead to drug distribution and exposure deviating significantly from clinical conditions. The greatest challenge for predictive modelling is, however, the heterogeneity of the target patient populations, in terms of both symptoms and pharmacology, probably reflecting differences in pathophysiology. In well-controlled clinical trials, a majority of patients shows less than 50% reduction in pain. A model that responds well to current analgesics should therefore predict efficacy only in a subset of patients within a diagnostic group. It follows that successful translation requires several models for each indication, reflecting critical pathophysiological processes, combined with data linking exposure levels with effect on target. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21371010

Knowledge and Acceptability of Long-Acting Reversible Contraception Among Adolescent Women Receiving School-Based Primary Care Services.

PubMed

Hoopes, Andrea J; Ahrens, Kym R; Gilmore, Kelly; Cady, Janet; Haaland, Wren L; Amies Oelschlager, Anne-Marie; Prager, Sarah

2016-07-01

A key strategy to reduce unintended adolescent pregnancies is to expand access to long-acting reversible contraceptive (LARC) methods, including intrauterine devices and subdermal contraceptive implants. LARC services can be provided to adolescents in school-based health and other primary care settings, yet limited knowledge and negative attitudes about LARC methods may influence adolescents' utilization of these methods. This study aimed to evaluate correlates of knowledge and acceptability of LARC methods among adolescent women at a school-based health center (SBHC). In this cross-sectional study, female patients receiving care at 2 SBHCs in Seattle, Washington completed an electronic survey about sexual and reproductive health. Primary outcomes were (1) LARC knowledge as measured by percentage correct of 10 true-false questions and (2) LARC acceptability as measured by participants reporting either liking the idea of having an intrauterine device (IUD)/subdermal implant or currently using one. A total of 102 students diverse in race/ethnicity and socioeconomic backgrounds completed the survey (mean age 16.2 years, range 14.4-19.1 years). Approximately half reported a lifetime history of vaginal sex. Greater LARC knowledge was associated with white race (regression coefficient [coef] = 26.8; 95% CI 13.3-40.4; P < .001), history of vaginal intercourse (coef = 29.9; 95% CI 17.1-42.7; P < .001), and current/prior LARC use (coef = 22.8; 95% CI 6.5-40.0; P = .007). Older age was associated with lower IUD acceptability (odds ratio = 0.53, 95% CI 0.30-0.94; P = .029) while history of intercourse was associated with greater implant acceptability (odds ratio 5.66, 95% CI 1.46-22.0; P = .012). Adolescent women in this SBHC setting had variable knowledge and acceptability of LARC. A history of vaginal intercourse was the strongest predictor of LARC acceptability. Our findings suggest a need for LARC counseling and education strategies, particularly for young women from diverse cultural backgrounds and those with less sexual experience. © The Author(s) 2016.

Knowledge and Acceptability of Long-Acting Reversible Contraception Among Adolescent Women Receiving School-Based Primary Care Services

PubMed Central

Hoopes, Andrea J.; Ahrens, Kym R.; Gilmore, Kelly; Cady, Janet; Haaland, Wren L.; Amies Oelschlager, Anne-Marie; Prager, Sarah

2016-01-01

Background: A key strategy to reduce unintended adolescent pregnancies is to expand access to long-acting reversible contraceptive (LARC) methods, including intrauterine devices and subdermal contraceptive implants. LARC services can be provided to adolescents in school-based health and other primary care settings, yet limited knowledge and negative attitudes about LARC methods may influence adolescents’ utilization of these methods. This study aimed to evaluate correlates of knowledge and acceptability of LARC methods among adolescent women at a school-based health center (SBHC). Methods: In this cross-sectional study, female patients receiving care at 2 SBHCs in Seattle, Washington completed an electronic survey about sexual and reproductive health. Primary outcomes were (1) LARC knowledge as measured by percentage correct of 10 true-false questions and (2) LARC acceptability as measured by participants reporting either liking the idea of having an intrauterine device (IUD)/subdermal implant or currently using one. Results: A total of 102 students diverse in race/ethnicity and socioeconomic backgrounds completed the survey (mean age 16.2 years, range 14.4-19.1 years). Approximately half reported a lifetime history of vaginal sex. Greater LARC knowledge was associated with white race (regression coefficient [coef] = 26.8; 95% CI 13.3-40.4; P < .001), history of vaginal intercourse (coef = 29.9; 95% CI 17.1-42.7; P < .001), and current/prior LARC use (coef = 22.8; 95% CI 6.5-40.0; P = .007). Older age was associated with lower IUD acceptability (odds ratio = 0.53, 95% CI 0.30-0.94; P = .029) while history of intercourse was associated with greater implant acceptability (odds ratio 5.66, 95% CI 1.46-22.0; P = .012). Discussion: Adolescent women in this SBHC setting had variable knowledge and acceptability of LARC. A history of vaginal intercourse was the strongest predictor of LARC acceptability. Our findings suggest a need for LARC counseling and education strategies, particularly for young women from diverse cultural backgrounds and those with less sexual experience. PMID:27067583

Chemical warfare nerve agents. A review of cardiopulmonary pathophysiology and resuscitation. Technical report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Franz, D.R.

1986-12-01

The purpose of this document is to provide the medical research community with a digest of the open and internal literature related to cardiopulmonary pathophysiology, resuscitation, and animal modeling of chemical warfare nerve agent intoxication. Though not comprehensive, this review makes available to the reader a cross section of what research was done in this small but important part of the medical chemical defense research program between World War II and the early 1980's.

Exploring pain pathophysiology in patients.

PubMed

Sommer, Claudia

2016-11-04

Although animal models of pain have brought invaluable information on basic processes underlying pain pathophysiology, translation to humans is a problem. This Review will summarize what information has been gained by the direct study of patients with chronic pain. The techniques discussed range from patient phenotyping using quantitative sensory testing to specialized nociceptor neurophysiology, imaging methods of peripheral nociceptors, analyses of body fluids, genetics and epigenetics, and the generation of sensory neurons from patients via inducible pluripotent stem cells. Copyright © 2016, American Association for the Advancement of Science.

Using human brain imaging studies as a guide towards animal models of schizophrenia

PubMed Central

BOLKAN, Scott S.; DE CARVALHO, Fernanda D.; KELLENDONK, Christoph

2015-01-01

Schizophrenia is a heterogeneous and poorly understood mental disorder that is presently defined solely by its behavioral symptoms. Advances in genetic, epidemiological and brain imaging techniques in the past half century, however, have significantly advanced our understanding of the underlying biology of the disorder. In spite of these advances clinical research remains limited in its power to establish the causal relationships that link etiology with pathophysiology and symptoms. In this context, animal models provide an important tool for causally testing hypotheses about biological processes postulated to be disrupted in the disorder. While animal models can exploit a variety of entry points towards the study of schizophrenia, here we describe an approach that seeks to closely approximate functional alterations observed with brain imaging techniques in patients. By modeling these intermediate pathophysiological alterations in animals, this approach offers an opportunity to (1) tightly link a single functional brain abnormality with its behavioral consequences, and (2) to determine whether a single pathophysiology can causally produce alterations in other brain areas that have been described in patients. In this review we first summarize a selection of well-replicated biological abnormalities described in the schizophrenia literature. We then provide examples of animal models that were studied in the context of patient imaging findings describing enhanced striatal dopamine D2 receptor function, alterations in thalamo-prefrontal circuit function, and metabolic hyperfunction of the hippocampus. Lastly, we discuss the implications of findings from these animal models for our present understanding of schizophrenia, and consider key unanswered questions for future research in animal models and human patients. PMID:26037801

Altered brainstem auditory evoked potentials in a rat central sensitization model are similar to those in migraine

PubMed Central

Arakaki, Xianghong; Galbraith, Gary; Pikov, Victor; Fonteh, Alfred N.; Harrington, Michael G.

2014-01-01

Migraine symptoms often include auditory discomfort. Nitroglycerin (NTG)-triggered central sensitization (CS) provides a rodent model of migraine, but auditory brainstem pathways have not yet been studied in this example. Our objective was to examine brainstem auditory evoked potentials (BAEPs) in rat CS as a measure of possible auditory abnormalities. We used four subdermal electrodes to record horizontal (h) and vertical (v) dipole channel BAEPs before and after injection of NTG or saline. We measured the peak latencies (PLs), interpeak latencies (IPLs), and amplitudes for detectable waveforms evoked by 8, 16, or 32 KHz auditory stimulation. At 8 KHz stimulation, vertical channel positive PLs of waves 4, 5, and 6 (vP4, vP5, and vP6), and related IPLs from earlier negative or positive peaks (vN1-vP4, vN1-vP5, vN1-vP6; vP3-vP4, vP3-vP6) increased significantly 2 hours after NTG injection compared to the saline group. However, BAEP peak amplitudes at all frequencies, PLs and IPLs from the horizontal channel at all frequencies, and the vertical channel stimulated at 16 and 32 KHz showed no significant/consistent change. For the first time in the rat CS model, we show that BAEP PLs and IPLs ranging from putative bilateral medial superior olivary nuclei (P4) to the more rostral structures such as the medial geniculate body (P6) were prolonged 2 hours after NTG administration. These BAEP alterations could reflect changes in neurotransmitters and/or hypoperfusion in the midbrain. The similarity of our results with previous human studies further validates the rodent CS model for future migraine research. PMID:24680742

Potential Role of the Gut Microbiome in ALS: A Systematic Review.

PubMed

Wright, Michelle L; Fournier, Christina; Houser, Madelyn C; Tansey, Malú; Glass, Jonathan; Hertzberg, Vicki Stover

2018-01-01

Amyotrophic lateral sclerosis (ALS) etiology and pathophysiology are not well understood. Recent data suggest that dysbiosis of gut microbiota may contribute to ALS etiology and progression. This review aims to explore evidence of associations between gut microbiota and ALS etiology and pathophysiology. Databases were searched for publications relevant to the gut microbiome in ALS. Three publications provided primary evidence of changes in microbiome profiles in ALS. An ALS mouse model revealed damaged tight junction structure and increased permeability in the intestine versus controls along with a shifted microbiome profile, including decreased levels of butyrate-producing bacteria. In a subsequent publication, again using an ALS mouse model, researchers showed that dietary supplementation with butyrate relieved symptoms and lengthened both time to onset of weight loss and survival time. In a small study of ALS patients and healthy controls, investigators also found decreased levels of butyrate-producing bacteria. Essential for maintaining gut barrier integrity, butyrate is the preferred energy source of intestinal epithelial cells. Ten other articles were reviews and commentaries providing indirect support for a role of gut microbiota in ALS pathophysiology. Thus, these studies provide a modicum of evidence implicating gut microbiota in ALS disease, although more research is needed to confirm the connection and determine pathophysiologic mechanisms. Nurses caring for these patients need to understand the gut microbiome and its potential role in ALS in order to effectively counsel patients and their families about emerging therapies (e.g., prebiotics, probiotics, and fecal microbial transplant) and their off-label uses.

Cardiovascular metabolic syndrome: mediators involved in the pathophysiology from obesity to coronary heart disease.

PubMed

Roos, Cornelis J; Quax, Paul H A; Jukema, J Wouter

2012-02-01

Patients with obesity and diabetes mellitus are at increased risk for cardiovascular events and have a higher cardiovascular morbidity and mortality. This worse prognosis is partly explained by the late recognition of coronary heart disease in these patients, due to the absence of symptoms. Early identification of coronary heart disease is vital, to initiate preventive medical therapy and improve prognosis. At present, with the use of cardiovascular risk models, the identification of coronary heart disease in these patients remains inadequate. To this end, biomarkers should improve the early identification of patients at increased cardiovascular risk. The first part of this review describes the pathophysiologic pathway from obesity to coronary heart disease. The second part evaluates several mediators from this pathophysiologic pathway for their applicability as biomarkers for the identification of coronary heart disease.

Central Mechanisms in the Maintenance of Chronic Widespread Noninflammatory Muscle Pain

PubMed Central

DeSantana, Josimari M.; Sluka, Kathleen A.

2009-01-01

Chronic widespread pain (CWP) conditions such as fibromyalgia and myofascial syndromes are characterized by generalized pain, tenderness, morning stiffness, disturbed sleep, and pronounced fatigue. However, CWP pathophysiology is still unclear. A number of hypotheses have been proposed as the underlying pathophysiology of CWP: muscular dysfunction/ischemia, central sensitization, and a deficit in endogenous pain-modulating systems. This article reviews the current and emerging literature about the pathophysiology and neurobiology of chronic widespread musculoskeletal pain. Widespread musculoskeletal pain results in changes in the central nervous system in human subjects and animal models. These changes likely reflect alterations in supraspinal modulation of nociception, and include increases in excitatory and decreases in inhibitory modulation pathways. These alterations in excitation and inhibition likely drive changes observed in the spinal cord to result in central sensitization, and the consequent pain and hyperalgesia. PMID:18765138

Urinary pH as a Risk Factor for Stone Type

NASA Astrophysics Data System (ADS)

Sakhaee, Khashayar

2007-04-01

A high urinary pH is main risk factor for the calcium phosphate stone formation; however, its pathophysiologic mechanism has not been fully understood. The introduction of Topiramate in the treatment of various neurological disorders has been complicated by metabolic acidosis, significant hypocitraturia, elevated urinary pH, and calcium phosphate stone formation. This model provides a probe to investigate the pathophysiologic mechanism of calcium phosphate stone formation and perhaps to develop appropriate countermeasures in the future. On the other hand an unduly acidic urine predisposes one to uric acid nephrolithiasis. Our recent investigation linking low urinary pH, and defective renal ammoniagenesis to insulin resistance provides new knowledge to unfold the pathophysiology of uric acid nephrolithiasis. The metabolic profile leading to uric acid stone may emerge as one of the components of metabolic syndrome.

Interval Female Sterilization.

PubMed

Stuart, Gretchen S; Ramesh, Shanthi S

2018-01-01

Female sterilization is relied on by nearly one in three women aged 35-44 years in the United States. Sterilization procedures are among the most common procedures that obstetrician-gynecologists perform. The most frequent sterilization procedures include postpartum tubal ligation, laparoscopic tubal disruption or salpingectomy, and hysteroscopic tubal occlusion. The informed consent process for sterilization is crucial and requires shared decision-making between the patient and the health care provider. Counseling should include the specific risks and benefits of the specific surgical approaches. Additionally, women should be counseled on the alternatives to sterilization, including intrauterine contraceptives and subdermal contraceptive implants. Complications, including unplanned pregnancy after successful female sterilization, are rare. The objectives of this Clinical Expert Series are to describe the epidemiology of female sterilization, access to postpartum sterilization, advances in interval sterilization techniques, and clinical considerations in caring for women requesting sterilization.

Pregnancies associated with sperm concentrations below 10 million/ml in clinical studies of a potential male contraceptive method, monthly depot medroxyprogesterone acetate and testosterone esters.

PubMed

Barfield, A; Melo, J; Coutinho, E; Alvarez-Sanchez, F; Faundes, A; Brache, V; Leon, P; Frick, J; Bartsch, G; Weiske, W H; Brenner, P; Mishell, D; Bernstein, G; Ortiz, A

1979-08-01

A potential male contraceptive approach was evaluated in clinical trials involving monthly injections of depot medroxyprogesterone acetate and either subdermal implants of testosterone propionate or monthly injections of testosterone enanthate. Pregnancies occurred in partners of 9 men with recent sperm counts of 10 million/ml or below. In 5 of the 9 instances, the sperm counts were less than 1 million/ml. It appears that male contraceptive methods involving spermatogenic suppression may require attainment and maintenance of azoospermia. The pregnancy rate cannot be calculated, because the extent of other contraceptive use is uncertain. There were no spontaneous abortions. 6 pregnancies were carried to term, and all progeny were normal, based on physical examination at birth or 3 months after birth.

Endoscopic subcutaneous mastectomy: A novel and effective treatment for gynecomastia

PubMed Central

CAO, HUA; YANG, ZHI-XUE; SUN, YI-HUI; WU, HAO-RONG; JIANG, GUO-QIN

2013-01-01

The aim of this study was to evaluate the procedure for and efficacy of endoscopic subcutaneous mastectomy for gynecomastia. Endoscopic subcutaneous mastectomy was performed on 100 benign, palpable breast enlargements in 58 male patients who were followed-up for 15–63 months. The surgery was conducted with the insufflation of CO2 subdermally. No cases were converted to open surgery. The unilateral surgery time was 70–90 min. The mean volume of the resected tissue was 200 ml. All procedures were completed successfully, with satisfactory clinical effects and ideal esthetic results postoperatively. There were three cases (3%) of papillary epidermal partial necrosis; following removal of the dressing during the hospital stay, normal nipple sensation returned. Endoscopic subcutaneous mastectomy had good clinical effects and ideal cosmetic results and is an appropriate approach for gynecomastia. PMID:23837054

Highly deformable bones: unusual deformation mechanisms of seahorse armor.

PubMed

Porter, Michael M; Novitskaya, Ekaterina; Castro-Ceseña, Ana Bertha; Meyers, Marc A; McKittrick, Joanna

2013-06-01

Multifunctional materials and devices found in nature serve as inspiration for advanced synthetic materials, structures and robotics. Here, we elucidate the architecture and unusual deformation mechanisms of seahorse tails that provide prehension as well as protection against predators. The seahorse tail is composed of subdermal bony plates arranged in articulating ring-like segments that overlap for controlled ventral bending and twisting. The bony plates are highly deformable materials designed to slide past one another and buckle when compressed. This complex plate and segment motion, along with the unique hardness distribution and structural hierarchy of each plate, provide seahorses with joint flexibility while shielding them against impact and crushing. Mimicking seahorse armor may lead to novel bio-inspired technologies, such as flexible armor, fracture-resistant structures or prehensile robotics. Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Trypanosome transmission by Corethrella wirthi (Diptera: Chaoboridae) to the green treefrog, Hyla cinerea (Anura: Hylidae).

PubMed

Johnson, R N; Young, D G; Butler, J F

1993-09-01

Seventy-two percent of 215 male green tree frog, Hyla cinerea (Schneider), captured in Alachua and Levy counties, FL, between April and mid-September 1978 and 1979 were infected with an undescribed Trypanosoma sp. None of the 31 female frogs captured concurrently was infected. Periodic sampling of the peripheral blood from the infected male frogs showed that the trypanosomes were present in high numbers only at night. Conspecific trypanosomes also were found in the mid and hind guts of female Corethrella wirthi Stone flies collected on or near male frogs in the field. Transmission of the parasite to uninfected frogs was demonstrated by exposure of male and female frogs to naturally infected flies and to parasites injected subdermally. This is the first report of parasite transmission by a species of Corethrella.

The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy.

PubMed

Petraglia, Anthony L; Plog, Benjamin A; Dayawansa, Samantha; Dashnaw, Matthew L; Czerniecka, Katarzyna; Walker, Corey T; Chen, Michael; Hyrien, Ollivier; Iliff, Jeffrey J; Deane, Rashid; Huang, Jason H; Nedergaard, Maiken

2014-01-01

An animal model of chronic traumatic encephalopathy (CTE) is essential for further understanding the pathophysiological link between repetitive head injury and the development of chronic neurodegenerative disease. We previously described a model of repetitive mild traumatic brain injury (mTBI) in mice that encapsulates the neurobehavioral spectrum characteristic of patients with CTE. We aimed to study the pathophysiological mechanisms underlying this animal model. Our previously described model allows for controlled, closed head impacts to unanesthetized mice. Briefly, 12-week-old mice were divided into three groups: Control, single, and repetitive mTBI. Repetitive mTBI mice received six concussive impacts daily, for 7 days. Mice were then subsequently sacrificed for macro- and micro-histopathologic analysis at 7 days, 1 month, and 6 months after the last TBI received. Brain sections were immunostained for glial fibrillary acidic protein (GFAP) for astrocytes, CD68 for activated microglia, and AT8 for phosphorylated tau protein. Brains from single and repetitive mTBI mice lacked macroscopic tissue damage at all time-points. Single mTBI resulted in an acute rea ctive astrocytosis at 7 days and increased phospho-tau immunoreactivity that was present acutely and at 1 month, but was not persistent at 6 months. Repetitive mTBI resulted in a more marked neuroinflammatory response, with persistent and widespread astrogliosis and microglial activation, as well as significantly elevated phospho-tau immunoreactivity to 6-months. The neuropathological findings in this new model of repetitive mTBI resemble some of the histopathological hallmarks of CTE, including increased astrogliosis, microglial activation, and hyperphosphorylated tau protein accumulation.

Modeling the Pathophysiology of Phonotraumatic Vocal Hyperfunction with a Triangular Glottal Model of the Vocal Folds

ERIC Educational Resources Information Center

Galindo, Gabriel E.; Peterson, Sean D.; Erath, Byron D.; Castro, Christian; Hillman, Robert E.; Zañartu, Matías

2017-01-01

Purpose: Our goal was to test prevailing assumptions about the underlying biomechanical and aeroacoustic mechanisms associated with phonotraumatic lesions of the vocal folds using a numerical lumped-element model of voice production. Method: A numerical model with a triangular glottis, posterior glottal opening, and arytenoid posturing is…

New Concepts in Complex Regional Pain Syndrome

PubMed Central

Tajerian, Maral; Clark, J David

2015-01-01

SYNOPSIS Despite the severe pain and disability associated with Complex Regional Pain Syndrome (CRPS), our lack of understanding of the pathophysiological mechanisms supporting this enigmatic condition prevents the rational design of new therapies, a situation that is frustrating both to the physician and the patient. The following review will highlight some of the mechanisms thought to be involved in the pathophysiology of CRPS in preclinical models and CRPS patients, with the ultimate goal that understanding these mechanisms will lead to the design of efficacious, mechanism-based treatments available to the clinic. PMID:26611388

Pathophysiological Responses in Rat and Mouse Models of Radiation-Induced Brain Injury.

PubMed

Yang, Lianhong; Yang, Jianhua; Li, Guoqian; Li, Yi; Wu, Rong; Cheng, Jinping; Tang, Yamei

2017-03-01

The brain is the major dose-limiting organ in patients undergoing radiotherapy for assorted conditions. Radiation-induced brain injury is common and mainly occurs in patients receiving radiotherapy for malignant head and neck tumors, arteriovenous malformations, or lung cancer-derived brain metastases. Nevertheless, the underlying mechanisms of radiation-induced brain injury are largely unknown. Although many treatment strategies are employed for affected individuals, the effects remain suboptimal. Accordingly, animal models are extremely important for elucidating pathogenic radiation-associated mechanisms and for developing more efficacious therapies. So far, models employing various animal species with different radiation dosages and fractions have been introduced to investigate the prevention, mechanisms, early detection, and management of radiation-induced brain injury. However, these models all have limitations, and none are widely accepted. This review summarizes the animal models currently set forth for studies of radiation-induced brain injury, especially rat and mouse, as well as radiation dosages, dose fractionation, and secondary pathophysiological responses.

New Insights into Therapeutic Strategies for the Treatment of Peritoneal Fibrosis: Learning from Histochemical Analyses of Animal Models

PubMed Central

Kitamura, Mineaki; Nishino, Tomoya; Obata, Yoko; Ozono, Yoshiyuki; Koji, Takehiko; Kohno, Shigeru

2014-01-01

Encapsulating peritoneal sclerosis (EPS) is a fatal complication that can occur in patients undergoing long-term peritoneal dialysis. It is characterized by bowel obstruction and marked sclerotic thickening of the peritoneal membrane. Although the mechanisms underlying the development of EPS are complex, angiogenesis, inflammation, and peritoneal fibrosis are known to be essential factors. Now, several animal models that exhibit EPS have pathophysiology similar to that of human EPS and have been proposed for use in research to provide insights into it. Recent histochemical methods also help us to understand the pathophysiology of EPS. Advances in basic research based on the findings in those animal models have enabled the development of several strategies for the prevention and treatment of EPS. We describe here interventional studies in some animal models for peritoneal fibrosis, one of the histological disorders findings characteristic to EPS, and we highlight the need for a sophisticated animal model that closely resembles human conditions. PMID:25392567

Tics and Tourette's: update on pathophysiology and tic control.

PubMed

Ganos, Christos

2016-08-01

To describe recent advances in the pathophysiology of tics and Tourette syndrome, and novel insights on tic control. The cortico-basal ganglia-thalamo-cortical loops are implicated in generation of tics. Disruption of GABAergic inhibition lies at the core of tic pathophysiology, but novel animal models also implicate cholinergic and histaminergic neurotransmission. Tourette syndrome patients have altered awareness of volition and enhanced formation of habits. Premonitory urges are not the driving force behind all tics. The intensity of premonitory urges depends on patients' capacity to perceive interoceptive signals. The insular cortex is a key structure in this process. The trait intensity of premonitory urges is not a prerequisite of voluntary tic inhibition, a distinct form of motor control. Voluntary tic inhibition is most efficient in the body parts that tic the least. The prefrontal cortex is associated with the capacity to inhibit tics. The management of tics includes behavioral, pharmacological and surgical interventions. Treatment recommendations differ based on patients' age. The study of Tourette syndrome pathophysiology involves different neural disciplines and provides novel, exciting insights of brain function in health and disease. These in turn provide the basis for innovative treatment approaches of tics and their associations.

Mechanistic approach to the pathophysiology of target organ damage in hypertension from studies in a human model with characteristics opposite to hypertension: Bartter's and Gitelman's syndromes.

PubMed

Calò, L A; Maiolino, G

2015-07-01

Extensive studies using Bartter's/Gitelman's syndrome patients have provided insights into the angiotensin II (Ang II) signaling pathways involved in the regulation of vascular tone and cardiovascular-renal remodeling. The renin-angiotensin-aldosterone system is activated in these syndromes, however, patients do not develop hypertension and cardiovascular remodeling and clinically manifest conditions opposite to hypertension. The short- and the long-term signaling of Ang II remains an important matter of investigation to shed light on mechanisms responsible for the pathophysiology of hypertension and its long-term complications. The long-term signaling of Ang II is involved in the pathophysiology of cardiovascular-renal remodeling and inflammatory responses in which the balance between RhoA/Rho kinase pathway and NO system plays a crucial role. In this brief review, the results of our studies in Bartter's and Gitelman's syndromes are reported on these processes. The information obtained from these studies can clarify, confirm or be used to extend the biochemical mechanisms responsible for the pathophysiology of hypertension and its long-term complications and could offer further chances to identify additional potential significant targets of therapy.

Pathophysiological relationships between heart failure and depression and anxiety.

PubMed

Chapa, Deborah W; Akintade, Bimbola; Son, Heesook; Woltz, Patricia; Hunt, Dennis; Friedmann, Erika; Hartung, Mary Kay; Thomas, Sue Ann

2014-04-01

Depression and anxiety are common comorbid conditions in patients with heart failure. Patients with heart failure and depression have increased mortality. The association of anxiety with increased mortality in patients with heart failure is not established. The purpose of this article is to illustrate the similarities of the underlying pathophysiology of heart failure, depression, and anxiety by using the Biopsychosocial Holistic Model of Cardiovascular Health. Depression and anxiety affect biological processes of cardiovascular function in patients with heart failure by altering neurohormonal function via activation of the hypothalamic-pituitary-adrenal axis, autonomic dysregulation, and activation of cytokine cascades and platelets. Patients with heart failure and depression or anxiety may exhibit a continued cycle of heart failure progression, increased depression, and increased anxiety. Understanding the underlying pathophysiological relationships in patients with heart failure who experience comorbid depression and/or anxiety is critical in order to implement appropriate treatments, educate patients and caregivers, and educate other health professionals.

Tau, amyloid, and cascading network failure across the Alzheimer's disease spectrum.

PubMed

Jones, David T; Graff-Radford, Jonathan; Lowe, Val J; Wiste, Heather J; Gunter, Jeffrey L; Senjem, Matthew L; Botha, Hugo; Kantarci, Kejal; Boeve, Bradley F; Knopman, David S; Petersen, Ronald C; Jack, Clifford R

2017-12-01

Functionally related brain regions are selectively vulnerable to Alzheimer's disease pathophysiology. However, molecular markers of this pathophysiology (i.e., beta-amyloid and tau aggregates) have discrepant spatial and temporal patterns of progression within these selectively vulnerable brain regions. Existing reductionist pathophysiologic models cannot account for these large-scale spatiotemporal inconsistencies. Within the framework of the recently proposed cascading network failure model of Alzheimer's disease, however, these large-scale patterns are to be expected. This model postulates the following: 1) a tau-associated, circumscribed network disruption occurs in brain regions specific to a given phenotype in clinically normal individuals; 2) this disruption can trigger phenotype independent, stereotypic, and amyloid-associated compensatory brain network changes indexed by changes in the default mode network; 3) amyloid deposition marks a saturation of functional compensation and portends an acceleration of the inciting phenotype specific, and tau-associated, network failure. With the advent of in vivo molecular imaging of tau pathology, combined with amyloid and functional network imaging, it is now possible to investigate the relationship between functional brain networks, tau, and amyloid across the disease spectrum within these selectively vulnerable brain regions. In a large cohort (n = 218) spanning the Alzheimer's disease spectrum from young, amyloid negative, cognitively normal subjects to Alzheimer's disease dementia, we found several distinct spatial patterns of tau deposition, including 'Braak-like' and 'non-Braak-like', across functionally related brain regions. Rather than arising focally and spreading sequentially, elevated tau signal seems to occur system-wide based on inferences made from multiple cross-sectional analyses we conducted looking at regional patterns of tau signal. Younger age-of-disease-onset was associated with 'non-Braak-like' patterns of tau, suggesting an association with atypical clinical phenotypes. As predicted by the cascading network failure model of Alzheimer's disease, we found that amyloid is a partial mediator of the relationship between functional network failure and tau deposition in functionally connected brain regions. This study implicates large-scale brain networks in the pathophysiology of tau deposition and offers support to models incorporating large-scale network physiology into disease models linking tau and amyloid, such as the cascading network failure model of Alzheimer's disease. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease

PubMed Central

Rieder, Florian; Kessler, Sean; Sans, Miquel

2012-01-01

Fibrosis is a serious condition complicating chronic inflammatory processes affecting the intestinal tract. Advances in this field that rely on human studies have been slow and seriously restricted by practical and logistic reasons. As a consequence, well-characterized animal models of intestinal fibrosis have emerged as logical and essential systems to better define and understand the pathophysiology of fibrosis. In point of fact, animal models allow the execution of mechanistic studies as well as the implementation of clinical trials with novel, pathophysiology-based therapeutic approaches. This review provides an overview of the currently available animal models of intestinal fibrosis, taking into consideration the methods of induction, key characteristics of each model, and underlying mechanisms. Currently available models will be classified into seven categories: spontaneous, gene-targeted, chemical-, immune-, bacteria-, and radiation-induced as well as postoperative fibrosis. Each model will be discussed in regard to its potential to create research opportunities to gain insights into the mechanisms of intestinal fibrosis and stricture formation and assist in the development of effective and specific antifibrotic therapies. PMID:22878121

Mutual reinforcement of pathophysiological host-microbe interactions in intestinal stasis models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Touw, Ketrija; Ringus, Daina L.; Hubert, Nathaniel

Chronic diseases arise when there is mutual reinforcement of pathophysiological processes that cause an aberrant steady state. Such a sequence of events may underlie chronic constipation, which has been associated with dysbiosis of the gut. In this study we hypothesized that assemblage of microbial communities, directed by slow gastrointestinal transit, affects host function in a way that reinforces constipation and further maintains selection on microbial communities. In our study, we used two models – an opioid-induced consti- pation model in mice, and a humanized mouse model where germ-free mice were colonized with stool from a patient with constipation-predominant irritable bowelmore » syndrome (IBS-C) in humans. We examined the impact of pharmacologically (loperamide)-induced constipation (PIC) and IBS-C on the structural and functional profile of the gut microbiota. Germ-free (GF) mice were colonized with microbiota from PIC donor mice and IBS-C patients to determine how the microbiota affects the host. PIC and IBS-C promoted changes in the gut microbiota, characterized by increased relative abundance of Bacteroides ovatus and Parabacteroides distasonis in both models. PIC mice exhibited decreased luminal concentrations of butyrate in the cecum and altered metabolic profiles of the gut microbiota. Colonization of GF mice with PIC-associated mice cecal or human IBS-C fecal microbiota significantly increased GI transit time when compared to control microbiota recipients. IBS-C-associated gut microbiota also impacted colonic contractile properties. Lastly, our findings support the concept that constipation is characterized by dis- ease-associated steady states caused by reinforcement of pathophysiological factors in host-microbe interactions.« less

Mutual reinforcement of pathophysiological host-microbe interactions in intestinal stasis models

DOE PAGES

Touw, Ketrija; Ringus, Daina L.; Hubert, Nathaniel; ...

2017-03-20

Chronic diseases arise when there is mutual reinforcement of pathophysiological processes that cause an aberrant steady state. Such a sequence of events may underlie chronic constipation, which has been associated with dysbiosis of the gut. In this study we hypothesized that assemblage of microbial communities, directed by slow gastrointestinal transit, affects host function in a way that reinforces constipation and further maintains selection on microbial communities. In our study, we used two models – an opioid-induced consti- pation model in mice, and a humanized mouse model where germ-free mice were colonized with stool from a patient with constipation-predominant irritable bowelmore » syndrome (IBS-C) in humans. We examined the impact of pharmacologically (loperamide)-induced constipation (PIC) and IBS-C on the structural and functional profile of the gut microbiota. Germ-free (GF) mice were colonized with microbiota from PIC donor mice and IBS-C patients to determine how the microbiota affects the host. PIC and IBS-C promoted changes in the gut microbiota, characterized by increased relative abundance of Bacteroides ovatus and Parabacteroides distasonis in both models. PIC mice exhibited decreased luminal concentrations of butyrate in the cecum and altered metabolic profiles of the gut microbiota. Colonization of GF mice with PIC-associated mice cecal or human IBS-C fecal microbiota significantly increased GI transit time when compared to control microbiota recipients. IBS-C-associated gut microbiota also impacted colonic contractile properties. Lastly, our findings support the concept that constipation is characterized by dis- ease-associated steady states caused by reinforcement of pathophysiological factors in host-microbe interactions.« less

The 9-11 Commission's invitation to imagine: a pathophysiology-based approach to critical care of nuclear explosion victims.

PubMed

Manthous, Constantine A; Jackson, William L

2007-03-01

The successful management of mass casualties arising from detonation of a nuclear device (NDD) would require significant preparation at all levels of the healthcare system. This article briefly outlines previously published models of destruction and casualties, details approaches to on-site triage and medical evacuation, and offers pathophysiology-based suggestions for treatment of the critically injured. Documentation from previous bomb blasts and nuclear accidents is reviewed to assist in forecasting needs of both systems and patients in the event of an NDD in a major metropolitan area. This review extracts data from previously published models of destruction and casualties projected from an NDD, the primary literature detailing observations of patients' pathophysiology following NDDs in Japan and relevant nuclear accidents, and available contemporary resources for first responders and healthcare providers. The blast and radiation exposures that accompany an NDD will significantly affect local and regional public resources. Morbidity and mortality likely to arise in the setting of dose-dependent organ dysfunction may be minimized by rigorous a priori planning/training for field triage decisions, coordination of medical and civil responses to effect rapid responses and medical evacuation routes, radiation-specific interventions, and modern intensive care. Although the responses of emergency and healthcare systems following NDD will vary depending on the exact mechanism, magnitude, and location of the event, dose exposures and individual pathophysiology evolution are reasonably predictable. Triage decisions, resource requirements, and bedside therapeutic plans can be evidence-based and can be developed rapidly with appropriate preparation and planning.

Impact of gastrointestinal disease states on oral drug absorption - implications for formulation design - a PEARRL review.

PubMed

Effinger, Angela; O'Driscoll, Caitriona M; McAllister, Mark; Fotaki, Nikoletta

2018-05-16

Drug product performance in patients with gastrointestinal (GI) diseases can be altered compared to healthy subjects due to pathophysiological changes. In this review, relevant differences in patients with inflammatory bowel diseases, coeliac disease, irritable bowel syndrome and short bowel syndrome are discussed and possible in vitro and in silico tools to predict drug product performance in this patient population are assessed. Drug product performance was altered in patients with GI diseases compared to healthy subjects, as assessed in a limited number of studies for some drugs. Underlying causes can be observed pathophysiological alterations such as the differences in GI transit time, the composition of the GI fluids and GI permeability. Additionally, alterations in the abundance of metabolising enzymes and transporter systems were observed. The effect of the GI diseases on each parameter is not always evident as it may depend on the location and the state of the disease. The impact of the pathophysiological change on drug bioavailability depends on the physicochemical characteristics of the drug, the pharmaceutical formulation and drug metabolism. In vitro and in silico methods to predict drug product performance in patients with GI diseases are currently limited but could be a useful tool to improve drug therapy. Development of suitable in vitro dissolution and in silico models for patients with GI diseases can improve their drug therapy. The likeliness of the models to provide accurate predictions depends on the knowledge of pathophysiological alterations, and thus, further assessment of physiological differences is essential. © 2018 Royal Pharmaceutical Society.

The Relevance of Mouse Models for Investigating Age-Related Bone Loss in Humans

PubMed Central

2013-01-01

Mice are increasingly used for investigation of the pathophysiology of osteoporosis because their genome is easily manipulated, and their skeleton is similar to that of humans. Unlike the human skeleton, however, the murine skeleton continues to grow slowly after puberty and lacks osteonal remodeling of cortical bone. Yet, like humans, mice exhibit loss of cancellous bone, thinning of cortical bone, and increased cortical porosity with advancing age. Histologic evidence in mice and humans alike indicates that inadequate osteoblast-mediated refilling of resorption cavities created during bone remodeling is responsible. Mouse models of progeria also show bone loss and skeletal defects associated with senescence of early osteoblast progenitors. Additionally, mouse models of atherosclerosis, which often occurs in osteoporotic participants, also suffer bone loss, suggesting that common diseases of aging share pathophysiological pathways. Knowledge of the causes of skeletal fragility in mice should therefore be applicable to humans if inherent limitations are recognized. PMID:23689830

Modeling Autism by SHANK Gene Mutations in Mice

PubMed Central

Jiang, Yong-hui; Ehlers, Michael D.

2013-01-01

Summary Shank family proteins (Shank1, Shank2, and Shank3) are synaptic scaffolding proteins that organize an extensive protein complex at the postsynaptic density (PSD) of excitatory glutamatergic synapses. Recent human genetic studies indicate that SHANK family genes (SHANK1, SHANK2, and SHANK3) are causative genes for idiopathic autism spectrum disorders (ASD). Neurobiological studies of Shank mutations in mice support a general hypothesis of synaptic dysfunction in the pathophysiology of ASD. However, the molecular diversity of SHANK family gene products, as well as the heterogeneity in human and mouse phenotypes, pose challenges to modeling human SHANK mutations. Here, we review the molecular genetics of SHANK mutations in human ASD and discuss recent findings where such mutations have been modeled in mice. Conserved features of synaptic dysfunction and corresponding behaviors in Shank mouse mutants may help dissect the pathophysiology of ASD, but also highlight divergent phenotypes that arise from different mutations in the same gene. PMID:23583105

Pathophysiological appraisal of a rat model of total hepatic ischemia with an extracorporeal portosystemic shunt.

PubMed

Suzuki, S; Nakamura, S; Sakaguchi, T; Mitsuoka, H; Tsuchiya, Y; Kojima, Y; Konno, H; Baba, S

1998-11-01

Animal models of total hepatic ischemia (THI) and reperfusion injury are restricted by concomitant splanchnic congestion. This study was performed to determine the requirement suitable for an extracorporeal portosystemic shunt (PSS) to maintain the intestinal integrity in a rat model of THI. Using a polyethylene tube (0.86 or 1 mm i.d.), PSS was placed between the mesenteric and jugular veins. Comparison was done between THI models with or without PSS and a partial ischemia model with hepatectomy of the nonischemic lobes. Well-tolerated hepatic ischemic period, portal pressure after 10 min of hepatic ischemia, portal endotoxin levels at 1 h after reperfusion, histological features of the small bowel just before reperfusion, and local jejunal and ileal blood hemoglobin oxygen saturation index (ISO2) were compared among the models. Animals without PSS poorly tolerated 30 min of THI. Animals receiving THI with PSS or partial hepatic ischemia tolerated a longer ischemic period (60 min) with a significantly higher small bowel ISO2, lower portal pressure and endotoxin levels (P < 0.01), and less histological damage of the small bowel when compared to those receiving THI without PSS. Portal endotoxin levels after THI with PSS using a 1-mm i.d. tube as well as partial hepatic ischemia were significantly lower than those after THI with PSS using a 0.86-mm i.d. tube. THI with PSS using a 1-mm i.d. tube was strikingly similar to partial hepatic ischemia in the pathophysiological profile during hepatic ischemia. PSS with a tube 1 mm or more in inner diameter offers pathophysiological advantages in experiments on THI and reperfusion. Copyright 1998 Academic Press.

The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.

PubMed

Jentsch, J D; Roth, R H

1999-03-01

Administration of noncompetitive NMDA/glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, to humans induces a broad range of schizophrenic-like symptomatology, findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia. Moreover, a history of experimental investigations of the effects of these drugs in animals suggests that NMDA receptor antagonists may model some behavioral symptoms of schizophrenia in nonhuman subjects. In this review, the usefulness of PCP administration as a potential animal model of schizophrenia is considered. To support the contention that NMDA receptor antagonist administration represents a viable model of schizophrenia, the behavioral and neurobiological effects of these drugs are discussed, especially with regard to differing profiles following single-dose and long-term exposure. The neurochemical effects of NMDA receptor antagonist administration are argued to support a neurobiological hypothesis of schizophrenia, which includes pathophysiology within several neurotransmitter systems, manifested in behavioral pathology. Future directions for the application of NMDA receptor antagonist models of schizophrenia to preclinical and pathophysiological research are offered.

Contribution of a new electrophysiologic test to Morton's neuroma diagnosis.

PubMed

Pardal-Fernández, José Manuel; Palazón-García, Elena; Hernández-Fernández, Francisco; de Cabo, Carlos

2014-06-01

Morton's neuroma causes metatarsalgia due to the interdigital neuropathy. The small nerve diameter compromises their evaluation in image studies. To overcome this problem we propose a new electrophysiological test. We conducted a prospective case-control study performing a orthodromic electroneurography using subdermal electrodes in controls and patients to assess the validity. Additionally all patients were tested with magnetic resonance. Some patients required surgery and subsequent histological evaluation. The new ENG procedure showed higher sensitivity and specificity. Methodological standardization was easy and the test was well tolerated by the subjects. Our test demonstrated remarkable diagnostic efficiency, and also was able to identify symptomatic patients undetected by magnetic resonance, which underlines the lack of correlation between the size and intensity of the lesion. This new electrophysiological method appears to be a highly sensitivity, well-tolerated, simple and low-cost for Morton's neuroma diagnosis. Copyright © 2014 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.

Avoiding and treating dermal filler complications.

PubMed

Lemperle, Gottfried; Rullan, Peter P; Gauthier-Hazan, Nelly

2006-09-01

All fillers are associated with the risk of both early and late complications. Early side effects such as swelling, redness, and bruising occur after intradermal or subdermal injections. The patient has to be aware of and accept these risks. Adverse events that last longer than 2 weeks can be attributable to technical shortcomings (e.g., too superficial an implantation of a long-lasting filler substance). Such adverse events can be treated with intradermal 5-fluorouracil, steroid injections, vascular lasers, or intense pulsed light, and later with dermabrasion or shaving. Late adverse events also include immunologic phenomena such as late-onset allergy and nonallergic foreign body granuloma. Both react well to intralesional steroid injections, which often have to be repeated to establish the right dose. Surgical excisions shall remain the last option and are indicated for hard lumps in the lips and visible hard nodules or hard granuloma in the subcutaneous fat.

A feasiblity study of an ultrasonic test phantom arm

NASA Astrophysics Data System (ADS)

Schneider, Philip

This thesis is a feasibility study for the creation of a test phantom that replicates the physiological features, from an acoustic and mechanical standpoint, of that of a human arm. Physiological feature set includes; Heart, Arteries, Veins, Bone, Muscle, Fat, Skin, and Dermotographic Features (finger prints). Mechanical Aspects include, vascular compression and distention, elasticity of tissue layers, mechanics of human heart. The end goal of which to have a working understanding of each component in order to create a controllable, real time, physiologically accurate, test phantom for a wide range of ultrasonic based applications. These applications can range from devices like wearable technologies to medical training, to biometric "Liveness" detection methods. The proposed phantom would allow for a number of natural bodily functions to be measured including but not limited to vascular mapping, blood pressure, heart rate, subdermal imaging, and general ultrasonic imaging.

Fullerene nanomaterials potentiate hair growth.

PubMed

Zhou, Zhiguo; Lenk, Robert; Dellinger, Anthony; MacFarland, Darren; Kumar, Krishan; Wilson, Stephen R; Kepley, Christopher L

2009-06-01

Hair loss is a common symptom resulting from a wide range of disease processes and can lead to stress in affected individuals. The purpose of this study was to examine the effect of fullerene nanomaterials on hair growth. We used shaved mice as well as SKH-1 "bald" mice to determine if fullerene-based compounds could affect hair growth and hair follicle numbers. In shaved mice, fullerenes increase the rate of hair growth as compared with mice receiving vehicle only. In SKH-1 hairless mice fullerene derivatives given topically or subdermally markedly increased hair growth. This was paralleled by a significant increase in the number of hair follicles in fullerene-treated mice as compared with those mice treated with vehicle only. The fullerenes also increased hair growth in human skin sections maintained in culture. These studies have wide-ranging implications for those conditions leading to hair loss, including alopecia, chemotherapy, and reactions to various chemicals.

Embolization of a contraceptive implant into the pulmonary vasculature in an adolescent female.

PubMed

Gao, Gabriel T; Binder, William

2018-06-01

Nexplanon is a long-acting 4cm radio-opaque rod shaped contraceptive device implanted in the subdermal layer of the inner, upper arm. Complications from implantation are uncommon and mostly local and minor, including infection at the implantation site with resulting cellulitis or abscess, hematoma, abnormal scar formation, or local damage to nerves and blood vessels. Intravascular insertion is estimated to be at 1.3 per million Nexplanon implants, and migration and embolization is a rare complication of this device. We present a case report of a 16year old female who presented to the pediatric emergency department with subjective dyspnea and an embolized contraceptive device within a subsegmental branch of the left lower lobe pulmonary artery. After discussion with consultants, interventional radiology was able to successful retrieve the device without complication. Copyright © 2018 Elsevier Inc. All rights reserved.

Moving Ahead with the Schizophrenia Concept: From the Elephant to the Mouse

PubMed Central

Keshavan, Matcheri S; Nasrallah, Henry A; Tandon, Rajiv

2012-01-01

The current construct of schizophrenia as a unitary disease is far from satisfactory, and is in need of reconceptualization. The first five papers in our “facts” series reviewed what is known about schizophrenia to date, and a limited number of key facts appear to stand out. Schizophrenia is characterized by persistent cognitive deficits, positive and negative symptoms typically beginning in youth, substantive heritability, and brain structural, functional and neurochemical alterations including dopaminergic dysregulation. Several pathophysiological models have been proposed with differing interpretations of the illness, like the fabled six blind Indian men groping different parts of an elephant coming up with different conclusions. However, accumulating knowledge is integrating the several extant models of schizophrenia etiopathogenesis into unifying constructs; we discuss an example, involving a neurodevelopmental imbalance in excitatory/inhibitory neural systems leading to impaired neural plasticity. This imbalance, which may be proximal to clinical manifestations, could result from a variety of genetic, epigenetic and environmental causes, as well as pathophysiological processes such as inflammation and oxidative stress. Such efforts to “connect the dots” (and visualizing the elephant) are still limited by the substantial clinical, pathological, and etiological heterogeneity of schizophrenia and its blurred boundaries with several other psychiatric disorders leading to a “fuzzy cluster” of overlapping syndromes, thereby reducing the content, discriminant and predictive validity of a unitary construct of this illness. The way ahead involves several key directions: a) choosing valid phenotype definitions increasingly derived from translational neuroscience; b) addressing clinical heterogeneity by a cross-diagnostic dimensional and a staging approach to psychopathology; c) addressing pathophysiological heterogeneity by elucidating independent families of “extended” intermediate phenotypes and pathophysiological processes (e.g. altered excitatory/inhibitory, salience or executive circuitries, oxidative stress systems) that traverse structural, functional, neurochemical and molecular domains; d) resolving etiologic heterogeneity by mapping genomic and environmental factors and their interactions to syndromal and specific pathophysiological signatures; e) separating causal factors from consequences and compensatory phenomena; and f) formulating or reformulating hypotheses that can be refuted/tested, perhaps in the mouse or other experimental models. These steps will likely lead to the current entity of schizophrenia being usefully deconstructed and reconfigured into phenotypically overlapping, but etiopathologically unique and empirically testable component entities (similar to mental retardation, epilepsy or cancer syndromes). The mouse may be the way to rescue the trapped elephant! PMID:21316923

Molecular pathophysiology of cerebral edema

PubMed Central

Gerzanich, Volodymyr; Simard, J Marc

2015-01-01

Advancements in molecular biology have led to a greater understanding of the individual proteins responsible for generating cerebral edema. In large part, the study of cerebral edema is the study of maladaptive ion transport. Following acute CNS injury, cells of the neurovascular unit, particularly brain endothelial cells and astrocytes, undergo a program of pre- and post-transcriptional changes in the activity of ion channels and transporters. These changes can result in maladaptive ion transport and the generation of abnormal osmotic forces that, ultimately, manifest as cerebral edema. This review discusses past models and current knowledge regarding the molecular and cellular pathophysiology of cerebral edema. PMID:26661240

Discrete Pathophysiology is Uncommon in Patients with Nonspecific Arm Pain.

PubMed

Kortlever, Joost T P; Janssen, Stein J; Molleman, Jeroen; Hageman, Michiel G J S; Ring, David

2016-06-01

Nonspecific symptoms are common in all areas of medicine. Patients and caregivers can be frustrated when an illness cannot be reduced to a discrete pathophysiological process that corresponds with the symptoms. We therefore asked the following questions: 1) Which demographic factors and psychological comorbidities are associated with change from an initial diagnosis of nonspecific arm pain to eventual identification of discrete pathophysiology that corresponds with symptoms? 2) What is the percentage of patients eventually diagnosed with discrete pathophysiology, what are those pathologies, and do they account for the symptoms? We evaluated 634 patients with an isolated diagnosis of nonspecific upper extremity pain to see if discrete pathophysiology was diagnosed on subsequent visits to the same hand surgeon, a different hand surgeon, or any physician within our health system for the same pain. There were too few patients with discrete pathophysiology at follow-up to address the primary study question. Definite discrete pathophysiology that corresponded with the symptoms was identified in subsequent evaluations by the index surgeon in one patient (0.16% of all patients) and cured with surgery (nodular fasciitis). Subsequent doctors identified possible discrete pathophysiology in one patient and speculative pathophysiology in four patients and the index surgeon identified possible discrete pathophysiology in four patients, but the five discrete diagnoses accounted for only a fraction of the symptoms. Nonspecific diagnoses are not harmful. Prospective randomized research is merited to determine if nonspecific, descriptive diagnoses are better for patients than specific diagnoses that imply pathophysiology in the absence of discrete verifiable pathophysiology.

Ammonia-induced brain swelling and neurotoxicity in an organotypic slice model

PubMed Central

Back, Adam; Tupper, Kelsey Y.; Bai, Tao; Chiranand, Paulpoj; Goldenberg, Fernando D.; Frank, Jeffrey I.; Brorson, James R.

2013-01-01

Objectives Acute liver failure produces cerebral dysfunction and edema, mediated in part by elevated ammonia concentrations, often leading to coma and death. The pathophysiology of cerebral edema in acute liver failure is incompletely understood. In vitro models of the cerebral effects of acute liver failure have predominately consisted of dissociated astrocyte cultures or acute brain slices. We describe a stable long-term culture model incorporating both neural and glial elements in a three-dimensional tissue structure offering significant advantages to the study of astrocytic-neuronal interactions in the pathophysiology of cerebral edema and dysfunction in acute liver failure. Methods We utilized chronic organotypic slice cultures from mouse forebrain, applying ammonium acetate in iso-osmolar fashion for 72 hours. Imaging of slice thickness to assess for tissue swelling was accomplished in living slices with optical coherence tomography, and confocal microscopy of fluorescence immunochemical and histochemical staining served to assess astrocyte and neuronal numbers, morphology, and volume in the fixed brain slices. Results Ammonia exposure at 1–10 mM produced swelling of immunochemically-identified astrocytes, and at 10 mM resulted in macroscopic tissue swelling, with slice thickness increasing by about 30%. Astrocytes were unchanged in number. In contrast, 10 mM ammonia treatment severely disrupted neuronal morphology and reduced neuronal survival at 72 hours by one-half. Discussion Elevated ammonia produces astrocytic swelling, tissue swelling, and neuronal toxicity in cerebral tissues. Ammonia-treated organotypic brain slice cultures provide an in vitro model of cerebral effects of conditions relevant to acute liver failure, applicable to pathophysiological investigations. PMID:22196764

A new glucocerebrosidase-deficient neuronal cell model provides a tool to probe pathophysiology and therapeutics for Gaucher disease

PubMed Central

Westbroek, Wendy; Nguyen, Matthew; Siebert, Marina; Lindstrom, Taylor; Burnett, Robert A.; Aflaki, Elma; Jung, Olive; Tamargo, Rafael; Rodriguez-Gil, Jorge L.; Acosta, Walter; Hendrix, An; Behre, Bahafta; Tayebi, Nahid; Fujiwara, Hideji; Sidhu, Rohini; Renvoise, Benoit; Ginns, Edward I.; Dutra, Amalia; Pak, Evgenia; Cramer, Carole; Ory, Daniel S.; Pavan, William J.

2016-01-01

ABSTRACT Glucocerebrosidase is a lysosomal hydrolase involved in the breakdown of glucosylceramide. Gaucher disease, a recessive lysosomal storage disorder, is caused by mutations in the gene GBA1. Dysfunctional glucocerebrosidase leads to accumulation of glucosylceramide and glycosylsphingosine in various cell types and organs. Mutations in GBA1 are also a common genetic risk factor for Parkinson disease and related synucleinopathies. In recent years, research on the pathophysiology of Gaucher disease, the molecular link between Gaucher and Parkinson disease, and novel therapeutics, have accelerated the need for relevant cell models with GBA1 mutations. Although induced pluripotent stem cells, primary rodent neurons, and transfected neuroblastoma cell lines have been used to study the effect of glucocerebrosidase deficiency on neuronal function, these models have limitations because of challenges in culturing and propagating the cells, low yield, and the introduction of exogenous mutant GBA1. To address some of these difficulties, we established a high yield, easy-to-culture mouse neuronal cell model with nearly complete glucocerebrosidase deficiency representative of Gaucher disease. We successfully immortalized cortical neurons from embryonic null allele gba−/− mice and the control littermate (gba+/+) by infecting differentiated primary cortical neurons in culture with an EF1α-SV40T lentivirus. Immortalized gba−/− neurons lack glucocerebrosidase protein and enzyme activity, and exhibit a dramatic increase in glucosylceramide and glucosylsphingosine accumulation, enlarged lysosomes, and an impaired ATP-dependent calcium-influx response; these phenotypical characteristics were absent in gba+/+ neurons. This null allele gba−/− mouse neuronal model provides a much-needed tool to study the pathophysiology of Gaucher disease and to evaluate new therapies. PMID:27482815

Effect of phospholipids and their molecular species on cholesterol solubility and nucleation in human and model biles.

PubMed Central

Halpern, Z; Moshkowitz, M; Laufer, H; Peled, Y; Gilat, T

1993-01-01

Much research in the pathophysiology of gall stones has been devoted to various molecular species of bile salts. Recent findings have shown the importance of phospholipids in biliary pathophysiology. In the present study the addition of increasing doses of egg lecithin to human and model biles progressively prolonged the nucleation time. Concurrently biliary cholesterol was shifted from the vesicular to the non-vesicular carrier(s) while the cholesterol/phospholipid ratio of the remaining vesicles was progressively lowered. Model bile solutions of identical lipid concentration were prepared using phosphatidylcholine, phosphatidylserine, and phosphatidylethanolamine as the only phospholipid. With phosphatidylethanolamine most of the cholesterol was shifted to the vesicular carrier while phosphatidylserine shifted most of the cholesterol to the non-vesicular carrier(s). With phosphatidylcholine the cholesterol was distributed in both carriers. Phosphatidyl choline species composed of various acyl fatty acids in the sn-1 and sn-2 positions were used as the sole phospholipid in otherwise identical model bile solutions. With palmitic acid in the sn-1 position and arachidonic acid in the sn-2 position most of the cholesterol was found in the non-vesicular carrier. When stearic acid was used in sn-2 position instead of arachidonic acid most of the cholesterol was found in the vesicular carrier. These and other variations in phospholipid molecular species shifted cholesterol among its carriers and also modified the nucleation time of model biles. Most of these effects were also found upon addition of the various phospholipid species to human biles. These findings show the importance of phospholipid species in biliary pathophysiology and may be useful when trying to manipulate cholesterol carriers and solubility in bile. PMID:8432440

Work-Related Musculoskeletal Disorders of the Hand and Wrist: Epidemiology, Pathophysiology, and Sensorimotor Changes

PubMed Central

Barr, Ann E.; Barbe, Mary F.; Clark, Brian D.

2006-01-01

The purpose of this commentary is to present recent epidemiological findings regarding work-related musculoskeletal disorders (WMSDs) of the hand and wrist, and to summarize experimental evidence of underlying tissue pathophysiology and sensorimotor changes in WMSDs. Sixty-five percent of the 333 800 newly reported cases of occupational illness in 2001 were attributed to repeated trauma. WMSDs of the hand and wrist are associated with the longest absences from work and are, therefore, associated with greater lost productivity and wages than those of other anatomical regions. Selected epidemiological studies of hand/wrist WMSDs published since 1998 are reviewed and summarized. Results from selected animal studies concerning underlying tissue pathophysiology in response to repetitive movement or tissue loading are reviewed and summarized. To the extent possible, corroborating evidence in human studies for various tissue pathomechanisms suggested in animal models is presented. Repetitive, hand-intensive movements, alone or in combination with other physical, nonphysical, and nonoccupational risk factors, contribute to the development of hand/wrist WMSDs. Possible pathophysiological mechanisms of tissue injury include inflammation followed by repair and/or fibrotic scarring, peripheral nerve injury, and central nervous system reorganization. Clinicians should consider all of these pathomechanisms when examining and treating patients with hand/wrist WMSDs. PMID:15552707

The pathophysiology of Peyronie's disease.

PubMed

El-Sakka, Ahmed I; Salabas, Emre; Dinçer, Murat; Kadioglu, Ates

2013-09-01

To review the contemporary knowledge of the pathophysiology of Peyronie's disease (PD). Medline was searched for papers published in English from 2000 to March 2013, using the keywords 'Peyronie's disease' and 'pathophysiology'. More than 300 relevant articles were identified for the purpose of this review. Unfortunately only a few studies had a high level of evidence, and the remaining studies were not controlled in their design. Many theories have been proposed to explain the cause of PD, but the true pathogenesis of PD remains an enigma. Identifying particular growth factors and the specific genes responsible for the induction of PD have been the ultimate goal of research over the past several decades. This would provide the means to devise a possible gene therapy for this devastating condition. We discuss present controversies and new discoveries related to the pathophysiology of this condition. PD is one of the most puzzling diseases in urology. The pathogenesis remains uncertain and there is still controversy about the best management. The pathogenesis of PD has been explored in animal models, cell cultures and clinical trials, but the results have led to further questions. New research on the aetiology and pathogenesis of PD is needed, and which will hopefully improve the understanding and management for patients with this frustrating disease.

An elastography framework for use in dermoscopy

NASA Astrophysics Data System (ADS)

Miga, Michael I.; Ou, Jao J.; Ellis, Darrel L.

2007-03-01

Multiple skin conditions exist which involve clinically significant changes in elastic properties. Early detection of such changes may prove critical in formulating a proper treatment plan. However, most diagnoses still rely primarily on visual inspection followed by biopsy for histological analysis. As a result, there would be considerable clinical benefit if a noninvasive technology to study the skin were available. The primary hypothesis of this work is that skin elasticity may serve as an important method for assisting diagnosis and treatment. Perhaps the most apparent application would be for the differentiation of skin cancers, which are a growing health concern in the United States as total annual cases are now being reported in the millions by the American Cancer Society. In this paper, we use our novel modality independent elastography (MIE) method to perform dermoscopic skin elasticity evaluation. The framework involves applying a lateral stretching to the skin in which dermoscopic images are acquired before and after mechanical excitation. Once collected, an iterative elastographic reconstruction method is used to generate images of tissue elastic properties and is based on a twodimensional (2-D) membrane model framework. Simulation studies are performed that show the effects of three-dimensional data, varying subdermal tissue thickness, and nonlinear large deformations on the framework. In addition, a preliminary in vivo reconstruction is demonstrated. The results are encouraging and indicate good localization with satisfactory degrees of elastic contrast resolution.

Involvement of nitric oxide in the wound bed microcirculatory change during negative pressure wound therapy.

PubMed

Sano, Hitomi; Ichioka, Shigeru

2015-08-01

This study investigated the role of nitric oxide (NO) in the mechanism of blood flow increase in the wound bed during negative pressure wound therapy (NPWT). We developed an improved experimental model that allowed visualisation of the wound bed microcirculation under NPWT. Wounds were created on the mouse ear, taking care to preserve the subdermal vascular plexus, because the wound bed microcirculation was visualised using an intravital microscope system. We investigated whether application of a NO synthase inhibitor (N(G) -nitro-l-arginine methyl ester: L-NAME) might diminish the effect of the NPWT in increasing the wound blood flow. The experimental animals were divided into a negative pressure group (negative pressure of -125 mmHg applied to the wound for 5 minutes; n = 8), and a negative pressure plus L-NAME group (administration of L-NAME prior to application of the negative pressure; n = 8). In the negative pressure group, significant increase of blood flow was observed at 1 minute after the negative pressure application, which was sustained until 5 minutes. On the contrary, in the negative pressure plus L-NAME group, no significant changes were observed throughout the period of observation. These findings suggest that NO synthesis is involved in the wound bed microcirculatory change induced by NPWT. © 2013 The Authors. International Wound Journal © 2013 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia

PubMed Central

Park, Sung Ok; Wankhede, Mamta; Lee, Young Jae; Choi, Eun-Jung; Fliess, Naime; Choe, Se-Woon; Oh, Seh-Hoon; Walter, Glenn; Raizada, Mohan K.; Sorg, Brian S.; Oh, S. Paul

2009-01-01

Arteriovenous malformations (AVMs) are vascular anomalies where arteries and veins are directly connected through a complex, tangled web of abnormal arteries and veins instead of a normal capillary network. AVMs in the brain, lung, and visceral organs, including the liver and gastrointestinal tract, result in considerable morbidity and mortality. AVMs are the underlying cause of three major clinical symptoms of a genetic vascular dysplasia termed hereditary hemorrhagic telangiectasia (HHT), which is characterized by recurrent nosebleeds, mucocutaneous telangiectases, and visceral AVMs and caused by mutations in one of several genes, including activin receptor–like kinase 1 (ALK1). It remains unknown why and how selective blood vessels form AVMs, and there have been technical limitations to observing the initial stages of AVM formation. Here we present in vivo evidence that physiological or environmental factors such as wounds in addition to the genetic ablation are required for Alk1-deficient vessels to develop to AVMs in adult mice. Using the dorsal skinfold window chamber system, we have demonstrated for what we believe to be the first time the entire course of AVM formation in subdermal blood vessels by using intravital bright-field images, hyperspectral imaging, fluorescence recordings of direct arterial flow through the AV shunts, and vascular casting techniques. We believe our data provide novel insights into the pathogenetic mechanisms of HHT and potential therapeutic approaches. PMID:19805914

Cross-linked hyaluronic acid in pressure ulcer prevention.

PubMed

Beniamino, P; Vadalà, M; Laurino, C

2016-07-02

Long-term bedridden patients are at high risk of acquring pressure ulcers (PUs). In this group of patients, prevention is necessary to cut the health costs, improve quality of life and reduce the mortality. Here, we evaluated the effectiveness of a cross-linked hyaluronic acid (HA) as plastic bulking-agent filling and remodelling the deep dermis and subcutaneous space of the skin areas exposed to the risk of necrosis. Our work hypothesis has been to inflate a sub-dermal elastic cushion, filled with a natural ECM component, with the aim to induce a stronger tissue background resistant to the ulcerative process. All the patients had an increased risk of PUs, at the sacral, ileum or heel skin. Patients were being nursed accordingly to the standard orthopaedic ward management with a pressure relieveing air mattress. The standard protocol consisted in body mobilisation every 3 hours, 24 hours a day and accurate cleaning of the skin with liquid soap and water without any towel friction and without adding any cream or lotion for the skin protection. Our filling protocol enclosed: accurate disinfection of the skin to be injected with povidone-iodine solution, followed by a local anaesthesia with 28G 13 mm needle, injecting 1.5 ml of 1% xylocaine. Then slow, deep, subcutaneous injection of cross-linked HA was performed with a 18G long needle, in order to deliver a homogeneous, soft gel layer underneath and around the whitish erythematous skin edges at risk of ulceration. Patients' tolerability of the compound and adverse events were also recorded. There were 15 patients (78-94 years old) who participated in the study. All tolerated the procedure very well and no serious side effects were declared. No skin pressure ulceration was detected in the four weeks follow-up Conclusion: We have demonstrated the safety and tolerability of a cross-linked HA subdermal injection in PUs prevention. The compound stratifies in a soft, elastic, interstitial bulk into the deep dermis, thus reducing the exogenous pressure stress: thus, the induction of a thick hydrophilic substrate supports adequate mesenchymal and blood cells traffic to immediately restore any early or impending damage to the skin. The authors certify that there is no conflict of interest with any financial organisation regarding the material discussed in the manuscript.

Assessing the validity and reliability of self-report data on contraception use in the MObile Technology for Improved Family Planning (MOTIF) randomised controlled trial.

PubMed

Smith, Chris; Edwards, Phil; Free, Caroline

2018-03-15

A variety of different approaches to measuring contraceptive use have been used or proposed, either to assess current use or adherence over time, using subjective or objective measures. This paper reports an overview of approaches to measuring adherence to the oral contraceptive, intra-uterine device, sub-dermal implant, and injectable and describes how we assessed contraception use in the MObile Technology for Improved Family Planning (MOTIF) trial in Cambodia. We summarise and discuss advantages and disadvantages of different subjective and objective approaches to measuring adherence to the oral contraceptive, intra-uterine device, sub-dermal implant, and injectable such as self-reports, clinic records, electronic monitoring devices, clinical examination and biomarkers. For the MOTIF trial, we did not consider it feasible to measure objective contraception use as many participants lived a long distance from the clinic and we were concerned whether it was appropriate to ask women to return to clinic for a physical examination simply to verify self-report information already provided. We aimed to assess the validity of the four-month data with 50 participants, calculating the sensitivity and specificity of self-reported data compared with objective measurement. For the 46 valid measurements obtained, the sensitivity and specificity was 100% for self-reported contraception use compared to objective measurement but this study had some limitations. To assess reliability of self-report data we compared calendar data collected on effective contraception use at months 1-4 post-abortion, collected separately at four and 12 months. Agreement ranged from 80 to 84% with a kappa statistic ranging from 0·59 to 0·67 indicating fair to good agreement. There is no perfect method of assessing contraception use and researchers designing future studies should give consideration of what to measure, for example current use or detailed patterns of use over time, and remain mindful of what will be feasible and acceptable to the study population. Although self-reported data on contraception use are considered less reliable, and prone to social desirability bias, it is often the standard approach for contraception research and provides data comparable to previous studies. ClinicalTrials.gov Identifier: NCT01823861 . Registered: March 30, 2013.

The Pathophysiology of Repetitive Concussive Traumatic Brain Injury in Experimental Models; New Developments and Open Questions

PubMed Central

Brody, David L; Benetatos, Joseph; Bennett, Rachel E; Klemenhagen, Kristen C; Donald, Christine L Mac

2015-01-01

In recent years, there has been an increasing interest in the pathophysiology of repetitive concussive traumatic brain injury (rcTBI) in large part due to the association with dramatic cases of progressive neurological deterioration in professional athletes, military personnel, and others. However, our understanding of the pathophysiology of rcTBI is less advanced than for more severe brain injuries. Most prominently, the mechanisms underlying traumatic axonal injury, microglial activation, amyloid-beta accumulation, and progressive tau pathology are not yet known. In addition, the role of injury to dendritic spine cytoskeletal structures, vascular reactivity impairments, and microthrombi are intriguing and subjects of ongoing inquiry. Methods for quantitative analysis of axonal injury, dendritic injury, and synaptic loss need to be refined for the field to move forward in a rigorous fashion. We and others are attempting to develop translational approaches to assess these specific pathophysiological events in both animals and humans to facilitate clinically relevant pharmacodynamic assessments of candidate therapeutics. In this article, we review and discuss several of the recent experimental results from our lab and others. We include new initial data describing the difficulty in modeling progressive tau pathology in experimental rcTBI, and results demonstrating that sertraline can alleviate social interaction deficits and depressive-like behaviors following experimental rcTBI plus foot shock stress. Furthermore, we propose a discrete set of open, experimentally tractable questions that may serve as a framework for future investigations. In addition, we also raise several important questions that are less experimentally tractable at this time, in hopes that they may stimulate future methodological developments to address them. PMID:25684677

The power of yeast to model diseases of the powerhouse of the cell

PubMed Central

Baile, Matthew G.; Claypool, Steven M

2013-01-01

Mitochondria participate in a variety of cellular functions. As such, mitochondrial diseases exhibit numerous clinical phenotypes. Because mitochondrial functions are highly conserved between humans and Saccharomyces cerevisiae, yeast are an excellent model to study mitochondrial disease, providing insight into both physiological and pathophysiological processes. PMID:23276920

Implications of sodium hydrogen exchangers in various brain diseases.

PubMed

Verma, Vivek; Bali, Anjana; Singh, Nirmal; Jaggi, Amteshwar Singh

2015-09-01

Na+/H+ exchangers (NHEs) are the transporter proteins that play an important role in intracellular pH (pHi) regulation, cell differentiation and cell volume and that mediate transepithelial Na+ and HCO3- absorption on the basis of chemical gradients across the plasma membrane. Its activation causes an increase in intracellular Na+, which further leads to Ca+ overload and cell death. The pharmacological inhibition of these transporter proteins prevents myocardial infarction and other heart diseases like congestive heart failure in experimental animal models as well as in clinical situations. The more recent studies have implicated the role of these exchangers in the pathophysiology of brain diseases. Out of nine NHE isoforms, NHE-1 is the major isoform present in the brain and regulates the trans-cellular ion transport through blood-brain barrier membrane, and alteration in their function leads to severe brain abnormalities. NHEs were shown to be involved in pathophysiologies of many brain diseases like epilepsy, Alzheimer's disease, neuropathic pain and ischemia/reperfusion-induced cerebral injury. Na+/H+-exchanger inhibitors (e.g., amiloride and cariporide) produce protective effects on ischemia/reperfusion-induced brain injury (e.g., stroke), exhibit good antiepileptic potential and attenuate neuropathic pain in various animal models. The present review focuses on the pathophysiological role of these ion exchangers in different brain diseases with possible mechanisms.

Pathophysiological analyses of leptomeningeal heterotopia using gyrencephalic mammals.

PubMed

Matsumoto, Naoyuki; Kobayashi, Naoki; Uda, Natsu; Hirota, Miwako; Kawasaki, Hiroshi

2018-03-15

Leptomeningeal glioneuronal heterotopia (LGH) is a focal malformation of the cerebral cortex and frequently found in patients with thanatophoric dysplasia (TD). The pathophysiological mechanisms underlying LGH formation are still largely unclear because of difficulties in obtaining brain samples from human TD patients. Recently, we established a new animal model for analysing cortical malformations of human TD by utilizing our genetic manipulation technique for gyrencephalic carnivore ferrets. Here we investigated the pathophysiological mechanisms underlying the formation of LGH using our TD ferrets. We found that LGH was formed during corticogenesis in TD ferrets. Interestingly, we rarely found Ki-67-positive and phospho-histone H3-positive cells in LGH, suggesting that LGH formation does not involve cell proliferation. We uncovered that vimentin-positive radial glial fibers and doublecortin-positive migrating neurons were accumulated in LGH. This result may indicate that preferential cell migration into LGH underlies LGH formation. Our findings provide novel mechanistic insights into the pathogenesis of LGH in TD.

Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS

PubMed Central

2016-01-01

There is accumulating evidence that immune dysregulation contributes to the pathophysiology of obsessive-compulsive disorder (OCD), Tourette syndrome, and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). The mechanistic details of this pathophysiology, however, remain unclear. Here we focus on one particular component of the immune system: microglia, the brain's resident immune cells. The role of microglia in neurodegenerative diseases has been understood in terms of classic, inflammatory activation, which may be both a consequence and a cause of neuronal damage. In OCD and Tourette syndrome, which are not characterized by frank neural degeneration, the potential role of microglial dysregulation is much less clear. Here we review the evidence for a neuroinflammatory etiology and microglial dysregulation in OCD, Tourette syndrome, and PANDAS. We also explore new hypotheses as to the potential contributions of microglial abnormalities to pathophysiology, beyond neuroinflammation, including failures in neuroprotection, lack of support for neuronal survival, and abnormalities in synaptic pruning. Recent advances in neuroimaging and animal model work are creating new opportunities to elucidate these issues. PMID:28053994

Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS.

PubMed

Frick, Luciana; Pittenger, Christopher

2016-01-01

There is accumulating evidence that immune dysregulation contributes to the pathophysiology of obsessive-compulsive disorder (OCD), Tourette syndrome, and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). The mechanistic details of this pathophysiology, however, remain unclear. Here we focus on one particular component of the immune system: microglia, the brain's resident immune cells. The role of microglia in neurodegenerative diseases has been understood in terms of classic, inflammatory activation, which may be both a consequence and a cause of neuronal damage. In OCD and Tourette syndrome, which are not characterized by frank neural degeneration, the potential role of microglial dysregulation is much less clear. Here we review the evidence for a neuroinflammatory etiology and microglial dysregulation in OCD, Tourette syndrome, and PANDAS. We also explore new hypotheses as to the potential contributions of microglial abnormalities to pathophysiology, beyond neuroinflammation, including failures in neuroprotection, lack of support for neuronal survival, and abnormalities in synaptic pruning. Recent advances in neuroimaging and animal model work are creating new opportunities to elucidate these issues.

Noninflammatory Joint Contractures Arising from Immobility: Animal Models to Future Treatments

PubMed Central

Wong, Kayleigh; Trudel, Guy; Laneuville, Odette

2015-01-01

Joint contractures, defined as the limitation in the passive range of motion of a mobile joint, can be classified as noninflammatory diseases of the musculoskeletal system. The pathophysiology is not well understood; limited information is available on causal factors, progression, the pathophysiology involved, and prediction of response to treatment. The clinical heterogeneity of joint contractures combined with the heterogeneous contribution of joint connective tissues to joint mobility presents challenges to the study of joint contractures. Furthermore, contractures are often a symptom of a wide variety of heterogeneous disorders that are in many cases multifactorial. Extended immobility has been identified as a causal factor and evidence is provided from both experimental and epidemiology studies. Of interest is the involvement of the joint capsule in the pathophysiology of joint contractures and lack of response to remobilization. While molecular pathways involved in the development of joint contractures are being investigated, current treatments focus on physiotherapy, which is ineffective on irreversible contractures. Future treatments may include early diagnosis and prevention. PMID:26247029

Tailoring nanoparticle designs to target cancer based on tumor pathophysiology

PubMed Central

Sykes, Edward A.; Dai, Qin; Sarsons, Christopher D.; Chen, Juan; Rocheleau, Jonathan V.; Hwang, David M.; Zheng, Gang; Cramb, David T.; Rinker, Kristina D.; Chan, Warren C. W.

2016-01-01

Nanoparticles can provide significant improvements in the diagnosis and treatment of cancer. How nanoparticle size, shape, and surface chemistry can affect their accumulation, retention, and penetration in tumors remains heavily investigated, because such findings provide guiding principles for engineering optimal nanosystems for tumor targeting. Currently, the experimental focus has been on particle design and not the biological system. Here, we varied tumor volume to determine whether cancer pathophysiology can influence tumor accumulation and penetration of different sized nanoparticles. Monte Carlo simulations were also used to model the process of nanoparticle accumulation. We discovered that changes in pathophysiology associated with tumor volume can selectively change tumor uptake of nanoparticles of varying size. We further determine that nanoparticle retention within tumors depends on the frequency of interaction of particles with the perivascular extracellular matrix for smaller nanoparticles, whereas transport of larger nanomaterials is dominated by Brownian motion. These results reveal that nanoparticles can potentially be personalized according to a patient’s disease state to achieve optimal diagnostic and therapeutic outcomes. PMID:26884153

Inflammation in the pathophysiology of essential hypertension.

PubMed

Montecucco, Fabrizio; Pende, Aldo; Quercioli, Alessandra; Mach, François

2011-01-01

In spite of the huge amount of research recently performed in this area, the pathogenesis of human hypertension remains elusive. Thus, hypertension has to be defined as "essential" for the majority of patients with high blood pressure. Given the lack of animal models useful to investigate essential hypertension, we analyze and discuss both clinical and basic research studies indicating that essential hypertension should be considered as a potential multifactorial inflammatory disease. The pathophysiology of essential hypertension might result from interactions between genetic and environmental factors. Morphological abnormalities in the renal parenchyma and arteries have also been shown to determine hypertension. Inflammatory processes might induce renal vasoconstriction, ischemia and injury that can sustain systemic hypertension. Arterial and tubulointerstitial infiltration of inflammatory cells in response to renal damage might further increase renal and vascular alterations through the production of oxidants and other soluble inflammatory mediators. The present review gives an update regarding the latest research on the possible direct role of inflammation in the pathophysiology of essential hypertension.

Electrophysiology of Basal Ganglia and Cortex in Models of Parkinson Disease

PubMed Central

Ellens, Damien J.; Leventhal, Daniel K.

2014-01-01

Incomplete understanding of the systems-level pathophysiology of Parkinson Disease (PD) remains a significant barrier to improving its treatment. Substantial progress has been made, however, due to the availability of neurotoxins that selectively target monoaminergic (in particular, dopaminergic) neurons. This review discusses the in vivo electrophysiology of basal ganglia (BG), thalamic, and cortical regions after dopamine-depleting lesions. These include firing rate changes, neuronal burst-firing, neuronal oscillations, and neuronal synchrony that result from a combination of local microanatomic changes and network-level interactions. While much is known of the clinical and electrophysiological phenomenology of dopamine loss, a critical gap in our conception of PD pathophysiology is the link between them. We discuss potential mechanisms by which these systems-level electrophysiological changes may emerge, as well as how they may relate to clinical parkinsonism. Proposals for an updated understanding of BG function are reviewed, with an emphasis on how emerging frameworks will guide future research into the pathophysiology and treatment of PD. PMID:23948994

Imaging the pathophysiology of major depressive disorder - from localist models to circuit-based analysis

PubMed Central

2014-01-01

The neuroimaging literature of Major Depressive Disorder (MDD) has grown substantially over the last several decades, facilitating great advances in the identification of specific brain regions, neurotransmitter systems and networks associated with depressive illness. Despite this progress, fundamental questions remain about the pathophysiology and etiology of MDD. More importantly, this body of work has yet to directly influence clinical practice. It has long been a goal for the fields of clinical psychology and psychiatry to have a means of making objective diagnoses of mental disorders. Frustratingly little movement has been achieved on this front, however, and the 'gold-standard’ of diagnostic validity and reliability remains expert consensus. In light of this challenge, the focus of the current review is to provide a critical summary of key findings from different neuroimaging approaches in MDD research, including structural, functional and neurochemical imaging studies. Following this summary, we discuss some of the current conceptual obstacles to better understanding the pathophysiology of depression, and conclude with recommendations for future neuroimaging research. PMID:24606595

A systems approach to bone pathophysiology.

PubMed

Weiss, Aaron J; Lipshtat, Azi; Mechanick, Jeffrey I

2010-11-01

With evolving interest in multiscalar biological systems one could assume that reductionist approaches may not fully describe biological complexity. Instead, tools such as mathematical modeling, network analysis, and other multiplexed clinical- and research-oriented tests enable rapid analyses of high-throughput data parsed at the genomic, proteomic, metabolomic, and physiomic levels. A physiomic-level approach allows for recursive horizontal and vertical integration of subsystem coupling across and within spatiotemporal scales. Additionally, this methodology recognizes previously ignored subsystems and the strong, nonintuitively obvious and indirect connections among physiological events that potentially account for the uncertainties in medicine. In this review, we flip the reductionist research paradigm and review the concept of systems biology and its applications to bone pathophysiology. Specifically, a bone-centric physiome model is presented that incorporates systemic-level processes with their respective therapeutic implications. © 2010 New York Academy of Sciences.

Molecular Basis for Group B β -hemolytic Streptococcal Disease

NASA Astrophysics Data System (ADS)

Hellerqvist, Carl G.; Sundell, Hakan; Gettins, Peter

1987-01-01

Group B β -hemolytic Streptococcus (GBS) is a major pathogen affecting newborns. We have investigated the molecular mechanism underlying the respiratory distress induced in sheep after intravenous injection of a toxin produced by this organism. The pathophysiological response is characterized by pulmonary hypertension, followed by granulocytopenia and increased pulmonary vascular permeability to protein. 31P NMR studies of GBS toxin and model components before and after reductive alkaline hydrolysis demonstrated that phosphodiester residues are an integral part of the GBS toxin. Reductive alkaline treatment cleaves phosphate esters from secondary and primary alcohols and renders GBS toxin nontoxic in the sheep model and inactive as a mediator of elastase release in vitro from isolated human granulocytes. We propose that the interaction of cellular receptors with mannosyl phosphodiester groups plays an essential role in the pathophysiological response to GBS toxin.

MicroPET imaging and transgenic models: a blueprint for Alzheimer's disease clinical research.

PubMed

Zimmer, Eduardo R; Parent, Maxime J; Cuello, A Claudio; Gauthier, Serge; Rosa-Neto, Pedro

2014-11-01

Over the past decades, developments in neuroimaging have significantly contributed to the understanding of Alzheimer's disease (AD) pathophysiology. Specifically, positron emission tomography (PET) imaging agents targeting amyloid deposition have provided unprecedented opportunities for refining in vivo diagnosis, monitoring disease propagation, and advancing AD clinical trials. Furthermore, the use of a miniaturized version of PET (microPET) in transgenic (Tg) animals has been a successful strategy for accelerating the development of novel radiopharmaceuticals. However, advanced applications of microPET focusing on the longitudinal propagation of AD pathophysiology or therapeutic strategies remain in their infancy. This review highlights what we have learned from microPET imaging in Tg models displaying amyloid and tau pathology, and anticipates cutting-edge applications with high translational value to clinical research. Copyright © 2014 Elsevier Ltd. All rights reserved.

Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition.

PubMed

Neto-Neves, Evandro M; Brown, Mary B; Zaretskaia, Maria V; Rezania, Samin; Goodwill, Adam G; McCarthy, Brian P; Persohn, Scott A; Territo, Paul R; Kline, Jeffrey A

2017-04-01

Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor-dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

The multi-factorial origins of Chronic Traumatic Encephalopathy (CTE) symptomology in post-career athletes: The athlete post-career adjustment (AP-CA) model.

PubMed

Gaetz, Michael

2017-05-01

CTE has two prominent components: the pathophysiology that is detected in the brain postmortem and the symptomology that is present in the interval between retirement and end of life. CTE symptomology has been noted to include memory difficulties, aggression, depression, explosivity, and executive dysfunction at early stages progressing to problems with attention, mood swings, visuospatial difficulties, confusion, progressive dementia, and suicidality (e.g. McKee et al. (2012), Omalu et al. (2010a-c), McKee et al. (2009)). There are a number of assumptions embedded within the current CTE literature: The first is the assumption that CTE symptomology reported by athletes and their families is the product of the pathophysiology change detected post-mortem (e.g. McKee et al. (2009)). At present, there is little scientific evidence to suggest that all CTE symptomology is the product of CTE pathophysiology. It has been assumed that CTE pathophysiology causes CTE symptomology (Meehan et al. (2015), Iverson et al. (2016)) but this link has never been scientifically validated. The purpose of the present work is to provide a multi-factorial theoretical framework to account for the symptomology reported by some athletes who sustain neurotrauma during their careers that will lead to a more systematic approach to understanding post-career symptomology. There is significant overlap between the case reports of athletes with post-mortem diagnoses of CTE, and symptom profiles of those with a history of substance use, chronic pain, and athlete career transition stress. The athlete post-career adjustment (AP-CA) model is intended to explain some of the symptoms that athletes experience at the end of their careers or during retirement. The AP-CA model consists of four elements: neurotrauma, chronic pain, substance use, and career transition stress. Based on the existing literature, it is clear that any one of the four elements of the AP-CA model can account for a significant number of CTE symptoms. In addition, depression can be a chronic lifelong co-morbid condition that may be present prior to an athletic career, or may be developed secondary to any of the model elements as shown in Fig. 1. Notably, neurotrauma is a necessary, but not a sufficient condition, for the development of CTE symptomology. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acute graft-versus-host disease: from the bench to the bedside

PubMed Central

Blazar, Bruce R.

2009-01-01

During the past decade, progress in basic immunology has been impressive. In parallel, whereas our understanding of the pathophysiology of acute graft-versus-host disease (GVHD) has greatly improved, so has our knowledge of the complexities of the immune system. Much of the immunobiology of acute GVHD has been gleaned from preclinical models and far less from correlations with clinical observations or therapeutic interventions. In this review, we summarize some of the major advances in GVHD pathophysiology, including the translation of these from the bench to the bedside, and discuss preclinical approaches that warrant further exploration in the clinic. PMID:19713461

Reform in Teaching Preclinical Pathophysiology

ERIC Educational Resources Information Center

Li, Yong-Yu; Li, Kun; Yao, Hong; Xu, Xiao-Juan; Cai, Qiao-Lin

2015-01-01

Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff…

New insights into the molecular pathophysiology of fragile X syndrome and therapeutic perspectives from the animal model.

PubMed

Busquets-Garcia, Arnau; Maldonado, Rafael; Ozaita, Andrés

2014-08-01

Fragile X syndrome is the most common monogenetic form of intellectual disability and is a leading cause of autism. This syndrome is produced by the reduced transcription of the fragile X mental retardation (FMR1) gene, and it is characterized by a range of symptoms heterogeneously expressed in patients such as cognitive impairment, seizure susceptibility, altered pain sensitivity and anxiety. The recent advances in the understanding of the pathophysiological mechanisms involved have opened novel potential therapeutic approaches identified in preclinical rodent models as a necessary preliminary step for the subsequent evaluation in patients. Among those possible therapeutic approaches, the modulation of the metabotropic glutamate receptor signaling or the GABA receptor signaling have focused most of the attention. New findings in the animal models open other possible therapeutic approaches such as the mammalian target of rapamycin signaling pathway or the endocannabinoid system. This review summarizes the emerging data recently obtained in preclinical models of fragile X syndrome supporting these new therapeutic perspectives. Copyright © 2014 Elsevier Ltd. All rights reserved.

An Analytical Model for Determining Two-Dimensional Receptor-Ligand Kinetics

PubMed Central

Cheung, Luthur Siu-Lun; Konstantopoulos, Konstantinos

2011-01-01

Cell-cell adhesive interactions play a pivotal role in major pathophysiological vascular processes, such as inflammation, infection, thrombosis, and cancer metastasis, and are regulated by hemodynamic forces generated by blood flow. Cell adhesion is mediated by the binding of receptors to ligands, which are both anchored on two-dimensional (2-D) membranes of apposing cells. Biophysical assays have been developed to determine the unstressed (no-force) 2-D affinity but fail to disclose its dependence on force. Here we develop an analytical model to estimate the 2-D kinetics of diverse receptor-ligand pairs as a function of force, including antibody-antigen, vascular selectin-ligand, and bacterial adhesin-ligand interactions. The model can account for multiple bond interactions necessary to mediate adhesion and resist detachment amid high hemodynamic forces. Using this model, we provide a generalized biophysical interpretation of the counterintuitive force-induced stabilization of cell rolling observed by a select subset of receptor-ligand pairs with specific intrinsic kinetic properties. This study enables us to understand how single-molecule and multibond biophysics modulate the macroscopic cell behavior in diverse pathophysiological processes. PMID:21575567

Virtual Patients and Sensitivity Analysis of the Guyton Model of Blood Pressure Regulation: Towards Individualized Models of Whole-Body Physiology

PubMed Central

Moss, Robert; Grosse, Thibault; Marchant, Ivanny; Lassau, Nathalie; Gueyffier, François; Thomas, S. Randall

2012-01-01

Mathematical models that integrate multi-scale physiological data can offer insight into physiological and pathophysiological function, and may eventually assist in individualized predictive medicine. We present a methodology for performing systematic analyses of multi-parameter interactions in such complex, multi-scale models. Human physiology models are often based on or inspired by Arthur Guyton's whole-body circulatory regulation model. Despite the significance of this model, it has not been the subject of a systematic and comprehensive sensitivity study. Therefore, we use this model as a case study for our methodology. Our analysis of the Guyton model reveals how the multitude of model parameters combine to affect the model dynamics, and how interesting combinations of parameters may be identified. It also includes a “virtual population” from which “virtual individuals” can be chosen, on the basis of exhibiting conditions similar to those of a real-world patient. This lays the groundwork for using the Guyton model for in silico exploration of pathophysiological states and treatment strategies. The results presented here illustrate several potential uses for the entire dataset of sensitivity results and the “virtual individuals” that we have generated, which are included in the supplementary material. More generally, the presented methodology is applicable to modern, more complex multi-scale physiological models. PMID:22761561

Evaluation of a Decision Support System for Obstructive Sleep Apnea with Nonlinear Analysis of Respiratory Signals.

PubMed

Kaimakamis, Evangelos; Tsara, Venetia; Bratsas, Charalambos; Sichletidis, Lazaros; Karvounis, Charalambos; Maglaveras, Nikolaos

2016-01-01

Obstructive Sleep Apnea (OSA) is a common sleep disorder requiring the time/money consuming polysomnography for diagnosis. Alternative methods for initial evaluation are sought. Our aim was the prediction of Apnea-Hypopnea Index (AHI) in patients potentially suffering from OSA based on nonlinear analysis of respiratory biosignals during sleep, a method that is related to the pathophysiology of the disorder. Patients referred to a Sleep Unit (135) underwent full polysomnography. Three nonlinear indices (Largest Lyapunov Exponent, Detrended Fluctuation Analysis and Approximate Entropy) extracted from two biosignals (airflow from a nasal cannula, thoracic movement) and one linear derived from Oxygen saturation provided input to a data mining application with contemporary classification algorithms for the creation of predictive models for AHI. A linear regression model presented a correlation coefficient of 0.77 in predicting AHI. With a cutoff value of AHI = 8, the sensitivity and specificity were 93% and 71.4% in discrimination between patients and normal subjects. The decision tree for the discrimination between patients and normal had sensitivity and specificity of 91% and 60%, respectively. Certain obtained nonlinear values correlated significantly with commonly accepted physiological parameters of people suffering from OSA. We developed a predictive model for the presence/severity of OSA using a simple linear equation and additional decision trees with nonlinear features extracted from 3 respiratory recordings. The accuracy of the methodology is high and the findings provide insight to the underlying pathophysiology of the syndrome. Reliable predictions of OSA are possible using linear and nonlinear indices from only 3 respiratory signals during sleep. The proposed models could lead to a better study of the pathophysiology of OSA and facilitate initial evaluation/follow up of suspected patients OSA utilizing a practical low cost methodology. ClinicalTrials.gov NCT01161381.

'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia'.

PubMed

Abeti, R; Parkinson, M H; Hargreaves, I P; Angelova, P R; Sandi, C; Pook, M A; Giunti, P; Abramov, A Y

2016-05-26

Friedreich's ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, cerebellar granule cells, from a validated FRDA mouse model. By using live cell imaging and biochemical techniques we were able to demonstrate that mitochondria are deregulated in neurons from the YG8R FRDA mouse model, causing a decrease in mitochondrial membrane potential (▵Ψm) due to an inhibition of Complex I, which is partially compensated by an overactivation of Complex II. This complex activity imbalance leads to ROS generation in both mitochondrial matrix and cytosol, which results in glutathione depletion and increased lipid peroxidation. Preventing this increase in lipid peroxidation, in neurons, protects against in cell death. This work describes the pathophysiological properties of the mitochondria in neurons from a FRDA mouse model and shows that lipid peroxidation could be an important target for novel therapeutic strategies in FRDA, which still lacks a cure.

Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy.

PubMed

Baek, Jin Hyen; D'Agnillo, Felice; Vallelian, Florence; Pereira, Claudia P; Williams, Matthew C; Jia, Yiping; Schaer, Dominik J; Buehler, Paul W

2012-04-01

Massive transfusion of blood can lead to clinical complications, including multiorgan dysfunction and even death. Such severe clinical outcomes have been associated with longer red blood cell (rbc) storage times. Collectively referred to as the rbc storage lesion, rbc storage results in multiple biochemical changes that impact intracellular processes as well as membrane and cytoskeletal properties, resulting in cellular injury in vitro. However, how the rbc storage lesion triggers pathophysiology in vivo remains poorly defined. In this study, we developed a guinea pig transfusion model with blood stored under standard blood banking conditions for 2 (new), 21 (intermediate), or 28 days (old blood). Transfusion with old but not new blood led to intravascular hemolysis, acute hypertension, vascular injury, and kidney dysfunction associated with pathophysiology driven by hemoglobin (Hb). These adverse effects were dramatically attenuated when the high-affinity Hb scavenger haptoglobin (Hp) was administered at the time of transfusion with old blood. Pathologies observed after transfusion with old blood, together with the favorable response to Hp supplementation, allowed us to define the in vivo consequences of the rbc storage lesion as storage-related posttransfusion hemolysis producing Hb-driven pathophysiology. Hb sequestration by Hp might therefore be a therapeutic modality for enhancing transfusion safety in severely ill or massively transfused patients.

State of the field: An informatics-based systematic review of the SOD1-G93A amyotrophic lateral sclerosis transgenic mouse model

PubMed Central

Kim, Renaid B.; Irvin, Cameron W.; Tilva, Keval R.; Mitchell, Cassie S.

2016-01-01

Numerous sub-cellular through system-level disturbances have been identified in over 1300 articles examining the superoxide dismutase-1 guanine 93 to alanine (SOD1-G93A) transgenic mouse amyotrophic lateral sclerosis (ALS) pathophysiology. Manual assessment of such a broad literature base is daunting. We performed a comprehensive informatics-based systematic review or ‘field analysis’ to agnostically compute and map the current state of the field. Text mining of recaptured articles was used to quantify published data topic breadth and frequency. We constructed a nine-category pathophysiological function-based ontology to systematically organize and quantify the field's primary data. Results demonstrated that the distribution of primary research belonging to each category is: systemic measures an motor function, 59%; inflammation, 46%; cellular energetics, 37%; proteomics, 31%; neural excitability, 22%; apoptosis, 20%; oxidative stress, 18%; aberrant cellular chemistry, 14%; axonal transport, 10%. We constructed a SOD1-G93A field map that visually illustrates and categorizes the 85% most frequently assessed sub-topics. Finally, we present the literature-cited significance of frequently published terms and uncover thinly investigated areas. In conclusion, most articles individually examine at least two categories, which is indicative of the numerous underlying pathophysiological interrelationships. An essential future path is examination of cross-category pathophysiological interrelationships and their co-correspondence to homeostatic regulation and disease progression. PMID:25998063

The Atlas of Physiology and Pathophysiology: Web-based multimedia enabled interactive simulations.

PubMed

Kofranek, Jiri; Matousek, Stanislav; Rusz, Jan; Stodulka, Petr; Privitzer, Pavol; Matejak, Marek; Tribula, Martin

2011-11-01

The paper is a presentation of the current state of development for the Atlas of Physiology and Pathophysiology (Atlas). Our main aim is to provide a novel interactive multimedia application that can be used for biomedical education where (a) simulations are combined with tutorials and (b) the presentation layer is simplified while the underlying complexity of the model is retained. The development of the Atlas required the cooperation of many professionals including teachers, system analysts, artists, and programmers. During the design of the Atlas, tools were developed that allow for component-based creation of simulation models, creation of interactive multimedia and their final coordination into a compact unit based on the given design. The Atlas is a freely available online application, which can help to explain the function of individual physiological systems and the causes and symptoms of their disorders. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Time perception impairs sensory-motor integration in Parkinson’s disease

PubMed Central

2013-01-01

It is well known that perception and estimation of time are fundamental for the relationship between humans and their environment. However, this temporal information processing is inefficient in patients with Parkinson’ disease (PD), resulting in temporal judgment deficits. In general, the pathophysiology of PD has been described as a dysfunction in the basal ganglia, which is a multisensory integration station. Thus, a deficit in the sensorimotor integration process could explain many of the Parkinson symptoms, such as changes in time perception. This physiological distortion may be better understood if we analyze the neurobiological model of interval timing, expressed within the conceptual framework of a traditional information-processing model called “Scalar Expectancy Theory”. Therefore, in this review we discuss the pathophysiology and sensorimotor integration process in PD, the theories and neural basic mechanisms involved in temporal processing, and the main clinical findings about the impact of time perception in PD. PMID:24131660

The Ion Channel TRPA1 Is Required for Chronic Itch

PubMed Central

Wilson, Sarah R.; Nelson, Aislyn M.; Batia, Lyn; Morita, Takeshi; Estandian, Daniel; Owens, David M.; Lumpkin, Ellen A.; Bautista, Diana M.

2013-01-01

Chronic itch is a debilitating condition that affects one in 10 people. Little is known about the molecules that mediate chronic itch in primary sensory neurons and skin. We demonstrate that the ion channel TRPA1 is required for chronic itch. Using a mouse model of chronic itch, we show that scratching evoked by impaired skin barrier is abolished in TRPA1-deficient animals. This model recapitulates many of the pathophysiological hallmarks of chronic itch that are observed in prevalent human diseases such as atopic dermatitis and psoriasis, including robust scratching, extensive epidermal hyperplasia, and dramatic changes in gene expression in sensory neurons and skin. Remarkably, TRPA1 is required for both transduction of chronic itch signals to the CNS and for the dramatic skin changes triggered by dry-skin-evoked itch and scratching. These data suggest that TRPA1 regulates both itch transduction and pathophysiological changes in the skin that promote chronic itch. PMID:23719797

Light-induced depigmentation in planarians models the pathophysiology of acute porphyrias.

PubMed

Stubenhaus, Bradford M; Dustin, John P; Neverett, Emily R; Beaudry, Megan S; Nadeau, Leanna E; Burk-McCoy, Ethan; He, Xinwen; Pearson, Bret J; Pellettieri, Jason

2016-05-31

Porphyrias are disorders of heme metabolism frequently characterized by extreme photosensitivity. This symptom results from accumulation of porphyrins, tetrapyrrole intermediates in heme biosynthesis that generate reactive oxygen species when exposed to light, in the skin of affected individuals. Here we report that in addition to producing an ommochrome body pigment, the planarian flatworm Schmidtea mediterranea generates porphyrins in its subepithelial pigment cells under physiological conditions, and that this leads to pigment cell loss when animals are exposed to intense visible light. Remarkably, porphyrin biosynthesis and light-induced depigmentation are enhanced by starvation, recapitulating a common feature of some porphyrias - decreased nutrient intake precipitates an acute manifestation of the disease. Our results establish planarians as an experimentally tractable animal model for research into the pathophysiology of acute porphyrias, and potentially for the identification of novel pharmacological interventions capable of alleviating porphyrin-mediated photosensitivity or decoupling dieting and fasting from disease pathogenesis.

Functional neurological symptom disorder (conversion disorder): A role for microglial-based plasticity mechanisms?

PubMed

Stephenson, Chris P; Baguley, Ian J

2018-02-01

Functional Neurological Symptom Disorder (FND) is a relatively common neurological condition, accounting for approximately 3-6% of neurologist referrals. FND is considered a transient disorder of neuronal function, sometimes linked to physical trauma and psychological stress. Despite this, chronic disability is common, for example, around 40% of adults with motor FND have permanent disability. Building on current theoretical models, this paper proposes that microglial dysfunction could perpetuate functional changes within acute motor FND, thus providing a pathophysiological mechanism underlying the chronic stage of the motor FND phenotypes seen clinically. Core to our argument is microglia's dual role in modulating neuroimmunity and their control of synaptic plasticity, which places them at a pathophysiological nexus wherein coincident physical trauma and psychological stress could cause long-term change in neuronal networks without producing macroscopic structural abnormality. This model proposes a range of hypotheses that are testable with current technologies. Copyright © 2017. Published by Elsevier Ltd.

Reform in teaching preclinical pathophysiology.

PubMed

Li, Yong-Yu; Li, Kun; Yao, Hong; Xu, Xiao-Juan; Cai, Qiao-Lin

2015-12-01

Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff in Chinese Departments of Pathophysiology generally consists of full-time instructors or lecturers who teach medical students. These lecturers are sometimes lacking in clinic knowledge and experiences. To overcome this, in recent years, we have been trying to bring new trends in teaching pathophysiology into our curriculum. Our purpose in writing this article was to share our experiences with our colleagues and peers worldwide in the hope that the insights we have gained in pathophysiology teaching will be of some value to educators who advocate teaching reform in medical schools. Copyright © 2015 The American Physiological Society.

Computational Nosology and Precision Psychiatry

PubMed Central

Redish, A. David; Gordon, Joshua A.

2017-01-01

This article provides an illustrative treatment of psychiatric morbidity that offers an alternative to the standard nosological model in psychiatry. It considers what would happen if we treated diagnostic categories not as causes of signs and symptoms, but as diagnostic consequences of psychopathology and pathophysiology. This reformulation (of the standard nosological model) opens the door to a more natural description of how patients present—and of their likely responses to therapeutic interventions. In brief, we describe a model that generates symptoms, signs, and diagnostic outcomes from latent psychopathological states. In turn, psychopathology is caused by pathophysiological processes that are perturbed by (etiological) causes such as predisposing factors, life events, and therapeutic interventions. The key advantages of this nosological formulation include (i) the formal integration of diagnostic (e.g., DSM) categories and latent psychopathological constructs (e.g., the dimensions of the Research Domain Criteria); (ii) the provision of a hypothesis or model space that accommodates formal, evidence-based hypothesis testing (using Bayesian model comparison); and (iii) the ability to predict therapeutic responses (using a posterior predictive density), as in precision medicine. These and other advantages are largely promissory at present: The purpose of this article is to show what might be possible, through the use of idealized simulations. PMID:29400354

The impact of IUGR on pancreatic islet development and β-cell function.

PubMed

Boehmer, Brit H; Limesand, Sean W; Rozance, Paul J

2017-11-01

Placental insufficiency is a primary cause of intrauterine growth restriction (IUGR). IUGR increases the risk of developing type 2 diabetes mellitus (T2DM) throughout life, which indicates that insults from placental insufficiency impair β-cell development during the perinatal period because β-cells have a central role in the regulation of glucose tolerance. The severely IUGR fetal pancreas is characterized by smaller islets, less β-cells, and lower insulin secretion. Because of the important associations among impaired islet growth, β-cell dysfunction, impaired fetal growth, and the propensity for T2DM, significant progress has been made in understanding the pathophysiology of IUGR and programing events in the fetal endocrine pancreas. Animal models of IUGR replicate many of the observations in severe cases of human IUGR and allow us to refine our understanding of the pathophysiology of developmental and functional defects in islet from IUGR fetuses. Almost all models demonstrate a phenotype of progressive loss of β-cell mass and impaired β-cell function. This review will first provide evidence of impaired human islet development and β-cell function associated with IUGR and the impact on glucose homeostasis including the development of glucose intolerance and diabetes in adulthood. We then discuss evidence for the mechanisms regulating β-cell mass and insulin secretion in the IUGR fetus, including the role of hypoxia, catecholamines, nutrients, growth factors, and pancreatic vascularity. We focus on recent evidence from experimental interventions in established models of IUGR to understand better the pathophysiological mechanisms linking placental insufficiency with impaired islet development and β-cell function. © 2017 Society for Endocrinology.

Pathophysiology of infantile pulmonary arterial hypertension induced by monocrotaline.

PubMed

Dias-Neto, Marina; Luísa-Neves, Ana; Pinho, Sónia; Gonçalves, Nádia; Mendes, Maria; Eloy, Catarina; Lopes, José M; Gonçalves, Daniel; Ferreira-Pinto, Manuel; Leite-Moreira, Adelino F; Henriques-Coelho, Tiago

2015-06-01

Pediatric pulmonary arterial hypertension (PAH) presents certain specific features. In this specific age group, experimental models to study the pathophysiology of PAH are lacking. To characterize hemodynamic, morphometric, and histological progression as well as the expression of neurohumoral factors and regulators of cardiac transcription in an infantile model of PAH induced by monocrotaline (MCT), eight-day-old Wistar rats were randomly injected with MCT (30 mg/kg, sc, n = 95) or equal volume of saline solution (n = 92). Animals were instrumented for biventricular hemodynamic recording 7, 14, and 21 days after MCT, whereas samples were collected at 1, 3, 7, 14, and 21 days after MCT. Different time point postinjections were defined for further analysis. Hearts and lungs were collected for morphometric characterization, assessment of right- and left-ventricle (RV and LV) cardiomyocyte diameter and collagen type-I and type-III ratio, RV collagen volume fraction, and pulmonary vessels wall thickness. mRNA quantification was undertaken for brain natriuretic peptide (BNP), endothelin-1 (ET-1), and for cardiac transcription regulators (HOP and Islet1). Animals treated with MCT at the 8th day of life presented RV hypertrophy since day 14 after MCT injection. There were no differences on the RV collagen volume fraction or collagen type-I and type-III ratio. Pulmonary vascular remodelling and PAH were present on day 21, which were accompanied by an increased expression of BNP, ET-1, HOP, and Islet1. The infantile model of MCT-induced PAH can be useful for the study of its pathophysiology and to test new therapeutic targets in pediatric age group.

Transforming pathophysiology instruction through narrative pedagogy and Socratic questioning.

PubMed

Rogge, M M

2001-01-01

Pathophysiology, heavily content driven, has typically been taught through the use of traditional behavioral pedagogy and a reliance on the formal lecture. The author describes the limitations of this approach to teaching pathophysiology and describes the use of narrative pedagogy and Socratic questioning as alternative methods of instruction to augment lecture methods. Specific strategies for transforming traditional classroom teaching by using Socratic questions in a pathophysiology course for nurse practitioners are described. Student and faculty reactions to the initial efforts to transform pathophysiology instruction are also described.

Translational systems biology: introduction of an engineering approach to the pathophysiology of the burn patient.

PubMed

An, Gary; Faeder, James; Vodovotz, Yoram

2008-01-01

The pathophysiology of the burn patient manifests the full spectrum of the complexity of the inflammatory response. In the acute phase, inflammation may have negative effects via capillary leak, the propagation of inhalation injury, and development of multiple organ failure. Attempts to mediate these processes remain a central subject of burn care research. Conversely, inflammation is a necessary prologue and component in the later stage processes of wound healing. Despite the volume of information concerning the cellular and molecular processes involved in inflammation, there exists a significant gap between the knowledge of mechanistic pathophysiology and the development of effective clinical therapeutic regimens. Translational systems biology (TSB) is the application of dynamic mathematical modeling and certain engineering principles to biological systems to integrate mechanism with phenomenon and, importantly, to revise clinical practice. This study will review the existing applications of TSB in the areas of inflammation and wound healing, relate them to specific areas of interest to the burn community, and present an integrated framework that links TSB with traditional burn research.

A cognitive perspective on medical expertise: theory and implication.

PubMed

Schmidt, H G; Norman, G R; Boshuizen, H P

1990-10-01

A new theory of the development of expertise in medicine is outlined. Contrary to existing views, this theory assumes that expertise is not so much a matter of superior reasoning skills or in-depth knowledge of pathophysiological states as it is based on cognitive structures that describe the features of prototypical or even actual patients. These cognitive structures, referred to as "illness scripts," contain relatively little knowledge about pathophysiological causes of symptoms and complaints but a wealth of clinically relevant information about disease, its consequences, and the context under which illness develops. By contrast, intermediate-level students without clinical experience typically use pathophysiological, causal models of disease when solving problems. The authors review evidence supporting the theory and discuss its implications for the understanding of five phenomena extensively documented in the clinical-reasoning literature: (1) content specificity in diagnostic performance; (2) typical differences in data-gathering techniques between medical students and physicians; (3) difficulties involved in setting standards; (4) a decline in performance on certain measures of clinical reasoning with increasing expertise; and (5) a paradoxical association between errors and longer response times in visual diagnosis.

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

PubMed Central

Mook-Kanamori, Barry B.; Geldhoff, Madelijn; van der Poll, Tom; van de Beek, Diederik

2011-01-01

Summary: Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae, which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy. PMID:21734248

Pediatric IBS: an overview on pathophysiology, diagnosis and treatment.

PubMed

Chogle, Ashish; Mintjens, Stijn; Saps, Miguel

2014-04-01

Irritable bowel syndrome (IBS) is a common disorder in children and adults. The pathogenesis and pathophysiology of IBS remains incompletely understood. The biopsychosocial model, which conceptualizes chronic pain as a dysregulation of the gut-brain-homeostasis with peripheral and central factors mutually influencing each other, is the most accepted framework to explain IBS. Twin and family aggregation studies suggest a genetic component that does not exclusively explain the higher prevalence of IBS in certain families. Social learning (environmental factors) and maladaptive coping predispose children to develop IBS with greater disability and more frequent medical consultations. Early-life events constitute an additional risk factor for the development of IBS and other functional gastrointestinal disorders (FGIDs). Children with a history of cow's milk protein hypersensitivity or abdominal surgeries have a higher prevalence of IBS and other FGIDs years later. IBS frequently follows an episode of acute gastrointestinal inflammation (infectious or non-infectious). This article discusses the importance, known pathophysiological mechanisms, clinical approach, and evidence-based therapeutic options for the management of IBS in children and adolescents. Copyright 2014, SLACK Incorporated.

Pathophysiology of major depressive disorder: mechanisms involved in etiology are not associated with clinical progression.

PubMed

Verduijn, J; Milaneschi, Y; Schoevers, R A; van Hemert, A M; Beekman, A T F; Penninx, B W J H

2015-09-29

Meta-analyses support the involvement of different pathophysiological mechanisms (inflammation, hypothalamic-pituitary (HPA)-axis, neurotrophic growth and vitamin D) in major depressive disorder (MDD). However, it remains unknown whether dysregulations in these mechanisms are more pronounced when MDD progresses toward multiple episodes and/or chronicity. We hypothesized that four central pathophysiological mechanisms of MDD are not only involved in etiology, but also associated with clinical disease progression. Therefore, we expected to find increasingly more dysregulation across consecutive stages of MDD progression. The sample from the Netherlands Study of Depression and Anxiety (18-65 years) consisted of 230 controls and 2333 participants assigned to a clinical staging model categorizing MDD in eight stages (0, 1A, 1B, 2, 3A, 3B, 3C and 4), from familial risk at MDD (stage 0) to chronic MDD (stage 4). Analyses of covariance examined whether pathophysiological mechanism markers (interleukin (IL)-6, C-reactive protein (CRP), cortisol, brain-derived neurotrophic factor and vitamin D) showed a linear trend across controls, those at risk for MDD (stages 0, 1A and 1B), and those with full-threshold MDD (stages 2, 3A, 3B, 3C and 4). Subsequently, pathophysiological differences across separate stages within those at risk and with full-threshold MDD were examined. A linear increase of inflammatory markers (CRP P=0.026; IL-6 P=0.090), cortisol (P=0.025) and decrease of vitamin D (P<0.001) was found across the entire sample (for example, from controls to those at risk and those with full-threshold MDD). Significant trends of dysregulations across stages were present in analyses focusing on at-risk individuals (IL-6 P=0.050; cortisol P=0.008; vitamin D P<0.001); however, no linear trends were found in dysregulations for any of the mechanisms across more progressive stages of full-threshold MDD. Our results support that the examined pathophysiological mechanisms are involved in MDD's etiology. These same mechanisms, however, are less important in clinical progression from first to later MDD episodes and toward chronicity.

Pathophysiology of major depressive disorder: mechanisms involved in etiology are not associated with clinical progression

PubMed Central

Verduijn, J; Milaneschi, Y; Schoevers, R A; van Hemert, A M; Beekman, A T F; Penninx, B W J H

2015-01-01

Meta-analyses support the involvement of different pathophysiological mechanisms (inflammation, hypothalamic–pituitary (HPA)-axis, neurotrophic growth and vitamin D) in major depressive disorder (MDD). However, it remains unknown whether dysregulations in these mechanisms are more pronounced when MDD progresses toward multiple episodes and/or chronicity. We hypothesized that four central pathophysiological mechanisms of MDD are not only involved in etiology, but also associated with clinical disease progression. Therefore, we expected to find increasingly more dysregulation across consecutive stages of MDD progression. The sample from the Netherlands Study of Depression and Anxiety (18–65 years) consisted of 230 controls and 2333 participants assigned to a clinical staging model categorizing MDD in eight stages (0, 1A, 1B, 2, 3A, 3B, 3C and 4), from familial risk at MDD (stage 0) to chronic MDD (stage 4). Analyses of covariance examined whether pathophysiological mechanism markers (interleukin (IL)-6, C-reactive protein (CRP), cortisol, brain-derived neurotrophic factor and vitamin D) showed a linear trend across controls, those at risk for MDD (stages 0, 1A and 1B), and those with full-threshold MDD (stages 2, 3A, 3B, 3C and 4). Subsequently, pathophysiological differences across separate stages within those at risk and with full-threshold MDD were examined. A linear increase of inflammatory markers (CRP P=0.026; IL-6 P=0.090), cortisol (P=0.025) and decrease of vitamin D (P<0.001) was found across the entire sample (for example, from controls to those at risk and those with full-threshold MDD). Significant trends of dysregulations across stages were present in analyses focusing on at-risk individuals (IL-6 P=0.050; cortisol P=0.008; vitamin D P<0.001); however, no linear trends were found in dysregulations for any of the mechanisms across more progressive stages of full-threshold MDD. Our results support that the examined pathophysiological mechanisms are involved in MDD’s etiology. These same mechanisms, however, are less important in clinical progression from first to later MDD episodes and toward chronicity. PMID:26418277

Current distribution in tissues with conducted electrical weapons operated in drive-stun mode.

PubMed

Panescu, Dorin; Kroll, Mark W; Brave, Michael

2016-08-01

The TASER® conducted electrical weapon (CEW) is best known for delivering electrical pulses that can temporarily incapacitate subjects by overriding normal motor control. The alternative drive-stun mode is less understood and the goal of this paper is to analyze the distribution of currents in tissues when the CEW is operated in this mode. Finite element modeling (FEM) was used to approximate current density in tissues with boundary electrical sources placed 40 mm apart. This separation was equivalent to the distance between drive-stun mode TASER X26™, X26P, X2 CEW electrodes located on the device itself and between those located on the expended CEW cartridge. The FEMs estimated the amount of current flowing through various body tissues located underneath the electrodes. The FEM simulated the attenuating effects of both a thin and of a normal layer of fat. The resulting current density distributions were used to compute the residual amount of current flowing through deeper layers of tissue. Numerical modeling estimated that the skin, fat and skeletal muscle layers passed at least 86% or 91% of total CEW current, assuming a thin or normal fat layer thickness, respectively. The current density and electric field strength only exceeded thresholds which have increased probability for ventricular fibrillation (VFTJ), or for cardiac capture (CCTE), in the skin and the subdermal fat layers. The fat layer provided significant attenuation of drive-stun CEW currents. Beyond the skeletal muscle layer, only fractional amounts of the total CEW current were estimated to flow. The regions presenting risk for VF induction or for cardiac capture were well away from the typical heart depth.

Comparative biology of cystic fibrosis animal models.

PubMed

Fisher, John T; Zhang, Yulong; Engelhardt, John F

2011-01-01

Animal models of human diseases are critical for dissecting mechanisms of pathophysiology and developing therapies. In the context of cystic fibrosis (CF), mouse models have been the dominant species by which to study CF disease processes in vivo for the past two decades. Although much has been learned through these CF mouse models, limitations in the ability of this species to recapitulate spontaneous lung disease and several other organ abnormalities seen in CF humans have created a need for additional species on which to study CF. To this end, pig and ferret CF models have been generated by somatic cell nuclear transfer and are currently being characterized. These new larger animal models have phenotypes that appear to closely resemble human CF disease seen in newborns, and efforts to characterize their adult phenotypes are ongoing. This chapter will review current knowledge about comparative lung cell biology and cystic fibrosis transmembrane conductance regulator (CFTR) biology among mice, pigs, and ferrets that has implications for CF disease modeling in these species. We will focus on methods used to compare the biology and function of CFTR between these species and their relevance to phenotypes seen in the animal models. These cross-species comparisons and the development of both the pig and the ferret CF models may help elucidate pathophysiologic mechanisms of CF lung disease and lead to new therapeutic approaches.

Filament formation associated with spirochetal infection: a comparative approach to Morgellons disease

PubMed Central

Middelveen, Marianne J; Stricker, Raphael B

2011-01-01

Bovine digital dermatitis is an emerging infectious disease that causes lameness, decreased milk production, and weight loss in livestock. Proliferative stages of bovine digital dermatitis demonstrate keratin filament formation in skin above the hooves in affected animals. The multifactorial etiology of digital dermatitis is not well understood, but spirochetes and other coinfecting microorganisms have been implicated in the pathogenesis of this veterinary illness. Morgellons disease is an emerging human dermopathy characterized by the presence of filamentous fibers of undetermined composition, both in lesions and subdermally. While the etiology of Morgellons disease is unknown, there is serological and clinical evidence linking this phenomenon to Lyme borreliosis and coinfecting tick-borne agents. Although the microscopy of Morgellons filaments has been described in the medical literature, the structure and pathogenesis of these fibers is poorly understood. In contrast, most microscopy of digital dermatitis has focused on associated pathogens and histology rather than the morphology of late-stage filamentous fibers. Clinical, laboratory, and microscopic characteristics of these two diseases are compared. PMID:22253541

Filament formation associated with spirochetal infection: a comparative approach to Morgellons disease.

PubMed

Middelveen, Marianne J; Stricker, Raphael B

2011-01-01

Bovine digital dermatitis is an emerging infectious disease that causes lameness, decreased milk production, and weight loss in livestock. Proliferative stages of bovine digital dermatitis demonstrate keratin filament formation in skin above the hooves in affected animals. The multifactorial etiology of digital dermatitis is not well understood, but spirochetes and other coinfecting microorganisms have been implicated in the pathogenesis of this veterinary illness. Morgellons disease is an emerging human dermopathy characterized by the presence of filamentous fibers of undetermined composition, both in lesions and subdermally. While the etiology of Morgellons disease is unknown, there is serological and clinical evidence linking this phenomenon to Lyme borreliosis and coinfecting tick-borne agents. Although the microscopy of Morgellons filaments has been described in the medical literature, the structure and pathogenesis of these fibers is poorly understood. In contrast, most microscopy of digital dermatitis has focused on associated pathogens and histology rather than the morphology of late-stage filamentous fibers. Clinical, laboratory, and microscopic characteristics of these two diseases are compared.

Patients' perspectives about why they have their contraceptive Implanon NXT device removed early.

PubMed

Flore, Meike; Chen, Xiaoshuang Lilly; Bonney, Andrew; Mullan, Judy; Dijkmans-Hadley, Bridget; Hodgkins, Adam; Evans, Gina; Frew, Haley; Lloyd, Gail

2016-10-01

Women with long-acting, reversible contraceptive devices inserted may choose to remove them prior to their planned expiry dates. The objective of this study was to explore Australian women's experiences with the etonogestrel subdermal contraceptive implant (Implanon NXT) and why they had it removed early. Semi-structured interviews were conducted with 18 women between June 2013 and January 2014. Transcriptions of the audio-taped interviews were analysed using a constant comparative analysis framework. Two core themes of participants' responses that were identified in this study were influences on choice of contraception, which included convenience and information sources; and influences on removal of contraception, which included side effects and their negative impacts on relationships and financial costs. This study highlights that women's experiences with side effects contribute to the early removal of long-acting contraceptive devices such as Implanon NXT. This study emphasises the importance of general practitioners (GPs) in providing comprehensive information about the benefits and potential side effects associated with using these implants.

Macrolane (large particle biphasic hyaluronic acid) filler injection for correction of defect contour after liposuction.

PubMed

Cerqua, Sandro; Angelucci, Francesco

2013-08-01

In a minority of patients undergoing liposuction, superficial irregularities (or skin depression) in the operated area may occur. Macrolane is a gel composed of hyaluronic acid (HA), used for volume restoration of soft tissues. In this study, the authors investigated the effectiveness, maintenance, and safety of Macrolane as a "non-surgical" treatment to correct skin depression after liposuction. Twelve female patients were included. Macrolane was injected at a subdermal superficial plane using an intramuscular or spinal needle. In all patients, Macrolane was successful in correcting skin depression. No relevant side effects were observed. At 8 months post-injection, a persistence of correction of 60-70% was still present in 90% of the patients. In conclusion, Macrolane filler injections are a predictable, safe, and long-lasting non-surgical procedure to fill contour defects that arise after liposuction, and represent a good option for patients who refuse to undergo an additional surgery to fill the arisen skin depressions.

Lessons learnt from the introduction of the contraceptive implant in South Africa

PubMed

Pleaner, M; Morroni, C; Smit, J; Lince-Deroche, N; Chersich, M; Mullick, S; Pillay, D; Makua, M; Rees, H

2017-10-01

In 2014, South Africa (SA) introduced the subdermal contraceptive implant with the aim of expanding the contraceptive method mix and availability of long-acting reversible methods in the public sector. Three years on, concerns have been raised about the decline in uptake, early implant removals and challenges in service delivery. This article explores the lessons learnt from the introduction of contraceptive technologies elsewhere and applies these to the SA context. Drawing on the World Health Organization’s conceptual framework for the introduction of new contraceptive methods, and subsequent literature on the topic, lessons are classified into six cross-cutting themes. Recommendations highlight the need for SA to review and explore strategies to strengthen current implant services, including the provision of improved provider training aimed at sensitive, client-centred approaches; increased community engagement; and improved systems for programmatic monitoring and evaluation. With implementation of these recommendations, worrying trends in the provision of implants could be reversed. Creative Commons Attribution - NonCommercial Works License (CC BY-NC 4.0)

Interpreting intracorporeal landscapes: how patients visualize pathophysiology and utilize medical images in their understanding of chronic musculoskeletal illness.

PubMed

Moore, Andrew J; Richardson, Jane C; Bernard, Miriam; Sim, Julius

2018-02-26

Medical science and other sources, such as the media, increasingly inform the general public's understanding of disease. There is often discordance between this understanding and the diagnostic interpretations of health care practitioners (HCPs). In this paper - based on a supra-analysis of qualitative interview data from two studies of joint pain, including osteoarthritis - we investigate how people imagine and make sense of the pathophysiology of their illness, and how these understandings may affect self-management behavior. We then explore how HCPs' use of medical images and models can inform patients' understanding. In conceptualizing their illness to make sense of their experience of the disease, individuals often used visualizations of their inner body; these images may arise from their own lay understanding, or may be based on images provided by HCPs. When HCPs used anatomical models or medical images judiciously, patients' orientation to their illness changed. Including patients in a more collaborative diagnostic event that uses medical images and visual models to support explanations about their condition may help them to achieve a more meaningful understanding of their illness and to manage their condition more effectively. Implications for Rehabilitation Chronic musculoskeletal pain is a leading cause of pain and years lived with disability, and despite its being common, patients and healthcare professionals often have a different understanding of the underlying disease. An individual's understanding of his or her pathophysiology plays an important role in making sense of painful joint conditions and in decision-making about self-management and care. Including patients in a more collaborative diagnostic event using medical images and anatomical models to support explanations about their symptoms may help them to better understand their condition and manage it more effectively. Using visually informed explanations and anatomical models may also help to reassure patients about the safety and effectiveness of core treatments such as physical exercise and thereby help restore or improve patients' activity levels and return to social participation.

Diagnostic reasoning and underlying knowledge of students with preclinical patient contacts in PBL.

PubMed

Diemers, Agnes D; van de Wiel, Margje W J; Scherpbier, Albert J J A; Baarveld, Frank; Dolmans, Diana H J M

2015-12-01

Medical experts have access to elaborate and integrated knowledge networks consisting of biomedical and clinical knowledge. These coherent knowledge networks enable them to generate more accurate diagnoses in a shorter time. However, students' knowledge networks are less organised and students have difficulties linking theory and practice and transferring acquired knowledge. Therefore we wanted to explore the development and transfer of knowledge of third-year preclinical students on a problem-based learning (PBL) course with real patient contacts. Before and after a 10-week PBL course with real patients, third-year medical students were asked to think out loud while diagnosing four types of paper patient problems (two course cases and two transfer cases), and explain the underlying pathophysiological mechanisms of the patient features. Diagnostic accuracy and time needed to think through the cases were measured. The think-aloud protocols were transcribed verbatim and different types of knowledge were coded and quantitatively analysed. The written pathophysiological explanations were translated into networks of concepts. Both the concepts and the links between concepts in students' networks were compared to model networks. Over the course diagnostic accuracy increased, case-processing time decreased, and students used less biomedical and clinical knowledge during diagnostic reasoning. The quality of the pathophysiological explanations increased: the students used more concepts, especially more model concepts, and they used fewer wrong concepts and links. The findings differed across course and transfer cases. The effects were generally less strong for transfer cases. Students' improved diagnostic accuracy and the improved quality of their knowledge networks suggest that integration of biomedical and clinical knowledge took place during a 10-week course. The differences between course and transfer cases demonstrate that transfer is complex and time-consuming. We therefore suggest offering students many varied patient contacts with the same underlying pathophysiological mechanism and encouraging students to link biomedical and clinical knowledge. © 2015 John Wiley & Sons Ltd.

Attenuation of Activity in an Endogenous Analgesia Circuit by Ongoing Pain in the Rat

PubMed Central

Ferrari, Luiz F.; Gear, Robert W.; Levine, Jon D.

2010-01-01

Analgesic efficacy varies depending on the pain syndrome being treated. One reason for this may be a differential effect of individual pain syndromes on the function of endogenous pain control circuits at which these drugs act to produce analgesia. To test this hypothesis we examined the effects of diverse (i.e., ongoing inflammatory, neuropathic, or chronic widespread) pain syndromes on analgesia induced by activation of an opioid-mediated noxious stimulus-induced endogenous pain control circuit. This circuit was activated by subdermal capsaicin injection at a site remote from the site of nociceptive testing. Analgesia was not affected by carrageenan-induced inflammatory pain nor the early-phase of oxaliplatin neuropathy (a complication of cancer chemotherapy). However, the duration of analgesia was markedly shorter in the late-phase of oxaliplatin neuropathy and in alcoholic neuropathy. A model of fibromyalgia syndrome produced by chronic unpredictable stress and proinflammatory cytokines also shortened analgesia duration, but so did the same stress alone. Therefore, since chronic pain can activate neuroendocrine stress axes, we tested whether they are involved in the attenuation of analgesic duration induced by these pain syndromes. Rats in which the sympathoadrenal axis was ablated by adrenal medullectomy showed normal duration pain-induced analgesia in groups with either late-phase oxaliplatin neuropathy, alcoholic neuropathy, or exposure to sound stress. These results support the suggestion that pain syndromes can modulate activity in endogenous pain control circuits, and this effect is sympathoadrenal dependent. PMID:20943910

Chimeric Mice with Competent Hematopoietic Immunity Reproduce Key Features of Severe Lassa Fever.

PubMed

Oestereich, Lisa; Lüdtke, Anja; Ruibal, Paula; Pallasch, Elisa; Kerber, Romy; Rieger, Toni; Wurr, Stephanie; Bockholt, Sabrina; Pérez-Girón, José V; Krasemann, Susanne; Günther, Stephan; Muñoz-Fontela, César

2016-05-01

Lassa fever (LASF) is a highly severe viral syndrome endemic to West African countries. Despite the annual high morbidity and mortality caused by LASF, very little is known about the pathophysiology of the disease. Basic research on LASF has been precluded due to the lack of relevant small animal models that reproduce the human disease. Immunocompetent laboratory mice are resistant to infection with Lassa virus (LASV) and, to date, only immunodeficient mice, or mice expressing human HLA, have shown some degree of susceptibility to experimental infection. Here, transplantation of wild-type bone marrow cells into irradiated type I interferon receptor knockout mice (IFNAR-/-) was used to generate chimeric mice that reproduced important features of severe LASF in humans. This included high lethality, liver damage, vascular leakage and systemic virus dissemination. In addition, this model indicated that T cell-mediated immunopathology was an important component of LASF pathogenesis that was directly correlated with vascular leakage. Our strategy allows easy generation of a suitable small animal model to test new vaccines and antivirals and to dissect the basic components of LASF pathophysiology.

Irritable bowel syndrome in children: Current knowledge, challenges and opportunities

PubMed Central

Devanarayana, Niranga Manjuri; Rajindrajith, Shaman

2018-01-01

Irritable bowel syndrome (IBS) is a common and troublesome disorder in children with an increasing prevalence noted during the past two decades. It has a significant effect on the lives of affected children and their families and poses a significant burden on healthcare systems. Standard symptom-based criteria for diagnosis of pediatric IBS have changed several times during the past two decades and there are some differences in interpreting symptoms between different cultures. This has posed a problem when using them to diagnose IBS in clinical practice. A number of potential patho-physiological mechanisms have been described, but so far the exact underlying etiology of IBS is unclear. A few potential therapeutic modalities have been tested in children and only a small number of them have shown some benefit. In addition, most of the described patho-physiological mechanisms and treatment options are based on adult studies. These have surfaced as challenges when dealing with pediatric IBS and they need to be overcome for effective management of children with IBS. Recently suggested top-down and bottom-up models help integrating reported patho-physiological mechanisms and will provide an opportunity for better understanding of the diseases process. Treatment trials targeting single treatment modalities are unlikely to have clinically meaningful therapeutic effects on IBS with multiple integrating patho-physiologies. Trials focusing on multiple combined pharmacological and non-pharmacological therapies are likely to yield more benefit. In addition to treatment, in the future, attention should be paid for possible prevention strategies for IBS. PMID:29881232

Identification of novel mRNAs and lncRNAs associated with mouse experimental colitis and human inflammatory bowel disease.

PubMed

Rankin, Carl Robert; Theodorou, Evangelos; Law, Ivy Ka Man; Rowe, Lorraine; Kokkotou, Efi; Pekow, Joel; Wang, Jiafang; Martin, Martin G; Pothoulakis, Charalabos; Padua, David Miguel

2018-06-28

Inflammatory bowel disease (IBD) is a complex disorder that is associated with significant morbidity. While many recent advances have been made with new diagnostic and therapeutic tools, a deeper understanding of its basic pathophysiology is needed to continue this trend towards improving treatments. By utilizing an unbiased, high-throughput transcriptomic analysis of two well-established mouse models of colitis, we set out to uncover novel coding and non-coding RNAs that are differentially expressed in the setting of colonic inflammation. RNA-seq analysis was performed using colonic tissue from two mouse models of colitis, a dextran sodium sulfate induced model and a genetic-induced model in mice lacking IL-10. We identified 81 coding RNAs that were commonly altered in both experimental models. Of these coding RNAs, 12 of the human orthologs were differentially expressed in a transcriptomic analysis of IBD patients. Interestingly, 5 of the 12 of human differentially expressed genes have not been previously identified as IBD-associated genes, including ubiquitin D. Our analysis also identified 15 non-coding RNAs that were differentially expressed in either mouse model. Surprisingly, only three non-coding RNAs were commonly dysregulated in both of these models. The discovery of these new coding and non-coding RNAs expands our transcriptional knowledge of mouse models of IBD and offers additional targets to deepen our understanding of the pathophysiology of IBD.

The Trilayer Approach of Teaching Physiology, Pathophysiology, and Pharmacology Concepts in a First-Year Pharmacy Course: The TLAT Model

ERIC Educational Resources Information Center

Islam, Mohammed A.; Sabnis, Gauri; Farris, Fred

2017-01-01

This paper describes the development, implementation, and students' perceptions of a new trilayer approach of teaching (TLAT). The TLAT model involved blending lecture, in-class group activities, and out-of-class assignments on selected content areas and was implemented initially in a first-year integrated pharmacy course. Course contents were…

Middle Cerebral Artery Occlusion Model of Stroke in Rodents: A Step-by-Step Approach

PubMed Central

Shahjouei, Shima; Cai, Peter Y.; Ansari, Saeed; Sharififar, Sharareh; Azari, Hassan; Ganji, Sarah; Zand, Ramin

2016-01-01

Stroke is one of the leading causes of morbidity and mortality in developed countries and an immense amount of medical care resources are devoted to combat the poststroke debilitating consequences. The key to develop effective and clinically applicable treatment methodologies is a better understanding of the pathophysiology of the disease, including the root causes and targets for pharmacology. Developing these foundations requires the use of standard animal models that mimic the physicochemical process of the diseases that can reliably replicate results in order to test and fine-tune therapeutic modalities. Middle cerebral artery occlusion (MCAO), endothelin-1-induced ischemic stroke, photothrombosis, devascularization, embolization, and spontaneous infarction using hemorrhage are some examples of different animal models. Reliability of MCAO has been proved and due to the ability to induce reperfusion similar to tissue plasminogen activator (tPA) therapy, this model is widely used in preclinical studies. Here, we describe a detailed methodology on how to develop MCAO stroke in rodents using intra-arterial insertion of filament to occlude the middle cerebral artery. This approach allows for the study of a wide array of basic pathophysiology mechanisms, regenerative medicine and rehabilitation therapy. PMID:26958146

Modeling Chronic Traumatic Encephalopathy: The Way Forward for Future Discovery.

PubMed

Turner, Ryan C; Lucke-Wold, Brandon P; Logsdon, Aric F; Robson, Matthew J; Lee, John M; Bailes, Julian E; Dashnaw, Matthew L; Huber, Jason D; Petraglia, Anthony L; Rosen, Charles L

2015-01-01

Despite the extensive media coverage associated with the diagnosis of chronic traumatic encephalopathy (CTE), our fundamental understanding of the disease pathophysiology remains in its infancy. Only recently have scientific laboratories and personnel begun to explore CTE pathophysiology through the use of preclinical models of neurotrauma. Some studies have shown the ability to recapitulate some aspects of CTE in rodent models, through the use of various neuropathological, biochemical, and/or behavioral assays. Many questions related to CTE development, however, remain unanswered. These include the role of impact severity, the time interval between impacts, the age at which impacts occur, and the total number of impacts sustained. Other important variables such as the location of impacts, character of impacts, and effect of environment/lifestyle and genetics also warrant further study. In this work, we attempt to address some of these questions by exploring work previously completed using single- and repetitive-injury paradigms. Despite some models producing some deficits similar to CTE symptoms, it is clear that further studies are required to understand the development of neuropathological and neurobehavioral features consistent with CTE-like features in rodents. Specifically, acute and chronic studies are needed that characterize the development of tau-based pathology.

Modeling Chronic Traumatic Encephalopathy: The Way Forward for Future Discovery

PubMed Central

Turner, Ryan C.; Lucke-Wold, Brandon P.; Logsdon, Aric F.; Robson, Matthew J.; Lee, John M.; Bailes, Julian E.; Dashnaw, Matthew L.; Huber, Jason D.; Petraglia, Anthony L.; Rosen, Charles L.

2015-01-01

Despite the extensive media coverage associated with the diagnosis of chronic traumatic encephalopathy (CTE), our fundamental understanding of the disease pathophysiology remains in its infancy. Only recently have scientific laboratories and personnel begun to explore CTE pathophysiology through the use of preclinical models of neurotrauma. Some studies have shown the ability to recapitulate some aspects of CTE in rodent models, through the use of various neuropathological, biochemical, and/or behavioral assays. Many questions related to CTE development, however, remain unanswered. These include the role of impact severity, the time interval between impacts, the age at which impacts occur, and the total number of impacts sustained. Other important variables such as the location of impacts, character of impacts, and effect of environment/lifestyle and genetics also warrant further study. In this work, we attempt to address some of these questions by exploring work previously completed using single- and repetitive-injury paradigms. Despite some models producing some deficits similar to CTE symptoms, it is clear that further studies are required to understand the development of neuropathological and neurobehavioral features consistent with CTE-like features in rodents. Specifically, acute and chronic studies are needed that characterize the development of tau-based pathology. PMID:26579067

Smoke-induced seed germination in California chaparral

USGS Publications Warehouse

Keeley, J.E.; Fotheringham, C.J.

1998-01-01

The California chaparral community has a rich flora of species with different mechanisms for cuing germination to postfire conditions. Heat shock triggers germination of certain species but has no stimulatory effect on a great many other postfire species that are chemically stimulated by combustion products. Previous reports have shown that charred wood will induce germination, and here we report that smoke also induces germination in these same species. Smoke is highly effective, often inducing 100% germination in deeply dormant seed populations with 0% control germination. Smoke induces germination both directly and indirectly by aqueous or gaseous transfer from soil to seeds. Neither nitrate nor ammonium ions were effective in stimulating germination of smoke-stimulated species, nor were most of the quantitatively important gases generated by biomass smoke. Nitrogen dioxide, however, was very effective at inducing germination in Caulanthus heterophyllus (Brassicaceae), Emmenanthe penduliflora (Hydrophyllaceae), Phacelia grandiflora (Hydrophyllaceae), and Silene multinervia (Caryophyllaceae). Three species, Dendromecon rigida (Papaveraceae), Dicentra chrysantha, and Trichostema lanatum (Lamiaceae), failed to germinate unless smoke treatment was coupled with prior treatment of 1 yr soil storage. Smoke-stimulated germination was found in 25 chaparral species, representing 11 families, none of which were families known for heat-shock-stimulated germination. Seeds of smoke-stimulated species have many analogous characteristics that separate them from most heat-shock-stimulated seeds, including: (1) outer seed coats that are highly textured, (2) a poorly developed outer cuticle, (3) absence of a dense palisade tissue in the seed coat, and (4) a subdermal membrane that is semipermeable, allowing water passage but blocking entry of large (molecular mass > 500) solutes. Tentative evidence suggests that permeability characteristics of this subdermal layer are altered by smoke. While the mechanism behind smoke-induced germination is not known, it appears that smoke may be involved in overcoming different blocks to germination in different species. For example, in Emmenanthe penduliflora, NO2 in smoke was sufficient to induce germination, and most forms of physical or chemical scarification also induced germination. For Romneya coulteri, NO2 alone failed to induce germination, and scarified seeds required addition of gibberellic acid. In Dicentra chrysantha, none of these treatments, nor smoke alone, induced germination, but germination was triggered by a combination of soil burial followed by smoke treatment. Smoke-stimulated species differed substantially in the duration of smoke exposure required to induce germination, and this was inversely correlated with tolerance to smoke exposure. We suggest that such differences in response may affect postfire community structure.

The cerebral basis of Parkinsonian tremor: A network perspective.

PubMed

Helmich, Rick C

2018-02-01

Tremor in Parkinson's disease is a poorly understood sign. Although it is one of the clinical hallmarks of the disease, its pathophysiology remains unclear. It is clear that tremor involves different neural mechanisms than bradykinesia and rigidity, the other core motor signs of Parkinson's disease. In particular, the role of dopamine in tremor has been heavily debated given clinical observations that tremor has a variable response to dopaminergic medication. From a neuroscience perspective, tremor is also a special sign; unlike other motor signs, it has a clear electrophysiological signature (frequency, phase, and power). These unique features of tremor, and newly available neuroimaging methods, have sparked investigations into the pathophysiology of tremor. In this review, evidence will be discussed for the idea that parkinsonian tremor results from increased interactions between the basal ganglia and the cerebello-thalamo-cortical circuit, driven by altered dopaminergic projections to nodes within both circuits, and modulated by context-dependent factors, such as psychological stress. Models that incorporate all of these features may help our understanding of the pathophysiology of tremor and interindividual differences between patients. One example that will be discussed in this article is the "dimmer-switch" model. According to this model, cerebral activity related to parkinsonian tremor first arises in the basal ganglia and is then propagated to the cerebello-thalamo-cortical circuit, where the tremor rhythm is maintained and amplified. In the future, detailed knowledge about the architecture of the tremor circuitry in individual patients ("tremor fingerprints") may provide new, mechanism-based treatments for this debilitating motor sign. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

Phenotypic heterogeneity in lung capillary and extra-alveolar endothelial cells. Increased extra-alveolar endothelial permeability is sufficient to decrease compliance.

PubMed

Lowe, Kevin; Alvarez, Diego; King, Judy; Stevens, Troy

2007-11-01

In acute respiratory distress syndrome, pulmonary vascular permeability increases, causing intravascular fluid and protein to move into the lung's interstitium. The classic model describing the formation of pulmonary edema suggests that fluid crossing the capillary endothelium is drawn by negative interstitial pressure into the potential space surrounding extra-alveolar vessels and, as interstitial pressure builds, is forced into the alveolar air space. However, the validity of this model is challenged by animal models of acute lung injury in which extra-alveolar vessels are more permeable than capillaries under a variety of conditions. In the current study, we sought to determine whether extravascular fluid accumulation can be produced because of increased permeability of either the capillary or extra-alveolar endothelium, and whether different pathophysiology results from such site-specific increases in permeability. We perfused isolated lungs with either the plant alkaloid thapsigargin, which increases extra-alveolar endothelial permeability, or with 4alpha-phorbol 12, 13-didecanoate, which increases capillary endothelial permeability. Both treatments produced equal increases in whole lung vascular permeability, but caused fluid accumulations in separate anatomical compartments. Light microscopy of isolated lungs showed that thapsigargin caused fluid cuffing of large vessels, while 4alpha-phorbol 12, 13-didecanoate caused alveolar flooding. Dynamic compliance was reduced in lungs with cuffing of large vessels, but not in lungs with alveolar flooding. Phenotypic differences between vascular segments resulted in site-specific increases in permeability, which have different pathophysiological outcomes. Our findings suggest that insults leading to acute respiratory distress syndrome may increase permeability in extra-alveolar or capillary vascular segments, resulting in different pathophysiological sequela.

Oxygen consumption of keloids and hypertrophic scars.

PubMed

Ichioka, Shigeru; Ando, Taichi; Shibata, Masahiro; Sekiya, Naomi; Nakatsuka, Takashi

2008-02-01

The oxygen consumption of keloids and hypertrophic scars has never been quantitatively presented, although abnormal metabolic conditions must be associated with their pathophysiology. We invented an original measurement system equipped with a Clark oxygen electrode for ex vivo samples. The measurement of a mouse wound-healing model revealed immature repairing tissues consumed more oxygen than mature tissues. This finding is in accord with the current thinking and supported the validity of our measurement system. The analysis of fresh human samples clearly demonstrated the high oxygen consumption rate of keloid hypertrophic scars and the comparatively low consumption of mature scars. A high oxygen consuming potential, as well as insufficient oxygen diffusion, may possibly contribute to the pathophysiology of keloids and hypertrophic scars.

Obesity, metabolic dysfunction and cardiac fibrosis: pathophysiologic pathways, molecular mechanisms and therapeutic opportunities

PubMed Central

Cavalera, Michele; Wang, Junhong; Frangogiannis, Nikolaos G

2014-01-01

Cardiac fibrosis is strongly associated with obesity and metabolic dysfunction and may contribute to the increased incidence of heart failure, atrial arrhythmias and sudden cardiac death in obese subjects. Our review discusses the evidence linking obesity and myocardial fibrosis in animal models and human patients, focusing on the fundamental pathophysiologic alterations that may trigger fibrogenic signaling, the cellular effectors of fibrosis and the molecular signals that may regulate the fibrotic response. Obesity is associated with a wide range of pathophysiologic alterations (such as pressure and volume overload, metabolic dysregulation, neurohumoral activation and systemic inflammation); their relative role in mediating cardiac fibrosis is poorly defined. Activation of fibroblasts likely plays a major role in obesity-associated fibrosis; however, inflammatory cells, cardiomyocytes and vascular cells may also contribute to fibrogenic signaling. Several molecular processes have been implicated in regulation of the fibrotic response in obesity. Activation of the Renin-Angiotensin-Aldosterone System, induction of Transforming Growth Factor-β, oxidative stress, advanced glycation end-products (AGEs), endothelin-1, Rho-kinase signaling, leptin-mediated actions and upregulation of matricellular proteins (such as thrombospondin-1) may play a role in the development of fibrosis in models of obesity and metabolic dysfunction. Moreover, experimental evidence suggests that obesity and insulin resistance profoundly affect the fibrotic and remodeling response following cardiac injury. Understanding the pathways implicated in obesity-associated fibrosis may lead to development of novel therapies to prevent heart failure and to attenuate post-infarction cardiac remodeling in obese patients. PMID:24880146

[From "deadly quartet" to "metabolic syndrome". An analysis of its clinical relevance].

PubMed

Vancheri, Federico; Burgio, Antonio; Dovico, Rossana

2007-03-01

The metabolic syndrome denotes a clustering of specific risk factors for both cardiovascular disease and type 2 diabetes, whose underlying pathophysiology is believed to include insulin resistance. It has been widely reported that the syndrome is a simple clinical tool to identify people at high long term risk of cardiovascular disease and diabetes. However, its clinical importance is under debate. There are substantial uncertainties about the clinical definition of the syndrome, as to whether the risk factors clustering indicates a single unifying disorder, whether the risk conferred by the condition as a whole is higher risk than its individual components, and whether its predictive value of future cardiovascular events or diabetes is greater than established predicting models such as the Framingham Risk Score and the Diabetes Risk Score. We undertook an extensive review of the literature. Our analysis indicates that current definitions of the syndrome are incomplete or ambiguous, more than one pathophysiological process underlies the syndrome, although the combination of insulin resistance and hyperinsulinemia are related to most cases; the risk associated with the syndrome is no greater than that explained by the presence of its components, and the syndrome is less effective in predicting the future development of cardiovascular events and diabetes than established predicting models. Although the syndrome has some importance in understanding the pathophysiology of cardiovascular and diabetes risk factors clustering, its use as a clinical syndrome is not justified by current data.

Efficacy of prone position in acute respiratory distress syndrome patients: A pathophysiology-based review

PubMed Central

Koulouras, Vasilios; Papathanakos, Georgios; Papathanasiou, Athanasios; Nakos, Georgios

2016-01-01

Acute respiratory distress syndrome (ARDS) is a syndrome with heterogeneous underlying pathological processes. It represents a common clinical problem in intensive care unit patients and it is characterized by high mortality. The mainstay of treatment for ARDS is lung protective ventilation with low tidal volumes and positive end-expiratory pressure sufficient for alveolar recruitment. Prone positioning is a supplementary strategy available in managing patients with ARDS. It was first described 40 years ago and it proves to be in alignment with two major ARDS pathophysiological lung models; the “sponge lung” - and the “shape matching” -model. Current evidence strongly supports that prone positioning has beneficial effects on gas exchange, respiratory mechanics, lung protection and hemodynamics as it redistributes transpulmonary pressure, stress and strain throughout the lung and unloads the right ventricle. The factors that individually influence the time course of alveolar recruitment and the improvement in oxygenation during prone positioning have not been well characterized. Although patients’ response to prone positioning is quite variable and hard to predict, large randomized trials and recent meta-analyses show that prone position in conjunction with a lung-protective strategy, when performed early and in sufficient duration, may improve survival in patients with ARDS. This pathophysiology-based review and recent clinical evidence strongly support the use of prone positioning in the early management of severe ARDS systematically and not as a rescue maneuver or a last-ditch effort. PMID:27152255

Towards anatomic scale agent-based modeling with a massively parallel spatially explicit general-purpose model of enteric tissue (SEGMEnT_HPC).

PubMed

Cockrell, Robert Chase; Christley, Scott; Chang, Eugene; An, Gary

2015-01-01

Perhaps the greatest challenge currently facing the biomedical research community is the ability to integrate highly detailed cellular and molecular mechanisms to represent clinical disease states as a pathway to engineer effective therapeutics. This is particularly evident in the representation of organ-level pathophysiology in terms of abnormal tissue structure, which, through histology, remains a mainstay in disease diagnosis and staging. As such, being able to generate anatomic scale simulations is a highly desirable goal. While computational limitations have previously constrained the size and scope of multi-scale computational models, advances in the capacity and availability of high-performance computing (HPC) resources have greatly expanded the ability of computational models of biological systems to achieve anatomic, clinically relevant scale. Diseases of the intestinal tract are exemplary examples of pathophysiological processes that manifest at multiple scales of spatial resolution, with structural abnormalities present at the microscopic, macroscopic and organ-levels. In this paper, we describe a novel, massively parallel computational model of the gut, the Spatially Explicitly General-purpose Model of Enteric Tissue_HPC (SEGMEnT_HPC), which extends an existing model of the gut epithelium, SEGMEnT, in order to create cell-for-cell anatomic scale simulations. We present an example implementation of SEGMEnT_HPC that simulates the pathogenesis of ileal pouchitis, and important clinical entity that affects patients following remedial surgery for ulcerative colitis.

The science and necessity of using animal models in the study of necrotizing enterocolitis.

PubMed

Ares, Guillermo J; McElroy, Steven J; Hunter, Catherine J

2018-02-01

Necrotizing enterocolitis (NEC) remains one of the highest causes of mortality and of acute and long-term morbidity in premature infants. Multiple factors are involved in the pathophysiology of NEC including the immaturity of the immune system and the complex changing composition of the intestinal microbiome. This is compounded by the fact that the premature infant should ideally still be a developing fetus and has an immature intestinal tract. Because these complexities are beyond the scope of studies in single-cell cultures, animal models are absolutely essential to understand the mechanisms involved in the pathophysiology of NEC and the effects of inflammation on the immature intestinal tract. To this end, investigators have utilized many different species (e.g., rats, mice, rabbits, quails, piglets, and non-human primates) and conditions to develop models of NEC. Each animal has distinct advantages and drawbacks related to its preterm viability, body size, genetic variability, and cost. The choice of animal model is strongly influenced by the scientific question being addressed. While no model perfectly mimics human NEC, each has greatly improved our understanding of disease. Examples of recent discoveries in NEC pathogenesis and prevention underscore the importance of continued animal research in NEC. Copyright © 2018 Elsevier Inc. All rights reserved.

Modeling the Pathophysiology of Phonotraumatic Vocal Hyperfunction With a Triangular Glottal Model of the Vocal Folds

PubMed Central

Galindo, Gabriel E.; Peterson, Sean D.; Erath, Byron D.; Castro, Christian; Hillman, Robert E.

2017-01-01

Purpose Our goal was to test prevailing assumptions about the underlying biomechanical and aeroacoustic mechanisms associated with phonotraumatic lesions of the vocal folds using a numerical lumped-element model of voice production. Method A numerical model with a triangular glottis, posterior glottal opening, and arytenoid posturing is proposed. Normal voice is altered by introducing various prephonatory configurations. Potential compensatory mechanisms (increased subglottal pressure, muscle activation, and supraglottal constriction) are adjusted to restore an acoustic target output through a control loop that mimics a simplified version of auditory feedback. Results The degree of incomplete glottal closure in both the membranous and posterior portions of the folds consistently leads to a reduction in sound pressure level, fundamental frequency, harmonic richness, and harmonics-to-noise ratio. The compensatory mechanisms lead to significantly increased vocal-fold collision forces, maximum flow-declination rate, and amplitude of unsteady flow, without significantly altering the acoustic output. Conclusion Modeling provided potentially important insights into the pathophysiology of phonotraumatic vocal hyperfunction by demonstrating that compensatory mechanisms can counteract deterioration in the voice acoustic signal due to incomplete glottal closure, but this also leads to high vocal-fold collision forces (reflected in aerodynamic measures), which significantly increases the risk of developing phonotrauma. PMID:28837719

miRwayDB: a database for experimentally validated microRNA-pathway associations in pathophysiological conditions

PubMed Central

Das, Sankha Subhra; Saha, Pritam

2018-01-01

Abstract MicroRNAs (miRNAs) are well-known as key regulators of diverse biological pathways. A series of experimental evidences have shown that abnormal miRNA expression profiles are responsible for various pathophysiological conditions by modulating genes in disease associated pathways. In spite of the rapid increase in research data confirming such associations, scientists still do not have access to a consolidated database offering these miRNA-pathway association details for critical diseases. We have developed miRwayDB, a database providing comprehensive information of experimentally validated miRNA-pathway associations in various pathophysiological conditions utilizing data collected from published literature. To the best of our knowledge, it is the first database that provides information about experimentally validated miRNA mediated pathway dysregulation as seen specifically in critical human diseases and hence indicative of a cause-and-effect relationship in most cases. The current version of miRwayDB collects an exhaustive list of miRNA-pathway association entries for 76 critical disease conditions by reviewing 663 published articles. Each database entry contains complete information on the name of the pathophysiological condition, associated miRNA(s), experimental sample type(s), regulation pattern (up/down) of miRNA, pathway association(s), targeted member of dysregulated pathway(s) and a brief description. In addition, miRwayDB provides miRNA, gene and pathway score to evaluate the role of a miRNA regulated pathways in various pathophysiological conditions. The database can also be used for other biomedical approaches such as validation of computational analysis, integrated analysis and prediction of computational model. It also offers a submission page to submit novel data from recently published studies. We believe that miRwayDB will be a useful tool for miRNA research community. Database URL: http://www.mirway.iitkgp.ac.in PMID:29688364

Flap preconditioning by pressure-controlled cupping in a rat model.

PubMed

Koh, Kyung S; Park, Sung Woo; Oh, Tae Suk; Choi, Jong Woo

2016-08-01

Flap survival is essential for the success of soft-tissue reconstruction. Accordingly, various surgical and medical methods aim to increase flap survival. Because flap survival is affected by the innate vascular supply, traditional preconditioning methods mainly target vasodilatation or vascular reorientation to increase blood flow to the tissue. External stress on the skin, such as an external volume expander or cupping, induces vascular remodeling, and these approaches have been used in the fat grafting field and in traditional Asian medicine. In the present study, we used a rat random-pattern dorsal flap model to study the effectiveness of preconditioning with an externally applied device (cupping) at the flap site that directly applied negative pressure to the skin. The device, the pressure-controlled cupping, is connected to negative pressure vacuum device providing accurate pressure control from 0 mm Hg to -200 mm Hg. Flap surgery was performed after preconditioning under -25 mm Hg suction pressure for 30 min a day for 5 d, followed by 9 d of postoperative observation. Flap survival was assessed as the area of viable tissue and was compared between the preconditioned group and a control group. The preconditioned group showed absolute percentage increase of flap viability relative to the entire flap by 19.0± 7.6% (average 70.1% versus 51.0%). Tissue perfusion of entire flap, evaluated by laser Doppler imaging system, was improved with absolute percentage increase by 24.2± 10.4% (average 77.4% versus 53.1%). Histologic analysis of hematoxylin and eosin, CD31, and Masson-trichrome staining showed increased vascular density in the subdermal plexus and more organized collagen production with hypertrophy of the attached muscle. Our study suggests that flap preconditioning caused by controlled noninvasive suction induces vascular remodeling that increases tissue perfusion and improves flap survival in a rat model. Copyright © 2016 Elsevier Inc. All rights reserved.

Oxidant Induced Changes in Mitochondria and Calcium Dynamicsin the Pathophysiology of Alzheimer's Disease

PubMed Central

Gibson, Gary E.; Karuppagounder, Saravanan S.; Shi, Qingli

2009-01-01

Considerable data supports the hypothesis that mitochondrial abnormalities link gene defects and/or environmental insults to the neurodegenerative process The interaction of oxidants with calcium and the mitochondrial enzymes of the tricarboxylic acid (TCA) cycle are central to that relationship. Abnormalities that were discovered in brains or fibroblasts from patients with Alzheimer's Disease (AD) have been modeled in vitro and in vivo to assess their pathophysiological importance and to determine how they might be reversed. The conclusions are consistent with the hypothesis that the AD-related abnormalities result from oxidative stress. The selection of compounds for reversal is complex because the actions of the relevant compounds vary under different conditions such as cell redox states and acute vs chronic changes. However, the models that have been developed are useful for testing the effectiveness of the potential medications. The results suggest that the reversal of the mitochondrial deficits and a reduction in oxidative stress will reduce the clinical and pathological changes and benefit patients. PMID:19076444

Modelling urea-cycle disorder citrullinemia type 1 with disease-specific iPSCs.

PubMed

Yoshitoshi-Uebayashi, Elena Yukie; Toyoda, Taro; Yasuda, Katsutaro; Kotaka, Maki; Nomoto, Keiko; Okita, Keisuke; Yasuchika, Kentaro; Okamoto, Shinya; Takubo, Noriyuki; Nishikubo, Toshiya; Soga, Tomoyoshi; Uemoto, Shinji; Osafune, Kenji

2017-05-06

Citrullinemia type 1 (CTLN1) is a urea cycle disorder (UCD) caused by mutations of the ASS1 gene, which is responsible for production of the enzyme argininosuccinate synthetase (ASS), and classically presented as life-threatening hyperammonemia in newborns. Therapeutic options are limited, and neurological sequelae may persist. To understand the pathophysiology and find novel treatments, induced pluripotent stem cells (iPSCs) were generated from a CTLN1 patient and differentiated into hepatocyte-like cells (HLCs). CTLN1-HLCs have lower ureagenesis, recapitulating part of the patient's phenotype. l-arginine, an amino acid clinically used for UCD treatment, improved this phenotype in vitro. Metabolome analysis revealed an increase in tricarboxylic acid (TCA) cycle metabolites in CTLN1, suggesting a connection between CTLN1 and the TCA cycle. This CTLN1-iPSC model improves the understanding of CTLN1 pathophysiology and can be used to pursue new therapeutic approaches. Copyright © 2017 Elsevier Inc. All rights reserved.

Current challenges and problems in teaching pathophysiology in Ukraine - another reaction to Churilov's paper.

PubMed

Ataman, Oleksandr V

2017-12-01

Pathophysiology in Ukraine has rich traditions and achievements in the scientific areas, as well as in teaching academic discipline. Its history, the main Ukrainian scientific schools and their famous representatives are briefly described. The content of existing study program, the main approaches to teaching, and some methodological and organizational problems needed to be solved are characterized. The necessity and usefulness of developing and implementing the three separate courses of discipline (Essential, Clinical and Advanced Pathophysiology) are substantiated. The place of Pathophysiology in the training of physicians with different kinds of their future activity is discussed. Relation of teaching Pathophysiology to Translational and Personalized Medicine is tried to be shown.

[Modeling of experimental hypertension by chronic salt loading combined with a low-protein diet in Wistar rats].

PubMed

Strekalova, V V; Khachirov, D G; Dedenkov, A N; Suvorov, Iu I; Shvatsabaia, I K

1989-01-01

Combination of chronic salt loading with protein-poor diet produces experimental hypertension with natrium consumption near to physiological. The present model is characterized, compared to the existing one, by stage development, moderate arterial blood pressure elevation and absence of "salt toxicosis" and may be thus considered more adequate for experimental investigation of primary arterial hypertension pathophysiology.

Dietary restrictions in healing among speakers of Iquito, an endangered language of the Peruvian Amazon

PubMed Central

2011-01-01

Background Ethnobotanical research was carried out with speakers of Iquito, a critically endangered Amazonian language of the Zaparoan family. The study focused on the concept of "dieting" (siyan++ni in Iquito), a practice involving prohibitions considered necessary to the healing process. These restrictions include: 1) foods and activities that can exacerbate illness, 2) environmental influences that conflict with some methods of healing (e.g. steam baths or enemas) and 3) foods and activities forbidden by the spirits of certain powerful medicinal plants. The study tested the following hypotheses: H1 - Each restriction will correlate with specific elements in illness explanatory models and H2 - Illnesses whose explanatory models have personalistic elements will show a greater number and variety of restrictions than those based on naturalistic reasoning. Methods The work was carried out in 2009 and 2010 in the Alto Nanay region of Peru. In structured interviews, informants gave explanatory models for illness categories, including etiologies, pathophysiologies, treatments and dietary restrictions necessary for 49 illnesses. Seventeen botanical vouchers for species said to have powerful spirits that require diets were also collected. Results All restrictions found correspond to some aspect of illness explanatory models. Thirty-five percent match up with specific illness etiologies, 53% correspond to particular pathophysiologies, 18% correspond with overall seriousness of the illness and 18% are only found with particular forms of treatment. Diets based on personalistic reasoning have a significantly higher average number of restrictions than those based on naturalistic reasoning. Conclusions Dieting plays a central role in healing among Iquito speakers. Specific prohibitions can be explained in terms of specific aspects of illness etiologies, pathophysiologies and treatments. Although the Amazonian literature contains few studies focusing on dietary proscriptions over a wide range of illnesses, some specific restrictions reported here do correspond with trends seen in other Amazonian societies, particularly those related to sympathetic reasoning and for magical and spiritual uses of plants. PMID:21745400

Dietary restrictions in healing among speakers of Iquito, an endangered language of the Peruvian Amazon.

PubMed

Jernigan, Kevin A

2011-07-11

Ethno botanical research was carried out with speakers of Iquitos, a critically endangered Amazonian language of the Zaparoan family. The study focused on the concept of "dieting" (siyan++ni in Iquitos), a practice involving prohibitions considered necessary to the healing process. These restrictions include: 1) foods and activities that can exacerbate illness, 2) environmental influences that conflict with some methods of healing (e.g. steam baths or enemas) and 3) foods and activities forbidden by the spirits of certain powerful medicinal plants. The study tested the following hypotheses: H1--Each restriction will correlate with specific elements in illness explanatory models and H2--Illnesses whose explanatory models have personality elements will show a greater number and variety of restrictions than those based on naturalistic reasoning. The work was carried out in 2009 and 2010 in the Alto Nanay region of Peru. In structured interviews, informants gave explanatory models for illness categories, including etiologies, pathophysiologies, treatments and dietary restrictions necessary for 49 illnesses. Seventeen botanical vouchers for species said to have powerful spirits that require diets were also collected. All restrictions found correspond to some aspect of illness explanatory models. Thirty-five percent match up with specific illness etiologies, 53% correspond to particular pathophysiologies, 18% correspond with overall seriousness of the illness and 18% are only found with particular forms of treatment. Diets based on personalistic reasoning have a significantly higher average number of restrictions than those based on naturalistic reasoning. Dieting plays a central role in healing among Iquitos speakers. Specific prohibitions can be explained in terms of specific aspects of illness etiologies, pathophysiologies and treatments. Although the Amazonian literature contains few studies focusing on dietary proscriptions over a wide range of illnesses, some specific restrictions reported here do correspond with trends seen in other Amazonian societies, particularly those related to sympathetic reasoning and for magical and spiritual uses of plants.

The pathophysiology of delayed ejaculation

PubMed Central

2016-01-01

Delayed ejaculation (DE) is probably least studied, and least understood of male sexual dysfunctions, with an estimated prevalence of 1–4% of the male population. Pathophysiology of DE is multifactorial and including psychosexual-behavioral and cultural factors, disruption of ejaculatory apparatus, central and peripheral neurotransmitters, hormonal or neurochemical ejaculatory control and psychosocial factors. Although knowledge of the physiology of the DE has increased in the last two decade, our understanding of the different pathophysiological process of the causes of DE remains limited. To provide a systematic update on the pathophysiology of DE. A systematic review of Medline and PubMed for relevant publications on ejaculatory dysfunction (EjD), DE, retarded ejaculation, inhibited ejaculation, and climax was performed. The search was limited to the articles published between the January 1960 and December 2015 in English. Of 178 articles, 105 were selected for this review. Only those publications relevant to the pathophysiology, epidemiology and prevalence of DE were included. The pathophysiology of DE involves cerebral sensory areas, motor centers, and several spinal nuclei that are tightly interconnected. The biogenic, psychogenic and other factors strongly affect the pathophysiology of DE. Despite the many publications on this disorder, there still is a paucity of publications dedicated to the subject. PMID:27652227

Animal models of asthma: utility and limitations.

PubMed

Aun, Marcelo Vivolo; Bonamichi-Santos, Rafael; Arantes-Costa, Fernanda Magalhães; Kalil, Jorge; Giavina-Bianchi, Pedro

2017-01-01

Clinical studies in asthma are not able to clear up all aspects of disease pathophysiology. Animal models have been developed to better understand these mechanisms and to evaluate both safety and efficacy of therapies before starting clinical trials. Several species of animals have been used in experimental models of asthma, such as Drosophila , rats, guinea pigs, cats, dogs, pigs, primates and equines. However, the most common species studied in the last two decades is mice, particularly BALB/c. Animal models of asthma try to mimic the pathophysiology of human disease. They classically include two phases: sensitization and challenge. Sensitization is traditionally performed by intraperitoneal and subcutaneous routes, but intranasal instillation of allergens has been increasingly used because human asthma is induced by inhalation of allergens. Challenges with allergens are performed through aerosol, intranasal or intratracheal instillation. However, few studies have compared different routes of sensitization and challenge. The causative allergen is another important issue in developing a good animal model. Despite being more traditional and leading to intense inflammation, ovalbumin has been replaced by aeroallergens, such as house dust mites, to use the allergens that cause human disease. Finally, researchers should define outcomes to be evaluated, such as serum-specific antibodies, airway hyperresponsiveness, inflammation and remodeling. The present review analyzes the animal models of asthma, assessing differences between species, allergens and routes of allergen administration.

An introductory characterization of a combat-casualty-care relevant swine model of closed head injury resulting from exposure to explosive blast.

PubMed

Bauman, Richard A; Ling, Geoffrey; Tong, Lawrence; Januszkiewicz, Adolph; Agoston, Dennis; Delanerolle, Nihal; Kim, Young; Ritzel, Dave; Bell, Randy; Ecklund, James; Armonda, Rocco; Bandak, Faris; Parks, Steven

2009-06-01

Explosive blast has been extensively used as a tactical weapon in Operation Iraqi Freedom (OIF) and more recently in Operation Enduring Freedom(OEF). The polytraumatic nature of blast injuries is evidence of their effectiveness,and brain injury is a frequent and debilitating form of this trauma. In-theater clinical observations of brain-injured casualties have shown that edema, intracranial hemorrhage, and vasospasm are the most salient pathophysiological characteristics of blast injury to the brain. Unfortunately, little is known about exactly how an explosion produces these sequelae as well as others that are less well documented. Consequently, the principal objective of the current report is to present a swine model of explosive blast injury to the brain. This model was developed during Phase I of the DARPA (Defense Advanced Research Projects Agency) PREVENT (Preventing Violent Explosive Neurotrauma) blast research program. A second objective is to present data that illustrate the capabilities of this model to study the proximal biomechanical causes and the resulting pathophysiological, biochemical,neuropathological, and neurological consequences of explosive blast injury to the swine brain. In the concluding section of this article, the advantages and limitations of the model are considered, explosive and air-overpressure models are compared, and the physical properties of an explosion are identified that potentially contributed to the in-theater closed head injuries resulting from explosions of improvised explosive devices (IEDs).

Modeling and Theories of Pathophysiology and Physiology of the Basal Ganglia–Thalamic–Cortical System: Critical Analysis

PubMed Central

Montgomery Jr., Erwin B.

2016-01-01

Theories impact the movement disorders clinic, not only affecting the development of new therapies but determining how current therapies are used. Models are theories that are procedural rather than declarative. Theories and models are important because, as argued by Kant, one cannot know the thing-in-itself (das Ding an sich) and only a model is knowable. Further, biological variability forces higher level abstraction relevant for all variants. It is that abstraction that is raison d’être of theories and models. Theories “connect the dots” to move from correlation to causation. The necessity of theory makes theories helpful or counterproductive. Theories and models of the pathophysiology and physiology of the basal ganglia–thalamic–cortical system do not spontaneously arise but have a history and consequently are legacies. Over the last 40 years, numerous theories and models of the basal ganglia have been proposed only to be forgotten or dismissed, rarely critiqued. It is not harsh to say that current popular theories positing increased neuronal activities in the Globus Pallidus Interna (GPi), excessive beta oscillations and increased synchronization not only fail to provide an adequate explication but are inconsistent with many observations. It is likely that their shared intellectual and epistemic inheritance plays a factor in their shared failures. These issues are critically examined. How one is to derive theories and models and have hope these will be better is explored as well. PMID:27708569

Animal models of gastrointestinal and liver diseases. Animal models of acute and chronic pancreatitis

PubMed Central

Zhan, Xianbao; Wang, Fan; Bi, Yan

2016-01-01

Animal models of pancreatitis are useful for elucidating the pathogenesis of pancreatitis and developing and testing novel interventions. In this review, we aim to summarize the most commonly used animal models, overview their pathophysiology, and discuss their strengths and limitations. We will also briefly describe common animal study procedures and refer readers to more detailed protocols in the literature. Although animal models include pigs, dogs, opossums, and other animals, we will mainly focus on rodent models because of their popularity. Autoimmune pancreatitis and genetically engineered animal models will be reviewed elsewhere. PMID:27418683

Activation of UCPs gene expression in skeletal muscle can be independent on both circulating fatty acids and food intake. Involvement of ROS in a model of mouse cancer cachexia.

PubMed

Busquets, Sílvia; Almendro, Vanessa; Barreiro, Esther; Figueras, Maite; Argilés, Josep M; López-Soriano, Francisco J

2005-01-31

Implantation of a fast growing tumour to mice (Lewis lung carcinoma) resulted in a clear cachectic state characterized by a profound muscle wasting. This was accompanied by a significant increase in both UCP2 and UCP3 gene expression in skeletal muscle and heart. Interestingly, this increase in gene expression was not linked to a rise in circulating fatty acids or in a decrease in food intake, as previously reported in other pathophysiological states. These results question the concept that hyperlipaemia is the only factor controlling UCP gene expression in different pathophysiological conditions. In addition, the present work suggests that UCPs might participate in a counter-regulatory mechanism to lower the production of ROS.

Pathophysiology and Treatment of Memory Dysfunction after Traumatic Brain Injury

PubMed Central

Paterno, Rosalia; Folweiler, Kaitlin A.; Cohen, Akiva S.

2018-01-01

Memory is fundamental to everyday life, and cognitive impairments resulting from traumatic brain injury (TBI) have devastating effects on TBI survivors. A contributing component to memory impairments caused by TBI are alterations in the neural circuits associated with memory function. In this review, we aim to bring together experimental findings that characterize behavioral memory deficits and the underlying pathophysiology of memory-involved circuits after TBI. While there is little doubt that TBI causes memory and cognitive dysfunction, it is difficult to conclude which memory phase i.e., encoding, maintenance or retrieval is specifically altered by TBI. This is most likely due to variation in behavioral protocols and experimental models. Additionally we review a selection of experimental treatments that hold translational potential to mitigate memory dysfunction following injury. PMID:28500417

Pathophysiology 220.

ERIC Educational Resources Information Center

Smith, Lori

A description is provided of a course, "Pathophysiology 220," designed to provide junior nursing students at the University of Michigan's School of Nursing with theoretical knowledge of a broad range of pathophysiological conditions. Section I discusses the place of the course in the curriculum, the allotment of class time, course requirements,…

Heatstroke Pathophysiology: The Energy Depletion Model

DTIC Science & Technology

1989-06-12

likely explanation (19) for the net loss of K+ from working muscle and the hyperkalemia seen during exercise (83). Sejersted (77) has made an important...31 50. Kreisberg, R.A., L.F. Pennington, and B.R. Boshell. Lactate turnover and gluconeogenesis in normal and obese humans. Diabetes 19:53-63, 1970

Trauma is Danger

DTIC Science & Technology

2011-01-01

self interactions and thereby neglect most traumatic injuries , the Danger model abandons this classical concept [ 2 ]. The Danger model theorizes that...June 2011 References 1. Keel M, Trentz O: Pathophysiology of polytrauma. Injury 2005, 36:691-709. 2 . Matzinger P: Tolerance, danger, and the extended... ischemia - reperfusion . J Exp Med 2005, 201:1135-1143. 27. Huang LF, Yao YM, Zhang LT, Dong N, Yu Y, Sheng ZY: The effect of high- mobility group box 1

Cellular and Animal Studies: Insights into Pathophysiology and Therapy of PCOS.

PubMed

Indran, Inthrani Raja; Lee, Bao Hui; Yong, Eu-Leong

2016-11-01

Basic science studies have advanced our understanding of the role of key enzymes in the steroidogenesis pathway and those that affect the pathophysiology of PCOS. Studies with ovarian theca cells taken from women with PCOS have demonstrated increased androgen production due to increased CYP17A1 and HSD3B2 enzyme activities. Furthermore, overexpression of DENND1A variant 2 in normal theca cells resulted in a PCOS phenotype with increased androgen production. Notably, cellular steroidogenesis models have facilitated the understanding of the mechanistic effects of pharmacotherapies, including insulin sensitizers (e.g., pioglitazone and metformin) used for the treatment of insulin resistance in PCOS, on androgen production. In addition, animal models of PCOS have provided a critical platform to study the effects of therapeutic agents in a manner closer to the physiological state. Indeed, recent breakthroughs have demonstrated that natural derivatives such as the dietary medium-chain fatty acid decanoic acid (DA) can restore estrous cyclicity and lower androgen levels in an animal model of PCOS, thus laying the platform for novel therapeutic developments in PCOS. This chapter reviews the current understanding on the pathways modulating androgen biosynthesis, and the cellular and animal models that form the basis for preclinical research in PCOS, and sets the stage for clinical research. Copyright © 2016. Published by Elsevier Ltd.

Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia

PubMed Central

Jaunarajs, K.L. Eskow; Bonsi, P.; Chesselet, M.F.; Standaert, D.G.; Pisani, A.

2015-01-01

Dystonia is a movement disorder of both genetic and non-genetic causes, which typically results in twisted posturing due to abnormal muscle contraction. Evidence from dystonia patients and animal models of dystonia indicate a crucial role for the striatal cholinergic system in the pathophysiology of dystonia. In this review, we focus on striatal circuitry and the centrality of the acetylcholine system in the function of the basal ganglia in the control of voluntary movement and ultimately clinical manifestion of movement disorders. We consider the impact of cholinergic interneurons (ChIs) on dopamine-acetylcholine interactions and examine new evidence for impairment of ChIs in dysfunction of the motor systems producing dystonic movements, particularly in animal models. We have observed paradoxical excitation of ChIs in the presence of dopamine D2 receptor agonists and impairment of striatal synaptic plasticity in a mouse model of DYT1 dystonia, which are improved by administration of recently developed M1 receptor antagonists. These findings have been confirmed across multiple animal models of DYT1 dystonia and may represent a common endophenotype by which to investigate dystonia induced by other types of genetic and non-genetic causes and to investigate the potential effectiveness of pharmacotherapeutics and other strategies to improve dystonia. PMID:25697043

Animal Models of Bipolar Mania: The Past, Present and Future

PubMed Central

Logan, Ryan W.; McClung, Colleen A.

2015-01-01

Bipolar disorder (BD) is the sixth leading cause of disability in the world according to the World Health Organization and affects nearly 6 million (~2.5% of the population) adults in the United State alone each year. BD is primarily characterized by mood cycling of depressive (e.g., helplessness, reduced energy and activity, and anhedonia) and manic (e.g., increased energy and hyperactivity, reduced need for sleep, impulsivity, reduced anxiety and depression), episodes. The following review describes several animal models of bipolar mania with a focus on more recent findings using genetically modified mice, including several with the potential of investigating the mechanisms underlying ‘mood’ cycling (or behavioral switching in rodents). We discuss whether each of these models satisfy criteria of validity (i.e., face, predictive, and construct), while highlighting their strengths and limitations. Animal models are helping to address critical questions related to pathophysiology of bipolar mania, in an effort to more clearly define necessary targets of first-line medications, lithium and valproic acid, and to discover novel mechanisms with the hope of developing more effective therapeutics. Future studies will leverage new technologies and strategies for integrating animal and human data to reveal important insights into the etiology, pathophysiology, and treatment of BD. PMID:26314632

A critical appraisal of experimental intracerebral hemorrhage research

PubMed Central

MacLellan, Crystal L; Paquette, Rosalie; Colbourne, Frederick

2012-01-01

The likelihood of translating therapeutic interventions for stroke rests on the quality of preclinical science. Given the limited success of putative treatments for ischemic stroke and the reasons put forth to explain it, we sought to determine whether such problems hamper progress for intracerebral hemorrhage (ICH). Approximately 10% to 20% of strokes result from an ICH, which results in considerable disability and high mortality. Several animal models reproduce ICH and its underlying pathophysiology, and these models have been widely used to evaluate treatments. As yet, however, none has successfully translated. In this review, we focus on rodent models of ICH, highlighting differences among them (e.g., pathophysiology), issues with experimental design and analysis, and choice of end points. A Pub Med search for experimental ICH (years: 2007 to 31 July 2011) found 121 papers. Of these, 84% tested neuroprotectants, 11% tested stem cell therapies, and 5% tested rehabilitation therapies. We reviewed these to examine study quality (e.g., use of blinding procedures) and choice of end points (e.g., behavioral testing). Not surprisingly, the problems that have plagued the ischemia field are also prevalent in ICH literature. Based on these data, several recommendations are put forth to facilitate progress in identifying effective treatments for ICH. PMID:22293989

The pathophysiology of human obstructive cholestasis is mimicked in cholestatic Gold Syrian hamsters.

PubMed

van Golen, Rowan F; Olthof, Pim B; de Haan, Lianne R; Coelen, Robert J; Pechlivanis, Alexandros; de Keijzer, Mark J; Weijer, Ruud; de Waart, Dirk R; van Kuilenburg, André B P; Roelofsen, Jeroen; Gilijamse, Pim W; Maas, Martinus A; Lewis, Matthew R; Nicholson, Jeremy K; Verheij, Joanne; Heger, Michal

2018-03-01

Obstructive cholestasis causes liver injury via accumulation of toxic bile acids (BAs). Therapeutic options for cholestatic liver disease are limited, partially because the available murine disease models lack translational value. Profiling of time-related changes following bile duct ligation (BDL) in Gold Syrian hamsters revealed a biochemical response similar to cholestatic patients in terms of BA pool composition, alterations in hepatocyte BA transport and signaling, suppression of BA production, and adapted BA metabolism. Hamsters tolerated cholestasis well for up to 28days and progressed relatively slowly to fibrotic liver injury. Hepatocellular necrosis was absent, which coincided with preserved intrahepatic energy levels and only mild oxidative stress. The histological response to cholestasis in hamsters was similar to the changes seen in 17 patients with prolonged obstructive cholestasis caused by cholangiocarcinoma. Hamsters moreover upregulated hepatic fibroblast growth factor 15 (Fgf15) expression in response to BDL, which is a cytoprotective adaptation to cholestasis that hitherto had only been documented in cholestatic human livers. Hamster models should therefore be added to the repertoire of animal models used to study the pathophysiology of cholestatic liver disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Central Sensitivity Syndromes: Mounting Pathophysiologic Evidence to Link Fibromyalgia with other Common Chronic Pain Disorders

PubMed Central

Kindler, Lindsay L.; Bennett, Robert M.; Jones, Kim D.

2009-01-01

Objective To review emerging data from the fields of nursing, rheumatology, dentistry, gastroenterology, gynecology, neurology, and orthopedics that supports or disputes pathophysiologic similarities in pain syndromes studied by each specialty. Methods A literature search was performed through PubMed and Ovid using the terms fibromyalgia, temporomandibular joint disorder, irritable bowel syndrome, irritable bladder/interstitial cystitis, headache, chronic low back pain, chronic neck pain, functional syndromes and somatization. Each term was linked with pathophysiology and/or central sensitization. This paper presents a review of relevant articles with a specific goal of identifying pathophysiological findings related to nociceptive processing. Results The extant literature presents considerable overlap in the pathophysiology of these diagnoses. Given the psychosomatic lens through which many of these disorders are viewed, demonstration of evidence based links supporting shared pathophysiology between these disorders could provide direction to clinicians and researchers working to treat these diagnoses. Conclusions Central sensitivity syndromes denotes an emerging nomenclature that could be embraced by researchers investigating each of these disorders. Moreover, a shared paradigm would be useful in promoting cross-fertilization between researchers. Scientists and clinicians could most effectively forward the understanding and treatment of fibromyalgia and other common chronic pain disorders through an appreciation of their shared pathophysiology. PMID:21349445

Detrusor after-contraction: a new insight.

PubMed

Valentini, Francoise A; Marti, Brigitte G; Robain, Gilberte; Nelson, Pierre P

2015-01-01

Detrusor after-contractions (DAC) are non-common in adults. Both definition (nothing in ICS reports) and significance (artefact, link with detrusor overactivity (DO) or bladder outlet obstruction (BOO)) remain discussed. Our purpose was to carry out an analysis of the urodynamic parameters during voidings with DAC and, using the VBN model, to simulate pathophysiological conditions able to explain both voiding phase and DAC. From large urodynamic database of patients referred for evaluation of lower urinary tract dysfunction, DAC were observed in 60 patients (5.7%). Criteria for DAC were post-void residual <30mL and increase of detrusor pressure >10cmH(2)O. VBN model was used for analysis of both pressure and flow curves, and simulations of pathophysiological conditions. Onset of DAC (ODAC) occurred when Q=7.3±5.7mL/s and bladder volume=17.9±15.4mL. Urgency-frequency syndrome and urodynamic diagnosis of DO were the more frequent scenarios associated with DAC. ODAC was associated to an inversion of the slope of detrusor pressure curve without any perturbation in flow curve. Among tested pathophysiological hypothesis (great, abnormal, detrusor force, sphincter contraction), none allowed restoring all recorded curves (flow rate, voiding pressure and DAC). No urodynamic characteristic of the first part of voiding is an index of occurrence of DAC. ODAC is a significant phenomenon linked with the bladder collapse. DAC is not associated with BOO but more probably with DO and appears as the result of local conditions in an almost empty bladder (concentration of stresses around a transducer); thus DAC seems of weak clinical significance.

IL-22/STAT3-Induced Increases in SLURP1 Expression within Psoriatic Lesions Exerts Antimicrobial Effects against Staphylococcus aureus.

PubMed

Moriwaki, Yasuhiro; Takada, Kiyoko; Nagasaki, Toshinori; Kubo, Natsuki; Ishii, Tomohiro; Kose, Kazuaki; Kageyama, Taihei; Tsuji, Shoutaro; Kawashima, Koichiro; Misawa, Hidemi

2015-01-01

SLURP1 is the causal gene for Mal de Meleda (MDM), an autosomal recessive skin disorder characterized by diffuse palmoplantar keratoderma and transgressive keratosis. Moreover, although SLURP1 likely serves as an important proliferation/differentiation factor in keratinocytes, the possible relation between SLURP1 and other skin diseases, such as psoriasis and atopic dermatitis, has not been studied, and the pathophysiological control of SLURP1 expression in keratinocytes is largely unknown. Our aim was to examine the involvement of SLURP1 in the pathophysiology of psoriasis using an imiquimod (IMQ)-induced psoriasis model mice and normal human epidermal keratinocytes (NHEKs). SLURP1 expression was up-regulated in the skin of IMQ-induced psoriasis model mice. In NHEKs stimulated with the inflammatory cytokines IL-17, IL-22 and TNF-α, which are reportedly expressed in psoriatic lesions, SLURP1 mRNA expression was significantly up-regulated by IL-22 but not the other two cytokines. The stimulatory effect of IL-22 was completely suppressed in NHEKs treated with a STAT3 inhibitor or transfected with siRNA targeting STAT3. Because IL-22 induces production of antimicrobial proteins in epithelial cells, the antibacterial activity of SLURP1 was assessed against Staphylococcus aureus (S. aureus), which is known to be associated with disease severity in psoriasis. SLURP1 significantly suppressed the growth of S. aureus. These results indicate SLURP1 participates in pathophysiology of psoriasis by regulating keratinocyte proliferation and differentiation, and by suppressing the growth of S. aureus.

Liver protein profiles in insulin receptor-knockout mice reveal novel molecules involved in the diabetes pathophysiology.

PubMed

Capuani, Barbara; Della-Morte, David; Donadel, Giulia; Caratelli, Sara; Bova, Luca; Pastore, Donatella; De Canio, Michele; D'Aguanno, Simona; Coppola, Andrea; Pacifici, Francesca; Arriga, Roberto; Bellia, Alfonso; Ferrelli, Francesca; Tesauro, Manfredi; Federici, Massimo; Neri, Anna; Bernardini, Sergio; Sbraccia, Paolo; Di Daniele, Nicola; Sconocchia, Giuseppe; Orlandi, Augusto; Urbani, Andrea; Lauro, Davide

2015-05-01

Liver has a principal role in glucose regulation and lipids homeostasis. It is under a complex control by substrates such as hormones, nutrients, and neuronal impulses. Insulin promotes glycogen synthesis, lipogenesis, and lipoprotein synthesis and inhibits gluconeogenesis, glycogenolysis, and VLDL secretion by modifying the expression and enzymatic activity of specific molecules. To understand the pathophysiological mechanisms leading to metabolic liver disease, we analyzed liver protein patterns expressed in a mouse model of diabetes by proteomic approaches. We used insulin receptor-knockout (IR(-/-)) and heterozygous (IR(+/-)) mice as a murine model of liver metabolic dysfunction associated with diabetic ketoacidosis and insulin resistance. We evaluated liver fatty acid levels by microscopic examination and protein expression profiles by orthogonal experimental strategies using protein 2-DE MALDI-TOF/TOF and peptic nLC-MS/MS shotgun profiling. Identified proteins were then loaded into Ingenuity Pathways Analysis to find possible molecular networks. Twenty-eight proteins identified by 2-DE analysis and 24 identified by nLC-MS/MS shotgun were differentially expressed among the three genotypes. Bioinformatic analysis revealed a central role of high-mobility group box 1/2 and huntigtin never reported before in association with metabolic and related liver disease. A different modulation of these proteins in both blood and hepatic tissue further suggests their role in these processes. These results provide new insight into pathophysiology of insulin resistance and hepatic steatosis and could be useful in identifying novel biomarkers to predict risk for diabetes and its complications. Copyright © 2015 the American Physiological Society.

Pathophysiological Bases of Comorbidity: Traumatic Brain Injury and Post-Traumatic Stress Disorder.

PubMed

Kaplan, Gary B; Leite-Morris, Kimberly A; Wang, Lei; Rumbika, Kendra K; Heinrichs, Stephen C; Zeng, Xiang; Wu, Liquan; Arena, Danielle T; Teng, Yang D

2018-01-15

The high rates of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) diagnoses encountered in recent years by the United States Veterans Affairs Healthcare System have increased public awareness and research investigation into these conditions. In this review, we analyze the neural mechanisms underlying the TBI/PTSD comorbidity. TBI and PTSD present with common neuropsychiatric symptoms including anxiety, irritability, insomnia, personality changes, and memory problems, and this overlap complicates diagnostic differentiation. Interestingly, both TBI and PTSD can be produced by overlapping pathophysiological changes that disrupt neural connections termed the "connectome." The neural disruptions shared by PTSD and TBI and the comorbid condition include asymmetrical white matter tract abnormalities and gray matter changes in the basolateral amygdala, hippocampus, and prefrontal cortex. These neural circuitry dysfunctions result in behavioral changes that include executive function and memory impairments, fear retention, fear extinction deficiencies, and other disturbances. Pathophysiological etiologies can be identified using experimental models of TBI, such as fluid percussion or blast injuries, and for PTSD, using models of fear conditioning, retention, and extinction. In both TBI and PTSD, there are discernible signs of neuroinflammation, excitotoxicity, and oxidative damage. These disturbances produce neuronal death and degeneration, axonal injury, and dendritic spine dysregulation and changes in neuronal morphology. In laboratory studies, various forms of pharmacological or psychological treatments are capable of reversing these detrimental processes and promoting axonal repair, dendritic remodeling, and neurocircuitry reorganization, resulting in behavioral and cognitive functional enhancements. Based on these mechanisms, novel neurorestorative therapeutics using anti-inflammatory, antioxidant, and anticonvulsant agents may promote better outcomes for comorbid TBI and PTSD.

Fragile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development.

PubMed

Pop, Andreea S; Gomez-Mancilla, Baltazar; Neri, Giovanni; Willemsen, Rob; Gasparini, Fabrizio

2014-03-01

Fragile X syndrome (FXS) is considered the leading inherited cause of intellectual disability and autism. In FXS, the fragile X mental retardation 1 (FMR1) gene is silenced and the fragile X mental retardation protein (FMRP) is not expressed, resulting in the characteristic features of the syndrome. Despite recent advances in understanding the pathophysiology of FXS, there is still no cure for this condition; current treatment is symptomatic. Preclinical research is essential in the development of potential therapeutic agents. This review provides an overview of the preclinical evidence supporting metabotropic glutamate receptor 5 (mGluR5) antagonists as therapeutic agents for FXS. According to the mGluR theory of FXS, the absence of FMRP leads to enhanced glutamatergic signaling via mGluR5, which leads to increased protein synthesis and defects in synaptic plasticity including enhanced long-term depression. As such, efforts to develop agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. Animal models, particularly the Fmr1 knockout mouse model, have become invaluable in exploring therapeutic approaches on an electrophysiological, behavioral, biochemical, and neuroanatomical level. Two direct approaches are currently being investigated for FXS treatment: reactivating the FMR1 gene and compensating for the lack of FMRP. The latter approach has yielded promising results, with mGluR5 antagonists showing efficacy in clinical trials. Targeting mGluR5 is a valid approach for the development of therapeutic agents that target the underlying pathophysiology of FXS. Several compounds are currently in development, with encouraging results.

Addressing the Complexity of Tourette's Syndrome through the Use of Animal Models

PubMed Central

Nespoli, Ester; Rizzo, Francesca; Boeckers, Tobias M.; Hengerer, Bastian; Ludolph, Andrea G.

2016-01-01

Tourette's syndrome (TS) is a neurodevelopmental disorder characterized by fluctuating motor and vocal tics, usually preceded by sensory premonitions, called premonitory urges. Besides tics, the vast majority—up to 90%—of TS patients suffer from psychiatric comorbidities, mainly attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). The etiology of TS remains elusive. Genetics is believed to play an important role, but it is clear that other factors contribute to TS, possibly altering brain functioning and architecture during a sensitive phase of neural development. Clinical brain imaging and genetic studies have contributed to elucidate TS pathophysiology and disease mechanisms; however, TS disease etiology still is poorly understood. Findings from genetic studies led to the development of genetic animal models, but they poorly reflect the pathophysiology of TS. Addressing the role of neurotransmission, brain regions, and brain circuits in TS disease pathomechanisms is another focus area for preclinical TS model development. We are now in an interesting moment in time when numerous innovative animal models are continuously brought to the attention of the public. Due to the diverse and largely unknown etiology of TS, there is no single preclinical model featuring all different aspects of TS symptomatology. TS has been dissected into its key symptomst hat have been investigated separately, in line with the Research Domain Criteria concept. The different rationales used to develop the respective animal models are critically reviewed, to discuss the potential of the contribution of animal models to elucidate TS disease mechanisms. PMID:27092043

Towards Anatomic Scale Agent-Based Modeling with a Massively Parallel Spatially Explicit General-Purpose Model of Enteric Tissue (SEGMEnT_HPC)

PubMed Central

Cockrell, Robert Chase; Christley, Scott; Chang, Eugene; An, Gary

2015-01-01

Perhaps the greatest challenge currently facing the biomedical research community is the ability to integrate highly detailed cellular and molecular mechanisms to represent clinical disease states as a pathway to engineer effective therapeutics. This is particularly evident in the representation of organ-level pathophysiology in terms of abnormal tissue structure, which, through histology, remains a mainstay in disease diagnosis and staging. As such, being able to generate anatomic scale simulations is a highly desirable goal. While computational limitations have previously constrained the size and scope of multi-scale computational models, advances in the capacity and availability of high-performance computing (HPC) resources have greatly expanded the ability of computational models of biological systems to achieve anatomic, clinically relevant scale. Diseases of the intestinal tract are exemplary examples of pathophysiological processes that manifest at multiple scales of spatial resolution, with structural abnormalities present at the microscopic, macroscopic and organ-levels. In this paper, we describe a novel, massively parallel computational model of the gut, the Spatially Explicitly General-purpose Model of Enteric Tissue_HPC (SEGMEnT_HPC), which extends an existing model of the gut epithelium, SEGMEnT, in order to create cell-for-cell anatomic scale simulations. We present an example implementation of SEGMEnT_HPC that simulates the pathogenesis of ileal pouchitis, and important clinical entity that affects patients following remedial surgery for ulcerative colitis. PMID:25806784

Pharmacological and Physiological Characterization of the Tremulous Jaw Movement Model of Parkinsonian Tremor: Potential Insights into the Pathophysiology of Tremor

PubMed Central

Collins-Praino, Lyndsey E.; Paul, Nicholas E.; Rychalsky, Kristen L.; Hinman, James R.; Chrobak, James J.; Senatus, Patrick B.; Salamone, John D.

2011-01-01

Tremor is a cardinal symptom of parkinsonism, occurring early on in the disease course and affecting more than 70% of patients. Parkinsonian resting tremor occurs in a frequency range of 3–7 Hz and can be resistant to available pharmacotherapy. Despite its prevalence, and the significant decrease in quality of life associated with it, the pathophysiology of parkinsonian tremor is poorly understood. The tremulous jaw movement (TJM) model is an extensively validated rodent model of tremor. TJMs are induced by conditions that also lead to parkinsonism in humans (i.e., striatal DA depletion, DA antagonism, and cholinomimetic activity) and reversed by several antiparkinsonian drugs (i.e., DA precursors, DA agonists, anticholinergics, and adenosine A2A antagonists). TJMs occur in the same 3–7 Hz frequency range seen in parkinsonian resting tremor, a range distinct from that of dyskinesia (1–2 Hz), and postural tremor (8–14 Hz). Overall, these drug-induced TJMs share many characteristics with human parkinsonian tremor, but do not closely resemble tardive dyskinesia. The current review discusses recent advances in the validation of the TJM model, and illustrates how this model is being used to develop novel therapeutic strategies, both surgical and pharmacological, for the treatment of parkinsonian resting tremor. PMID:21772815

Catamenial Epilepsy: Discovery of an Extrasynaptic Molecular Mechanism for Targeted Therapy.

PubMed

Reddy, Doodipala Samba

2016-01-01

Catamenial epilepsy is a type of refractory epilepsy characterized by seizure clusters around perimenstrual or periovulatory period. The pathophysiology of catamenial epilepsy still remains unclear, yet there are few animal models to study this gender-specific disorder. The pathophysiology of perimenstrual catamenial epilepsy involves the withdrawal of the progesterone-derived GABAergic neurosteroids due to the decline in progesterone level at the time of menstruation. These manifestations can be faithfully reproduced in rodents by specific neuroendocrine manipulations. Since mice and rats, like humans, have ovarian cycles with circulating hormones, they appear to be suitable animal models for studies of perimenstrual seizures. Recently, we created specific experimental models to mimic perimenstrual seizures. Studies in rat and mouse models of catamenial epilepsy show enhanced susceptibility to seizures or increased seizure exacerbations following neurosteroid withdrawal. During such a seizure exacerbation period, there is a striking decrease in the anticonvulsant effect of commonly prescribed antiepileptics, such as benzodiazepines, but an increase in the anticonvulsant potency of exogenous neurosteroids. We discovered an extrasynaptic molecular mechanism of catamenial epilepsy. In essence, extrasynaptic δGABA-A receptors are upregulated during perimenstrual-like neuroendocrine milieu. Consequently, there is enhanced antiseizure efficacy of neurosteroids in catamenial models because δGABA-A receptors confer neurosteroid sensitivity and greater seizure protection. Molecular mechanisms such as these offer a strong rationale for the clinical development of a neurosteroid replacement therapy for catamenial epilepsy.

An in vitro model of murine middle ear epithelium.

PubMed

Mulay, Apoorva; Akram, Khondoker M; Williams, Debbie; Armes, Hannah; Russell, Catherine; Hood, Derek; Armstrong, Stuart; Stewart, James P; Brown, Steve D M; Bingle, Lynne; Bingle, Colin D

2016-11-01

Otitis media (OM), or middle ear inflammation, is the most common paediatric disease and leads to significant morbidity. Although understanding of underlying disease mechanisms is hampered by complex pathophysiology it is clear that epithelial abnormalities underpin the disease. There is currently a lack of a well-characterised in vitro model of the middle ear (ME) epithelium that replicates the complex cellular composition of the middle ear. Here, we report the development of a novel in vitro model of mouse middle ear epithelial cells (mMECs) at an air-liquid interface (ALI) that recapitulates the characteristics of the native murine ME epithelium. We demonstrate that mMECs undergo differentiation into the varied cell populations seen within the native middle ear. Proteomic analysis confirmed that the cultures secrete a multitude of innate defence proteins from their apical surface. We showed that the mMECs supported the growth of the otopathogen, nontypeable Haemophilus influenzae (NTHi), suggesting that the model can be successfully utilised to study host-pathogen interactions in the middle ear. Overall, our mMEC culture system can help to better understand the cell biology of the middle ear and improve our understanding of the pathophysiology of OM. The model also has the potential to serve as a platform for validation of treatments designed to reverse aspects of epithelial remodelling that underpin OM development. © 2016. Published by The Company of Biologists Ltd.

Nitrergic Mechanisms for Management of Recurrent Priapism

PubMed Central

Anele, Uzoma A.; Burnett, Arthur L.

2015-01-01

Introduction Priapism is a condition involving prolonged penile erection unrelated to sexual interest or desire. The ischemic type, including its recurrent variant, is often associated with both physical and psychological complications. As such, management is of critical importance. Ideal therapies for recurrent priapism should address its underlying pathophysiology. Aim To review the available literature on priapism management approaches particularly related to nitrergic mechanisms. Methods A literature review of the pathophysiology and management of priapism was performed using PubMed. Main Outcome Measure Publications pertaining to mechanisms of the molecular pathophysiology of priapism. Results Nitrergic mechanisms are characterized as major players in the molecular pathophysiology of priapism. PDE5 inhibitors represent an available therapeutic option with demonstrated ability in attenuating these underlying nitrergic derangements. Several additional signaling pathways have been found to play a role in the molecular pathophysiology of priapism and have also been associated with these nitrergic mechanisms. Conclusion An increasing understanding of the molecular pathophysiology of priapism has led to the discovery of new potential targets. Several mechanism-based therapeutic approaches may become available in the future. PMID:26478814

Pathophysiology of Pulmonary Hypertension in Chronic Parenchymal Lung Disease.

PubMed

Singh, Inderjit; Ma, Kevin Cong; Berlin, David Adam

2016-04-01

Pulmonary hypertension commonly complicates chronic obstructive pulmonary disease and interstitial lung disease. The association of chronic lung disease and pulmonary hypertension portends a worse prognosis. The pathophysiology of pulmonary hypertension differs in the presence or absence of lung disease. We describe the physiological determinants of the normal pulmonary circulation to better understand the pathophysiological factors implicated in chronic parenchymal lung disease-associated pulmonary hypertension. This review will focus on the pathophysiology of 3 forms of chronic lung disease-associated pulmonary hypertension: idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and sarcoidosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Microfocused ultrasound for skin tightening.

PubMed

MacGregor, Jennifer L; Tanzi, Elizabeth L

2013-03-01

The demand for noninvasive skin tightening procedures is increasing as patients seek safe and effective alternatives to aesthetic surgical procedures of the face, neck, and body. Over the past decade, radiofrequency and infrared laser devices have been popularized owing to their ability to deliver controlled heat to the dermis, stimulate neocollagenesis, and effect modest tissue tightening with minimal recovery. However, these less invasive approaches are historically associated with inferior efficacy so that surgery still remains the treatment of choice to address moderate to severe tissue laxity. Microfocused ultrasound was recently introduced as a novel energy modality for transcutaneous heat delivery that reaches the deeper subdermal connective tissue in tightly focused zones at consistent programmed depths. The goal is to produce a deeper wound healing response at multiple levels with robust collagen remodeling and a more durable clinical response. The Ulthera device (Ulthera, Inc, Meza, AZ), with refined microfocused ultrasound technology, has been adapted specifically for skin tightening and lifting with little recovery or risk of complications since its introduction in 2009. As clinical parameters are studied and optimized, enhanced efficacy and consistency of clinical improvement is expected.

Association between Propionibacterium acnes and frozen shoulder: a pilot study.

PubMed

Bunker, Tim D; Boyd, Matthew; Gallacher, Sian; Auckland, Cressida R; Kitson, Jeff; Smith, Chris D

2014-10-01

Frozen shoulder has not previously been shown to be associated with infection. The present study set out to confirm the null hypothesis that there is no relationship between infection and frozen shoulder using two modern scientific methods, extended culture and polymerase chain reaction (PCR) for bacterial nucleic acids. A prospective cohort of 10 patients undergoing arthroscopic release for stage II idiopathic frozen shoulder had two biopsies of tissue taken from the affected shoulder joint capsule at the time of surgery, along with control biopsies of subdermal fat. The biopsies and controls were examined with extended culture and PCR for microbial nucleic acid. Eight of the 10 patients had positive findings on extended culture in their shoulder capsule and, in six of these, Propionibacterium acnes was present. The findings mean that we must reject the null hypothesis that there is no relationship between infection and frozen shoulder. More studies are urgently needed to confirm or refute these findings. If they are confirmed, this could potentially lead to new and effective treatments for this common, painful and disabling condition. Could P. acnes be the Helicobacter of frozen shoulder?

[Use of indocyanine green angiography in reconstructive surgery: Brief review].

PubMed

Echalier, C; Pluvy, I; Pauchot, J

2016-12-01

The success of flap surgery is highly dependant of vascularisation, according to the principle of dermal and subdermal perfusion. This principle requires compatible dimensions for the survival of the flap. Indocyanine green angiography (ICG), a technique enabling an assessment of vascularization by fluorescence, has received a considerable impetus during the last two decades. The purpose of this article was to conduct a review on this technique and to evaluate its relevance in flap surgery. We reviewed all articles referenced on PubMed from 1995 till 2015 using a search combining the terms 'indocyanine green', 'flap', 'near-infrared', 'fluorescence', 'imaging' OR 'angiography'. One hundred fifty five articles were found and among those thirty-four were selected. ICG is a reliable technique to locate perforants vessels, to determine the outlines of the flat and evaluate its per- and postoperative viability and to appraise anastomoses. This technique allows a reliable and real-time assessment of potential necrotic areas and an improvement in the detection of complications compared to conventional techniques. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Near-Infrared Irradiation Increases Length of Axial Pattern Flap Survival in Rats.

PubMed

Yasunaga, Yoshichika; Matsuo, Kiyoshi; Tanaka, Yohei; Yuzuriha, Shunsuke

2017-01-01

Objective: We previously reported that near-infrared irradiation nonthermally induces long-lasting vasodilation of the subdermal plexus by causing apoptosis of vascular smooth muscle cells. To clarify the possible application of near-infrared irradiation to prevent skin flap necrosis, we evaluated the length of axial pattern flap survival in rats by near-infrared irradiation. Methods: A bilaterally symmetric island skin flap was elevated under the panniculus carnosus on the rat dorsum. Half of the flap was subjected to near-infrared irradiation just before flap elevation with a device that simulates solar radiation, which has a specialized contact cooling apparatus to avoid thermal effects. The length of flap survival of the near-infrared irradiated side was measured 7 days after flap elevation and compared with the nonirradiated side. Results: The irradiated side showed elongation of flap survival compared with the nonirradiated side (73.3 ± 11.7 mm vs 67.3 ± 14.9 mm, respectively, P = .03). Conclusions: Near-infrared irradiation increases the survival length of axial pattern flaps in rats.

The evolving role of hyaluronic acid fillers for facial volume restoration and contouring: a Canadian overview

PubMed Central

Muhn, Channy; Rosen, Nathan; Solish, Nowell; Bertucci, Vince; Lupin, Mark; Dansereau, Alain; Weksberg, Fred; Remington, B Kent; Swift, Arthur

2012-01-01

Recent advancements, including more versatile facial fillers, refined injection techniques and the adoption of a global facial approach, have contributed to improved patient outcome and increased patient satisfaction. Nine Canadian specialists (eight dermatologists, one plastic surgeon) collaborated to develop an overview on volume restoration and contouring based on published literature and their collective clinical experience. The specialists concurred that optimal results in volume restoration and contouring depend on correcting deficiencies at various layers of the facial envelope. This includes creating a foundation for deep structural support in the supraperiosteal or submuscular plane; volume repletion of subcutaneous fat compartments; and the reestablishment of dermal and subdermal support to minimize cutaneous rhytids, grooves and furrows. It was also agreed that volume restoration and contouring using a global facial approach is essential to create a natural, youthful appearance in facial aesthetics. A comprehensive non-surgical approach should therefore incorporate combining fillers such as high-viscosity, low-molecular-weight hyaluronic acid (LMWHA) for structural support and hyaluronic acid (HA) for lines, grooves and furrows with neuromodulators, lasers and energy devices. PMID:23071398

The brief life of Norplant® in Brazil: controversies and reassemblages between science, society and State.

PubMed

Pimentel, Ana Cristina de Lima; Jannotti, Cláudia Bonan; Gaudenzi, Paula; Teixeira, Luiz Antonio da Silva

2017-01-01

Norplant® is the brand name of the world's first registered subdermal hormonal contraceptive implant, developed by the laboratories of the Population Council, an international organisation working in the area of fertility and population growth. The article revisits the trajectory of this contraceptive in Brazil from its arrival through clinical trials to its eventual ban in 1986 by the Brazilian regulatory agency responsible for approving medications at the time. Its circulation generated controversies related to research practices, side effects and political uses of the drug as a birth control method. This article focuses its analysis on the divergences related to research practices. It uses a controversy analysis technique, reviewing the versions of those involved, investigating their understandings and the effects that this object generated in their networks. Norplant® provoked displacements and associations between civil society groups, State authorities, scientists and physicians, industry, pharmaceutical products, research procedures, bureaucratic instruments, and the female users of the contraceptives. Scientific styles of medical thought were shaken up and new forms of thinking about scientific autonomy began to be discussed in the country.

Family planning in the teen population.

PubMed

Hillard, P J

1993-12-01

As an increasing percentage of adolescents reach their sexual debut at younger ages, effective contraceptive methods, which will decrease the risks of unintended pregnancies and sexually transmitted diseases (STDs), become even more critical. Contraceptive methods which are less 'compliance-dependent', such as the implantable subdermal levonorgestrel and the injectable depot formulation of medroxyprogesterone acetate, are popular in adolescents but careful counseling before method selection and on-going counseling when side-effects are experienced are necessary and essential. The use of condoms to decrease the risks of STDs will continue to be important for adolescents, and it remains to be seen what impact the long-term methods will have on effective condom use. Adolescents' access to abortions when contraceptive methods fail, or when no method is used, is being challenged with state laws which mandate parental notification or permission. A greater knowledge about the option of emergency contraception could potentially lead to increased use of this method, particularly when the option of medications such as RU486 becomes available. The potential for a reduction in unintended pregnancies in adolescents, and a reduced need for abortions is a welcome prospect.

Pathophysiology and Toxicokinetic Studies of Blue-Green Algae Intoxication in the Swine Model

DTIC Science & Technology

1987-08-31

bovine aer, albamin caused similar reductions !u toxicity, suggesting nonspecific protein binding. Saturation at the N-methyldehydroalanine of MCYST-A...need to conserve toxin and the goal of creating a model for naturally occurring toxicosis caused us to evaluate the oral administration of microcystin...the isolated ileal loop preparation. Pancreatic enzymes and protein-binding were examined as 2 possible causes for the low oral toxicity of MCYST-A

Anatomy and Pathophysiology of Spinal Cord Injury Associated With Regional Anesthesia and Pain Medicine: 2015 Update.

PubMed

Neal, Joseph M; Kopp, Sandra L; Pasternak, Jeffrey J; Lanier, William L; Rathmell, James P

2015-01-01

In March 2012, the American Society of Regional Anesthesia and Pain Medicine convened its second Practice Advisory on Neurological Complications in Regional Anesthesia and Pain Medicine. This update is based on the proceedings of that conference and relevant information published since its conclusion. This article updates previously described information on the pathophysiology of spinal cord injury and adds new material on spinal stenosis, blood pressure control during neuraxial blockade, neuraxial injury subsequent to transforaminal procedures, cauda equina syndrome/local anesthetic neurotoxicity/arachnoiditis, and performing regional anesthetic or pain medicine procedures in patients concomitantly receiving general anesthesia or deep sedation. Recommendations are based on extensive review of research on humans or employing animal models, case reports, pathophysiology research, and expert opinion. The pathophysiology of spinal cord injury associated with regional anesthetic techniques is reviewed in depth, including that related to mechanical trauma from direct needle/catheter injury or mass lesions, spinal cord ischemia or vascular injury from direct needle/catheter trauma, and neurotoxicity from local anesthetics, adjuvants, or antiseptics. Specific recommendations are offered that may reduce the likelihood of spinal cord injury associated with regional anesthetic or interventional pain medicine techniques. The practice advisory's recommendations may, in select cases, reduce the likelihood of injury. However, many of the described injuries are neither predictable nor preventable based on our current state of knowledge. Since publication of initial recommendations in 2008, new information has enhanced our understanding of 5 specific entities: spinal stenosis, blood pressure control during neuraxial anesthesia, neuraxial injury subsequent to transforaminal techniques, cauda equina syndrome/local anesthetic neurotoxicity/arachnoiditis, and performing regional anesthetic or pain procedures in patients concomitantly receiving general anesthesia or deep sedation.

Convergent evidence for abnormal striatal synaptic plasticity in dystonia

PubMed Central

Peterson, David A.; Sejnowski, Terrence J.; Poizner, Howard

2010-01-01

Dystonia is a functionally disabling movement disorder characterized by abnormal movements and postures. Although substantial recent progress has been made in identifying genetic factors, the pathophysiology of the disease remains a mystery. A provocative suggestion gaining broader acceptance is that some aspect of neural plasticity may be abnormal. There is also evidence that, at least in some forms of dystonia, sensorimotor “use” may be a contributing factor. Most empirical evidence of abnormal plasticity in dystonia comes from measures of sensorimotor cortical organization and physiology. However, the basal ganglia also play a critical role in sensorimotor function. Furthermore, the basal ganglia are prominently implicated in traditional models of dystonia, are the primary targets of stereotactic neurosurgical interventions, and provide a neural substrate for sensorimotor learning influenced by neuromodulators. Our working hypothesis is that abnormal plasticity in the basal ganglia is a critical link between the etiology and pathophysiology of dystonia. In this review we set up the background for this hypothesis by integrating a large body of disparate indirect evidence that dystonia may involve abnormalities in synaptic plasticity in the striatum. After reviewing evidence implicating the striatum in dystonia, we focus on the influence of two neuromodulatory systems: dopamine and acetylcholine. For both of these neuromodulators, we first describe the evidence for abnormalities in dystonia and then the means by which it may influence striatal synaptic plasticity. Collectively, the evidence suggests that many different forms of dystonia may involve abnormal plasticity in the striatum. An improved understanding of these altered plastic processes would help inform our understanding of the pathophysiology of dystonia, and, given the role of the striatum in sensorimotor learning, provide a principled basis for designing therapies aimed at the dynamic processes linking etiology to pathophysiology of the disease. PMID:20005952

Is Physiology the Locus of Health/Health Promotion?

ERIC Educational Resources Information Center

Zbilut, Joseph P.

2008-01-01

A current trend in physiology education involves the use of clinical vignettes to demonstrate the importance of knowing normal physiology to appreciate pathophysiology. Although laudable, in effect, such tactics promote the so-called "disease" model of medicine while at the same time suggesting that the only utility for the knowledge of physiology…

Education Models for Teaching Adults about Modifying Dietary Carbohydrate and Controlling Weight

ERIC Educational Resources Information Center

Cleamons, Vincient M.

2018-01-01

The prevalence of diabetes and other pathophysiological conditions has been correlated with the incidence of obesity. A large portion of an adult community in the northwestern United States suffers from excessive weight that has been linked to premature mortality rates and certain forms of diabetes. Excess calories from carbohydrate have been…

Iron overload cardiomyopathy: from diagnosis to management.

PubMed

Díez-López, Carles; Comín-Colet, Josep; González-Costello, José

2018-05-01

Iron overload cardiomyopathy (IOC) is an important predictor of prognosis in a significant number of patients with hereditary hemochromatosis and hematologic diseases. Its prevalence is increasing because of improved treatment strategies, which significantly improve life expectancy. We will review diagnosis, treatment, and recent findings in the field. The development of preclinical translational disease models during the last years have helped our understanding of specific disease pathophysiological pathways that might eventually change the outcomes of these patients. IOC is an overlooked disease because of the progressive silent disease pattern and the lack of physicians' expertise. It mainly affects patients with hemochromatosis and hematologic diseases and its prevalence is expected to increase with the improvement in life expectancy of hematologic disorders. Early diagnosis of IOC in patients at risk by means of biochemical parameters and cardiac imaging can lead to early treatment and improved prognosis. The mainstay of treatment of IOC is conventional heart failure treatment, combined with phlebotomies or iron chelation in the context of anemia. The development of preclinical models has provided a comprehensive look into specific pathophysiological pathways with potential treatment strategies that must be sustained by future randomized trials.

Controversies and Evolving New Mechanisms in Subarachnoid Hemorrhage

PubMed Central

Chen, Sheng; Feng, Hua; Sherchan, Prativa; Klebe, Damon; Zhao, Gang; Sun, Xiaochuan; Zhang, Jianmin; Tang, Jiping; Zhang, John H.

2013-01-01

Despite decades of study, subarachnoid hemorrhage (SAH) continues to be a serious and significant health problem in the United States and worldwide. The mechanisms contributing to brain injury after SAH remain unclear. Traditionally, most in vivo research has heavily emphasized the basic mechanisms of SAH over the pathophysiological or morphological changes of delayed cerebral vasospasm after SAH. Unfortunately, the results of clinical trials based on this premise have mostly been disappointing, implicating some other pathophysiological factors, independent of vasospasm, as contributors to poor clinical outcomes. Delayed cerebral vasospasm is no longer the only culprit. In this review, we summarize recent data from both experimental and clinical studies of SAH and discuss the vast array of physiological dysfunctions following SAH that ultimately lead to cell death. Based on the progress in neurobiological understanding of SAH, the terms “early brain injury” and “delayed brain injury” are used according to the temporal progression of SAH-induced brain injury. Additionally, a new concept of the vasculo-neuronal-glia triad model for SAH study is highlighted and presents the challenges and opportunities of this model for future SAH applications. PMID:24076160

Pathophysiological Approaches of Acute Respiratory Distress syndrome: Novel Bases for Study of Lung Injury

PubMed Central

Castillo, R.L; Carrasco Loza, R; Romero-Dapueto, C

2015-01-01

Experimental approaches have been implemented to research the lung damage related-mechanism. These models show in animals pathophysiological events for acute respiratory distress syndrome (ARDS), such as neutrophil activation, reactive oxygen species burst, pulmonary vascular hypertension, exudative edema, and other events associated with organ dysfunction. Moreover, these approaches have not reproduced the clinical features of lung damage. Lung inflammation is a relevant event in the develop of ARDS as component of the host immune response to various stimuli, such as cytokines, antigens and endotoxins. In patients surviving at the local inflammatory states, transition from injury to resolution is an active mechanism regulated by the immuno-inflammatory signaling pathways. Indeed, inflammatory process is regulated by the dynamics of cell populations that migrate to the lung, such as neutrophils and on the other hand, the role of the modulation of transcription factors and reactive oxygen species (ROS) sources, such as nuclear factor kappaB and NADPH oxidase. These experimental animal models reproduce key components of the injury and resolution phases of human ALI/ARDS and provide a methodology to explore mechanisms and potential new therapies. PMID:26312099

Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic

PubMed Central

Krystal, John H.; Abdallah, Chadi G.; Averill, Lynette A.; Kelmendi, Benjamin; Harpaz-Rotem, Ilan; Sanacora, Gerard; Southwick, Steven M.; Duman, Ronald S.

2018-01-01

Purpose of Review Studies of the neurobiology and treatment of PTSD have highlighted many aspects of the pathophysiology of this disorder that might be relevant to treatment. The purpose of this review is to highlight the potential clinical importance of an often-neglected consequence of stress models in animals that may be relevant to PTSD: the stress-related loss of synaptic connectivity. Recent Findings Here, we will briefly review evidence that PTSD might be a “synaptic disconnection syndrome” and highlight the importance of this perspective for the emerging therapeutic application of ketamine as a potential rapid-acting treatment for this disorder that may work, in part, by restoring synaptic connectivity. Summary Synaptic disconnection may contribute to the profile of PTSD symptoms that may be targeted by novel pharmacotherapeutics. PMID:28844076

Epidermal Growth Factor Receptor Transactivation: Mechanisms, Pathophysiology, and Potential Therapies in the Cardiovascular System.

PubMed

Forrester, Steven J; Kawai, Tatsuo; O'Brien, Shannon; Thomas, Walter; Harris, Raymond C; Eguchi, Satoru

2016-01-01

Epidermal growth factor receptor (EGFR) activation impacts the physiology and pathophysiology of the cardiovascular system, and inhibition of EGFR activity is emerging as a potential therapeutic strategy to treat diseases including hypertension, cardiac hypertrophy, renal fibrosis, and abdominal aortic aneurysm. The capacity of G protein-coupled receptor (GPCR) agonists, such as angiotensin II (AngII), to promote EGFR signaling is called transactivation and is well described, yet delineating the molecular processes and functional relevance of this crosstalk has been challenging. Moreover, these critical findings are dispersed among many different fields. The aim of our review is to highlight recent advancements in defining the signaling cascades and downstream consequences of EGFR transactivation in the cardiovascular renal system. We also focus on studies that link EGFR transactivation to animal models of the disease, and we discuss potential therapeutic applications.

Dense Deposit Disease and C3 Glomerulopathy

PubMed Central

Barbour, Thomas D.; Pickering, Matthew C.; Terence Cook, H.

2013-01-01

Summary C3 glomerulopathy refers to those renal lesions characterized histologically by predominant C3 accumulation within the glomerulus, and pathogenetically by aberrant regulation of the alternative pathway of complement. Dense deposit disease is distinguished from other forms of C3 glomerulopathy by its characteristic appearance on electron microscopy. The extent to which dense deposit disease also differs from other forms of C3 glomerulopathy in terms of clinical features, natural history, and outcomes of treatment including renal transplantation is less clear. We discuss the pathophysiology of C3 glomerulopathy, with evidence for alternative pathway dysregulation obtained from affected individuals and complement factor H (Cfh)-deficient animal models. Recent linkage studies in familial C3 glomerulopathy have shown genomic rearrangements in the Cfh-related genes, for which the novel pathophysiologic concept of Cfh deregulation has been proposed. PMID:24161036

[Pathophysiology of myopia: nature versus nurture].

PubMed

Cassagne, M; Malecaze, F; Soler, V

2014-05-01

Myopia is the most frequent refractive disorder in the world. It has become a real Public Health problem, due to its frequency and to high myopia-related blinding complications. Myopic progression depends on genetic and environmental factors. Genetic studies have identified more than forty candidate genes that take part in pathophysiological pathways, from retinal phototransduction to axial lengthening via scleral remodelling. Environmental factors also influence scleral remodelling by way of visual perception. In the case of predominant attention to near tasks, a physiological feedback loop leads to axial growth. This phenomenon, called active emmetropization, is particularly obvious in animal models and in some human populations. To date, research has failed to identify a molecule common to all the implicated metabolic pathways which could be a target for an effective preventive treatment against myopic progression. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Recent progress in the genetics of spontaneously hypertensive rats.

PubMed

Pravenec, M; Křen, V; Landa, V; Mlejnek, P; Musilová, A; Šilhavý, J; Šimáková, M; Zídek, V

2014-01-01

The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and accompanying metabolic disturbances. Recent advances in sequencing of genomes of BN-Lx and SHR progenitors of the BXH/HXB recombinant inbred (RI) strains as well as accumulation of multiple data sets of intermediary phenotypes in the RI strains, including mRNA and microRNA abundance, quantitative metabolomics, proteomics, methylomics or histone modifications, will make it possible to systematically search for genetic variants involved in regulation of gene expression and in the etiology of complex pathophysiological traits. New advances in manipulation of the rat genome, including efficient transgenesis and gene targeting, will enable in vivo functional analyses of selected candidate genes to identify QTL at the molecular level or to provide insight into mechanisms whereby targeted genes affect pathophysiological traits in the SHR.

Role of Polyamines in Asthma Pathophysiology

PubMed Central

2018-01-01

Asthma is a complex disease of airways, where the interactions of immune and structural cells result in disease outcomes with airway remodeling and airway hyper-responsiveness. Polyamines, which are small-sized, natural super-cations, interact with negatively charged intracellular macromolecules, and altered levels of polyamines and their interactions have been associated with different pathological conditions including asthma. Elevated levels of polyamines have been reported in the circulation of asthmatic patients as well as in the lungs of a murine model of asthma. In various studies, polyamines were found to potentiate the pathogenic potential of inflammatory cells, such as mast cells and granulocytes (eosinophils and neutrophils), by either inducing the release of their pro-inflammatory mediators or prolonging their life span. Additionally, polyamines were crucial in the differentiation and alternative activation of macrophages, which play an important role in asthma pathology. Importantly, polyamines cause airway smooth muscle contraction and thus airway hyper-responsiveness, which is the key feature in asthma pathophysiology. High levels of polyamines in asthma and their active cellular and macromolecular interactions indicate the importance of the polyamine pathway in asthma pathogenesis; therefore, modulation of polyamine levels could be a suitable approach in acute and severe asthma management. This review summarizes the possible roles of polyamines in different pathophysiological features of asthma. PMID:29316647

Toll-like receptor-4 signaling pathway in aorta aging and diseases: "its double nature".

PubMed

Balistreri, Carmela Rita; Ruvolo, Giovanni; Lio, Domenico; Madonna, Rosalinda

2017-09-01

Recent advances in the field of innate immunity have revealed a complex role of innate immune signaling pathways in both tissue homeostasis and disease. Among them, the Toll-like receptor 4 (TLR-4) pathways has been linked to various pathophysiological conditions, such as cardiovascular diseases (CVDs). This has been interrogated by developing multiple laboratory tools that have shown in animal models and clinical conditions, the involvement of the TLR-4 signaling pathway in the pathophysiology of different CVDs, such as atherosclerosis, ischemic heart disease, heart failure, ischemia-reperfusion injury and aorta aneurysm. Among these, aorta aneurysm, a very complex pathological condition with uncertain etiology and fatal complications (i.e. dissection and rupture), has been associated with the occurrence of high risk cardiovascular conditions, including thrombosis and embolism. In this review, we discuss the possible role of TLR-4 signaling pathway in the development of aorta aneurysm, considering the emerging evidence from ongoing investigations. Our message is that emphasizing the role of TLR-4 signaling pathway in aorta aneurysm may serve as a starting point for future studies, leading to a better understanding of the pathophysiological basis and perhaps the effective treatment of this difficult human disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

Gastrointestinal neuroendocrine peptides/amines in inflammatory bowel disease

PubMed Central

El-Salhy, Magdy; Solomon, Tefera; Hausken, Trygve; Gilja, Odd Helge; Hatlebakk, Jan Gunnar

2017-01-01

Inflammatory bowel disease (IBD) is a chronic recurrent condition whose etiology is unknown, and it includes ulcerative colitis, Crohn’s disease, and microscopic colitis. These three diseases differ in clinical manifestations, courses, and prognoses. IBD reduces the patients’ quality of life and is an economic burden to both the patients and society. Interactions between the gastrointestinal (GI) neuroendocrine peptides/amines (NEPA) and the immune system are believed to play an important role in the pathophysiology of IBD. Moreover, the interaction between GI NEPA and intestinal microbiota appears to play also a pivotal role in the pathophysiology of IBD. This review summarizes the available data on GI NEPA in IBD, and speculates on their possible role in the pathophysiology and the potential use of this information when developing treatments. GI NEPA serotonin, the neuropeptide Y family, and substance P are proinflammatory, while the chromogranin/secretogranin family, vasoactive intestinal peptide, somatostatin, and ghrelin are anti-inflammatory. Several innate and adaptive immune cells express these NEPA and/or have receptors to them. The GI NEPA are affected in patients with IBD and in animal models of human IBD. The GI NEPA are potentially useful for the diagnosis and follow-up of the activity of IBD, and are candidate targets for treatments of this disease. PMID:28811704

GLUTAMATE ABNORMALITIES IN OBSESSIVE COMPULSIVE DISORDER: NEUROBIOLOGY, PATHOPHYSIOLOGY, AND TREATMENT

PubMed Central

Pittenger, Christopher; Bloch, Michael H.; Williams, Kyle

2011-01-01

Obsessive compulsive disorder is prevalent, disabling, incompletely understood, and often resistant to current therapies. Established treatments consist of specialized cognitive-behavioral psychotherapy and pharmacotherapy with medications targeting serotonergic and dopaminergic neurotransmission. However, remission is rare, and more than a quarter of OCD sufferers receive little or no benefit from these approaches, even when they are optimally delivered. New insights into the disorder, and new treatment strategies, are urgently needed. Recent evidence suggests that the ubiquitous excitatory neurotransmitter glutamate is dysregulated in OCD, and that this dysregulation may contribute to the pathophysiology of the disorder. Here we review the current state of this evidence, including neuroimaging studies, genetics, neurochemical investigations, and insights from animal models. Finally, we review recent findings from small clinical trials of glutamate-modulating medications in treatment-refractory OCD. The precise role of glutamate dysregulation in OCD remains unclear, and we lack blinded, well-controlled studies demonstrating therapeutic benefit from glutamate-modulating agents. Nevertheless, the evidence supporting some important perturbation of glutamate in the disorder is increasingly strong. This new perspective on the pathophysiology of OCD, which complements the older focus on monoaminergic neurotransmission, constitutes an important focus of current research and a promising area for the ongoing development of new therapeutics. PMID:21963369

Animal models of gastrointestinal and liver diseases. Animal models of acute and chronic pancreatitis.

PubMed

Zhan, Xianbao; Wang, Fan; Bi, Yan; Ji, Baoan

2016-09-01

Animal models of pancreatitis are useful for elucidating the pathogenesis of pancreatitis and developing and testing novel interventions. In this review, we aim to summarize the most commonly used animal models, overview their pathophysiology, and discuss their strengths and limitations. We will also briefly describe common animal study procedures and refer readers to more detailed protocols in the literature. Although animal models include pigs, dogs, opossums, and other animals, we will mainly focus on rodent models because of their popularity. Autoimmune pancreatitis and genetically engineered animal models will be reviewed elsewhere. Copyright © 2016 the American Physiological Society.

Spontaneous Trigeminal Allodynia in Rats: A Model of Primary Headache

PubMed Central

Oshinsky, Michael L.; Sanghvi, Menka M.; Maxwell, Christina R.; Gonzalez, Dorian; Spangenberg, Rebecca J.; Cooper, Marnie; Silberstein, Stephen D.

2014-01-01

Animal models are essential for studying the pathophysiology of headache disorders and as a screening tool for new therapies. Most animal models modify a normal animal in an attempt to mimic migraine symptoms. They require manipulation to activate the trigeminal nerve or dural nociceptors. At best, they are models of secondary headache. No existing model can address the fundamental question: How is a primary headache spontaneously initiated? In the process of obtaining baseline periorbital von Frey thresholds in a wild-type Sprague-Dawley rat, we discovered a rat with spontaneous episodic trigeminal allodynia (manifested by episodically changing periorbital pain threshold). Subsequent mating showed that the trait is inherited. Animals with spontaneous trigeminal allodynia allow us to study the pathophysiology of primary recurrent headache disorders. To validate this as a model for migraine, we tested the effects of clinically proven acute and preventive migraine treatments on spontaneous changes in rat periorbital sensitivity. Sumatriptan, ketorolac, and dihydroergotamine temporarily reversed the low periorbital pain thresholds. Thirty days of chronic valproic acid treatment prevented spontaneous changes in trigeminal allodynia. After discontinuation, the rats returned to their baseline of spontaneous episodic threshold changes. We also tested the effects of known chemical human migraine triggers. On days when the rats did not have allodynia and showed normal periorbital von Frey thresholds, glycerol trinitrate and calcitonin gene related peptide induced significant decreases in the periorbital pain threshold. This model can be used as a predictive model for drug development and for studies of putative biomarkers for headache diagnosis and treatment. PMID:22963523

What is precise pathophysiology in development of hypertension in pregnancy? Precision medicine requires precise physiology and pathophysiology.

PubMed

Gao, Qinqin; Tang, Jiaqi; Li, Na; Liu, Bailin; Zhang, Mengshu; Sun, Miao; Xu, Zhice

2018-02-01

It is widely accepted that placental ischemia is central in the evolution of hypertension in pregnancy. Many studies and reviews have targeted placental ischemia to explain mechanisms for initiating pregnancy hypertension. The placenta is rich in blood vessels, which are the basis for developing placental ischemia. However, is the physiology of placental vessels the same as that of nonplacental vessels? What is the pathophysiology of placental vessels in development of pregnancy hypertension? This review aims to provide a comprehensive summary of special features of placental vascular regulations and the pathophysiological changes linked to preeclamptic conditions. Interestingly, some popular theories or accepted concepts could be based on our limited knowledge and evidence regarding placental vascular physiology, pharmacology and pathophysiology. New views raised could offer interesting ideas for future investigation of mechanisms as well as targets for pregnancy hypertension. Copyright © 2017 Elsevier Ltd. All rights reserved.

Epidemiology and pathogenesis of posttraumatic headache.

PubMed

Packard, R C

1999-02-01

This article presents an overview of the epidemiology and pathophysiology of posttraumatic headache. It reviews definitions of mild head injury (MHI), mild traumatic brain injury (MTBI), and concussion, and discusses the confusion that often occurs with these terms. Headache types and their pathophysiology are examined in detail. Just as the exact pathophysiology is unknown for migraine and other types of headache, the exact pathophysiology of headache after trauma is also still unknown in many cases. Possible connections between head or neck injuries and headache are reviewed, as well as hypothesized neurochemical changes that may occur in both migraine and traumatic brain injury (TBI). Psychological and legal factors are also considered.

Inflammatory and Other Biomarkers: Role in Pathophysiology and Prediction of Gestational Diabetes Mellitus

PubMed Central

Abell, Sally K.; De Courten, Barbora; Boyle, Jacqueline A.; Teede, Helena J.

2015-01-01

Understanding pathophysiology and identifying mothers at risk of major pregnancy complications is vital to effective prevention and optimal management. However, in current antenatal care, understanding of pathophysiology of complications is limited. In gestational diabetes mellitus (GDM), risk prediction is mostly based on maternal history and clinical risk factors and may not optimally identify high risk pregnancies. Hence, universal screening is widely recommended. Here, we will explore the literature on GDM and biomarkers including inflammatory markers, adipokines, endothelial function and lipids to advance understanding of pathophysiology and explore risk prediction, with a goal to guide prevention and treatment of GDM. PMID:26110385

Pathophysiology of chronic pancreatitis induced by dibutyltin dichloride joint ethanol in mice

PubMed Central

Zhang, Hong; Liu, Bin; Xu, Xiao-Fan; Jiang, Ting-Ting; Zhang, Xiao-Qin; Shi, Ying-Li; Chen, Yu; Liu, Fang; Gu, Jie; Zhu, Lin-Jia; Wu, Nan

2016-01-01

AIM: To search for a new chronic pancreatitis model in mice suitable for investigating the pathophysiological processes leading to pancreatic fibrosis. METHODS: The mice were randomly divided into 2 groups (n = 50), control group and model group. The mice in model group were given ethanol (10%) in drinking water after injection of dibutyltin dichloride (DBTC) (8 mg/kg BW) in tail vein. The mice in control group were injected with only solvent into tail vein (60% ethanol, 20% glycerine and 20% normal saline) and drank common water. At days 1, 7, 14, 28, and 56 after application of DBTC or solvent, 10 mice in one group were killed at each time point respectively. Blood was obtained by inferior vena cava puncture. The activity of amylase, concentration of bilirubin and hyaluronic acid in serum were assayed. The pancreas was taken to observe the pancreatic morphology by HE staining, and to characterize the pancreatic fibrosis by Masson staining. The expression of F4/80, CD3 and fibronectin (FN) were assayed by immuno-histochemistry or Immunofluorescence technique. Collagen type I (COL1A1) in pancreas were detected by Western blot. The expression of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA in the pancreas was assessed by real time PCR. RESULTS: DBTC induced an acute edematous pancreatitis within 1 d. The dilated acini, scattered acinar cell necrosis, and inflammatory cells were found at day 7. Extensive infiltration with inflammatory cells following deposition of connective tissue was observed at day 14. At day 28, level of pancreatic fibrosis was aggravated. The pancreatic tissue was replaced by an extended interstitial fibrosis at the end of 2 mo. There was significant difference in the level of amylase, bilirubin and hyaluronic acid in serum between control group and model group (P < 0.05). The level of COL1A1 and FN in pancreas increased. The expression of MMP-1 mRNA in pancreas decreased, but TIMP-1 mRNA increased at model group. CONCLUSION: DBTC joint Ethanol drinking can induce chronic pancreatitis in accordance with the pathophysiological modification of human. DBTC joint Ethanol-induced pancreatitis in mice is an effective and handy experimental method. The model is suitable to study the mechanism of pancreatic fibrosis in chronic pancreatitis. PMID:26973392

Pathophysiology of chronic pancreatitis induced by dibutyltin dichloride joint ethanol in mice.

PubMed

Zhang, Hong; Liu, Bin; Xu, Xiao-Fan; Jiang, Ting-Ting; Zhang, Xiao-Qin; Shi, Ying-Li; Chen, Yu; Liu, Fang; Gu, Jie; Zhu, Lin-Jia; Wu, Nan

2016-03-14

To search for a new chronic pancreatitis model in mice suitable for investigating the pathophysiological processes leading to pancreatic fibrosis. The mice were randomly divided into 2 groups (n = 50), control group and model group. The mice in model group were given ethanol (10%) in drinking water after injection of dibutyltin dichloride (DBTC) (8 mg/kg BW) in tail vein. The mice in control group were injected with only solvent into tail vein (60% ethanol, 20% glycerine and 20% normal saline) and drank common water. At days 1, 7, 14, 28, and 56 after application of DBTC or solvent, 10 mice in one group were killed at each time point respectively. Blood was obtained by inferior vena cava puncture. The activity of amylase, concentration of bilirubin and hyaluronic acid in serum were assayed. The pancreas was taken to observe the pancreatic morphology by HE staining, and to characterize the pancreatic fibrosis by Masson staining. The expression of F4/80, CD3 and fibronectin (FN) were assayed by immuno-histochemistry or Immunofluorescence technique. Collagen type I (COL1A1) in pancreas were detected by Western blot. The expression of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA in the pancreas was assessed by real time PCR. DBTC induced an acute edematous pancreatitis within 1 d. The dilated acini, scattered acinar cell necrosis, and inflammatory cells were found at day 7. Extensive infiltration with inflammatory cells following deposition of connective tissue was observed at day 14. At day 28, level of pancreatic fibrosis was aggravated. The pancreatic tissue was replaced by an extended interstitial fibrosis at the end of 2 mo. There was significant difference in the level of amylase, bilirubin and hyaluronic acid in serum between control group and model group (P < 0.05). The level of COL1A1 and FN in pancreas increased. The expression of MMP-1 mRNA in pancreas decreased, but TIMP-1 mRNA increased at model group. DBTC joint Ethanol drinking can induce chronic pancreatitis in accordance with the pathophysiological modification of human. DBTC joint Ethanol-induced pancreatitis in mice is an effective and handy experimental method. The model is suitable to study the mechanism of pancreatic fibrosis in chronic pancreatitis.

Animal models of gastrointestinal and liver diseases. Animal models of cystic fibrosis: gastrointestinal, pancreatic, and hepatobiliary disease and pathophysiology

PubMed Central

Olivier, Alicia K.; Gibson-Corley, Katherine N.

2015-01-01

Multiple organ systems, including the gastrointestinal tract, pancreas, and hepatobiliary systems, are affected by cystic fibrosis (CF). Many of these changes begin early in life and are difficult to study in young CF patients. Recent development of novel CF animal models has expanded opportunities in the field to better understand CF pathogenesis and evaluate traditional and innovative therapeutics. In this review, we discuss manifestations of CF disease in gastrointestinal, pancreatic, and hepatobiliary systems of humans and animal models. We also compare the similarities and limitations of animal models and discuss future directions for modeling CF. PMID:25591863

Pathophysiology of Non-Freezing Cold Injury

DTIC Science & Technology

1989-07-01

the leg. Salicylic acid was injected through the femoral vein at the end of some experiments to assay hydroxy radical (OH*). Our results demonstrated...pH 4.5); 50 J1 of 70% perchloric acid was then added to the mixtur,". The resultant mixture was degassed and filtered through a Rainin Nylon-66...consisting of a Model 510 pump and a Model 460 electrochemical detector. The hydroxylated products of salicylic acid were eluted with buffer (degassed and

A microengineered pathophysiological model of early-stage breast cancer.

PubMed

Choi, Yoonseok; Hyun, Eunjeh; Seo, Jeongyun; Blundell, Cassidy; Kim, Hee Chan; Lee, Eunhee; Lee, Su Hyun; Moon, Aree; Moon, Woo Kyung; Huh, Dongeun

2015-08-21

A mounting body of evidence in cancer research suggests that the local microenvironment of tumor cells has a profound influence on cancer progression and metastasis. In vitro studies on the tumor microenvironment and its pharmacological modulation, however, are often hampered by the technical challenges associated with creating physiological cell culture environments that integrate cancer cells with the key components of their native niche such as neighboring cells and extracellular matrix (ECM) to mimic complex microarchitecture of cancerous tissue. Using early-stage breast cancer as a model disease, here we describe a biomimetic microengineering strategy to reconstitute three-dimensional (3D) structural organization and microenvironment of breast tumors in human cell-based in vitro models. Specifically, we developed a microsystem that enabled co-culture of breast tumor spheroids with human mammary ductal epithelial cells and mammary fibroblasts in a compartmentalized 3D microfluidic device to replicate microarchitecture of breast ductal carcinoma in situ (DCIS). We also explored the potential of this breast cancer-on-a-chip system as a drug screening platform by evaluating the efficacy and toxicity of an anticancer drug (paclitaxel). Our microengineered disease model represents the first critical step towards recapitulating pathophysiological complexity of breast cancer, and may serve as an enabling tool to systematically examine the contribution of the breast cancer microenvironment to the progression of DCIS to an invasive form of the disease.

Pathophysiological changes of the cerebellum and brain stem in a rabbit model after superior petrosal vein sacrifice.

PubMed

Cheng, Lei; Guo, Pin; Liao, Yi-Wei; Zhang, Hong-Liang; Li, Huan-Ting; Yuan, Xianrui

2017-11-13

In certain surgical procedures sacrifice of the superior petrosal vein (SPV) is required. Previous studies have reported transient cerebellar edema, venous infarction or hemorrhage might occur after sectioning of the SPV. This study investigated the pathophysiological changes of cerebellum and brain stem after SPV sacrifice. Rabbits were divided into the operation group where the SPV was sacrificed and the control group where the SPV remained intact. Each group was further subdivided into 4, 8, 12, 24, 48 and 72 hours groups which represented the time period from sacrifice of the SPV to sacrifice of the rabbits. The water content (WC), Na + content, K + content and pathophysiological changes of cerebellum and brain stem tissue were measured. In comparison to the control, the WC and Na + content of cerebellar tissue were increased in the 4h, 8h, 12h and 24h operation subgroups (p<0.05), but only increased in the 4h subgroup of the brain stem tissue (p<0.05). The K + content of the cerebellar tissue decreased in the 4h, 8h, 12h and 24h operation subgroups (p<0.05) but only decreased in the 4h subgroup of brain stem tissue (p<0.05). Nissl staining and transmission electron microscopy demonstrated that cerebellar edema occurred in the 4h, 8h, 12h and 24h operation subgroups but not in the 48h and 72h subgroups. Brain stem edema occurred in the 4h operation subgroup. In summary, cerebellum and brain stem edema can be observed at different time points after sacrifice of the SPV in the rabbit model. ©2017 The Author(s).

Pathophysiology of chronic heart failure.

PubMed

Francis, G S

2001-05-07

Heart failure is a changing paradigm. The hemodynamic model, which served our needs well from the 1950s through the early 1980s, has now been largely abandoned, except for the management of decompensated patients in the hospital. The pathophysiology is exceedingly complex and involves structural changes, such as loss of myofilaments, apoptosis and disorganization of the cytoskeleton, as well as disturbances in Ca(2+) homeostasis, alteration in receptor density, signal transduction, and collagen synthesis. A more contemporary working hypothesis is that heart failure is a progressive disorder of left ventricular remodeling, usually resulting from an index event, that culminates in a clinical syndrome characterized by impaired cardiac function and circulatory congestion. This change in the framework of our understanding of the pathophysiology of heart failure is predicated on the results of numerous clinical trials conducted during the past 20 years. New therapies are now evolving that are designed to inhibit neuroendocrine and cytokine activation, whereas drugs specifically designed to heighten cardiac contractility and "unload" the left ventricle have proven to be unhelpful in long-term management of patients with chronic heart failure. However, the hemodynamic model is still relevant for patients in the hospital with decompensated heart failure, where positive inotropic drugs and vasodilators are still widely used. The modern treatment of chronic heart failure is now largely based on the neurohormonal hypothesis, which states that neuroendocrine activation is important in the progression of heart failure and that inhibition of neurohormones is likely to have long-term benefit with regard to morbidity and mortality. Thus, the evolution of treatment for chronic heart failure as a result of clinical trials has provided much enlightenment for our understanding of the fundamental biology of the disorder, a reversal of the usual flow of information from basic science to clinical investigation.

How do we make models that are useful in understanding partial epilepsies?

PubMed

Prince, David A

2014-01-01

The goals of constructing epilepsy models are (1) to develop approaches to prophylaxis of epileptogenesis following cortical injury; (2) to devise selective treatments for established epilepsies based on underlying pathophysiological mechanisms; and (3) use of a disease (epilepsy) model to explore brain molecular, cellular and circuit properties. Modeling a particular epilepsy syndrome requires detailed knowledge of key clinical phenomenology and results of human experiments that can be addressed in critically designed laboratory protocols. Contributions to understanding mechanisms and treatment of neurological disorders has often come from research not focused on a specific disease-relevant issue. Much of the foundation for current research in epilepsy falls into this category. Too strict a definition of the relevance of an experimental model to progress in preventing or curing epilepsy may, in the long run, slow progress. Inadequate exploration of the experimental target and basic laboratory results in a given model can lead to a failed effort and false negative or positive results. Models should be chosen based on the specific issues to be addressed rather than on convenience of use. Multiple variables including maturational age, species and strain, lesion type, severity and location, latency from injury to experiment and genetic background will affect results. A number of key issues in clinical and basic research in partial epilepsies remain to be addressed including the mechanisms active during the latent period following injury, susceptibility factors that predispose to epileptogenesis, injury - induced adaptive versus maladaptive changes, mechanisms of pharmaco-resistance and strategies to deal with multiple pathophysiological processes occurring in parallel.

Episodic Laryngeal Breathing Disorders: Literature Review and Proposal of Preliminary Theoretical Framework.

PubMed

Shembel, Adrianna C; Sandage, Mary J; Verdolini Abbott, Katherine

2017-01-01

The purposes of this literature review were (1) to identify and assess frameworks for clinical characterization of episodic laryngeal breathing disorders (ELBD) and their subtypes, (2) to integrate concepts from these frameworks into a novel theoretical paradigm, and (3) to provide a preliminary algorithm to classify clinical features of ELBD for future study of its clinical manifestations and underlying pathophysiological mechanisms. This is a literature review. Peer-reviewed literature from 1983 to 2015 pertaining to models for ELBD was searched using Pubmed, Ovid, Proquest, Cochrane Database of Systematic Reviews, and Google Scholar. Theoretical models for ELBD were identified, evaluated, and integrated into a novel comprehensive framework. Consensus across three salient models provided a working definition and inclusionary criteria for ELBD within the new framework. Inconsistencies and discrepancies within the models provided an analytic platform for future research. Comparison among three conceptual models-(1) Irritable larynx syndrome, (2) Dichotomous triggers, and (3) Periodic occurrence of laryngeal obstruction-showed that the models uniformly consider ELBD to involve episodic laryngeal obstruction causing dyspnea. The models differed in their description of source of dyspnea, in their inclusion of corollary behaviors, in their inclusion of other laryngeal-based behaviors (eg, cough), and types of triggers. The proposed integrated theoretical framework for ELBD provides a preliminary systematic platform for the identification of key clinical feature patterns indicative of ELBD and associated clinical subgroups. This algorithmic paradigm should evolve with better understanding of this spectrum of disorders and its underlying pathophysiological mechanisms. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Proteomic Profiling of Skin Fibroblasts as a Model of Schizophrenia.

PubMed

Wang, Lan; Rahmoune, Hassan; Guest, Paul C

2017-01-01

Since many aspects of schizophrenia are also manifested at the peripheral level in proliferating cell types, this chapter describes the analysis of skin fibroblasts biopsied from living patients. The method focuses on cell culture and sample preparation for characterization of the model. The resulting cell extracts can be analysed by any number of proteomic techniques for identification of biomarker candidates. This approach could help to elucidate the molecular mechanisms associated with the pathophysiology of schizophrenia and provide a useful model for a new target and drug discovery.

Examination of local and systemic in vivo responses to electrical injury using an electrical burn delivery system.

PubMed

Shupp, Jeffrey W; Moffatt, Lauren T; Nguyen, Thu; Ramella-Roman, Jessica C; Hammamieh, Rasha; Miller, Stacy-Ann; Leto, Ellen J; Jo, Daniel Y; Randad, Pranay R; Jett, Marti; Jeng, James C; Jordan, Marion H

2012-01-01

Electrical injuries are devastating and are difficult to manage due to the complexity of the tissue damage and physiological impacts. A paucity of literature exists which describes models for electrical injury. To date, those models have been used primarily to demonstrate thermal and morphological effects at the points of contact. Creating a more representative model for human injury and further elucidating the physics and pathophysiology of this unique form of tissue injury could be helpful in designing stage-appropriate therapy and improving limb salvage. An electrical burn delivery system was developed to accurately and reliably deliver electrical current at varying exposure times. A series of Sprague-Dawley rats were anesthetized and subjected to injury with 1000 V of direct current at incremental exposure times (2-20 seconds). Whole blood and plasma were obtained immediately before shock, immediately postinjury, and then hourly for 3 hours. Laser Doppler images of tissue adjacent to the entrance and exit wounds were obtained at the outlined time points to provide information on tissue perfusion. The electrical exposure was nonlethal in all animals. The size and the depth of contact injury increased in proportion to the exposure times and were reproducible. Skin adjacent to injury (both entrance and exit sites) exhibited marked edema within 30 minutes. In adjacent skin of upper extremity wounds, mean perfusion units increased immediately postinjury and then gradually decreased in proportion to the severity of the injuries. In the lower extremity, this phenomenon was only observed for short contact times, while longer contact times had marked malperfusion throughout. In the plasma, interleukin-10 and vascular endothelial growth factor levels were found to be augmented by injury. Systemic transcriptome analysis revealed promising information about signal networks involved in dermatological, connective tissue, and neurological pathophysiological processes. A reliable and reproducible in vivo model has been developed for characterizing the pathophysiology of high-tension electrical injury. Changes in perfusion were observed near and between entrance and exit wounds that appear consistent with injury severity. Further studies are underway to correlate differential mRNA expression with injury severity.

SU-F-I-67: Neurometabolic Effect Induced by Repeated Exposure to Dizocilpine On Prefrontal Cortex of Schizophrenic Animal Model Using In Vivo Proton Magnetic Resonance Spectroscopy at 9.4 T

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yoo, C-H; Lim, S-I; Asan Institute for Life Sciences, Asan Medical Center, Seoul

Purpose: Repeated exposure of dizocilpine (MK-801) can provide a pathophysiological model for progressive development of schizophrenia. In vivo proton magnetic resonance spectroscopy ({sup 1}H MRS) was widely used for non-invasive measurement of neurometabolites, and assessment of disease-induced neurometabolic alterations. The purpose of this study was to investigate neurometabolic alteration in prefrontal cortex (PFC) with respect to progression (from first-episode to chronic stage) of schizophrenia by using in vivo {sup 1}H MRS. Methods: We used high-field {sup 1}H MRS to investigate the neurometabolic alteration in the PFC region of the rats (N = 13) by comparing before and after 6 daymore » of MK-801 (0.5 mg/kg) treatment. A point-resolved spectroscopy (PRESS) sequence was used to obtain spectra in a 22.5 µL of volume of interest carefully located in PFC region with parameters like follow; repetition time, 5000ms; echo time (TE), 13.4 ms; averages = 256. Another experiment group (N = 11) were conducted behavior test by recording the behavior for 20 min. Results: All the rats showed hyperlocomotion, stereotyped behaviors before initiation of MRS. Significantly increased level (N = 7, p < 0.05) of N-acetylasrparate (NAA), glutamate (Glu), taurine and decreased level (N = 6, p < 0.05) of NAA, Glu and phosphocreatine were observed between baseline and day 6. Both metabolic alterations are consistent with results of first-episode and chronic schizophrenia respectively. Conclusion: From our findings, the repeated MK-801 model could be a pathophysiological model which can provide an insight into the transition from first-episode to chronic stage. This is first time to investigate effects of repeated MK-801 using high-field in vivo 1H MRS. We expect our findings can contribute to combining previous diverging results into one pathophysiological interpretation, which can postulate the origin of diverging results to the progression of schizophrenia.« less

Reclassification of clinical sleep disorders using traditional models of syndromic, neuroanatomic, pathophysiological and etiological diagnosis.

PubMed

Spitzer, A Robert

2014-09-01

Existing classifications of central nervous system sleep disorders do not often provide tools to diagnose the majority of patients complaining of sleep-related symptoms, nor always guide effective treatment. I present a novel classification system that completely separates clinical syndromes from anatomical localization, pathophysiology, and etiology. The clinical syndrome I present can describe the majority of patients, but can be fractionated into individual subgroups for further study. By then separating the anatomy and physiology from the symptoms, an avenue of research becomes available to study the different possible structures that regulate sleep, that may be damaged and cause syndromes of sleep dysfunction. Some of these may produce symptoms that overlap with narcolepsy and some may be distinct. Because the clinical syndrome should be distinguished from anatomy or physiology, I have proposed the term narcoleptiform syndrome for the clinical syndrome. The model also clearly separates etiology from anatomy in a classical neurological manner. This allows etiology, localization and symptoms to be studied separately. It is likely that different etiologies may produce damage in areas that produce similar syndromes. For example, in this model, different causes of damage to the orexin nucleus would result in the same clinical syndrome. This reinforces the concept of studying anatomy, symptoms and etiology separately. By studying the relationship of syndromes or symptoms to anatomic localization and pathophysiology, it should be possible to test novel approaches to treatment based on different underlying structure or function. For example, patients with lesions in the ventrolateral preoptic nucleus or the thalamic intralaminar nuclei may both present with insomnia symptoms but need different treatment; or they might present with symptoms overlapping narcolepsy (a narcoleptiform syndrome) yet need different treatment. In some cases, a single treatment may cross over more than one location, and the best predictor might be symptoms. These are issues that need to undergo careful study on a syndromic, anatomic and physiological bases. This novel model opens up new avenues for understanding central nervous system sleep disorders, providing testable hypotheses regarding diagnosis and treatment. Copyright © 2014 The Author. Published by Elsevier Ltd.. All rights reserved.

Sobol Sensitivity Analysis: A Tool to Guide the Development and Evaluation of Systems Pharmacology Models

PubMed Central

Trame, MN; Lesko, LJ

2015-01-01

A systems pharmacology model typically integrates pharmacokinetic, biochemical network, and systems biology concepts into a unifying approach. It typically consists of a large number of parameters and reaction species that are interlinked based upon the underlying (patho)physiology and the mechanism of drug action. The more complex these models are, the greater the challenge of reliably identifying and estimating respective model parameters. Global sensitivity analysis provides an innovative tool that can meet this challenge. CPT Pharmacometrics Syst. Pharmacol. (2015) 4, 69–79; doi:10.1002/psp4.6; published online 25 February 2015 PMID:27548289

Mathematical Modeling of Renal Hemodynamics in Physiology and Pathophysiology

PubMed Central

Sgouralis, Ioannis; Layton, Anita T.

2015-01-01

In addition to the excretion of metabolic waste and toxin, the kidney plays an indispensable role in regulating the balance of water, electrolyte, acid-base, and blood pressure. For the kidney to maintain proper functions, hemodynamic control is crucial. In this review, we describe representative mathematical models that have been developed to better understand the kidney's autoregulatory processes. We consider mathematical models that simulate glomerular filtration, and renal blood flow regulation by means of the myogenic response and tubuloglomerular feedback. We discuss the extent to which these modeling efforts have expanded the understanding of renal functions in health and disease. PMID:25765886

NOTE: Haemodynamic resistance model of monochorionic twin pregnancies complicated by acardiac twinning

NASA Astrophysics Data System (ADS)

Umur, Asli; van Gemert, Martin J. C.; van den Wijngaard, Jeroen P. H. M.; Ross, Michael G.; Nikkels, Peter G. J.

2004-07-01

An acardiac twin is a severely malformed monochorionic twin fetus that lacks most organs, particularly a heart. It grows during pregnancy, because it is perfused by its developmentally normal co-twin (called the pump twin) via a set of placental arterioarterial and venovenous anastomoses. The pump twin dies intrauterine or neonatally in about 50% of the cases due to congestive heart failure, polyhydramnios and prematurity. Because the pathophysiology of this pregnancy is currently incompletely understood, we modified our previous haemodynamic model of monochorionic twins connected by placental vascular anastomoses to include the analysis of acardiac twin pregnancies. We incorporated the fetoplacental circulation as a resistance circuit and used the fetal umbilical flow that perfuses the body to define fetal growth, rather than the placental flow as done previously. Using this modified model, we predicted that the pump twin has excess blood volume and increased mean arterial blood pressure compared to those in the acardiac twin. Placental perfusion of the acardiac twin is significantly reduced compared to normal, as a consequence of an increased venous pressure, possibly implying reduced acardiac placental growth. In conclusion, the haemodynamic analysis may contribute to an increased knowledge of the pathophysiologic consequences of an acardiac body mass for the pump twin.

Imaging of Small Animal Peripheral Artery Disease Models: Recent Advancements and Translational Potential

PubMed Central

Lin, Jenny B.; Phillips, Evan H.; Riggins, Ti’Air E.; Sangha, Gurneet S.; Chakraborty, Sreyashi; Lee, Janice Y.; Lycke, Roy J.; Hernandez, Clarissa L.; Soepriatna, Arvin H.; Thorne, Bradford R. H.; Yrineo, Alexa A.; Goergen, Craig J.

2015-01-01

Peripheral artery disease (PAD) is a broad disorder encompassing multiple forms of arterial disease outside of the heart. As such, PAD development is a multifactorial process with a variety of manifestations. For example, aneurysms are pathological expansions of an artery that can lead to rupture, while ischemic atherosclerosis reduces blood flow, increasing the risk of claudication, poor wound healing, limb amputation, and stroke. Current PAD treatment is often ineffective or associated with serious risks, largely because these disorders are commonly undiagnosed or misdiagnosed. Active areas of research are focused on detecting and characterizing deleterious arterial changes at early stages using non-invasive imaging strategies, such as ultrasound, as well as emerging technologies like photoacoustic imaging. Earlier disease detection and characterization could improve interventional strategies, leading to better prognosis in PAD patients. While rodents are being used to investigate PAD pathophysiology, imaging of these animal models has been underutilized. This review focuses on structural and molecular information and disease progression revealed by recent imaging efforts of aortic, cerebral, and peripheral vascular disease models in mice, rats, and rabbits. Effective translation to humans involves better understanding of underlying PAD pathophysiology to develop novel therapeutics and apply non-invasive imaging techniques in the clinic. PMID:25993289

Human Intestinal Enteroids: a New Model To Study Human Rotavirus Infection, Host Restriction, and Pathophysiology

PubMed Central

Saxena, Kapil; Blutt, Sarah E.; Ettayebi, Khalil; Zeng, Xi-Lei; Broughman, James R.; Crawford, Sue E.; Karandikar, Umesh C.; Sastri, Narayan P.; Conner, Margaret E.; Opekun, Antone R.; Graham, David Y.; Qureshi, Waqar; Sherman, Vadim; Foulke-Abel, Jennifer; In, Julie; Kovbasnjuk, Olga; Zachos, Nicholas C.; Donowitz, Mark

2015-01-01

ABSTRACT Human gastrointestinal tract research is limited by the paucity of in vitro intestinal cell models that recapitulate the cellular diversity and complex functions of human physiology and disease pathology. Human intestinal enteroid (HIE) cultures contain multiple intestinal epithelial cell types that comprise the intestinal epithelium (enterocytes and goblet, enteroendocrine, and Paneth cells) and are physiologically active based on responses to agonists. We evaluated these nontransformed, three-dimensional HIE cultures as models for pathogenic infections in the small intestine by examining whether HIEs from different regions of the small intestine from different patients are susceptible to human rotavirus (HRV) infection. Little is known about HRVs, as they generally replicate poorly in transformed cell lines, and host range restriction prevents their replication in many animal models, whereas many animal rotaviruses (ARVs) exhibit a broader host range and replicate in mice. Using HRVs, including the Rotarix RV1 vaccine strain, and ARVs, we evaluated host susceptibility, virus production, and cellular responses of HIEs. HRVs infect at higher rates and grow to higher titers than do ARVs. HRVs infect differentiated enterocytes and enteroendocrine cells, and viroplasms and lipid droplets are induced. Heterogeneity in replication was seen in HIEs from different patients. HRV infection and RV enterotoxin treatment of HIEs caused physiological lumenal expansion detected by time-lapse microscopy, recapitulating one of the hallmarks of rotavirus-induced diarrhea. These results demonstrate that HIEs are a novel pathophysiological model that will allow the study of HRV biology, including host restriction, cell type restriction, and virus-induced fluid secretion. IMPORTANCE Our research establishes HIEs as nontransformed cell culture models to understand human intestinal physiology and pathophysiology and the epithelial response, including host restriction of gastrointestinal infections such as HRV infection. HRVs remain a major worldwide cause of diarrhea-associated morbidity and mortality in children ≤5 years of age. Current in vitro models of rotavirus infection rely primarily on the use of animal rotaviruses because HRV growth is limited in most transformed cell lines and animal models. We demonstrate that HIEs are novel, cellularly diverse, and physiologically relevant epithelial cell cultures that recapitulate in vivo properties of HRV infection. HIEs will allow the study of HRV biology, including human host-pathogen and live, attenuated vaccine interactions; host and cell type restriction; virus-induced fluid secretion; cell-cell communication within the epithelium; and the epithelial response to infection in cultures from genetically diverse individuals. Finally, drug therapies to prevent/treat diarrheal disease can be tested in these physiologically active cultures. PMID:26446608

Effects of a Proteasome Inhibitor on Cardiomyocytes in a Pressure-Overload Hypertrophy Rat Model: An Animal Study.

PubMed

Kim, In-Sub; Jo, Won-Min

2017-06-01

The ubiquitin-proteasome system (UPS) is an important pathway of proteolysis in pathologic hypertrophic cardiomyocytes. We hypothesize that MG132, a proteasome inhibitor, might prevent hypertrophic cardiomyopathy (CMP) by blocking the UPS. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and androgen receptor (AR) have been reported to be mediators of CMP and heart failure. This study drew upon pathophysiologic studies and the analysis of NF-κB and AR to assess the cardioprotective effects of MG132 in a left ventricular hypertrophy (LVH) rat model. We constructed a transverse aortic constriction (TAC)-induced LVH rat model with 3 groups: sham (TAC-sham, n=10), control (TAC-cont, n=10), and MG132 administration (TAC-MG132, n=10). MG-132 (0.1 mg/kg) was injected for 4 weeks in the TAC-MG132 group. Pathophysiologic evaluations were performed and the expression of AR and NF-κB was measured in the left ventricle. Fibrosis was prevalent in the pathologic examination of the TAC-cont model, and it was reduced in the TAC-MG132 group, although not significantly. Less expression of AR, but not NF-κB, was found in the TAC-MG132 group than in the TAC-cont group (p<0.05). MG-132 was found to suppress AR in the TAC-CMP model by blocking the UPS, which reduced fibrosis. However, NF-κB expression levels were not related to UPS function.

Mood disorders: neurocognitive models.

PubMed

Malhi, Gin S; Byrow, Yulisha; Fritz, Kristina; Das, Pritha; Baune, Bernhard T; Porter, Richard J; Outhred, Tim

2015-12-01

In recent years, a number of neurocognitive models stemming from psychiatry and psychology schools of thought have conceptualized the pathophysiology of mood disorders in terms of dysfunctional neural mechanisms that underpin and drive neurocognitive processes. Though these models have been useful for advancing our theoretical understanding and facilitating important lines of research, translation of these models and their application within the clinical arena have been limited-partly because of lack of integration and synthesis. Cognitive neuroscience provides a novel perspective for understanding and modeling mood disorders. This selective review of influential neurocognitive models develops an integrative approach that can serve as a template for future research and the development of a clinically meaningful framework for investigating, diagnosing, and treating mood disorders. A selective literature search was conducted using PubMed and PsychINFO to identify prominent neurobiological and neurocognitive models of mood disorders. Most models identify similar neural networks and brain regions and neuropsychological processes in the neurocognition of mood, however, they differ in terms of specific functions attached to neural processes and how these interact. Furthermore, cognitive biases, reward processing and motivation, rumination, and mood stability, which play significant roles in the manner in which attention, appraisal, and response processes are deployed in mood disorders, are not sufficiently integrated. The inclusion of interactions between these additional components enhances our understanding of the etiology and pathophysiology of mood disorders. Through integration of key cognitive functions and understanding of how these interface with neural functioning within neurocognitive models of mood disorders, a framework for research can be created for translation to diagnosis and treatment of mood disorders. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Small animal models of cardiovascular disease: tools for the study of the roles of metabolic syndrome, dyslipidemia, and atherosclerosis.

PubMed

Russell, James C; Proctor, Spencer D

2006-01-01

Cardiovascular disease, the leading cause of death in much of the modern world, is the common symptomatic end stage of a number of distinct diseases and, therefore, is multifactorial and polygenetic in character. The two major underlying causes are disorders of lipid metabolism and metabolic syndrome. The ability to develop preventative and ameliorative treatments will depend on animal models that mimic human disease processes. The focus of this review is to identify suitable animal models and insights into cardiovascular disease achieved to date using such models. The ideal animal model of cardiovascular disease will mimic the human subject metabolically and pathophysiologically, will be large enough to permit physiological and metabolic studies, and will develop end-stage disease comparable to those in humans. Given the complex multifactorial nature of cardiovascular disease, no one species will be suitable for all studies. Potential larger animal models are problematic due to cost, ethical considerations, or poor pathophysiological comparability to humans. Rabbits require high-cholesterol diets to develop cardiovascular disease, and there are no rabbit models of metabolic syndrome. Spontaneous mutations in rats provide several complementary models of obesity, hyperlipidemia, insulin resistance, and type 2 diabetes, one of which spontaneously develops cardiovascular disease and ischemic lesions. The mouse, like normal rats, is characteristically resistant to cardiovascular disease, although genetically altered strains respond to cholesterol feeding with atherosclerosis, but not with end-stage ischemic lesions. The most useful and valid species/strains for the study of cardiovascular disease appear to be small rodents, rats, and mice. This fragmented field would benefit from a consensus on well-characterized appropriate models for the study of different aspects of cardiovascular disease and a renewed emphasis on the biology of underlying diseases.

Imaging Alzheimer's disease pathophysiology with PET

PubMed Central

Schilling, Lucas Porcello; Zimmer, Eduardo R.; Shin, Monica; Leuzy, Antoine; Pascoal, Tharick A.; Benedet, Andréa L.; Borelli, Wyllians Vendramini; Palmini, André; Gauthier, Serge; Rosa-Neto, Pedro

2016-01-01

ABSTRACT Alzheimer's disease (AD) has been reconceptualised as a dynamic pathophysiological process characterized by preclinical, mild cognitive impairment (MCI), and dementia stages. Positron emission tomography (PET) associated with various molecular imaging agents reveals numerous aspects of dementia pathophysiology, such as brain amyloidosis, tau accumulation, neuroreceptor changes, metabolism abnormalities and neuroinflammation in dementia patients. In the context of a growing shift toward presymptomatic early diagnosis and disease-modifying interventions, PET molecular imaging agents provide an unprecedented means of quantifying the AD pathophysiological process, monitoring disease progression, ascertaining whether therapies engage their respective brain molecular targets, as well as quantifying pharmacological responses. In the present study, we highlight the most important contributions of PET in describing brain molecular abnormalities in AD. PMID:29213438

Tone-Evoked Acoustic Change Complex (ACC) Recorded in a Sedated Animal Model.

PubMed

Presacco, Alessandro; Middlebrooks, John C

2018-05-10

The acoustic change complex (ACC) is a scalp-recorded cortical evoked potential complex generated in response to changes (e.g., frequency, amplitude) in an auditory stimulus. The ACC has been well studied in humans, but to our knowledge, no animal model has been evaluated. In particular, it was not known whether the ACC could be recorded under the conditions of sedation that likely would be necessary for recordings from animals. For that reason, we tested the feasibility of recording ACC from sedated cats in response to changes of frequency and amplitude of pure-tone stimuli. Cats were sedated with ketamine and acepromazine, and subdermal needle electrodes were used to record electroencephalographic (EEG) activity. Tones were presented from a small loudspeaker located near the right ear. Continuous tones alternated at 500-ms intervals between two frequencies or two levels. Neurometric functions were created by recording neural response amplitudes while systematically varying the magnitude of steps in frequency centered in octave frequency around 2, 4, 8, and 16 kHz, all at 75 dB SPL, or in decibel level around 75 dB SPL tested at 4 and 8 kHz. The ACC could be recorded readily under this ketamine/azepromazine sedation. In contrast, ACC could not be recorded reliably under any level of isoflurane anesthesia that was tested. The minimum frequency (expressed as Weber fractions (df/f)) or level steps (expressed in dB) needed to elicit ACC fell in the range of previous thresholds reported in animal psychophysical tests of discrimination. The success in recording ACC in sedated animals suggests that the ACC will be a useful tool for evaluation of other aspects of auditory acuity in normal hearing and, presumably, in electrical cochlear stimulation, especially for novel stimulation modes that are not yet feasible in humans.

EGFR transactivation: mechanisms, pathophysiology and potential therapies in cardiovascular system

PubMed Central

Forrester, Steven J.; Kawai, Tatsuo; Elliott, Katherine J.; O’Brien, Shannon; Thomas, Walter; Harris, Raymond C.; Eguchi, Satoru

2017-01-01

Accumulating studies suggest that the epidermal growth factor receptor (EGFR) activation is associated with the physiology and pathophysiology of the cardiovascular system, and inhibition of EGFR activity is emerging as a potential therapeutic strategy to treat diseases, including hypertension, cardiac hypertrophy, renal fibrosis and abdominal aortic aneurysm. The capacity of G protein-coupled receptor (GPCR) agonists, such as angiotensin II (AngII), to promote EGFR signaling is well described – a process termed EGFR “transactivation” – yet delineating the molecular processes and functional relevance of this crosstalk has been challenging. Moreover, these critical findings are dispersed among many different fields. The aim of our review is to highlight the recent advancement of the signaling cascades and downstream consequences of EGFR transactivation within the cardiovascular renal system in vitro and in vivo. We will also focus on linking EGFR transactivation to animal models of the disease as well as the potential therapeutic applications. PMID:26566153

Thrombosis in Philadelphia negative classical myeloproliferative neoplasms: a narrative review on epidemiology, risk assessment, and pathophysiologic mechanisms.

PubMed

Ball, Somedeb; Thein, Kyaw Zin; Maiti, Abhishek; Nugent, Kenneth

2018-05-01

Thrombosis is common in cancer patients and is associated with increased morbidity and mortality. Myeloproliferative neoplasms (MPN) are common malignancies in elderly individuals and are known for a high incidence of thrombotic complications. Different risk factors have been identified in studies, and risk models have been developed to identify patients with MPN at higher risk for thrombosis. Several pathophysiological mechanisms help explain the increased likelihood of thrombosis in these patients. Factors, such as leukocyte and platelet activation leading to the formation of leukocyte-platelet aggregates, activation of the coagulation cascade by microparticles, high levels of inflammatory cytokines, and endothelial dysfunction have a crucial role in thrombosis in MPN patients. Recent studies have demonstrated a significant association between the allele burden of specific genetic mutations (mainly JAK2V617F) associated with MPN and the incidence of thrombotic events, thus suggesting a possible role for these mutations in thrombogenesis.

Inflammatory fatigue and sickness behaviour - lessons for the diagnosis and management of chronic fatigue syndrome.

PubMed

Arnett, S V; Clark, I A

2012-12-10

Persistent and severe fatigue is a common part of the presentation of a diverse range of disease processes. There is a growing body of evidence indicating a common inflammatory pathophysiology underlying many conditions where fatigue is a primary patient concern, including chronic fatigue syndrome. This review explores current models of how inflammatory mediators act on the central nervous system to produce fatigue and sickness behaviour, and the commonality of these processes in conditions as diverse as surgical trauma, infection, various cancers, inflammatory bowel disease, connective tissue diseases and autoimmune diseases. We also discuss evidence indicating chronic fatigue syndrome may have important pathophysiological similarities with cytokine mediated sickness behaviour, and what lessons can be applied from sickness behaviour to chronic fatigue syndrome with regards to the diagnosis and management. Copyright © 2012 Elsevier B.V. All rights reserved.

Impaired Functional Connectivity in the Prefrontal Cortex: A Mechanism for Chronic Stress-Induced Neuropsychiatric Disorders

PubMed Central

Negrón-Oyarzo, Ignacio; Aboitiz, Francisco; Fuentealba, Pablo

2016-01-01

Chronic stress-related psychiatric diseases, such as major depression, posttraumatic stress disorder, and schizophrenia, are characterized by a maladaptive organization of behavioral responses that strongly affect the well-being of patients. Current evidence suggests that a functional impairment of the prefrontal cortex (PFC) is implicated in the pathophysiology of these diseases. Therefore, chronic stress may impair PFC functions required for the adaptive orchestration of behavioral responses. In the present review, we integrate evidence obtained from cognitive neuroscience with neurophysiological research with animal models, to put forward a hypothesis that addresses stress-induced behavioral dysfunctions observed in stress-related neuropsychiatric disorders. We propose that chronic stress impairs mechanisms involved in neuronal functional connectivity in the PFC that are required for the formation of adaptive representations for the execution of adaptive behavioral responses. These considerations could be particularly relevant for understanding the pathophysiology of chronic stress-related neuropsychiatric disorders. PMID:26904302

Clinical and Biochemical Manifestations of Depression: Relation to the Neurobiology of Stress

PubMed Central

Gold, Phillip W.; Machado-Vieira, Rodrigo; Pavlatou, Maria G.

2015-01-01

Major depressive disorder (MDD) is a chronic, recurrent, and severe psychiatric disorder with high mortality and medical comorbidities. Stress-related pathways have been directly involved in the pathophysiology and treatment of MDD. The present paper provides an overview on the stress system as a model to understand key pathophysiological paradigms in MDD. These mechanisms involve behavioral, cognitive, and systemic manifestations and are also associated with the mechanisms of action of effective antidepressants. Aspects such as depression subtypes, inflammation, insulin resistance, oxidative stress, and prothrombotic states in critical brain circuits and periphery are critically appraised. Finally, new strategies for approaching treatment-resistant major depression and potential adverse effects associated with this complex and intricate network are highlighted. The authors used PubMed as the database for this review. Each author extracted relevant data and assessed the methodological quality of each study. PMID:25878903

Current concepts in the pathophysiology, evaluation, and diagnosis of compartment syndrome

NASA Technical Reports Server (NTRS)

Hargens, A. R.; Mubarak, S. J.

1998-01-01

This article reviews present knowledge of the pathophysiology and diagnosis of acute compartment syndromes. Recent results using compression of legs in normal volunteers provide objective data concerning local pressure thresholds for neuromuscular dysfunction in the anterior compartment. Results with this model indicate that a progression of neuromuscular deficits occurs when IMP increases to within 35 to 40 mm Hg of diastolic blood pressure. These findings provide useful information on the diagnosis and compression thresholds for acute compartment syndromes. Time factors are also important, however, and usually are incompletely known in most cases of acute compartment syndrome. Although the slit catheter is a very good technique for monitoring IMP during rest, these catheters and their associated extracorporeal transducer systems are not ideal. Recently developed miniature transducer-tipped catheters and, perhaps, future development of noninvasive techniques may provide accurate recordings of IMP in patients with acute compartment syndromes.

CHRONIC PERIPHERAL NERVE COMPRESSION DISRUPTS PARANODAL AXOGLIAL JUNCTIONS

PubMed Central

Otani, Yoshinori; Yermakov, Leonid M.; Dupree, Jeffrey L.; Susuki, Keiichiro

2016-01-01

Introduction Peripheral nerves are often exposed to mechanical stress leading to compression neuropathies. The pathophysiology underlying nerve dysfunction by chronic compression is largely unknown. Methods We analyzed molecular organization and fine structures at and near nodes of Ranvier in a compression neuropathy model in which a silastic tube was placed around the mouse sciatic nerve. Results Immunofluorescence study showed that clusters of cell adhesion complex forming paranodal axoglial junctions were dispersed with frequent overlap with juxtaparanodal components. These paranodal changes occurred without internodal myelin damage. The distribution and pattern of paranodal disruption suggests that these changes are the direct result of mechanical stress. Electron microscopy confirmed loss of paranodal axoglial junctions. Discussion Our data show that chronic nerve compression disrupts paranodal junctions and axonal domains required for proper peripheral nerve function. These results provide important clues toward better understanding of the pathophysiology underlying nerve dysfunction in compression neuropathies. PMID:27463510

Physiological phenotyping of dementias using emotional sounds.

PubMed

Fletcher, Phillip D; Nicholas, Jennifer M; Shakespeare, Timothy J; Downey, Laura E; Golden, Hannah L; Agustus, Jennifer L; Clark, Camilla N; Mummery, Catherine J; Schott, Jonathan M; Crutch, Sebastian J; Warren, Jason D

2015-06-01

Emotional behavioral disturbances are hallmarks of many dementias but their pathophysiology is poorly understood. Here we addressed this issue using the paradigm of emotionally salient sounds. Pupil responses and affective valence ratings for nonverbal sounds of varying emotional salience were assessed in patients with behavioral variant frontotemporal dementia (bvFTD) (n = 14), semantic dementia (SD) (n = 10), progressive nonfluent aphasia (PNFA) (n = 12), and AD (n = 10) versus healthy age-matched individuals (n = 26). Referenced to healthy individuals, overall autonomic reactivity to sound was normal in Alzheimer's disease (AD) but reduced in other syndromes. Patients with bvFTD, SD, and AD showed altered coupling between pupillary and affective behavioral responses to emotionally salient sounds. Emotional sounds are a useful model system for analyzing how dementias affect the processing of salient environmental signals, with implications for defining pathophysiological mechanisms and novel biomarker development.

Pathophysiologic Mechanisms in Heart Failure: Role of the Sympathetic Nervous System.

PubMed

Antoine, Steve; Vaidya, Gaurang; Imam, Haider; Villarreal, Daniel

2017-01-01

The syndrome of heart failure involves complex pathophysiologic mechanisms and is associated with extremely high-morbidity, mortality and economic costs. This growing global epidemic has diverse etiologies and is fundamentally characterized by dyshomeostasis between heart and kidneys, leading to development and progression of the cardiorenal syndrome. Excessive and sustained sympathoexcitation has emerged as a single prominent factor involved in the structural and functional dysfunction of multiple organ systems during this disease. Studies in experimental models of heart failure indicate that ablation of the renal nerves may help restore renal sodium and water equilibrium as well as the attenuation of adverse cardiac remodeling. With the recent development of minimally invasive endovascular renal denervation in humans, it is anticipated that this technology would become a novel and important paradigm shift in the management of heart failure. Copyright © 2017. Published by Elsevier Inc.

The ALFA project: A research platform to identify early pathophysiological features of Alzheimer's disease.

PubMed

Molinuevo, José Luis; Gramunt, Nina; Gispert, Juan Domingo; Fauria, Karine; Esteller, Manel; Minguillon, Carolina; Sánchez-Benavides, Gonzalo; Huesa, Gema; Morán, Sebastián; Dal-Ré, Rafael; Camí, Jordi

2016-06-01

The preclinical phase of Alzheimer's disease (AD) is optimal for identifying early pathophysiological events and developing prevention programs, which are shared aims of the ALFA project, including the ALFA registry and parent cohort and the nested ALFA+ cohort study. The ALFA parent cohort baseline visit included full cognitive evaluation, lifestyle habits questionnaires, DNA extraction, and MRI. The nested ALFA+ study adds wet and imaging biomarkers for deeper phenotyping. A total of 2743 participants aged 45 to 74 years were included in the ALFA parent cohort. We show that this cohort, mostly composed of cognitively normal offspring of AD patients, is enriched for AD genetic risk factors. The ALFA project represents a valuable infrastructure that will leverage with different studies and trials to prevent AD. The longitudinal ALFA+ cohort will serve to untangle the natural history of the disease and to model the preclinical stages to develop successful trials.

Pulmonary alveolar proteinosis: a pediatric case study.

PubMed

Thompson, C T; Tirone, P A

2000-01-01

Pulmonary alveolar proteinosis (PAP) is a rare, debilitating, sometimes fatal disease of uncertain etiology and pathophysiology. The medical literature defines the illness and describes current theories related to its pathophysiology. Little nursing literature addresses PAP. This case study describes and discusses nursing interventions utilized in the home management of a young, female adolescent with this illness. A retrospective analysis of the chart reveals investigative treatment involving daily subcutaneous injections of bacterially synthesized, granulocyte-macrophage colony-stimulating factor. Communication and collaboration among health care providers and identification of diverse issues influencing the health of the client resulted in the development of effective nursing interventions. Leininger's Theory of Transcultural Care Diversity and Universality provides a model for interpretation and generalization of nursing interventions. PAP can be managed successfully in the home, but more information on the illness and ethnic and age-specific responses to treatment is needed.

[Circadian blood pressure variation under several pathophysiological conditions including secondary hypertension].

PubMed

Imai, Yutaka; Hosaka, Miki; Satoh, Michihiro

2014-08-01

Abnormality of circadian blood pressure (BP) variation, i.e. non-dipper, riser, nocturnal hypertension etc, is brought by several pathophysiological conditions especially by secondary hypertension. These pathophysiological conditions are classified into several categories, i.e. disturbance of autonomic nervous system, metabolic disorder, endocrine disorder, disorder of Na and water excretion (e.g. sodium sensitivity), severe target organ damage and ischemia, cardiovascular complications and drug induced hypertension. Each pathophysiological condition which brings disturbance of circadian BP variation is included in several categories, e.g. diabetes mellitus is included in metabolic disorder, autonomic imbalance, sodium sensitivity and endocrine disorder. However, it seems that unified principle of the genesis of disturbance of circadian BP variation in many pathophysiological conditions is autonomic imbalance. Thus, it is concluded that disturbance of circadian BP variation is not purposive biological behavior but the result of autonomic imbalance which looks as if compensatory reaction such as exaggerated Na-water excretion during night in patient with Na-water retention who reveals disturbed circadian BP variation.

The rise of pathophysiologic research in the United States: the role of two Harvard hospitals.

PubMed

Tishler, Peter V

2013-01-01

Pathophysiologic research, the major approach to understanding and treating disease, was created in the 20th century, and two Harvard-affiliated hospitals, the Peter Bent Brigham Hospital and Boston City Hospital, played a key role in its development. After the Flexner Report of 1910, medical students were assigned clinical clerkships in teaching hospitals. Rockefeller-trained Francis Weld Peabody, who was committed to investigative, pathophysiologic research, was a critical leader in these efforts. At the Brigham, Harvard medical students observed patients closely and asked provocative questions about their diseases. Additionally, physicians returned from World War I with questions concerning the pathophysiology of wartime injuries. At the Boston City Hospital's new Thorndike Memorial Laboratory, Peabody fostered investigative question-based research by physicians. These physicians expanded pathophysiologic investigation from the 1920s. Post-war, Watson and Crick's formulation of the structure of DNA led shortly to modern molecular biology and new research approaches that are being furthered at the Boston Hospitals.

Urinary proteomics in renal pathophysiology: Impact of proteinuria.

PubMed

Sancho-Martínez, Sandra M; Prieto-García, Laura; Blanco-Gozalo, Víctor; Fontecha-Barriuso, Miguel; López-Novoa, José M; López-Hernández, Francisco J

2015-06-01

Urinary differential proteomics is used to study renal pathophysiological mechanisms, find novel markers of biological processes and renal diseases, and stratify patients according to proteomic profiles. The proteomic procedure determines the pathophysiological meaning and clinical relevance of results. Urine samples for differential proteomic studies are usually normalized by protein content, regardless of its pathophysiological characteristics. In the field of nephrology, this approach translates into the comparison of a different fraction of the total daily urine output between proteinuric and nonproteinuric samples. Accordingly, alterations in the level of specific proteins found by this method reflect the relative presence of individual proteins in the urine; but they do not necessarily show alterations in their daily excretion, which is a key parameter for the understanding of the pathophysiological meaning of urinary components. For renal pathophysiology studies and clinical biomarker identification or determination, an alternative proteomic concept providing complementary information is based on sample normalization by daily urine output, which directly informs on changes in the daily excretion of individual proteins. This is clinically important because daily excretion (rather than absolute or relative concentration) is the only self-normalized way to evaluate the real meaning of urinary parameters, which is also independent of urine concentration. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

3D modeling of cancer stem cell niche

PubMed Central

He, Jun; Xiong, Li; Li, Qinglong; Lin, Liangwu; Miao, Xiongying; Yan, Shichao; Hong, Zhangyong; Yang, Leping; Wen, Yu; Deng, Xiyun

2018-01-01

Cancer stem cells reside in a distinct microenvironment called niche. The reciprocal interactions between cancer stem cells and niche contribute to the maintenance and enrichment of cancer stem cells. In order to simulate the interactions between cancer stem cells and niche, three-dimensional models have been developed. These in vitro culture systems recapitulate the spatial dimension, cellular heterogeneity, and the molecular networks of the tumor microenvironment and show great promise in elucidating the pathophysiology of cancer stem cells and designing more clinically relavant treatment modalites. PMID:29416698

Mechanisms of Comorbidities Associated With the Metabolic Syndrome: Insights from the JCR:LA-cp Corpulent Rat Strain.

PubMed

Diane, Abdoulaye; Pierce, W David; Kelly, Sandra E; Sokolik, Sharon; Borthwick, Faye; Jacome-Sosa, Miriam; Mangat, Rabban; Pradillo, Jesus Miguel; Allan, Stuart McRae; Ruth, Megan R; Field, Catherine J; Hutcheson, Rebecca; Rocic, Petra; Russell, James C; Vine, Donna F; Proctor, Spencer D

2016-01-01

Obesity and its metabolic complications have emerged as the epidemic of the new millennia. The use of obese rodent models continues to be a productive component of efforts to understand the concomitant metabolic complications of this disease. In 1978, the JCR:LA-cp rat model was developed with an autosomal recessive corpulent ( cp ) trait resulting from a premature stop codon in the extracellular domain of the leptin receptor. Rats that are heterozygous for the cp trait are lean-prone, while those that are homozygous ( cp/cp ) spontaneously display the pathophysiology of obesity as well as a metabolic syndrome (MetS)-like phenotype. Over the years, there have been formidable scientific contributions that have originated from this rat model, much of which has been reviewed extensively up to 2008. The premise of these earlier studies focused on characterizing the pathophysiology of MetS-like phenotype that was spontaneously apparent in this model. The purpose of this review is to highlight areas of recent advancement made possible by this model including; emerging appreciation of the "thrifty gene" hypothesis in the context of obesity, the concept of how chronic inflammation may drive obesogenesis, the impact of acute forms of inflammation to the brain and periphery during chronic obesity, the role of dysfunctional insulin metabolism on lipid metabolism and vascular damage, and the mechanistic basis for altered vascular function as well as novel parallels between the human condition and the female JCR:LA-cp rat as a model for polycystic ovary disease (PCOS).

Animal models for Ebola and Marburg virus infections

PubMed Central

Nakayama, Eri; Saijo, Masayuki

2013-01-01

Ebola and Marburg hemorrhagic fevers (EHF and MHF) are caused by the Filoviridae family, Ebolavirus and Marburgvirus (ebolavirus and marburgvirus), respectively. These severe diseases have high mortality rates in humans. Although EHF and MHF are endemic to sub-Saharan Africa. A novel filovirus, Lloviu virus, which is genetically distinct from ebolavirus and marburgvirus, was recently discovered in Spain where filoviral hemorrhagic fever had never been reported. The virulence of this virus has not been determined. Ebolavirus and marburgvirus are classified as biosafety level-4 (BSL-4) pathogens and Category A agents, for which the US government requires preparedness in case of bioterrorism. Therefore, preventive measures against these viral hemorrhagic fevers should be prepared, not only in disease-endemic regions, but also in disease-free countries. Diagnostics, vaccines, and therapeutics need to be developed, and therefore the establishment of animal models for EHF and MHF is invaluable. Several animal models have been developed for EHF and MHF using non-human primates (NHPs) and rodents, which are crucial to understand pathophysiology and to develop diagnostics, vaccines, and therapeutics. Rhesus and cynomolgus macaques are representative models of filovirus infection as they exhibit remarkably similar symptoms to those observed in humans. However, the NHP models have practical and ethical problems that limit their experimental use. Furthermore, there are no inbred and genetically manipulated strains of NHP. Rodent models such as mouse, guinea pig, and hamster, have also been developed. However, these rodent models require adaptation of the virus to produce lethal disease and do not mirror all symptoms of human filovirus infection. This review article provides an outline of the clinical features of EHF and MHF in animals, including humans, and discusses how the animal models have been developed to study pathophysiology, vaccines, and therapeutics. PMID:24046765

Animal models for Ebola and Marburg virus infections.

PubMed

Nakayama, Eri; Saijo, Masayuki

2013-09-05

Ebola and Marburg hemorrhagic fevers (EHF and MHF) are caused by the Filoviridae family, Ebolavirus and Marburgvirus (ebolavirus and marburgvirus), respectively. These severe diseases have high mortality rates in humans. Although EHF and MHF are endemic to sub-Saharan Africa. A novel filovirus, Lloviu virus, which is genetically distinct from ebolavirus and marburgvirus, was recently discovered in Spain where filoviral hemorrhagic fever had never been reported. The virulence of this virus has not been determined. Ebolavirus and marburgvirus are classified as biosafety level-4 (BSL-4) pathogens and Category A agents, for which the US government requires preparedness in case of bioterrorism. Therefore, preventive measures against these viral hemorrhagic fevers should be prepared, not only in disease-endemic regions, but also in disease-free countries. Diagnostics, vaccines, and therapeutics need to be developed, and therefore the establishment of animal models for EHF and MHF is invaluable. Several animal models have been developed for EHF and MHF using non-human primates (NHPs) and rodents, which are crucial to understand pathophysiology and to develop diagnostics, vaccines, and therapeutics. Rhesus and cynomolgus macaques are representative models of filovirus infection as they exhibit remarkably similar symptoms to those observed in humans. However, the NHP models have practical and ethical problems that limit their experimental use. Furthermore, there are no inbred and genetically manipulated strains of NHP. Rodent models such as mouse, guinea pig, and hamster, have also been developed. However, these rodent models require adaptation of the virus to produce lethal disease and do not mirror all symptoms of human filovirus infection. This review article provides an outline of the clinical features of EHF and MHF in animals, including humans, and discusses how the animal models have been developed to study pathophysiology, vaccines, and therapeutics.

Concepts of scientific integrative medicine applied to the physiology and pathophysiology of catecholamine systems.

PubMed

Goldstein, David S

2013-10-01

This review presents concepts of scientific integrative medicine and relates them to the physiology of catecholamine systems and to the pathophysiology of catecholamine-related disorders. The applications to catecholamine systems exemplify how scientific integrative medicine links systems biology with integrative physiology. Concepts of scientific integrative medicine include (i) negative feedback regulation, maintaining stability of the body's monitored variables; (ii) homeostats, which compare information about monitored variables with algorithms for responding; (iii) multiple effectors, enabling compensatory activation of alternative effectors and primitive specificity of stress response patterns; (iv) effector sharing, accounting for interactions among homeostats and phenomena such as hyperglycemia attending gastrointestinal bleeding and hyponatremia attending congestive heart failure; (v) stress, applying a definition as a state rather than as an environmental stimulus or stereotyped response; (vi) distress, using a noncircular definition that does not presume pathology; (vii) allostasis, corresponding to adaptive plasticity of feedback-regulated systems; and (viii) allostatic load, explaining chronic degenerative diseases in terms of effects of cumulative wear and tear. From computer models one can predict mathematically the effects of stress and allostatic load on the transition from wellness to symptomatic disease. The review describes acute and chronic clinical disorders involving catecholamine systems-especially Parkinson disease-and how these concepts relate to pathophysiology, early detection, and treatment and prevention strategies in the post-genome era. Published 2013. Compr Physiol 3:1569-1610, 2013.

Studies on the Pathophysiology and Genetic Basis of Migraine

PubMed Central

Gasparini, Claudia F; Sutherland, Heidi G.; Griffiths, Lyn R

2013-01-01

Migraine is a neurological disorder that affects the central nervous system causing painful attacks of headache. A genetic vulnerability and exposure to environmental triggers can influence the migraine phenotype. Migraine interferes in many facets of people’s daily life including employment commitments and their ability to look after their families resulting in a reduced quality of life. Identification of the biological processes that underlie this relatively common affliction has been difficult because migraine does not have any clearly identifiable pathology or structural lesion detectable by current medical technology. Theories to explain the symptoms of migraine have focused on the physiological mechanisms involved in the various phases of headache and include the vascular and neurogenic theories. In relation to migraine pathophysiology the trigeminovascular system and cortical spreading depression have also been implicated with supporting evidence from imaging studies and animal models. The objective of current research is to better understand the pathways and mechanisms involved in causing pain and headache to be able to target interventions. The genetic component of migraine has been teased apart using linkage studies and both candidate gene and genome-wide association studies, in family and case-control cohorts. Genomic regions that increase individual risk to migraine have been identified in neurological, vascular and hormonal pathways. This review discusses knowledge of the pathophysiology and genetic basis of migraine with the latest scientific evidence from genetic studies. PMID:24403849

Concepts of Scientific Integrative Medicine Applied to the Physiology and Pathophysiology of Catecholamine Systems

PubMed Central

Goldstein, David S.

2016-01-01

This review presents concepts of scientific integrative medicine and relates them to the physiology of catecholamine systems and to the pathophysiology of catecholamine-related disorders. The applications to catecholamine systems exemplify how scientific integrative medicine links systems biology with integrative physiology. Concepts of scientific integrative medicine include (i) negative feedback regulation, maintaining stability of the body’s monitored variables; (ii) homeostats, which compare information about monitored variables with algorithms for responding; (iii) multiple effectors, enabling compensatory activation of alternative effectors and primitive specificity of stress response patterns; (iv) effector sharing, accounting for interactions among homeostats and phenomena such as hyperglycemia attending gastrointestinal bleeding and hyponatremia attending congestive heart failure; (v) stress, applying a definition as a state rather than as an environmental stimulus or stereotyped response; (vi) distress, using a noncircular definition that does not presume pathology; (vii) allostasis, corresponding to adaptive plasticity of feedback-regulated systems; and (viii) allostatic load, explaining chronic degenerative diseases in terms of effects of cumulative wear and tear. From computer models one can predict mathematically the effects of stress and allostatic load on the transition from wellness to symptomatic disease. The review describes acute and chronic clinical disorders involving catecholamine systems—especially Parkinson disease—and how these concepts relate to pathophysiology, early detection, and treatment and prevention strategies in the post-genome era. PMID:24265239

Early-onset and classical forms of type 2 diabetes show impaired expression of genes involved in muscle branched-chain amino acids metabolism.

PubMed

Hernández-Alvarez, María Isabel; Díaz-Ramos, Angels; Berdasco, María; Cobb, Jeff; Planet, Evarist; Cooper, Diane; Pazderska, Agnieszka; Wanic, Krzystof; O'Hanlon, Declan; Gomez, Antonio; de la Ballina, Laura R; Esteller, Manel; Palacin, Manuel; O'Gorman, Donal J; Nolan, John J; Zorzano, Antonio

2017-10-23

The molecular mechanisms responsible for the pathophysiological traits of type 2 diabetes are incompletely understood. Here we have performed transcriptomic analysis in skeletal muscle, and plasma metabolomics from subjects with classical and early-onset forms of type 2 diabetes (T2D). Focused studies were also performed in tissues from ob/ob and db/db mice. We document that T2D, both early and late onset, are characterized by reduced muscle expression of genes involved in branched-chain amino acids (BCAA) metabolism. Weighted Co-expression Networks Analysis provided support to idea that the BCAA genes are relevant in the pathophysiology of type 2 diabetes, and that mitochondrial BCAA management is impaired in skeletal muscle from T2D patients. In diabetic mice model we detected alterations in skeletal muscle proteins involved in BCAA metabolism but not in obese mice. Metabolomic analysis revealed increased levels of branched-chain keto acids (BCKA), and BCAA in plasma of T2D patients, which may result from the disruption of muscle BCAA management. Our data support the view that inhibition of genes involved in BCAA handling in skeletal muscle takes place as part of the pathophysiology of type 2 diabetes, and this occurs both in early-onset and in classical type 2 diabetes.

[Pathophysiology of hypertension : What are our current concepts?].

PubMed

Jordan, J

2015-03-01

In the year 2015, many questions regarding the pathophysiology of essential arterial hypertension remain unresolved. Substantial scientific progress has been made in various medical areas aided by novel molecular"omics" techniques. The findings could then be implemented in diagnostic and therapeutic procedures. In the field of hypertension research such methods have been applied in very large cohorts but have contributed less to pathophysiological understanding and clinical management than expected. The findings on the pathophysiological importance of baroreflex mechanisms, natriuretic peptides and osmotically inactive sodium storage discussed in this article all have something in common: all are based on small, carefully conducted human physiological investigations and often challenge current textbook knowledge. Nevertheless, these findings have opened up new research fields and are likely to affect clinical care.

Investigation of Antiangiogenic Mechanisms Using Novel Imaging Techniques

DTIC Science & Technology

2010-02-01

of the tumor environment can sensitize the tumor to conventional cytotoxic therapies. To this end, we employ the window chamber model to optically ...facilitate longitudinal, in vivo investigation into the parameters of interest. These include Doppler Optical Coherence Tomography for the measurement of... Optical Techniques, Tumor Pathophysiology, Treatment Response, Vascular Normalization 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18

[Pathophysiology of hormonal, immune, metabolic changes in acute and chronic pancreatitis. Experimental and clinical studies].

PubMed

Trubitsyna, I E; Chikunova, B Z; Tkachenko, E V; Tsaregorodtseva, T M; Vinokurova, L V; Varvanina, G G

2008-01-01

There is literature review of the acute and chronic pancreatitis experimental models. Patogenetic necrosis mechanisms with fibrosis progress in pancreas were revealed. The stimulation of the proteolytic enzymes synthesis and secretion, that was examined in experiments were compared with clinical examinations. The patients with chronic pancreatitis were investigated in the Central Research Institute of Gastroenterology.

[Physiopathology of overactive bladder syndrome].

PubMed

Sacco, Emilio

2012-01-01

The pathophysiology of OAB is complex, multifactorial and still largely unknown. Several pathophysiological mechanisms have been highlighted that may play a different role in different patient groups. There are now experimental evidences that support both the myogenic and neurogenic hypothesis, but in recent years the "integrative" hypothesis has been gaining more and more acceptance, where a disruption in the multiple interactions between different cell types (neurons, urothelium, interstitial cells, myocytes) and network functions represent a central element of lower urinary tract dysfunctions. Of utmost importance, a disorder in the urothelial sensory function and in the urothelial/suburothelial non-neural cholinergic system, favored by age and comorbidities, appears to be crucial for the development of the OAB. Neuroplastic and detrusor changes in OAB are broadly similar to those observed in bladders exposed to outlet obstruction, neuropathies, inflammation or aging, and may be driven by a common urothelial dysfunction. Several signaling substances and their receptors were found to be involved in central pathways of bidirectional communication between the different cell types in the bladder, and were shown to be modified in several animal models of OAB as well as in human models, indicating new potential therapeutic targets.

A calixpyrrole derivative acts as an antagonist to GPER, a G-protein coupled receptor: mechanisms and models

PubMed Central

Lappano, Rosamaria; Rosano, Camillo; Pisano, Assunta; Santolla, Maria Francesca; De Francesco, Ernestina Marianna; De Marco, Paola; Dolce, Vincenza; Ponassi, Marco; Felli, Lamberto; Cafeo, Grazia; Kohnke, Franz Heinrich; Abonante, Sergio; Maggiolini, Marcello

2015-01-01

ABSTRACT Estrogens regulate numerous pathophysiological processes, mainly by binding to and activating estrogen receptor (ER)α and ERβ. Increasing amounts of evidence have recently demonstrated that G-protein coupled receptor 30 (GPR30; also known as GPER) is also involved in diverse biological responses to estrogens both in normal and cancer cells. The classical ER and GPER share several features, including the ability to bind to identical compounds; nevertheless, some ligands exhibit opposed activity through these receptors. It is worth noting that, owing to the availability of selective agonists and antagonists of GPER for research, certain differential roles elicited by GPER compared with ER have been identified. Here, we provide evidence on the molecular mechanisms through which a calixpyrrole derivative acts as a GPER antagonist in different model systems, such as breast tumor cells and cancer-associated fibroblasts (CAFs) obtained from breast cancer patients. Our data might open new perspectives toward the development of a further class of selective GPER ligands in order to better dissect the role exerted by this receptor in different pathophysiological conditions. Moreover, calixpyrrole derivatives could be considered in future anticancer strategies targeting GPER in cancer cells. PMID:26183213

Cardiac microvascular rarefaction in hyperthyroidism-induced left ventricle dysfunction.

PubMed

Freitas, Felipe; Estato, Vanessa; Carvalho, Vinícius Frias; Torres, Rafael Carvalho; Lessa, Marcos Adriano; Tibiriçá, Eduardo

2013-10-01

The pathophysiology underlying hyperthyroidism-induced left ventricle (LV) dysfunction and hypertrophy directly involves the heart and indirectly involves the neuroendocrine systems. The effects of hyperthyroidism on the microcirculation are still controversial in experimental models. We investigated the effects of hyperthyroidism on the cardiac function and microcirculation of an experimental rat model. Male Wistar rats (170-250 g) were divided into two groups: the euthyroid group (n = 10), which was treated with 0.9% saline solution, and the hyperthyroid group (n = 10), which was treated with l-thyroxine (600 μg/kg/day, i.p.) during 14 days. An echocardiographic study was performed to evaluate the alterations in cardiac function, structure and geometry. The structural capillary density and the expression of angiotensin II AT1 receptor in the LV were analyzed using histochemistry and immunohistochemistry, respectively. Hyperthyroidism was found to induce profound cardiovascular alterations, such as systolic hypertension, tachycardia, LV dysfunction, cardiac hypertrophy, and myocardial fibrosis. This study demonstrates the existence of structural capillary rarefaction and the down-regulation of the cardiac angiotensin II AT1 receptor in the myocardium of hyperthyroid rats in comparison with euthyroid rats. Microvascular rarefaction may be involved in the pathophysiology of hyperthyroidism-induced cardiovascular alterations. © 2013 John Wiley & Sons Ltd.

Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice.

PubMed

Bondulich, Marie K; Jolinon, Nelly; Osborne, Georgina F; Smith, Edward J; Rattray, Ivan; Neueder, Andreas; Sathasivam, Kirupa; Ahmed, Mhoriam; Ali, Nadira; Benjamin, Agnesska C; Chang, Xiaoli; Dick, James R T; Ellis, Matthew; Franklin, Sophie A; Goodwin, Daniel; Inuabasi, Linda; Lazell, Hayley; Lehar, Adam; Richard-Londt, Angela; Rosinski, Jim; Smith, Donna L; Wood, Tobias; Tabrizi, Sarah J; Brandner, Sebastian; Greensmith, Linda; Howland, David; Munoz-Sanjuan, Ignacio; Lee, Se-Jin; Bates, Gillian P

2017-10-27

Huntington's disease (HD) is an inherited neurodegenerative disorder of which skeletal muscle atrophy is a common feature, and multiple lines of evidence support a muscle-based pathophysiology in HD mouse models. Inhibition of myostatin signaling increases muscle mass, and therapeutic approaches based on this are in clinical development. We have used a soluble ActRIIB decoy receptor (ACVR2B/Fc) to test the effects of myostatin/activin A inhibition in the R6/2 mouse model of HD. Weekly administration from 5 to 11 weeks of age prevented body weight loss, skeletal muscle atrophy, muscle weakness, contractile abnormalities, the loss of functional motor units in EDL muscles and delayed end-stage disease. Inhibition of myostatin/activin A signaling activated transcriptional profiles to increase muscle mass in wild type and R6/2 mice but did little to modulate the extensive Huntington's disease-associated transcriptional dysregulation, consistent with treatment having little impact on HTT aggregation levels. Modalities that inhibit myostatin signaling are currently in clinical trials for a variety of indications, the outcomes of which will present the opportunity to assess the potential benefits of targeting this pathway in HD patients.

Real time monitoring in-vivo micro-environment through the wound heal mechanism

NASA Astrophysics Data System (ADS)

Yan, Jack

2013-02-01

One of the In-vivo system's challenge is real time display the sensing information. Usually Ultrasound, CT, MRI, PET are used to get the internal information, this thesis proposed another approach to address the display challenge. Special nano-particles are in-taken or injected to living subject (usually into blood circulation) to sense and collect psychological information when the active particles pass through the tissues of interest. Using the wound healing mechanism, these activated particles (Information collected) can be drifted out to the wound area and adhibited close to the skin, then skin can show different color if the activated particles are concentrated enough in the specific area to create a skin screen. The skin screen can display the blood status, internal organ's temperature, pressure depending the nano-particles' function and their pathway. This approach can also be used to display in-body video if the particles are sensitive and selective enough. In the future, the skin screen can be bio-computer's monitor. The wound healing in an animal model normally divides in four phase: Hemostasis, Inflammation, Proliferation and Maturation. Hemostasis phase is to form a stable clot sealing the damaged vessel. Inflammation phase causes the blood vessels to become leaky releasing plasma and PMN's (polymorphonucleocytes) into the surrounding tissue and provide the first line of defense against infection. Proliferation phase involves replacement of dermal tissues and sometimes subdermal tissues in deeper wounds as well as contraction of the wound. Maturation phase remodels the dermal tissues mainly by fibroblast to produce greater tensile strength. The skin screen wound will be carefully controlled to be triggered at dermis layer.

Long-term inflammatory response to liquid injectable silicone, cartilage, and silicone sheet.

PubMed

Hizal, Evren; Buyuklu, Fuat; Ozdemir, B Handan; Erbek, Selim S

2014-11-01

To show and compare the long-term inflammatory responses to subdermal microdroplet injections of 1,000 centistoke (cS) and 5,000 cS liquid injectable silicone (LIS), and to assess the applicability of insulin pen as an alternative LIS delivery device in an animal model. Animal study. Eighteen healthy adult Sprague-Dawley rats were used. Two graft recipient sites and four injection sites were prepared on each rat's back for: 1) autogenous auricular cartilage graft; 2) silicone sheet; 3) 1,000 cS LIS injection with insulin syringe; 4) 1,000 cS LIS injection with insulin pen; 5) 5,000 cS LIS injection with insulin syringe; and 6) 5,000 cS LIS injection with insulin pen. The animals were followed up for 6 months, and skin biopsies were examined for the evaluation of LIS microdroplets in situ and the degree of inflammatory tissue response. Immunohistochemistry was used for the examination of macrophages and the density of microvessels. Biopsies from 17 animals were assessed. There was no statistically significant difference among the groups in terms of the number of lymphocytes (P = 0.081), macrophages (P = 0.857), and neutrophils (P = 0.995), the degree of vascular proliferation (P = 0.698), and the mean LIS microdroplet diameter (P = 0.540). Grossly, there was no sign of granuloma formation in any of the specimens. There is a low-grade, well-tolerated long-term inflammatory response to microdroplet injections of 1,000 cS and 5,000 cS LIS that is comparable to autogenous cartilage graft in rats. Standard dose delivery devices such as insulin pens can be used for controlled LIS injections. N/A. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.

Socioeconomic Status As a Risk Factor for Unintended Pregnancy in the Contraceptive CHOICE Project.

PubMed

Iseyemi, Abigail; Zhao, Qiuhong; McNicholas, Colleen; Peipert, Jeffrey F

2017-09-01

To evaluate the association of low socioeconomic status as an independent risk factor for unintended pregnancy. We performed a secondary analysis of data from the Contraceptive CHOICE project. Between 2007 and 2011, 9,256 participants were recruited and followed for up to 3 years. The primary outcome of interest was unintended pregnancy; the primary exposure variable was low socioeconomic status, defined as self-report of either receiving public assistance or having difficulty paying for basic necessities. Four contraceptive groups were evaluated: 1) long-acting reversible contraceptive method (hormonal or copper intrauterine device or subdermal implant); 2) depot medroxyprogesterone acetate injection; 3) oral contraceptive pills, a transdermal patch, or a vaginal ring; or 4) other or no method. Confounders were adjusted for in the multivariable Cox proportional hazard model to estimate the effect of socioeconomic status on risk of unintended pregnancy. Participants with low socioeconomic status experienced 515 unintended pregnancies during 14,001 women-years of follow-up (3.68/100 women-years; 95% CI 3.37-4.01) compared with 200 unintended pregnancies during 10,296 women-years (1.94/100 women-years; 95% CI 1.68-2.23) among participants without low socioeconomic status. Women with low socioeconomic status were more likely to have an unintended pregnancy (unadjusted hazard ratio [HR] 1.8, 95% CI 1.5-2.2). After adjusting for age, education level, insurance status, and history of unintended pregnancy, low socioeconomic status was associated with an increased risk of unintended pregnancy (adjusted HR 1.4, 95% CI 1.1-1.7). Despite the removal of cost barriers, low socioeconomic status is associated with a higher incidence of unintended pregnancy.

A computational model for simulating solute transport and oxygen consumption along the nephrons

PubMed Central

Vallon, Volker; Edwards, Aurélie

2016-01-01

The goal of this study was to investigate water and solute transport, with a focus on sodium transport (TNa) and metabolism along individual nephron segments under differing physiological and pathophysiological conditions. To accomplish this goal, we developed a computational model of solute transport and oxygen consumption (QO2) along different nephron populations of a rat kidney. The model represents detailed epithelial and paracellular transport processes along both the superficial and juxtamedullary nephrons, with the loop of Henle of each model nephron extending to differing depths of the inner medulla. We used the model to assess how changes in TNa may alter QO2 in different nephron segments and how shifting the TNa sites alters overall kidney QO2. Under baseline conditions, the model predicted a whole kidney TNa/QO2, which denotes the number of moles of Na+ reabsorbed per moles of O2 consumed, of ∼15, with TNa efficiency predicted to be significantly greater in cortical nephron segments than in medullary segments. The TNa/QO2 ratio was generally similar among the superficial and juxtamedullary nephron segments, except for the proximal tubule, where TNa/QO2 was ∼20% higher in superficial nephrons, due to the larger luminal flow along the juxtamedullary proximal tubules and the resulting higher, flow-induced transcellular transport. Moreover, the model predicted that an increase in single-nephron glomerular filtration rate does not significantly affect TNa/QO2 in the proximal tubules but generally increases TNa/QO2 along downstream segments. The latter result can be attributed to the generally higher luminal [Na+], which raises paracellular TNa. Consequently, vulnerable medullary segments, such as the S3 segment and medullary thick ascending limb, may be relatively protected from flow-induced increases in QO2 under pathophysiological conditions. PMID:27707705

Animal models of ulcerative colitis and their application in drug research

PubMed Central

Low, Daren; Nguyen, Deanna D; Mizoguchi, Emiko

2013-01-01

The specific pathogenesis underlying inflammatory bowel disease is complex, and it is even more difficult to decipher the pathophysiology to explain for the similarities and differences between two of its major subtypes, Crohn’s disease and ulcerative colitis (UC). Animal models are indispensable to pry into mechanistic details that will facilitate better preclinical drug/therapy design to target specific components involved in the disease pathogenesis. This review focuses on common animal models that are particularly useful for the study of UC and its therapeutic strategy. Recent reports of the latest compounds, therapeutic strategies, and approaches tested on UC animal models are also discussed. PMID:24250223

Animal models of post-traumatic stress disorder: face validity

PubMed Central

Goswami, Sonal; Rodríguez-Sierra, Olga; Cascardi, Michele; Paré, Denis

2013-01-01

Post-traumatic stress disorder (PTSD) is a debilitating condition that develops in a proportion of individuals following a traumatic event. Despite recent advances, ethical limitations associated with human research impede progress in understanding PTSD. Fortunately, much effort has focused on developing animal models to help study the pathophysiology of PTSD. Here, we provide an overview of animal PTSD models where a variety of stressors (physical, psychosocial, or psychogenic) are used to examine the long-term effects of severe trauma. We emphasize models involving predator threat because they reproduce human individual differences in susceptibility to, and in the long-term consequences of, psychological trauma. PMID:23754973

Mathematical modeling of renal hemodynamics in physiology and pathophysiology.

PubMed

Sgouralis, Ioannis; Layton, Anita T

2015-06-01

In addition to the excretion of metabolic waste and toxin, the kidney plays an indispensable role in regulating the balance of water, electrolyte, acid-base, and blood pressure. For the kidney to maintain proper functions, hemodynamic control is crucial. In this review, we describe representative mathematical models that have been developed to better understand the kidney's autoregulatory processes. We consider mathematical models that simulate glomerular filtration, and renal blood flow regulation by means of the myogenic response and tubuloglomerular feedback. We discuss the extent to which these modeling efforts have expanded the understanding of renal functions in health and disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Retinal vein occlusion: pathophysiology and treatment options.

PubMed

Karia, Niral

2010-07-30

This paper reviews the current thinking about retinal vein occlusion. It gives an overview of its pathophysiology and discusses the evidence behind the various established and emerging treatment paradigms.

A Unified Pathophysiological Construct of Diabetes and its Complications.

PubMed

Schwartz, Stanley S; Epstein, Solomon; Corkey, Barbara E; Grant, Struan F A; Gavin Iii, James R; Aguilar, Richard B; Herman, Mary E

2017-09-01

Advances in understanding diabetes mellitus (DM) through basic and clinical research have helped clarify and reunify a disease state fragmented into numerous etiologies and subtypes. It is now understood that a common pathophysiology drives the diabetic state throughout its natural history and across its varied clinical presentations, a pathophysiology involving metabolic insults, oxidative damage, and vicious cycles that aggravate and intensify organ dysfunction and damage. This new understanding of the disease requires that we revisit existing diagnostics and treatment approaches, which were built upon outmoded assumptions. 'The Common Pathophysiologic Origins of Diabetes Mellitus and its Complications Construct' is presented as a more accurate, foundational, and translatable construct of DM that helps make sense of the hitherto ambiguous findings of long-term outcome studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Pathophysiology of hypertension: what's new?].

PubMed

Büchner, Nikolaus; Vonend, Oliver; Rump, Lars Christian

2006-06-01

The pathophysiology of primary hypertension is still unresolved and appears more complex than ever. It is beyond the scope of this article to review all new scientific developments in this field. On clinical grounds, hypertension is divided into primary and secondary forms. Here, the authors discuss the pathophysiology of hypertension associated with three common disease entities showing a large overlap with primary hypertension: chronic kidney disease (CKD), obstructive sleep apnea (OSA), and hyperaldosteronism. Especially in CKD and OSA, the activation of the sympathetic nervous system plays a crucial role. It is the authors' belief that hypertension due to these three diseases is more common than previously appreciated and may account for about 20% of the hypertensive population. The knowledge of the underlying pathophysiology allows early diagnosis and guides optimal treatment of these hypertensive patients.

Nitroglycerin enhances the propagation of cortical spreading depression: comparative studies with sumatriptan and novel kynurenic acid analogues.

PubMed

Knapp, Levente; Szita, Bence; Kocsis, Kitti; Vécsei, László; Toldi, József

2017-01-01

The complex pathophysiology of migraine is not yet clearly understood; therefore, experimental models are essential for the investigation of the processes related to migraine headache, which include cortical spreading depression (CSD) and NO donor-induced neurovascular changes. Data on the assessment of drug efficacy in these models are often limited, which prompted us to investigate a novel combined migraine model in which an effective pharmacon could be more easily identified. In vivo electrophysiological experiments were performed to investigate the effect of nitroglycerin (NTG) on CSD induced by KCl application. In addition, sumatriptan and newly synthesized neuroactive substances (analogues of the neuromodulator kynurenic acid [KYNA]) were also tested. The basic parameters of CSDs were unchanged following NTG administration; however, propagation failure was decreased compared to the controls. Sumatriptan decreased the number of CSDs, whereas propagation failure was as minimal as in the NTG group. On the other hand, both of the KYNA analogues restored the ratio of propagation to the control level. The ratio of propagation appeared to be the indicator of the effect of NTG. This is the first study providing direct evidence that NTG influences CSD; furthermore, we observed different effects of sumatriptan and KYNA analogues. Sumatriptan changed the generation of CSDs, whereas the analogues acted on the propagation of the waves. Our experimental design overlaps with a large spectrum of processes present in migraine pathophysiology, and it can be a useful experimental model for drug screening.

Nitroglycerin enhances the propagation of cortical spreading depression: comparative studies with sumatriptan and novel kynurenic acid analogues

PubMed Central

Knapp, Levente; Szita, Bence; Kocsis, Kitti; Vécsei, László; Toldi, József

2017-01-01

Background The complex pathophysiology of migraine is not yet clearly understood; therefore, experimental models are essential for the investigation of the processes related to migraine headache, which include cortical spreading depression (CSD) and NO donor-induced neurovascular changes. Data on the assessment of drug efficacy in these models are often limited, which prompted us to investigate a novel combined migraine model in which an effective pharmacon could be more easily identified. Materials and methods In vivo electrophysiological experiments were performed to investigate the effect of nitroglycerin (NTG) on CSD induced by KCl application. In addition, sumatriptan and newly synthesized neuroactive substances (analogues of the neuromodulator kynurenic acid [KYNA]) were also tested. Results The basic parameters of CSDs were unchanged following NTG administration; however, propagation failure was decreased compared to the controls. Sumatriptan decreased the number of CSDs, whereas propagation failure was as minimal as in the NTG group. On the other hand, both of the KYNA analogues restored the ratio of propagation to the control level. Discussion The ratio of propagation appeared to be the indicator of the effect of NTG. This is the first study providing direct evidence that NTG influences CSD; furthermore, we observed different effects of sumatriptan and KYNA analogues. Sumatriptan changed the generation of CSDs, whereas the analogues acted on the propagation of the waves. Our experimental design overlaps with a large spectrum of processes present in migraine pathophysiology, and it can be a useful experimental model for drug screening. PMID:28053504

Bridging from Cells to Cognition in Autism Pathophysiology: Biological Pathways to Defective Brain Function and Plasticity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anderson, Matthew; Hooker, Brian S.; Herbert, Martha

We review evidence to support the model that autism may begin when a maternal environmental, infectious, or autoantibody insult causes inflammation which increases reactive oxygen species (ROS) production in the fetus, leading to fetal DNA damage (nuclear and mitochondrial), and that these inflammatory and oxidative stressors persist beyond early development (with potential further exacerbations), producing ongoing functional consequences. In organs with a high metabolic demand such as the central nervous system, the continued use of mitochondria with DNA damage may generate additional ROS which will activate the innate immune system leading to more ROS production. Such a mechanism would self-sustainmore » and possibly progressively worsen. The mitochondrial dysfunction and altered redox signal transduction pathways found in autism would conspire to activate both astroglia and microglia. These activated cells can then initiate a broad-spectrum proinflammatory gene response. Neurons may have acquired receptors for these inflammatory signals to inhibit neuronal signaling as a protection from excitotoxic damage during various pathologic insults (e.g., infection). In autism, over-zealous neuroinflammatory responses could not only influence neural developmental processes, but may more significantly impair neural signaling involved in cognition in an ongoing fashion. This model makes specific predictions in patients and experimental animal models and suggests a number of targets sites of intervention. Our model of potentially reversible pathophysiological mechanisms in autism motivates our hope that effective therapies may soon appear on the horizon.« less

Discerning apical and basolateral properties of HT-29/B6 and IPEC-J2 cell layers by impedance spectroscopy, mathematical modeling and machine learning.

PubMed

Schmid, Thomas; Bogdan, Martin; Günzel, Dorothee

2013-01-01

Quantifying changes in partial resistances of epithelial barriers in vitro is a challenging and time-consuming task in physiology and pathophysiology. Here, we demonstrate that electrical properties of epithelial barriers can be estimated reliably by combining impedance spectroscopy measurements, mathematical modeling and machine learning algorithms. Conventional impedance spectroscopy is often used to estimate epithelial capacitance as well as epithelial and subepithelial resistance. Based on this, the more refined two-path impedance spectroscopy makes it possible to further distinguish transcellular and paracellular resistances. In a next step, transcellular properties may be further divided into their apical and basolateral components. The accuracy of these derived values, however, strongly depends on the accuracy of the initial estimates. To obtain adequate accuracy in estimating subepithelial and epithelial resistance, artificial neural networks were trained to estimate these parameters from model impedance spectra. Spectra that reflect behavior of either HT-29/B6 or IPEC-J2 cells as well as the data scatter intrinsic to the used experimental setup were created computationally. To prove the proposed approach, reliability of the estimations was assessed with both modeled and measured impedance spectra. Transcellular and paracellular resistances obtained by such neural network-enhanced two-path impedance spectroscopy are shown to be sufficiently reliable to derive the underlying apical and basolateral resistances and capacitances. As an exemplary perturbation of pathophysiological importance, the effect of forskolin on the apical resistance of HT-29/B6 cells was quantified.

Percutaneous Transcatheter Mitral Valve Replacement: Patient-specific Three-dimensional Computer-based Heart Model and Prototyping.

PubMed

Vaquerizo, Beatriz; Theriault-Lauzier, Pascal; Piazza, Nicolo

2015-12-01

Mitral regurgitation is the most prevalent valvular heart disease worldwide. Despite the widespread availability of curative surgical intervention, a considerable proportion of patients with severe mitral regurgitation are not referred for treatment, largely due to the presence of left ventricular dysfunction, advanced age, and comorbid illnesses. Transcatheter mitral valve replacement is a promising therapeutic alternative to traditional surgical valve replacement. The complex anatomical and pathophysiological nature of the mitral valvular complex, however, presents significant challenges to the successful design and implementation of novel transcatheter mitral replacement devices. Patient-specific 3-dimensional computer-based models enable accurate assessment of the mitral valve anatomy and preprocedural simulations for transcatheter therapies. Such information may help refine the design features of novel transcatheter mitral devices and enhance procedural planning. Herein, we describe a novel medical image-based processing tool that facilitates accurate, noninvasive assessment of the mitral valvular complex, by creating precise three-dimensional heart models. The 3-dimensional computer reconstructions are then converted to a physical model using 3-dimensional printing technology, thereby enabling patient-specific assessment of the interaction between device and patient. It may provide new opportunities for a better understanding of the mitral anatomy-pathophysiology-device interaction, which is of critical importance for the advancement of transcatheter mitral valve replacement. Copyright © 2015 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

18 F-Fluoride positron emission tomography/computed tomography for noninvasive in vivo quantification of pathophysiological bone metabolism in experimental murine arthritis

PubMed Central

2014-01-01

Introduction Evaluation of disease severity in experimental models of rheumatoid arthritis is inevitably associated with assessment of structural bone damage. A noninvasive imaging technology allowing objective quantification of pathophysiological alterations of bone structure in rodents could substantially extend the methods used to date in preclinical arthritis research for staging of autoimmune disease severity or efficacy of therapeutical intervention. Sodium 18 F-fluoride (18 F-NaF) is a bone-seeking tracer well-suited for molecular imaging. Therefore, we systematically examined the use of 18 F-NaF positron emission tomography/computed tomography (PET/CT) in mice with glucose-6-phosphate isomerase (G6PI)–induced arthritis for quantification of pathological bone metabolism. Methods F-fluoride was injected into mice before disease onset and at various time points of progressing experimental arthritis. Radioisotope accumulation in joints in the fore- and hindpaws was analyzed by PET measurements. For validation of bone metabolism quantified by 18 F-fluoride PET, bone surface parameters of high-resolution μCT measurements were used. Results Before clinical arthritis onset, no distinct accumulation of 18 F-fluoride was detectable in the fore- and hindlimbs of mice immunized with G6PI. In the course of experimental autoimmune disease, 18 F-fluoride bone uptake was increased at sites of enhanced bone metabolism caused by pathophysiological processes of autoimmune disease. Moreover, 18 F-fluoride signaling at different stages of G6PI-induced arthritis was significantly correlated with the degree of bone destruction. CT enabled identification of exact localization of 18 F-fluoride signaling in bone and soft tissue. Conclusions The results of this study suggest that small-animal PET/CT using 18 F-fluoride as a tracer is a feasible method for quantitative assessment of pathophysiological bone metabolism in experimental arthritis. Furthermore, the possibility to perform repeated noninvasive measurements in vivo allows longitudinal study of therapeutical intervention monitoring. PMID:25053370

A translational in vivo model of trigeminal autonomic cephalalgias: therapeutic characterization.

PubMed

Akerman, Simon; Holland, Philip R; Summ, Oliver; Lasalandra, Michele P; Goadsby, Peter J

2012-12-01

Trigeminal autonomic cephalalgias are highly disabling primary headache disorders, characterized by severe unilateral head pain and associated ipsilateral cranial autonomic features. There is limited understanding of their pathophysiology and how and where treatments act to reduce symptoms; this is significantly hindered by a lack of animal models. We have developed the first animal model to explore trigeminal autonomic cephalalgias, using stimulation within the brainstem, at the level of the superior salivatory nucleus, to activate the trigeminal autonomic reflex arc. Using electrophysiological recording of neurons of the trigeminocervical complex and laser Doppler blood flow changes around the ipsilateral lacrimal duct, superior salivatory nucleus stimulation exhibited both neuronal trigeminovascular and cranial autonomic manifestations. These responses were specifically inhibited by the autonomic ganglion blocker hexamethonium bromide. These data demonstrate that brainstem activation may be the driver of both sensory and autonomic symptoms in these disorders, and part of this activation may be via the parasympathetic outflow to the cranial vasculature. Additionally, both sensory and autonomic manifestations were significantly inhibited by highly effective treatments for trigeminal autonomic cephalalgias, such as oxygen, indomethacin and triptans, and some part of their therapeutic action appears to be specifically on the parasympathetic outflow to the cranial vasculature. Treatments more used to migraine, such as naproxen and a calcitonin gene-related peptide receptor inhibitor, olcegepant, were less effective in this model. This is the first model to represent the phenotype of trigeminal autonomic cephalalgias and their response to therapies, and indicates the parasympathetic pathway may be uniquely involved in their pathophysiology and targeted to relieve symptoms.

Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease

PubMed Central

Lim, M. A.; Selak, M. A.; Xiang, Z.; Krainc, D.; Neve, R. L.; Kraemer, B. C.; Watts, J. L.

2012-01-01

A growing body of research indicates that amyotrophic lateral sclerosis (ALS) patients and mouse models of ALS exhibit metabolic dysfunction. A subpopulation of ALS patients possesses higher levels of resting energy expenditure and lower fat-free mass compared to healthy controls. Similarly, two mutant copper zinc superoxide dismutase 1 (mSOD1) mouse models of familial ALS possess a hypermetabolic phenotype. The pathophysiological relevance of the bioenergetic defects observed in ALS remains largely elusive. AMP-activated protein kinase (AMPK) is a key sensor of cellular energy status and thus might be activated in various models of ALS. Here, we report that AMPK activity is increased in spinal cord cultures expressing mSOD1, as well as in spinal cord lysates from mSOD1 mice. Reducing AMPK activity either pharmacologically or genetically prevents mSOD1-induced motor neuron death in vitro. To investigate the role of AMPK in vivo, we used Caenorhabditis elegans models of motor neuron disease. C. elegans engineered to express human mSOD1 (G85R) in neurons develops locomotor dysfunction and severe fecundity defects when compared to transgenic worms expressing human wild-type SOD1. Genetic reduction of aak-2, the ortholog of the AMPK α2 catalytic subunit in nematodes, improved locomotor behavior and fecundity in G85R animals. Similar observations were made with nematodes engineered to express mutant tat-activating regulatory (TAR) DNA-binding protein of 43 kDa molecular weight. Altogether, these data suggest that bioenergetic abnormalities are likely to be pathophysiologically relevant to motor neuron disease. PMID:22262909

Further characterization of repetitive behavior in C58 mice: developmental trajectory and effects of environmental enrichment.

PubMed

Muehlmann, A M; Edington, G; Mihalik, A C; Buchwald, Z; Koppuzha, D; Korah, M; Lewis, M H

2012-12-01

Aberrant repetitive behaviors are commonly observed in a variety of neurodevelopmental, neurological, and neuropsychiatric disorders. Little is known about the specific neurobiological mechanisms that underlie such behaviors, however, and effective treatments are lacking. Valid animal models can aid substantially in identifying pathophysiological factors mediating aberrant repetitive behavior and aid in treatment development. The C58 inbred mouse strain is a particularly promising model, and we have further characterized its repetitive behavior phenotype. Compared to C57BL/6 mice, C58 mice exhibit high rates of spontaneous hindlimb jumping and backward somersaulting reaching adult frequencies by 5 weeks post-weaning and adult temporal organization by 2 weeks post-weaning. The development of repetitive behavior in C58 mice was markedly attenuated by rearing these mice in larger, more complex environments. In addition to characterizing repetitive motor behavior, we also assessed related forms of inflexible behavior that reflect restricted and perseverative responding. Contrary to our hypothesis, C58 mice did not exhibit increased marble burying nor did they display reduced exploratory behavior in the holeboard task. The C58 strain appears to be a very useful model for the repetitive motor behavior characteristic of a number of clinical disorders. As an inbred mouse strain, studies using the C58 model can take full advantage of the tool kit of modern genetics and molecular neuroscience. This technical advantage makes the model a compelling choice for use in studies designed to elucidate the etiology and pathophysiology of aberrant repetitive behavior. Such findings should, in turn, translate into effective new treatments. Published by Elsevier B.V.

Dry eye disease: pathophysiology, classification, and diagnosis.

PubMed

Perry, Henry D

2008-04-01

Dry eye disease (DED) is a multifactorial disorder of the tear film and ocular surface that results in eye discomfort, visual disturbance, and often ocular surface damage. Although recent research has made progress in elucidating DED pathophysiology, currently there are no uniform diagnostic criteria. This article discusses the normal anatomy and physiology of the lacrimal functional unit and the tear film; the pathophysiology of DED; DED etiology, classification, and risk factors; and DED diagnosis, including symptom assessment and the roles of selected diagnostic tests.

Elucidating the Role of Neurotensin in the Pathophysiology and Management of Major Mental Disorders

PubMed Central

Boules, Mona M; Fredrickson, Paul; Muehlmann, Amber M; Richelson, Elliott

2014-01-01

Neurotensin (NT) is a neuropeptide that is closely associated with, and is thought to modulate, dopaminergic and other neurotransmitter systems involved in the pathophysiology of various mental disorders. This review outlines data implicating NT in the pathophysiology and management of major mental disorders such as schizophrenia, drug addiction, and autism. The data suggest that NT receptor analogs have the potential to be used as novel therapeutic agents acting through modulation of neurotransmitter systems dys-regulated in these disorders. PMID:25379273

Animal models of fibromyalgia

PubMed Central

2013-01-01

Animal models of disease states are valuable tools for developing new treatments and investigating underlying mechanisms. They should mimic the symptoms and pathology of the disease and importantly be predictive of effective treatments. Fibromyalgia is characterized by chronic widespread pain with associated co-morbid symptoms that include fatigue, depression, anxiety and sleep dysfunction. In this review, we present different animal models that mimic the signs and symptoms of fibromyalgia. These models are induced by a wide variety of methods that include repeated muscle insults, depletion of biogenic amines, and stress. All potential models produce widespread and long-lasting hyperalgesia without overt peripheral tissue damage and thus mimic the clinical presentation of fibromyalgia. We describe the methods for induction of the model, pathophysiological mechanisms for each model, and treatment profiles. PMID:24314231

On the ontological assumptions of the medical model of psychiatry: philosophical considerations and pragmatic tasks

PubMed Central

2010-01-01

A common theme in the contemporary medical model of psychiatry is that pathophysiological processes are centrally involved in the explanation, evaluation, and treatment of mental illnesses. Implied in this perspective is that clinical descriptors of these pathophysiological processes are sufficient to distinguish underlying etiologies. Psychiatric classification requires differentiation between what counts as normality (i.e.- order), and what counts as abnormality (i.e.- disorder). The distinction(s) between normality and pathology entail assumptions that are often deeply presupposed, manifesting themselves in statements about what mental disorders are. In this paper, we explicate that realism, naturalism, reductionism, and essentialism are core ontological assumptions of the medical model of psychiatry. We argue that while naturalism, realism, and reductionism can be reconciled with advances in contemporary neuroscience, essentialism - as defined to date - may be conceptually problematic, and we pose an eidetic construct of bio-psychosocial order and disorder based upon complex systems' dynamics. However we also caution against the overuse of any theory, and claim that practical distinctions are important to the establishment of clinical thresholds. We opine that as we move ahead toward both a new edition of the Diagnostic and Statistical Manual, and a proposed Decade of the Mind, the task at hand is to re-visit nosologic and ontologic assumptions pursuant to a re-formulation of diagnostic criteria and practice. PMID:20109176

Translational Systems Biology and Voice Pathophysiology

PubMed Central

Li, Nicole Y. K.; Abbott, Katherine Verdolini; Rosen, Clark; An, Gary; Hebda, Patricia A.; Vodovotz, Yoram

2011-01-01

Objectives/Hypothesis Personalized medicine has been called upon to tailor healthcare to an individual's needs. Evidence-based medicine (EBM) has advocated using randomized clinical trials with large populations to evaluate treatment effects. However, due to large variations across patients, the results are likely not to apply to an individual patient. We suggest that a complementary, systems biology approach using computational modeling may help tackle biological complexity in order to improve ultimate patient care. The purpose of the article is: 1) to review the pros and cons of EBM, and 2) to discuss the alternative systems biology method and present its utility in clinical voice research. Study Design Tutorial Methods Literature review and discussion. Results We propose that translational systems biology can address many of the limitations of EBM pertinent to voice and other health care domains, and thus complement current health research models. In particular, recent work using mathematical modeling suggests that systems biology has the ability to quantify the highly complex biologic processes underlying voice pathophysiology. Recent data support the premise that this approach can be applied specifically in the case of phonotrauma and surgically induced vocal fold trauma, and may have particular power to address personalized medicine. Conclusions We propose that evidence around vocal health and disease be expanded beyond a population-based method to consider more fully issues of complexity and systems interactions, especially in implementing personalized medicine in voice care and beyond. PMID:20025041

Proliferative vitreoretinopathy in the Swine-a new model.

PubMed

Umazume, Kazuhiko; Barak, Yoreh; McDonald, Kevin; Liu, Lanhsin; Kaplan, Henry J; Tamiya, Shigeo

2012-07-24

To develop a large animal model of proliferative vitreoretinopathy (PVR) in the swine to eventually study disease pathophysiology, as well as novel therapies. PVR was induced in domestic swine by creation of a posterior vitreous detachment, creation of a retinal detachment by the injection of subretinal fluid, and intravitreal injection of green fluorescent protein-positive retinal pigment epithelial (GFP+ RPE) cells. Control eyes had the same surgical procedures without RPE cell injection. PVR was clinically graded on days 3, 7, and 14. Animals were euthanized on day 14, and enucleated eyes were analyzed by light microscopy and immunohistochemistry. Injection of GFP+ RPE cells into the vitreous cavity produced localized, traction retinal detachments by day 14 in all eyes (14 of 14); in contrast, the retina spontaneously reattached by day 3 and remained attached in all control eyes (10 of 10). Contractile epiretinal membranes on the inner retinal surface that caused the traction retinal detachments consisted predominantly of GFP+ RPE cells. These cells stained positive for cytokeratin, confirming their epithelial origin, and also expressed α-SMA and fibronectin, markers for myofibroblasts and fibrosis, respectively. We established a swine PVR model that recapitulates key clinical features found in humans and, thus, can be used to study the pathophysiology of PVR, as well as new novel therapies. GFP+ RPE cells injected into the vitreous cavity formed contractile membranes on the inner retinal surface and caused localized traction retinal detachments.

Increased Muscle Stress-Sensitivity Induced by Selenoprotein N Inactivation in Mouse: A Mammalian Model for SEPN1-Related Myopathy

PubMed Central

Arbogast, Sandrine; Lainé, Jeanne; Vassilopoulos, Stéphane; Beuvin, Maud; Dubourg, Odile; Vignaud, Alban; Ferry, Arnaud; Krol, Alain; Allamand, Valérie; Guicheney, Pascale; Ferreiro, Ana; Lescure, Alain

2011-01-01

Selenium is an essential trace element and selenoprotein N (SelN) was the first selenium-containing protein shown to be directly involved in human inherited diseases. Mutations in the SEPN1 gene, encoding SelN, cause a group of muscular disorders characterized by predominant affection of axial muscles. SelN has been shown to participate in calcium and redox homeostasis, but its pathophysiological role in skeletal muscle remains largely unknown. To address SelN function in vivo, we generated a Sepn1-null mouse model by gene targeting. The Sepn1−/− mice had normal growth and lifespan, and were macroscopically indistinguishable from wild-type littermates. Only minor defects were observed in muscle morphology and contractile properties in SelN-deficient mice in basal conditions. However, when subjected to challenging physical exercise and stress conditions (forced swimming test), Sepn1−/− mice developed an obvious phenotype, characterized by limited motility and body rigidity during the swimming session, as well as a progressive curvature of the spine and predominant alteration of paravertebral muscles. This induced phenotype recapitulates the distribution of muscle involvement in patients with SEPN1-Related Myopathy, hence positioning this new animal model as a valuable tool to dissect the role of SelN in muscle function and to characterize the pathophysiological process. PMID:21858002

Polycystic ovarian disease: animal models.

PubMed

Mahajan, D K

1988-12-01

The reproductive systems of human beings and other vertebrates are grossly similar. In the ovary particularly, the biochemical and physiologic processes are identical not only in the formation of germ cells, the development of primordial follicles and their subsequent growth to Graafian follicles, and eventual ovulation but also in anatomic structure. In a noncarcinogenic human ovary, hypersecretion of androgen causes PCOD. Such hypersecretion may result from a nonpulsatile, constant elevated level of circulating LH or a disturbance in the action of neurotransmitters in the hypothalamus. In studying the pathophysiology of PCOD in humans, one must be aware of the limitations for manipulating the hypothalamic-pituitary axis. Although the rat is a polytocous rodent, the female has a regular ovarian cyclicity of 4 or 5 days, with distinct proestrus, estrus, and diestrus phases. Inasmuch as PCOD can be experimentally produced in the rat, that species is a good model for studying the pathophysiology of human PCOD. These PCOD models and their validity have been described: (1) estradiol-valerate, (2) DHA, (3) constant-light (LL), and (4) neonatally androgenized. Among these, the LL model is noninvasive and seems superior to the others for study of the pathophysiology of PCOD. The production of the polycystic ovarian condition in the rat by the injection of estrogens or androgens in neonate animals, or estradiol or DHA in adult rats, or the administration of antigonadotropins to these animals all cause a sudden appearance of the persistent estrus state by disturbing the metabolic and physiologic processes, whereas exposure of the adult rat to LL causes polycystic ovaries gradually, similar to what is seen in human idiopathic PCOD. After about 50 days of LL, the rat becomes anovulatory and the ovaries contain thickened tunica albuginea and many atretic follicles, and the tertiary follicles are considerably distended and cystic. The granulosa and theca cells appear normal histologically, although some of the stromal cells appear hypertrophic. The anatomic features consequent to polycystic ovaries resulting from LL are similar to those in human PCOD, and both rat and human PCOD ovarian cells still retain the ability to respond to FSH/LH, LHRH, and unilateral ovariectomy. In the estradiol valerate rat model, although the anatomy and physiology of the ovary resemble those of PCOD patients, the progressive degeneration of the hypothalamus and the altered response of the pituitary to LHRH make this model inappropriate for studying the hypothalamic-pituitary-ovarian axis in the polycystic ovary condition.(ABSTRACT TRUNCATED AT 400 WORDS)

Retinal vein occlusion: pathophysiology and treatment options

PubMed Central

Karia, Niral

2010-01-01

This paper reviews the current thinking about retinal vein occlusion. It gives an overview of its pathophysiology and discusses the evidence behind the various established and emerging treatment paradigms. PMID:20689798

Three-dimensional venous anatomy of the dermis observed using stereography

PubMed Central

Imanishi, Nobuaki; Kishi, Kazuo; Chang, Hak; Nakajima, Hideo; Aiso, Sadakazu

2008-01-01

Veins of the dermis have been investigated mainly by histological methods in the fields of anatomy and histology, and a large number of schemata of the veins have been depicted in a variety of textbooks. However, the schemata are usually two-dimensional and it is therefore difficult to envisage the actual vasculature of the dermal veins. In this study, we performed a stereographic study of the skin of three fresh cadavers that had been injected with radio-opaque dye, which was dispersed throughout the entire body. A venous network consisting of venous polygons of various sizes existed just under the dermis or in the deep zone of the dermis, which is generally called the subdermal venous plexus. There were many small vessels towards the inside of each venous polygon, and most of them ascended, branching off stereoscopically. Those branches anastomosed with each other, and they formed the dermal and subpapillary venous plexuses. However, there was little vascular connection between dermal venous plexuses of different venous polygons. The characteristic structure of the dermal venous plexus has been considered to bring about venous congestion of the skin in various clinical situations. PMID:18422525

Implementation of a Surface Electromyography-Based Upper Extremity Exoskeleton Controller Using Learning from Demonstration.

PubMed

Siu, Ho Chit; Arenas, Ana M; Sun, Tingxiao; Stirling, Leia A

2018-02-05

Upper-extremity exoskeletons have demonstrated potential as augmentative, assistive, and rehabilitative devices. Typical control of upper-extremity exoskeletons have relied on switches, force/torque sensors, and surface electromyography (sEMG), but these systems are usually reactionary, and/or rely on entirely hand-tuned parameters. sEMG-based systems may be able to provide anticipatory control, since they interface directly with muscle signals, but typically require expert placement of sensors on muscle bodies. We present an implementation of an adaptive sEMG-based exoskeleton controller that learns a mapping between muscle activation and the desired system state during interaction with a user, generating a personalized sEMG feature classifier to allow for anticipatory control. This system is robust to novice placement of sEMG sensors, as well as subdermal muscle shifts. We validate this method with 18 subjects using a thumb exoskeleton to complete a book-placement task. This learning-from-demonstration system for exoskeleton control allows for very short training times, as well as the potential for improvement in intent recognition over time, and adaptation to physiological changes in the user, such as those due to fatigue.

Association of viral hemorrhagic septicemia virus with epizootic hemorrhages of the skin in Pacific herring Clupea harengus pallasi from Prince William Sound and Kodiak Island, Alaska, USA

USGS Publications Warehouse

Meyers, T.R.; Short, S.; Lipson, K.; Batts, W.N.; Winton, J.R.; Wilcock, J.; Brown, E.

1994-01-01

Only one-third of the Pacific hernng Clupea harengus pallasi expected to spawn in Prince William Sound (PWS), Alaska, USA, in sprlng 1993 were observed. Of these herring, 15 to 43 '% had external ulcers or subdermal hemorrhages of the skln and fins. A rhabdovirus identified as the North American strain of viral hemorrhagic septicemia virus (VHSV) was isolated from affected herring and 1 Pacific cod Gadus macrocephalus with skin lesions from PWS, and from herring with similar lesions collected near Kodiak Island. No other pathogens were detected in the herring examined. Although VHSV may have been responsible for the skin lesions, there was no confirmed mass herring mortality observed in PWS; hence the actual cause of the reduced herring numbers is still unknown. The same strain of VHSV was subsequently isolated from captive juvenile herring collected from Auke Bay, Alaska, near Juneau, from herring in British Columbia, Canada, and from Puget Sound, Washington, USA. These findings suggest the virus is an opportunistic pathogen that is widely indigenous to Pacific herring populations in the Pacific Northwest and that herring are a significant marine reservoir for North American VHSV.

Mechanisms of electrode induced injury. Part 2: Clinical experience.

PubMed

Patterson, Terry; Stecker, Mark M; Netherton, Brett L

2007-06-01

In the previous paper in this series, basic mechanisms of electrode related injuries were discussed. In this paper, the discussion begins with some of the clinical aspects of burns. This is followed by a summary of the clinical literature on injuries produced by surface and subdermal electrodes. This clinical literature demonstrates that most electrode burns are related to the presence of high frequency electric fields (RF) created either by an electrosurgical unit or a magnetic resonance imaging (MRI) scanner. A smaller number of lesions are produced by low current, long duration direct current (DC) stimulation and during high current stimulation such as defibrillation. A discussion of the clinical complications from indwelling intracranial electrodes centers on electrodes placed for deep brain stimulation (DBS) that are currently used therapeutically in a wide array of neurologic disorders. The probability of considering a post-implant MRI scan is high and the safety of such scans is the focus of discussion. A very small number of adverse incidents have indicated a downward revision in the specific absorption rate recommendations for MRI examination with those patients who present with indwelling DBS leads and internal pulse generators. Continued vigilance when any type of electrode is used is important.

Effect of Isometric Hand Grip Exercises on Blood Flow and Placement of IV Catheters for Administration of Chemotherapy.

PubMed

Ozkaraman, Ayse; Yesilbalkan, Öznur Usta

2016-04-01

Complications may occur in the subcutaneous or subdermal tissues during IV administration of chemotherapy related to blood flow and catheter placement. Daily isometric hand grip exercises were evaluated for their effect on blood flow in the vessels of the nondominant arm before placement of IV catheters and the success rate of IV catheter placement on the first attempt. The study focused on patients with non-Hodgkin lymphoma receiving the first and second cycles of chemotherapy. The intervention group performed daily isometric hand grip exercises before chemotherapy with peripheral catheter insertion. The control group performed routine activities only. Blood flow was measured by ultrasound in the brachial artery (BA) and brachial vein (BV) of the nondominant arm before the first (T1) and second (T2) cycles of chemotherapy. Blood flow slightly increased in the intervention group at T2 compared to T1. In the control group, blood flow decreased in the BA and did not change in the BV at T2 compared to T1. The success rate for first-attempt placement of a peripheral IV catheter was the same for the intervention and control groups.

Association between Propionibacterium acnes and frozen shoulder: a pilot study

PubMed Central

Bunker, Tim D; Gallacher, Sian; Auckland, Cressida R; Kitson, Jeff; Smith, Chris D

2014-01-01

Background Frozen shoulder has not previously been shown to be associated with infection. The present study set out to confirm the null hypothesis that there is no relationship between infection and frozen shoulder using two modern scientific methods, extended culture and polymerase chain reaction (PCR) for bacterial nucleic acids. Methods A prospective cohort of 10 patients undergoing arthroscopic release for stage II idiopathic frozen shoulder had two biopsies of tissue taken from the affected shoulder joint capsule at the time of surgery, along with control biopsies of subdermal fat. The biopsies and controls were examined with extended culture and PCR for microbial nucleic acid. Results Eight of the 10 patients had positive findings on extended culture in their shoulder capsule and, in six of these, Propionibacterium acnes was present. Conclusions The findings mean that we must reject the null hypothesis that there is no relationship between infection and frozen shoulder. More studies are urgently needed to confirm or refute these findings. If they are confirmed, this could potentially lead to new and effective treatments for this common, painful and disabling condition. Could P. acnes be the Helicobacter of frozen shoulder? PMID:27582943

The Effect of Gene Variants on Levonorgestrel Pharmacokinetics When Combined With Antiretroviral Therapy Containing Efavirenz or Nevirapine.

PubMed

Neary, M; Lamorde, M; Olagunju, A; Darin, K M; Merry, C; Byakika-Kibwika, P; Back, D J; Siccardi, M; Owen, A; Scarsi, K K

2017-09-01

Reduced levonorgestrel concentrations from the levonorgestrel contraceptive implant was previously seen when given concomitantly with efavirenz. We sought to assess whether single nucleotide polymorphisms (SNPs) in genes involved in efavirenz and nevirapine metabolism were linked to these changes in levonorgestrel concentration. SNPs in CYP2B6, CYP2A6, NR1I2, and NR1I3 were analyzed. Associations of participant demographics and genotype with levonorgestrel pharmacokinetics were evaluated in HIV-positive women using the levonorgestrel implant plus efavirenz- or nevirapine-based antiretroviral therapy (ART), in comparison to ART-naïve women using multivariate linear regression. Efavirenz group: CYP2B6 516G>T was associated with lower levonorgestrel log 10 C max and log 10 AUC. CYP2B6 15582C>T was associated with lower log 10 AUC. Nevirapine group: CYP2B6 516G>T was associated with higher log 10 C max and lower log 10 C min . Pharmacogenetic variations influenced subdermal levonorgestrel pharmacokinetics in HIV-positive women, indicating that the magnitude of the interaction with non-nucleoside reverse transcriptase inhibitors (NNRTIs) is influenced by host genetics. © 2017 American Society for Clinical Pharmacology and Therapeutics.

Underwater hearing in the loggerhead turtle (Caretta caretta): a comparison of behavioral and auditory evoked potential audiograms.

PubMed

Martin, Kelly J; Alessi, Sarah C; Gaspard, Joseph C; Tucker, Anton D; Bauer, Gordon B; Mann, David A

2012-09-01

The purpose of this study was to compare underwater behavioral and auditory evoked potential (AEP) audiograms in a single captive adult loggerhead sea turtle (Caretta caretta). The behavioral audiogram was collected using a go/no-go response procedure and a modified staircase method of threshold determination. AEP thresholds were measured using subdermal electrodes placed beneath the frontoparietal scale, dorsal to the midbrain. Both methods showed the loggerhead sea turtle to have low frequency hearing with best sensitivity between 100 and 400 Hz. AEP testing yielded thresholds from 100 to 1131 Hz with best sensitivity at 200 and 400 Hz (110 dB re. 1 μPa). Behavioral testing using 2 s tonal stimuli yielded underwater thresholds from 50 to 800 Hz with best sensitivity at 100 Hz (98 dB re. 1 μPa). Behavioral thresholds averaged 8 dB lower than AEP thresholds from 100 to 400 Hz and 5 dB higher at 800 Hz. The results suggest that AEP testing can be a good alternative to measuring a behavioral audiogram with wild or untrained marine turtles and when time is a crucial factor.

Implementation of a Surface Electromyography-Based Upper Extremity Exoskeleton Controller Using Learning from Demonstration

PubMed Central

Arenas, Ana M.; Sun, Tingxiao

2018-01-01

Upper-extremity exoskeletons have demonstrated potential as augmentative, assistive, and rehabilitative devices. Typical control of upper-extremity exoskeletons have relied on switches, force/torque sensors, and surface electromyography (sEMG), but these systems are usually reactionary, and/or rely on entirely hand-tuned parameters. sEMG-based systems may be able to provide anticipatory control, since they interface directly with muscle signals, but typically require expert placement of sensors on muscle bodies. We present an implementation of an adaptive sEMG-based exoskeleton controller that learns a mapping between muscle activation and the desired system state during interaction with a user, generating a personalized sEMG feature classifier to allow for anticipatory control. This system is robust to novice placement of sEMG sensors, as well as subdermal muscle shifts. We validate this method with 18 subjects using a thumb exoskeleton to complete a book-placement task. This learning-from-demonstration system for exoskeleton control allows for very short training times, as well as the potential for improvement in intent recognition over time, and adaptation to physiological changes in the user, such as those due to fatigue. PMID:29401754

Evaluation of fingerprint deformation using optical coherence tomography

NASA Astrophysics Data System (ADS)

Gutierrez da Costa, Henrique S.; Maxey, Jessica R.; Silva, Luciano; Ellerbee, Audrey K.

2014-02-01

Biometric identification systems have important applications to privacy and security. The most widely used of these, print identification, is based on imaging patterns present in the fingers, hands and feet that are formed by the ridges, valleys and pores of the skin. Most modern print sensors acquire images of the finger when pressed against a sensor surface. Unfortunately, this pressure may result in deformations, characterized by changes in the sizes and relative distances of the print patterns, and such changes have been shown to negatively affect the performance of fingerprint identification algorithms. Optical coherence tomography (OCT) is a novel imaging technique that is capable of imaging the subsurface of biological tissue. Hence, OCT may be used to obtain images of subdermal skin structures from which one can extract an internal fingerprint. The internal fingerprint is very similar in structure to the commonly used external fingerprint and is of increasing interest in investigations of identify fraud. We proposed and tested metrics based on measurements calculated from external and internal fingerprints to evaluate the amount of deformation of the skin. Such metrics were used to test hypotheses about the differences of deformation between the internal and external images, variations with the type of finger and location inside the fingerprint.

Investigations of needle-free jet injections.

PubMed

Schramm-Baxter, J R; Mitragotri, S

2004-01-01

Jet injection is a needle-free drug delivery method in which a high-speed stream of fluid impacts the skin and delivers drugs. Although a number of jet injectors are commercially available, especially for insulin delivery, they have a low market share compared to needles possibly due to occasional pain associated with jet injection. Jets employed by the traditional jet injectors penetrate deep into the dermal and sub-dermal regions where the nerve endings are abundantly located. To eliminate the pain associated with jet injections, we propose to utilize microjets that penetrate only into the superficial region of the skin. However, the choice of appropriate jet parameters for this purpose is challenging owing to the multiplicity of factors that determine the penetration depth. Here, we describe the dependence of jet injections into human skin on the power of the jet. Dermal delivery of liquid jets was quantified using two measurements, penetration of a radiolabeled solute, mannitol, into skin and the shape of jet dispersion in the skin which was visualized using sulforhodamine B. The dependence of the amount of liquid delivered in the skin and the geometric measurements of jet dispersion on nozzle diameter and jet velocity was captured by a single parameter, jet power.

A systematic review of microwave-based therapy for axillary hyperhidrosis.

PubMed

Hsu, Tzu-Herng; Chen, Yu-Tsung; Tu, Yu-Kang; Li, Chien-Nien

2017-10-01

To systematically analyse the literature on the use of the microwave-based device for subdermal thermolysis of the axilla and its efficacy for the treatment of axillary hyperhidrosis. A systematic review was conducted using PubMed, Embase, SCOPUS and Cochrane databases on 2 June 2016. The inclusion criteria including: (1) studies with human subjects, (2) full-text articles published in English, (3) a microwave-based device used to treat axillary hyperhidrosis and (4) trials that precisely evaluated axillary hyperhidrosis. Exclusion criteria were the following: (1) studies that did not fit the inclusion criteria mentioned above and (2) case reports and reviews. We reviewed five clinical trials and 189 patients, all of which were published between 2012 and 2016. There was one randomized controlled trial, one retrospective study and the remainder were prospective studies. Although all of the studies were conducted with a small sample size, the results indicated that microwave-based device treatment of axillary hyperhidrosis had long-term efficacy with mild adverse effects. In addition, most patients were satisfied with the outcomes in these studies. Microwave-based device treatment may be an effective alternative treatment for axillary hyperhidrosis. However, further investigation is necessary to determine its long-term efficacy and safety.

Basal ganglia, movement disorders and deep brain stimulation: advances made through non-human primate research.

PubMed

Wichmann, Thomas; Bergman, Hagai; DeLong, Mahlon R

2018-03-01

Studies in non-human primates (NHPs) have led to major advances in our understanding of the function of the basal ganglia and of the pathophysiologic mechanisms of hypokinetic movement disorders such as Parkinson's disease and hyperkinetic disorders such as chorea and dystonia. Since the brains of NHPs are anatomically very close to those of humans, disease states and the effects of medical and surgical approaches, such as deep brain stimulation (DBS), can be more faithfully modeled in NHPs than in other species. According to the current model of the basal ganglia circuitry, which was strongly influenced by studies in NHPs, the basal ganglia are viewed as components of segregated networks that emanate from specific cortical areas, traverse the basal ganglia, and ventral thalamus, and return to the frontal cortex. Based on the presumed functional domains of the different cortical areas involved, these networks are designated as 'motor', 'oculomotor', 'associative' and 'limbic' circuits. The functions of these networks are strongly modulated by the release of dopamine in the striatum. Striatal dopamine release alters the activity of striatal projection neurons which, in turn, influences the (inhibitory) basal ganglia output. In parkinsonism, the loss of striatal dopamine results in the emergence of oscillatory burst patterns of firing of basal ganglia output neurons, increased synchrony of the discharge of neighboring basal ganglia neurons, and an overall increase in basal ganglia output. The relevance of these findings is supported by the demonstration, in NHP models of parkinsonism, of the antiparkinsonian effects of inactivation of the motor circuit at the level of the subthalamic nucleus, one of the major components of the basal ganglia. This finding also contributed strongly to the revival of the use of surgical interventions to treat patients with Parkinson's disease. While ablative procedures were first used for this purpose, they have now been largely replaced by DBS of the subthalamic nucleus or internal pallidal segment. These procedures are not only effective in the treatment of parkinsonism, but also in the treatment of hyperkinetic conditions (such as chorea or dystonia) which result from pathophysiologic changes different from those underlying Parkinson's disease. Thus, these interventions probably do not counteract specific aspects of the pathophysiology of movement disorders, but non-specifically remove the influence of the different types of disruptive basal ganglia output from the relatively intact portions of the motor circuitry downstream from the basal ganglia. Knowledge gained from studies in NHPs remains critical for our understanding of the pathophysiology of movement disorders, of the effects of DBS on brain network activity, and the development of better treatments for patients with movement disorders and other neurologic or psychiatric conditions.

Multi-Tissue Computational Modeling Analyzes Pathophysiology of Type 2 Diabetes in MKR Mice

PubMed Central

Kumar, Amit; Harrelson, Thomas; Lewis, Nathan E.; Gallagher, Emily J.; LeRoith, Derek; Shiloach, Joseph; Betenbaugh, Michael J.

2014-01-01

Computational models using metabolic reconstructions for in silico simulation of metabolic disorders such as type 2 diabetes mellitus (T2DM) can provide a better understanding of disease pathophysiology and avoid high experimentation costs. There is a limited amount of computational work, using metabolic reconstructions, performed in this field for the better understanding of T2DM. In this study, a new algorithm for generating tissue-specific metabolic models is presented, along with the resulting multi-confidence level (MCL) multi-tissue model. The effect of T2DM on liver, muscle, and fat in MKR mice was first studied by microarray analysis and subsequently the changes in gene expression of frank T2DM MKR mice versus healthy mice were applied to the multi-tissue model to test the effect. Using the first multi-tissue genome-scale model of all metabolic pathways in T2DM, we found out that branched-chain amino acids' degradation and fatty acids oxidation pathway is downregulated in T2DM MKR mice. Microarray data showed low expression of genes in MKR mice versus healthy mice in the degradation of branched-chain amino acids and fatty-acid oxidation pathways. In addition, the flux balance analysis using the MCL multi-tissue model showed that the degradation pathways of branched-chain amino acid and fatty acid oxidation were significantly downregulated in MKR mice versus healthy mice. Validation of the model was performed using data derived from the literature regarding T2DM. Microarray data was used in conjunction with the model to predict fluxes of various other metabolic pathways in the T2DM mouse model and alterations in a number of pathways were detected. The Type 2 Diabetes MCL multi-tissue model may explain the high level of branched-chain amino acids and free fatty acids in plasma of Type 2 Diabetic subjects from a metabolic fluxes perspective. PMID:25029527

Advances in mechanisms of allergy.

PubMed

Bochner, Bruce S; Busse, William W

2004-05-01

This review summarizes selected Mechanisms of Allergy articles appearing between 2002 and 2003 in the Journal of Allergy and Clinical Immunology. Articles chosen include those dealing with human airways disease pathophysiology, pharmacology, cell biology, cell recruitment, and genetics, as well as information from allergen challenge models in both human and nonhuman systems. When appropriate, articles from other journals have been included to supplement the topics being presented.

Casting the net broader to confirm our imaginations: the long road to treating wasting disorders

PubMed Central

2017-01-01

Abstract Wasting embraces muscle and tissue wasting in sarcopenia and cachexia. This article describes recent advances in the field published in the Journal of Cachexia, Sarcopenia and Muscle concerning diagnostic tools, biomarker development, pathophysiology, and treatment. Studies discussed herein embrace those on sarcopenia and cachexia in heart failure, chronic obstructive pulmonary disease, and cancer including also animal models. PMID:29168628

Pathophysiology, Diagnosis, and Treatment of Radiation Necrosis in the Brain

PubMed Central

MIYATAKE, Shin-Ichi; NONOGUCHI, Noasuke; FURUSE, Motomasa; YORITSUNE, Erina; MIYATA, Tomo; KAWABATA, Shinji; KUROIWA, Toshihiko

2015-01-01

New radiation modalities have made it possible to prolong the survival of individuals with malignant brain tumors, but symptomatic radiation necrosis becomes a serious problem that can negatively affect a patient’s quality of life through severe and lifelong effects. Here we review the relevant literature and introduce our original concept of the pathophysiology of brain radiation necrosis following the treatment of brain, head, and neck tumors. Regarding the pathophysiology of radiation necrosis, we introduce two major hypotheses: glial cell damage or vascular damage. For the differential diagnosis of radiation necrosis and tumor recurrence, we focus on the role of positron emission tomography. Finally, in accord with our hypothesis regarding the pathophysiology, we describe the promising effects of the anti-vascular endothelial growth factor antibody bevacizumab on symptomatic radiation necrosis in the brain. PMID:25744350

Physiology and pathophysiology of apoptosis in epithelial cells of the liver, pancreas, and intestine.

PubMed

Jones, B A; Gores, G J

1997-12-01

Cell death of gastrointestinal epithelial cells occurs by a process referred to as apoptosis. In this review, we succinctly define apoptosis and summarize the role of apoptosis in the physiology and pathophysiology of epithelial cells in the liver, pancreas, and small and large intestine. The physiological mediators regulating apoptosis in gastrointestinal epithelial cells, when known, are discussed. Selected pathophysiological consequences of excessive apoptosis and inhibition of apoptosis are used to illustrate the significance of apoptosis in disease processes. These examples demonstrate that excessive apoptosis may result in epithelial cell atrophy, injury, and dysfunction, whereas inhibition of apoptosis results in hyperplasia and promotes malignant transformation. The specific cellular mechanisms responsible for dysregulation of epithelial cell apoptosis during pathophysiological disturbances are emphasized. Potential future areas of physiological research regarding apoptosis in gastrointestinal epithelia are highlighted when appropriate.

An update on pancreatic pathophysiology (do we have to rewrite pancreatic pathophysiology?).

PubMed

Hammer, Heinz F

2014-02-01

This review focuses on seven aspects of physiology and pathophysiology of the exocrine pancreas that have been intensively discussed and studied within the past few years: (1) the role of neurohormonal mechanisms like melatonin, leptin, or ghrelin in the stimulation of pancreatic enzyme secretion; (2) the initiation processes of acute pancreatitis, like fusion of zymogen granules with lysosomes leading to intracellular activation of trypsinogen by the lysosomal enzyme cathepsin B, or autoactivation of trypsinogen; (3) the role of genes in the pathogenesis of acute pancreatitis; (4) the role of alcohol and constituents of alcoholic beverages in the pathogenesis of acute pancreatitis; (5) the role of pancreatic hypertension, neuropathy, and central mechanisms for the pathogenesis of pain in chronic pancreatitis; (6) the relation between exocrine pancreatic function and diabetes mellitus; and (7) pathophysiology, diagnosis and treatment of pancreatic steatorrhea.

Effectiveness of integrating case studies in online and face-to-face instruction of pathophysiology: a comparative study.

PubMed

Saleh, Suha M; Asi, Yara M; Hamed, Kastro M

2013-06-01

Due to growing demand from students and facilitated by innovations in educational technology, institutions of higher learning are increasingly offering online courses. Subjects in the hard sciences, such as pathophysiology, have traditionally been taught in the face-to-face format, but growing demand for preclinical science courses has compelled educators to incorporate online components into their classes to promote comprehension. Learning tools such as case studies are being integrated into such courses to aid in student interaction, engagement, and critical thinking skills. Careful assessment of pedagogical techniques is essential; hence, this study aimed to evaluate and compare student perceptions of the use of case studies in face-to-face and fully online pathophysiology classes. A series of case studies was incorporated into the curriculum of a pathophysiology class for both class modes (online and face to face). At the end of the semester, students filled out a survey assessing the effectiveness of the case studies. Both groups offered positive responses about the incorporation of case studies in the curriculum of the pathophysiology class. This study supports the argument that with proper use of innovative teaching tools, such as case studies, online pathophysiology classes can foster a sense of community and interaction that is typically only seen with face-to-face classes, based on student responses. Students also indicated that regardless of class teaching modality, use of case studies facilitates student learning and comprehension as well as prepares them for their future careers in health fields.

Pathology and pathophysiology of inhalational anthrax in a guinea pig model.

PubMed

Savransky, Vladimir; Sanford, Daniel C; Syar, Emily; Austin, Jamie L; Tordoff, Kevin P; Anderson, Michael S; Stark, Gregory V; Barnewall, Roy E; Briscoe, Crystal M; Lemiale-Biérinx, Laurence; Park, Sukjoon; Ionin, Boris; Skiadopoulos, Mario H

2013-04-01

Nonhuman primates (NHPs) and rabbits are the animal models most commonly used to evaluate the efficacy of medical countermeasures against anthrax in support of licensure under the FDA's "Animal Rule." However, a need for an alternative animal model may arise in certain cases. The development of such an alternative model requires a thorough understanding of the course and manifestation of experimental anthrax disease induced under controlled conditions in the proposed animal species. The guinea pig, which has been used extensively for anthrax pathogenesis studies and anthrax vaccine potency testing, is a good candidate for such an alternative model. This study was aimed at determining the median lethal dose (LD50) of the Bacillus anthracis Ames strain in guinea pigs and investigating the natural history, pathophysiology, and pathology of inhalational anthrax in this animal model following nose-only aerosol exposure. The inhaled LD50 of aerosolized Ames strain spores in guinea pigs was determined to be 5.0 × 10(4) spores. Aerosol challenge of guinea pigs resulted in inhalational anthrax with death occurring between 46 and 71 h postchallenge. The first clinical signs appeared as early as 36 h postchallenge. Cardiovascular function declined starting at 20 h postexposure. Hematogenous dissemination of bacteria was observed microscopically in multiple organs and tissues as early as 24 h postchallenge. Other histopathologic findings typical of disseminated anthrax included suppurative (heterophilic) inflammation, edema, fibrin, necrosis, and/or hemorrhage in the spleen, lungs, and regional lymph nodes and lymphocyte depletion and/or lymphocytolysis in the spleen and lymph nodes. This study demonstrated that the course of inhalational anthrax disease and the resulting pathology in guinea pigs are similar to those seen in rabbits and NHPs, as well as in humans.

Computer model for the cardiovascular system: development of an e-learning tool for teaching of medical students.

PubMed

Warriner, David Roy; Bayley, Martin; Shi, Yubing; Lawford, Patricia Victoria; Narracott, Andrew; Fenner, John

2017-11-21

This study combined themes in cardiovascular modelling, clinical cardiology and e-learning to create an on-line environment that would assist undergraduate medical students in understanding key physiological and pathophysiological processes in the cardiovascular system. An interactive on-line environment was developed incorporating a lumped-parameter mathematical model of the human cardiovascular system. The model outputs were used to characterise the progression of key disease processes and allowed students to classify disease severity with the aim of improving their understanding of abnormal physiology in a clinical context. Access to the on-line environment was offered to students at all stages of undergraduate training as an adjunct to routine lectures and tutorials in cardiac pathophysiology. Student feedback was collected on this novel on-line material in the course of routine audits of teaching delivery. Medical students, irrespective of their stage of undergraduate training, reported that they found the models and the environment interesting and a positive experience. After exposure to the environment, there was a statistically significant improvement in student performance on a series of 6 questions based on cardiovascular medicine, with a 33% and 22% increase in the number of questions answered correctly, p < 0.0001 and p < 0.001 respectively. Considerable improvement was found in students' knowledge and understanding during assessment after exposure to the e-learning environment. Opportunities exist for development of similar environments in other fields of medicine, refinement of the existing environment and further engagement with student cohorts. This work combines some exciting and developing fields in medical education, but routine adoption of these types of tool will be possible only with the engagement of all stake-holders, from educationalists, clinicians, modellers to, most importantly, medical students.

Pathology and Pathophysiology of Inhalational Anthrax in a Guinea Pig Model

PubMed Central

Savransky, Vladimir; Sanford, Daniel C.; Syar, Emily; Austin, Jamie L.; Tordoff, Kevin P.; Anderson, Michael S.; Stark, Gregory V.; Barnewall, Roy E.; Briscoe, Crystal M.; Lemiale-Biérinx, Laurence; Park, Sukjoon; Ionin, Boris

2013-01-01

Nonhuman primates (NHPs) and rabbits are the animal models most commonly used to evaluate the efficacy of medical countermeasures against anthrax in support of licensure under the FDA's “Animal Rule.” However, a need for an alternative animal model may arise in certain cases. The development of such an alternative model requires a thorough understanding of the course and manifestation of experimental anthrax disease induced under controlled conditions in the proposed animal species. The guinea pig, which has been used extensively for anthrax pathogenesis studies and anthrax vaccine potency testing, is a good candidate for such an alternative model. This study was aimed at determining the median lethal dose (LD50) of the Bacillus anthracis Ames strain in guinea pigs and investigating the natural history, pathophysiology, and pathology of inhalational anthrax in this animal model following nose-only aerosol exposure. The inhaled LD50 of aerosolized Ames strain spores in guinea pigs was determined to be 5.0 × 104 spores. Aerosol challenge of guinea pigs resulted in inhalational anthrax with death occurring between 46 and 71 h postchallenge. The first clinical signs appeared as early as 36 h postchallenge. Cardiovascular function declined starting at 20 h postexposure. Hematogenous dissemination of bacteria was observed microscopically in multiple organs and tissues as early as 24 h postchallenge. Other histopathologic findings typical of disseminated anthrax included suppurative (heterophilic) inflammation, edema, fibrin, necrosis, and/or hemorrhage in the spleen, lungs, and regional lymph nodes and lymphocyte depletion and/or lymphocytolysis in the spleen and lymph nodes. This study demonstrated that the course of inhalational anthrax disease and the resulting pathology in guinea pigs are similar to those seen in rabbits and NHPs, as well as in humans. PMID:23357384

Embryonic Mutant Huntingtin Aggregate Formation in Mouse Models of Huntington's Disease.

PubMed

Osmand, Alexander P; Bichell, Terry Jo; Bowman, Aaron B; Bates, Gillian P

2016-12-15

The role of aggregate formation in the pathophysiology of Huntington's disease (HD) remains uncertain. However, the temporal appearance of aggregates tends to correlate with the onset of symptoms and the numbers of neuropil aggregates correlate with the progression of clinical disease. Using highly sensitive immunohistochemical methods we have detected the appearance of diffuse aggregates during embryonic development in the R6/2 and YAC128 mouse models of HD. These are initially seen in developing axonal tracts and appear to spread throughout the cerebrum in the early neonate.

Anorexia in human and experimental animal models: physiological aspects related to neuropeptides.

PubMed

Yoshimura, Mitsuhiro; Uezono, Yasuhito; Ueta, Yoichi

2015-09-01

Anorexia, a loss of appetite for food, can be caused by various physiological and pathophysiological conditions. In this review, firstly, clinical aspects of anorexia nervosa are summarized in brief. Secondly, hypothalamic neuropeptides responsible for feeding regulation in each hypothalamic nucleus are discussed. Finally, three different types of anorexigenic animal models; dehydration-induced anorexia, cisplatin-induced anorexia and cancer anorexia-cachexia, are introduced. In conclusion, hypothalamic neuropeptides may give us novel insight to understand and find effective therapeutics strategy essential for various kinds of anorexia.

Vulvodynia: Definition, Prevalence, Impact, and Pathophysiological Factors.

PubMed

Pukall, Caroline F; Goldstein, Andrew T; Bergeron, Sophie; Foster, David; Stein, Amy; Kellogg-Spadt, Susan; Bachmann, Gloria

2016-03-01

Vulvodynia constitutes a highly prevalent form of chronic genital pain in women, and current information regarding its definition, prevalence, impact, and pathophysiologic factors involved is needed. To update the scientific evidence published in 2010 from the Third International Consultation of Sexual Medicine pertaining to the definition, prevalence, impact, and pathophysiologic factors of women's sexual pain. An expert committee, as part of the Fourth International Consultation of Sexual Medicine, comprised of researchers and clinicians from biological and social science disciplines, reviewed the scientific evidence on the definition, prevalence, impact, and pathophysiologic factors related to chronic genital pain. A review of the definition, prevalence, impact, and pathophysiological factors involved in vulvodynia. Vulvodynia is a prevalent and highly impactful genital pain condition. Numerous factors have been implicated in its development and maintenance. What is becoming increasingly apparent is that it likely represents the end point of different factors that can differ from patient to patient. Longitudinal research is needed to shed light on risk factors involved in the expression of vulvodynia, as well as in potential subgroups of affected patients, in order to develop an empirically supported treatment algorithm. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

An update on oxidative stress-mediated organ pathophysiology.

PubMed

Rashid, Kahkashan; Sinha, Krishnendu; Sil, Parames C

2013-12-01

Exposure to environmental pollutants and drugs can result in pathophysiological situations in the body. Research in this area is essential as the knowledge on cellular survival and death would help in designing effective therapeutic strategies that are needed for the maintenance of the normal physiological functions of the body. In this regard, naturally occurring bio-molecules can be considered as potential therapeutic targets as they are normally available in commonly consumed foodstuffs and are thought to have minimum side effects. This review article describes the detailed mechanisms of oxidative stress-mediated organ pathophysiology and the ultimate fate of the cells either to survive or to undergo necrotic or apoptotic death. The mechanisms underlying the beneficial role of a number of naturally occurring bioactive molecules in oxidative stress-mediated organ pathophysiology have also been included in the review. The review provides useful information about the recent progress in understanding the mechanism(s) of various types of organ pathophysiology, the complex cross-talk between these pathways, as well as their modulation in stressed conditions. Additionally, it suggests possible therapeutic applications of a number of naturally occurring bioactive molecules in conditions involving oxidative stress. Copyright © 2013 Elsevier Ltd. All rights reserved.

Pathophysiology of primary burning mouth syndrome with special focus on taste dysfunction: a review.

PubMed

Kolkka-Palomaa, M; Jääskeläinen, S K; Laine, M A; Teerijoki-Oksa, T; Sandell, M; Forssell, H

2015-11-01

Primary burning mouth syndrome (BMS) is a chronic oral condition characterized by burning pain often accompanied with taste dysfunction and xerostomia. The most compelling evidence concerning BMS pathophysiology comes from studies on the somatosensory system using neurophysiologic or psychophysical methods such as blink reflex, thermal quantitative sensory testing, as well as functional brain imaging. They have provided convincing evidence for neuropathic involvement at several levels of the somatosensory system in BMS pain pathophysiology. The number of taste function studies trying to substantiate the subjective taste disturbances or studies on salivary factors in BMS is much more limited, and most of them suffer from definitional and methodological problems. This review aims to critically evaluate the existing literature on the pathophysiology of BMS, paying special attention to the correctness of case selection and the methodology used in published studies, and to summarize the current state of knowledge. Based on the recognition of several gaps in the current understanding of the pathophysiology of BMS especially as regards taste and pain system interactions, the review ends with future scenarios for research in this area. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Congenital coronary artery anomalies: a bridge from embryology to anatomy and pathophysiology--a position statement of the development, anatomy, and pathology ESC Working Group.

PubMed

Pérez-Pomares, José María; de la Pompa, José Luis; Franco, Diego; Henderson, Deborah; Ho, Siew Yen; Houyel, Lucile; Kelly, Robert G; Sedmera, David; Sheppard, Mary; Sperling, Silke; Thiene, Gaetano; van den Hoff, Maurice; Basso, Cristina

2016-02-01

Congenital coronary artery anomalies are of major significance in clinical cardiology and cardiac surgery due to their association with myocardial ischaemia and sudden death. Such anomalies are detectable by imaging modalities and, according to various definitions, their prevalence ranges from 0.21 to 5.79%. This consensus document from the Development, Anatomy and Pathology Working Group of the European Society of Cardiology aims to provide: (i) a definition of normality that refers to essential anatomical and embryological features of coronary vessels, based on the integrated analysis of studies of normal and abnormal coronary embryogenesis and pathophysiology; (ii) an animal model-based systematic survey of the molecular and cellular mechanisms that regulate coronary blood vessel development; (iii) an organization of the wide spectrum of coronary artery anomalies, according to a comprehensive anatomical and embryological classification scheme; (iv) current knowledge of the pathophysiological mechanisms underlying symptoms and signs of coronary artery anomalies, with diagnostic and therapeutic implications. This document identifies the mosaic-like embryonic development of the coronary vascular system, as coronary cell types differentiate from multiple cell sources through an intricate network of molecular signals and haemodynamic cues, as the necessary framework for understanding the complex spectrum of coronary artery anomalies observed in human patients. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Renal denervation attenuates aldosterone expression and associated cardiovascular pathophysiology in angiotensin II-induced hypertension.

PubMed

Hong, Mo-Na; Li, Xiao-Dong; Chen, Dong-Rui; Ruan, Cheng-Chao; Xu, Jian-Zhong; Chen, Jing; Wu, Yong-Jie; Ma, Yu; Zhu, Ding-Liang; Gao, Ping-Jin

2016-10-18

The sympathetic nervous system interacts with the renin-angiotensin-aldosterone system (RAAS) contributing to cardiovascular diseases. In this study, we sought to determine if renal denervation (RDN) inhibits aldosterone expression and associated cardiovascular pathophysiological changes in angiotensin II (Ang II)-induced hypertension. Bilateral RDN or SHAM operation was performed before chronic 14-day Ang II subcutaneous infusion (200ng/kg/min) in male Sprague-Dawley rats. Bilateral RDN blunted Ang II-induced hypertension and ameliorated the mesenteric vascular dysfunction. Cardiovascular hypertrophy in response to Ang II was significantly attenuated by RDN as shown by histopathology and transthoracic echocardiography. Moreover, Ang II-induced vascular and myocardial inflammation and fibrosis were suppressed by RDN with concurrent decrease in fibronectin and collagen deposition, macrophage infiltration, and MCP-1 expression. Interestingly, RDN also inhibited Ang II-induced aldosterone expression in the plasma, kidney and heart. This was associated with the reduction of calcitonin gene-related peptide (CGRP) in the adrenal gland. Ang II promoted aldosterone secretion which was partly attenuated by CGRP in the adrenocortical cell line, suggesting a protective role of CGRP in this model. Activation of transforming growth factor-β (TGF-β)/Smad and mitogen-activated protein kinases (MAPKs) signaling pathway was both inhibited by RDN especially in the heart. These results suggest that the regulation of the renal sympathetic nerve in Ang II-induced hypertension and associated cardiovascular pathophysiological changes is likely mediated by aldosterone, with CGRP involvement.

Chronic Diffuse Pain and Functional Gastrointestinal Disorders After Traumatic Stress: Pathophysiology Through a Polyvagal Perspective

PubMed Central

Kolacz, Jacek; Porges, Stephen W.

2018-01-01

Chronic diffuse pain disorders, such as fibromyalgia, and functional gastrointestinal disorders (FGIDs), such as irritable bowel syndrome, place substantial burden on those affected and on the medical system. Despite their sizable impact, their pathophysiology is poorly understood. In contrast to an approach that focuses on the correlation between heart rate variability (HRV) and a specific organ or symptom, we propose that a bio-evolutionary threat-related autonomic response—as outlined in the Polyvagal Theory—may serve as a plausible explanation of how HRV, particularly respiratory sinus arrhythmia (RSA), would index the pathophysiology of these disorders. Evidence comes from: (1) the well-documented atypical autonomic regulation of the heart common to fibromyalgia and irritable bowel syndrome reflected in dampened RSA, (2) the neural architecture that integrates the heart, pain pathways, and the gastrointestinal tract, (3) the common physical co-morbidities shared by chronic diffuse pain and FGIDs, many of which are functionally regulated by the autonomic nervous system, (4) the elevated risk of chronic diffuse pain and FGIDs following traumatic stress or abuse, (5) and the elevated risk of chronic diffuse pain and FGIDs in individuals with anxiety and panic disorders. This novel conceptualization points to a pathogenesis rooted in changes to brain-body autonomic feedback loops in response to evolutionarily-salient threat cues, providing an integrated biopsychosocial model of chronic diffuse pain and FGIDs and suggesting new, non-pharmacological treatment strategies. PMID:29904631

Renal denervation attenuates aldosterone expression and associated cardiovascular pathophysiology in angiotensin II-induced hypertension

PubMed Central

Chen, Dong-Rui; Ruan, Cheng-Chao; Xu, Jian-Zhong; Chen, Jing; Wu, Yong-Jie; Ma, Yu; Zhu, Ding-Liang; Gao, Ping-Jin

2016-01-01

The sympathetic nervous system interacts with the renin-angiotensin-aldosterone system (RAAS) contributing to cardiovascular diseases. In this study, we sought to determine if renal denervation (RDN) inhibits aldosterone expression and associated cardiovascular pathophysiological changes in angiotensin II (Ang II)-induced hypertension. Bilateral RDN or SHAM operation was performed before chronic 14-day Ang II subcutaneous infusion (200ng/kg/min) in male Sprague-Dawley rats. Bilateral RDN blunted Ang II-induced hypertension and ameliorated the mesenteric vascular dysfunction. Cardiovascular hypertrophy in response to Ang II was significantly attenuated by RDN as shown by histopathology and transthoracic echocardiography. Moreover, Ang II-induced vascular and myocardial inflammation and fibrosis were suppressed by RDN with concurrent decrease in fibronectin and collagen deposition, macrophage infiltration, and MCP-1 expression. Interestingly, RDN also inhibited Ang II-induced aldosterone expression in the plasma, kidney and heart. This was associated with the reduction of calcitonin gene-related peptide (CGRP) in the adrenal gland. Ang II promoted aldosterone secretion which was partly attenuated by CGRP in the adrenocortical cell line, suggesting a protective role of CGRP in this model. Activation of transforming growth factor-β (TGF-β)/Smad and mitogen-activated protein kinases (MAPKs) signaling pathway was both inhibited by RDN especially in the heart. These results suggest that the regulation of the renal sympathetic nerve in Ang II-induced hypertension and associated cardiovascular pathophysiological changes is likely mediated by aldosterone, with CGRP involvement. PMID:27661131

Safety, Quality, and Acceptability of Contraceptive Subdermal Implant Provision by Community Health Extension Workers Versus Nurses and Midwives in Nigeria: Protocol for a Quasi-Experimental, Noninferiority Study

PubMed Central

Penfold, Suzanne; Alabi, Olalere; Ali, Moazzam; Hopkins, Kristen; Ngo, Thoai Dinh; Odogwu, Kingsley; Douthwaite, Megan; Ezire, Onoriode; Udoh, Uko; Effiom, Effiom; Munroe, Erik S

2018-01-01

Background As part of its Family Planning 2020 commitment, the Nigerian government is aiming for a contraceptive prevalence rate of 36% by 2018, and in 2014, approved a policy to allow community health extension workers (CHEWs), in addition to doctors, nurses, and midwives, to provide contraceptive subdermal implants. There is a lack of rigorous evidence on the safety of long-acting reversible contraceptive provision, such as implants, among lower cadres of health providers. Objective This study aimed to compare implant provision by CHEWs versus nurses and midwives up to 14 days post insertion. Methods The quasi-experimental, noninferiority study will take place in public sector facilities in Kaduna and Ondo States. In each state, we will select 60 facilities, and from these, we will select a total of 30 nurses and midwives and 30 CHEWs to participate. Selected providers will be trained to provide implant services. Once trained, providers will recruit a minimum of 8125 women aged between 18 and 49 years who request and are eligible for an implant, following comprehensive family planning counseling. During implant insertion, providers will record data about the process and any adverse events, and 14 days post insertion, providers will ask 4410 clients about adverse events arising from the implant. Supervisors will observe 792 implant insertions to assess service provision quality and ask clients about their satisfaction with the procedure. We will conclude noninferiority if the CI for the difference in the proportion of adverse events between CHEWs and nurses and midwives on the day of insertion or 14 days post insertion lies to the right of −2%. Results In September and October 2015, we trained 60 CHEWs and a total of 60 nurses and midwives from 12 local government areas (LGAs) in Kaduna and 23 LGAs in Ondo. Recruitment took place between November 2015 and December 2016. Data analysis is being finalized, and results are expected in March 2018. Conclusions The strength of this study is having a standard care (nurse and midwife provision) group with which CHEW provision can be compared. The intervention builds on existing training and supervision procedures, which increases the sustainability and scalability of CHEW implant provision. Important limitations include the lack of randomization due to nurses and midwives in Nigeria working in separate types of health care facilities compared with CHEWs, and that providers self-assess their own practices. It is unfeasible to observe all procedures independently, and observation may change practice. Although providers will be trained to conduct implant removals, the study time will be too short to reach the sample size required to make noninferiority comparisons for removals. Trial Registration ClinicalTrials.gov NCT03088722; https://clinicaltrials.gov/ct2/show/NCT03088722 (Archived by WebCite at http://www.webcitation.org/6xIHImWvu) PMID:29500162

Respiratory muscle dysfunction: a multicausal entity in the critically ill patient undergoing mechanical ventilation.

PubMed

Díaz, Magda C; Ospina-Tascón, Gustavo A; Salazar C, Blanca C

2014-02-01

Respiratory muscle dysfunction, particularly of the diaphragm, may play a key role in the pathophysiological mechanisms that lead to difficulty in weaning patients from mechanical ventilation. The limited mobility of critically ill patients, and of the diaphragm in particular when prolonged mechanical ventilation support is required, promotes the early onset of respiratory muscle dysfunction, but this can also be caused or exacerbated by other factors that are common in these patients, such as sepsis, malnutrition, advanced age, duration and type of ventilation, and use of certain medications, such as steroids and neuromuscular blocking agents. In this review we will study in depth this multicausal origin, in which a common mechanism is altered protein metabolism, according to the findings reported in various models. The understanding of this multicausality produced by the same pathophysiological mechanism could facilitate the management and monitoring of patients undergoing mechanical ventilation. Copyright © 2012 SEPAR. Published by Elsevier Espana. All rights reserved.

A novel pathogenesis of inflammatory bowel disease from the perspective of glyco-immunology.

PubMed

Shinzaki, Shinichiro; Iijima, Hideki; Fujii, Hironobu; Kamada, Yoshihiro; Naka, Tetsuji; Takehara, Tetsuo; Miyoshi, Eiji

2017-05-01

Oligosaccharide modifications play an essential role in various inflammatory diseases and cancers, but their pathophysiologic roles, especially in inflammation, are not clear. Inflammatory bowel disease (IBD) is an intractable chronic inflammatory disorder with an unknown aetiology, and the number of patients with IBD is increasing throughout the world. Certain types of immunosuppressant drugs, such as corticosteroids, are effective for IBD, suggesting that immune function is closely associated with the pathophysiology of IBD. Recent progress in the analysis of oligosaccharides revealed a role for oligosaccharides in intestinal inflammation based on both experimental models and human samples from IBD patients. Moreover, changes in the oligosaccharide structures on glycoproteins in the sera and tissue samples may serve as biomarkers of IBD. Here, we present current studies of IBD with regard to the immunologic aspects of glycobiology, suggesting a novel concept for IBD pathogenesis and the function of oligosaccharides on immune cells, termed "glyco-immunology". © The Authors 2017. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Collaborative translational research leading to multicenter clinical trials in Duchenne muscular dystrophy: the Cooperative International Neuromuscular Research Group (CINRG).

PubMed

Escolar, Diana M; Henricson, Erik K; Pasquali, Livia; Gorni, Ksenija; Hoffman, Eric P

2002-10-01

Progress in the development of rationally based therapies for Duchenne muscular dystrophy has been accelerated by encouraging multidisciplinary, multi-institutional collaboration between basic science and clinical investigators in the Cooperative International Research Group. We combined existing research efforts in pathophysiology by a gene expression profiling laboratory with the efforts of animal facilities capable of conducting high-throughput drug screening and toxicity testing to identify safe and effective drug compounds that target different parts of the pathophysiologic cascade in a genome-wide drug discovery approach. Simultaneously, we developed a clinical trial coordinating center and an international network of collaborating physicians and clinics where those drugs could be tested in large-scale clinical trials. We hope that by bringing together investigators at these facilities and providing the infrastructure to support their research, we can rapidly move new bench discoveries through animal model screening and into therapeutic testing in humans in a safe, timely and cost-effective setting.

Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis.

PubMed

Schneeberger, Marc; Gómez-Valadés, Alicia G; Altirriba, Jordi; Sebastián, David; Ramírez, Sara; Garcia, Ainhoa; Esteban, Yaiza; Drougard, Anne; Ferrés-Coy, Albert; Bortolozzi, Analía; Garcia-Roves, Pablo M; Jones, John G; Manadas, Bruno; Zorzano, Antonio; Gomis, Ramon; Claret, Marc

2015-07-21

Alterations in ER homeostasis have been implicated in the pathophysiology of obesity and type-2 diabetes (T2D). Acute ER stress induction in the hypothalamus produces glucose metabolism perturbations. However, the neurobiological basis linking hypothalamic ER stress with abnormal glucose metabolism remains unknown. Here, we report that genetic and induced models of hypothalamic ER stress are associated with alterations in systemic glucose homeostasis due to increased gluconeogenesis (GNG) independent of body weight changes. Defective alpha melanocyte-stimulating hormone (α-MSH) production underlies this metabolic phenotype, as pharmacological strategies aimed at rescuing hypothalamic α-MSH content reversed this phenotype at metabolic and molecular level. Collectively, our results posit defective α-MSH processing as a fundamental mediator of enhanced GNG in the context of hypothalamic ER stress and establish α-MSH deficiency in proopiomelanocortin (POMC) neurons as a potential contributor to the pathophysiology of T2D. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Immune-based strategies for mood disorders: facts and challenges.

PubMed

Colpo, Gabriela D; Leboyer, Marion; Dantzer, Robert; Trivedi, Mahdukar H; Teixeira, Antonio L

2018-02-01

Inflammation seems to play a role in the pathophysiology of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD). In the last years several studies have shown increased levels of inflammatory and/or immune markers in patients with mood disorders. Accordingly, the immune system has become a target of interest for the development of biomarkers and therapeutics for mood disorders. Areas covered: Here, we review the evidence showing low-grade inflammation in mood disorders and the studies evaluating immune-based strategies for the treatment of these conditions. Expert commentary: Clinical trials with non-steroidal anti-inflammatory drugs, polyunsaturated acids, N-acetylcysteine, anti-cytokines, physical activity and probiotics have provided promising results in terms of antidepressant efficacy in patients with MDD and BD. Regarding stem cells, only studies with animal models have been performed so far with interesting pre-clinical results. Due to the preliminary nature of the results, most of the clinical studies need to be replicated and/or confirmed in larger clinical settings, embracing the highly heterogeneous pathophysiology of mood disorders.

Present status of yellow fever: memorandum from a PAHO meeting.

PubMed

1986-01-01

An international seminar on the treatment and laboratory diagnosis of yellow fever, sponsored by the Pan American Health Organization (PAHO) and held in 1984, differed from previous meetings on yellow fever because of its emphasis on the care and management of patients and because the participants included specialists from several branches of medicine, such as hepatology, haematology, cardiology, infectious diseases, pathology and nephrology. The meeting reviewed the current status of yellow fever and problems associated with case-finding and notification; features of yellow fever in individual countries of Latin America; health services and facilities for medical care as they relate to diagnosis and management of cases; prevention strategies for and current status of immunization programmes; clinical and pathological aspects of yellow fever in humans; pathogenesis and pathophysiology of yellow fever in experimental animal models; clinical and specific laboratory diagnosis; treatment of the disease and of complications in the functioning of individual organ systems; prognosis and prognostic indicators; and directions for future clinical and experimental research on pathophysiology and treatment.

Abdominal Aortic Aneurysm: Evolving Controversies and Uncertainties.

PubMed

Carino, Davide; Sarac, Timur P; Ziganshin, Bulat A; Elefteriades, John A

2018-06-01

Abdominal aortic aneurysm (AAA) is defined as a permanent dilatation of the abdominal aorta that exceeds 3 cm. Most AAAs arise in the portion of abdominal aorta distal to the renal arteries and are defined as infrarenal. Most AAAs are totally asymptomatic until catastrophic rupture. The strongest predictor of AAA rupture is the diameter. Surgery is indicated to prevent rupture when the risk of rupture exceeds the risk of surgery. In this review, we aim to analyze this disease comprehensively, starting from an epidemiological perspective, exploring etiology and pathophysiology, and concluding with surgical controversies. We will pursue these goals by addressing eight specific questions regarding AAA: (1) Is the incidence of AAA increasing? (2) Are ultrasound screening programs for AAA effective? (3) What causes AAA: Genes versus environment? (4) Animal models: Are they really relevant? (5) What pathophysiology leads to AAA? (6) Indications for AAA surgery: Are surgeons over-eager to operate? (7) Elective AAA repair: Open or endovascular? (8) Emergency AAA repair: Open or endovascular?

A potential pathophysiological role for galectins and the renin-angiotensin system in preeclampsia.

PubMed

Blois, Sandra M; Dechend, Ralf; Barrientos, Gabriela; Staff, Anne Cathrine

2015-01-01

This review discusses a potential role of galectins and the renin-angiotensin system (RAS) in the pathophysiology of preeclampsia (PE). Preeclampsia affects between 3 and 5 % of all pregnancies and is a heterogeneous disease, which may be caused by multiple factors. The only cure is the delivery of the placenta, which may result in a premature delivery and baby. Probably due to its heterogeneity, PE studies in human have hitherto only led to the identification of a limited number of factors involved in the pathogenesis of the disease. Animal models, particularly in mice and rats, have been used to gain further insight into the molecular pathology behind PE. In this review, we discuss the picture emerging from human and animal studies pointing to galectins and the RAS being associated with the PE syndrome and affecting a broad range of cellular signaling components. Moreover, we review the epidemiological evidence for PE increasing the risk of future cardiovascular disease later in life.

Non-invasive detection of matrix-metalloproteinase activity in a mouse model of cerebral ischemia using multispectral optoacoustic tomography

NASA Astrophysics Data System (ADS)

Ni, Ruiqing; Vaas, Markus; Ren, Wuwei; Klohs, Jan

2018-02-01

Matrix metalloproteinases (MMPs) play important roles in the pathophysiology of cerebral ischemia. Here we visualized in vivo MMP activity in the transient middle cerebral artery occlusion (tMCAO) mouse model using multispectral optoacoustic imaging (MSOT) with a MMP-activatable probe. MSOT data was co-registered with structural magnetic resonance imaging (MRI) obtained at 7 T for localization of signal distribution. We demonstrated upregulated MMP signal within the focal ischemic lesion in the tMCAO mouse model using MSOT/MRI multimodal imaging. This convenient non-invasive method will allow repetitive measurement following the time course of MMP-lesion development in ischemic stroke animal model.

Animal models of traumatic brain injury

PubMed Central

Xiong, Ye; Mahmood, Asim; Chopp, Michael

2014-01-01

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity in both civilian life and the battlefield worldwide. Survivors of TBI frequently experience long-term disabling changes in cognition, sensorimotor function and personality. Over the past three decades, animal models have been developed to replicate the various aspects of human TBI, to better understand the underlying pathophysiology and to explore potential treatments. Nevertheless, promising neuroprotective drugs, which were identified to be effective in animal TBI models, have all failed in phase II or phase III clinical trials. This failure in clinical translation of preclinical studies highlights a compelling need to revisit the current status of animal models of TBI and therapeutic strategies. PMID:23329160

OCT monitoring of pathophysiological processes

NASA Astrophysics Data System (ADS)

Gladkova, Natalia D.; Shakhova, Natalia M.; Shakhov, Andrei; Petrova, Galina P.; Zagainova, Elena; Snopova, Ludmila; Kuznetzova, Irina N.; Chumakov, Yuri; Feldchtein, Felix I.; Gelikonov, Valentin M.; Gelikonov, Grigory V.; Kamensky, Vladislav A.; Kuranov, Roman V.; Sergeev, Alexander M.

1999-04-01

Based on results of clinical examination of about 200 patients we discuss capabilities of the optical coherence tomography (OCT) in monitoring and diagnosing of various pathophysiological processes. Performed in several clinical areas including dermatology, urology, laryngology, gynecology, and dentistry, our study shows the existence of common optical features in manifestation of a pathophysiological process in different organs. In this paper we focus at such universal tomographic optical signs for processes of inflammation, necrosis and tumor growth. We also present data on dynamical OCT monitoring of evolution of pathophysiological processes, both at the stage of disease development and following-up results of different treatments such as drug application, radiation therapy, cryodestruction, and laser vaporization. The discovered peculiarities of OCT images for structural and functional imaging of biological tissues can be put as a basis for application of this method for diagnosing of pathology, guidance of treatment, estimation of its adequacy and assessing of the healing process.

Acute pathophysiological processes after ischaemic and traumatic brain injury.

PubMed

Kunz, Alexander; Dirnagl, Ulrich; Mergenthaler, Philipp

2010-12-01

Ischaemic stroke and brain trauma are among the leading causes of mortality and long-term disability in the western world. Enormous endeavours have been made to elucidate the complex pathophysiology of ischaemic and traumatic brain injury with the intention of developing new therapeutic strategies for patients suffering from these devastating diseases. This article reviews the current knowledge on cascades that are activated after ischaemic and traumatic brain injury and that lead to progression of tissue damage. Main attention will be on pathophysiological events initiated after ischaemic stroke including excitotoxicity, oxidative/nitrosative stress, peri-infarct depolarizations, apoptosis and inflammation. Additionally, specific pathophysiological aspects after traumatic brain injury will be discussed along with their similarities and differences to ischaemic brain injury. This article provides prerequisites for understanding the therapeutic strategies for stroke and trauma patients which are addressed in other articles of this issue. Copyright © 2010 Elsevier Ltd. All rights reserved.

Animal Models of Substance Abuse and Addiction: Implications for Science, Animal Welfare, and Society

PubMed Central

Lynch, Wendy J; Nicholson, Katherine L; Dance, Mario E; Morgan, Richard W; Foley, Patricia L

2010-01-01

Substance abuse and addiction are well recognized public health concerns, with 2 NIH institutes (the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism) specifically targeting this societal problem. As such, this is an important area of research for which animal experiments play a critical role. This overview presents the importance of substance abuse and addiction in society; reviews the development and refinement of animal models that address crucial areas of biology, pathophysiology, clinical treatments, and drug screening for abuse liability; and discusses some of the unique veterinary, husbandry, and IACUC challenges associated with these models. PMID:20579432

Mathematical modeling of kidney transport.

PubMed

Layton, Anita T

2013-01-01

In addition to metabolic waste and toxin excretion, the kidney also plays an indispensable role in regulating the balance of water, electrolytes, nitrogen, and acid-base. In this review, we describe representative mathematical models that have been developed to better understand kidney physiology and pathophysiology, including the regulation of glomerular filtration, the regulation of renal blood flow by means of the tubuloglomerular feedback mechanisms and of the myogenic mechanism, the urine concentrating mechanism, epithelial transport, and regulation of renal oxygen transport. We discuss the extent to which these modeling efforts have expanded our understanding of renal function in both health and disease. Copyright © 2013 Wiley Periodicals, Inc.

Animal models of substance abuse and addiction: implications for science, animal welfare, and society.

PubMed

Lynch, Wendy J; Nicholson, Katherine L; Dance, Mario E; Morgan, Richard W; Foley, Patricia L

2010-06-01

Substance abuse and addiction are well recognized public health concerns, with 2 NIH institutes (the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism) specifically targeting this societal problem. As such, this is an important area of research for which animal experiments play a critical role. This overview presents the importance of substance abuse and addiction in society; reviews the development and refinement of animal models that address crucial areas of biology, pathophysiology, clinical treatments, and drug screening for abuse liability; and discusses some of the unique veterinary, husbandry, and IACUC challenges associated with these models.

Chikungunya Virus: Pathophysiology, Mechanism, and Modeling

PubMed Central

Ganesan, Vaishnavi K.; Reid, St Patrick

2017-01-01

Chikungunya virus (CHIKV), a mosquito-transmitted alphavirus, is recurring in epidemic waves. In the past decade and a half, the disease has resurged in several countries around the globe, with outbreaks becoming increasingly severe. Though CHIKV was first isolated in 1952, there remain significant gaps in knowledge of CHIKV biology, pathogenesis, transmission, and mechanism. Diagnosis is largely simplified and based on symptoms, while treatment is supportive rather than curative. Here we present an overview of the disease, the challenges that lie ahead for future research, and what directions current studies are headed towards, with emphasis on improvement of current animal models and potential use of 3D models. PMID:29194359

Defining the Pathophysiological Role of Tau in Experimental TBI

DTIC Science & Technology

2016-10-01

in AD. This pathway is a major source for excitatory innervation of hippocampus , a structure vital for memory formation. Damage to the EC or...hippocampal input pathway that is both preferentially vulnerable in early-stage AD and critically important for long-term memory . The model confines...structure and function of the hippocampus after single or repetitive mild TBI, and whether mild TBI exacerbates ongoing tauopathy to promote a chronic

Pathophysiology and Toxicokinetic Studies of Blue-Green Algae Intoxication in the Swine Model

DTIC Science & Technology

1991-06-26

perfusion, renal perfusion, and mean arterial and central venous pressures were decreased, and portal pressure increased. Liver iron and hemoglobin indicated...the lethal dose, aortic mean pressure and central venous pressure decreased significantly, while portal venous pressure significantly increased. The...8217" recorded on a poiygraphY and logged on a hemodynamic analyzer.𔄁 Mean aortic, central venous , and portal venous pressures were determined predosing

Experimental Septic Shock: Models and Mechanisms

DTIC Science & Technology

1976-06-14

the renal, hepatic, and pulmonary systems with severe pathophysiological effects on the liver circulation and metabolism (7,9,11,17,18,20). The...was sustained at values between 40 and 60 nmHg. Mean plasm glucose increased for the first several hours, then progressively fell to hypoglycemic...when the state of shock is severe and when death is imminent. On the other hand, hyperglycemia con- comitantly occurring with hypoinsulinemia, termed

Sida rhomboidea.Roxb extract alleviates pathophysiological changes in experimental in vivo and in vitro models of high fat diet/fatty acid induced non-alcoholic steatohepatitis.

PubMed

Thounaojam, Menaka C; Jadeja, Ravirajsinh N; Dandekar, Deven S; Devkar, Ranjitsinh V; Ramachandran, A V

2012-03-01

The present study was aim to evaluate protective role of Sida rhomboidea.Roxb (SR) extract against high fat diet/fatty acid induced pathophysiological alterations in experimental model of non-alcoholic steatohepatitis (NASH). Effect of SR extract on plasma levels of markers of hepatic damage, plasma and hepatic lipids, mitochondrial oxidative stress, status of enzymatic and non-enzymatic antioxidants and histopathological changes in liver tissue were evaluated in high fat diet fed C57BL/6J mice. Also, the effect of SR supplementation on lipid accumulation, lipid peroxidation, cytotoxicity and cell viability were evaluated in oleic acid treated HepG2 cells. Supplementation of NASH mice with SR extract prevented high fat diet induced elevation in plasma marker enzymes of liver damage, plasma and hepatic lipids, mitochondrial oxidative stress and compromised enzymatic and non-enzymatic antioxidant status. Further, addition of SR extract to in vitro HepG2 cells minimized oleic acid induced lipid accumulation, higher lipid peroxidation, cytotoxicity and reduced cell viability. These in vivo and in vitro studies suggest that SR extract has the potential of preventing high fat/fatty acid induced NASH mainly due to its hypolipidemic and antioxidant activities. Copyright © 2010 Elsevier GmbH. All rights reserved.

Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice.

PubMed

Cahill, Lindsay S; Gazdzinski, Lisa M; Tsui, Albert Ky; Zhou, Yu-Qing; Portnoy, Sharon; Liu, Elaine; Mazer, C David; Hare, Gregory Mt; Kassner, Andrea; Sled, John G

2017-03-01

Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO 2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia.

Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice

PubMed Central

Gazdzinski, Lisa M; Tsui, Albert KY; Zhou, Yu-Qing; Portnoy, Sharon; Liu, Elaine; Mazer, C David; Hare, Gregory MT; Kassner, Andrea; Sled, John G

2016-01-01

Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia. PMID:27165012

Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability

PubMed Central

Champion, Hunter C.; Campbell-Lee, Sally A.; Bivalacqua, Trinity J.; Manci, Elizabeth A.; Diwan, Bhalchandra A.; Schimel, Daniel M.; Cochard, Audrey E.; Wang, Xunde; Schechter, Alan N.; Noguchi, Constance T.; Gladwin, Mark T.

2007-01-01

Pulmonary hypertension is a highly prevalent complication of sickle cell disease and is a strong risk factor for early mortality. However, the pathophysiologic mechanisms leading to pulmonary vasculopathy remain unclear. Transgenic mice provide opportunities for mechanistic studies of vascular pathophysiology in an animal model. By microcardiac catheterization, all mice expressing exclusively human sickle hemoglobin had pulmonary hypertension, profound pulmonary and systemic endothelial dysfunction, and vascular instability characterized by diminished responses to authentic nitric oxide (NO), NO donors, and endothelium-dependent vasodilators and enhanced responses to vasoconstrictors. However, endothelium-independent vasodilation in sickle mice was normal. Mechanisms of vasculopathy in sickle mice involve global dysregulation of the NO axis: impaired constitutive nitric oxide synthase activity (NOS) with loss of endothelial NOS (eNOS) dimerization, increased NO scavenging by plasma hemoglobin and superoxide, increased arginase activity, and depleted intravascular nitrite reserves. Light microscopy and computed tomography revealed no plexogenic arterial remodeling or thrombi/emboli. Transplanting sickle marrow into wild-type mice conferred the same phenotype, and similar pathobiology was observed in a nonsickle mouse model of acute alloimmune hemolysis. Although the time course is shorter than typical pulmonary hypertension in human sickle cell disease, these results demonstrate that hemolytic anemia is sufficient to produce endothelial dysfunction and global dysregulation of NO. PMID:17158223

A calixpyrrole derivative acts as an antagonist to GPER, a G-protein coupled receptor: mechanisms and models.

PubMed

Lappano, Rosamaria; Rosano, Camillo; Pisano, Assunta; Santolla, Maria Francesca; De Francesco, Ernestina Marianna; De Marco, Paola; Dolce, Vincenza; Ponassi, Marco; Felli, Lamberto; Cafeo, Grazia; Kohnke, Franz Heinrich; Abonante, Sergio; Maggiolini, Marcello

2015-10-01

Estrogens regulate numerous pathophysiological processes, mainly by binding to and activating estrogen receptor (ER)α and ERβ. Increasing amounts of evidence have recently demonstrated that G-protein coupled receptor 30 (GPR30; also known as GPER) is also involved in diverse biological responses to estrogens both in normal and cancer cells. The classical ER and GPER share several features, including the ability to bind to identical compounds; nevertheless, some ligands exhibit opposed activity through these receptors. It is worth noting that, owing to the availability of selective agonists and antagonists of GPER for research, certain differential roles elicited by GPER compared with ER have been identified. Here, we provide evidence on the molecular mechanisms through which a calixpyrrole derivative acts as a GPER antagonist in different model systems, such as breast tumor cells and cancer-associated fibroblasts (CAFs) obtained from breast cancer patients. Our data might open new perspectives toward the development of a further class of selective GPER ligands in order to better dissect the role exerted by this receptor in different pathophysiological conditions. Moreover, calixpyrrole derivatives could be considered in future anticancer strategies targeting GPER in cancer cells. © 2015. Published by The Company of Biologists Ltd.

Lessons from Toxicology: Developing a 21st-Century Paradigm for Medical Research

PubMed Central

Austin, Christopher P.; Balapure, Anil K.; Birnbaum, Linda S.; Bucher, John R.; Fentem, Julia; Fitzpatrick, Suzanne C.; Fowle, John R.; Kavlock, Robert J.; Kitano, Hiroaki; Lidbury, Brett A.; Muotri, Alysson R.; Peng, Shuang-Qing; Sakharov, Dmitry; Seidle, Troy; Trez, Thales; Tonevitsky, Alexander; van de Stolpe, Anja; Whelan, Maurice; Willett, Catherine

2015-01-01

Summary Biomedical developments in the 21st century provide an unprecedented opportunity to gain a dynamic systems-level and human-specific understanding of the causes and pathophysiologies of disease. This understanding is a vital need, in view of continuing failures in health research, drug discovery, and clinical translation. The full potential of advanced approaches may not be achieved within a 20th-century conceptual framework dominated by animal models. Novel technologies are being integrated into environmental health research and are also applicable to disease research, but these advances need a new medical research and drug discovery paradigm to gain maximal benefits. We suggest a new conceptual framework that repurposes the 21st-century transition underway in toxicology. Human disease should be conceived as resulting from integrated extrinsic and intrinsic causes, with research focused on modern human-specific models to understand disease pathways at multiple biological levels that are analogous to adverse outcome pathways in toxicology. Systems biology tools should be used to integrate and interpret data about disease causation and pathophysiology. Such an approach promises progress in overcoming the current roadblocks to understanding human disease and successful drug discovery and translation. A discourse should begin now to identify and consider the many challenges and questions that need to be solved. PMID:26523530

Role of insular cortex in visceral hypersensitivity model in rats subjected to chronic stress.

PubMed

Yi, LiSha; Sun, HuiHui; Ge, Chao; Chen, Ying; Peng, HaiXia; Jiang, YuanXi; Wu, Ping; Tang, YinHan; Meng, QingWei; Xu, ShuChang

2014-12-30

Abnormal processing of visceral sensation at the level of the central nervous system has been proven to be important in the pathophysiologic mechanisms of stress related functional gastrointestinal disorders. However, the specific mechanism is still not clear. The insular cortex (IC) was considered as one important visceral sensory area. Moreover, the IC has been shown to be involved in various neuropsychiatric diseases such as panic disorders and post-traumatic stress disorder. However, whether the IC is important in psychological stress related visceral hypersensitivity has not been studied yet. In our study, through destruction of the bilateral IC, we explored whether the IC played a critical role in the formation of visceral hypersensitivity induced by chronic stress on rats. Chronic partial restraint stress was used to establish viscerally hypersensitive rat model. Bilateral IC lesions were generated by N-methyl-D-day (door) aspartate. After a recovery period of 7 days, 14-day consecutive restraint stress was performed. The visceromotor response to colorectal distension was monitored by recording electromyogram to measure rats׳ visceral sensitivity. We found that bilateral insular cortex lesion could markedly inhibit the formation of visceral hypersensitivity induced by chronic stress. The insular cortex plays a critical role in the pathophysiology of stress-related visceral hypersensitivity.

Aberrant temporal behavior of mismatch negativity generators in schizophrenia patients and subjects at clinical high risk for psychosis.

PubMed

Kim, Minah; Cho, Kang Ik Kevin; Yoon, Youngwoo Bryan; Lee, Tae Young; Kwon, Jun Soo

2017-02-01

Although disconnection syndrome has been considered a core pathophysiologic mechanism of schizophrenia, little is known about the temporal behavior of mismatch negativity (MMN) generators in individuals with schizophrenia or clinical high risk (CHR) for psychosis. MMN was assessed in 29 schizophrenia patients, 40 CHR subjects, and 47 healthy controls (HCs). Individual realistic head models and the minimum L2 norm algorithm were used to generate a current source density (CSD) model of MMN. The strength and time course of MMN CSD activity were calculated separately for the frontal and temporal cortices and were compared across brain regions and groups. Schizophrenia patients and CHR subjects displayed lower MMN CSD strength than HCs in both the temporal and frontal cortices. We found a significant time delay in MMN generator activity in the frontal cortex relative to that in the temporal cortex in HCs. However, the sequential temporo-frontal activities of MMN generators were disrupted in both the schizophrenia and CHR groups. Impairments and altered temporal behavior of MMN multiple generators were observed even in individuals at risk for psychosis. These findings suggest that aberrant MMN generator activity might be helpful in revealing the pathophysiology of schizophrenia. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Glibenclamide for the treatment of ischemic and hemorrhagic stroke.

PubMed

Caffes, Nicholas; Kurland, David B; Gerzanich, Volodymyr; Simard, J Marc

2015-03-04

Ischemic and hemorrhagic strokes are associated with severe functional disability and high mortality. Except for recombinant tissue plasminogen activator, therapies targeting the underlying pathophysiology of central nervous system (CNS) ischemia and hemorrhage are strikingly lacking. Sur1-regulated channels play essential roles in necrotic cell death and cerebral edema following ischemic insults, and in neuroinflammation after hemorrhagic injuries. Inhibiting endothelial, neuronal, astrocytic and oligodendroglial sulfonylurea receptor 1-transient receptor potential melastatin 4 (Sur1-Trpm4) channels and, in some cases, microglial KATP (Sur1-Kir6.2) channels, with glibenclamide is protective in a variety of contexts. Robust preclinical studies have shown that glibenclamide and other sulfonylurea agents reduce infarct volumes, edema and hemorrhagic conversion, and improve outcomes in rodent models of ischemic stroke. Retrospective studies suggest that diabetic patients on sulfonylurea drugs at stroke presentation fare better if they continue on drug. Additional laboratory investigations have implicated Sur1 in the pathophysiology of hemorrhagic CNS insults. In clinically relevant models of subarachnoid hemorrhage, glibenclamide reduces adverse neuroinflammatory and behavioral outcomes. Here, we provide an overview of the preclinical studies of glibenclamide therapy for CNS ischemia and hemorrhage, discuss the available data from clinical investigations, and conclude with promising preclinical results that suggest glibenclamide may be an effective therapeutic option for ischemic and hemorrhagic stroke.

Pharmacological models and approaches for pathophysiological conditions associated with hypoxia and oxidative stress.

PubMed

Farías, Jorge G; Herrera, Emilio A; Carrasco-Pozo, Catalina; Sotomayor-Zárate, Ramón; Cruz, Gonzalo; Morales, Paola; Castillo, Rodrigo L

2016-02-01

Hypoxia is the failure of oxygenation at the tissue level, where the reduced oxygen delivered is not enough to satisfy tissue demands. Metabolic depression is the physiological adaptation associated with reduced oxygen consumption, which evidently does not cause any harm to organs that are exposed to acute and short hypoxic insults. Oxidative stress (OS) refers to the imbalance between the generation of reactive oxygen species (ROS) and the ability of endogenous antioxidant systems to scavenge ROS, where ROS overwhelms the antioxidant capacity. Oxidative stress plays a crucial role in the pathogenesis of diseases related to hypoxia during intrauterine development and postnatal life. Thus, excessive ROS are implicated in the irreversible damage to cell membranes, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Here, we describe several pathophysiological conditions and in vivo and ex vivo models developed for the study of hypoxic and oxidative stress injury. We reviewed existing literature on the responses to hypoxia and oxidative stress of the cardiovascular, renal, reproductive, and central nervous systems, and discussed paradigms of chronic and intermittent hypobaric hypoxia. This systematic review is a critical analysis of the advantages in the application of some experimental strategies and their contributions leading to novel pharmacological therapies. Copyright © 2015 Elsevier Inc. All rights reserved.

A new rabbit model for the study of early brain injury after subarachnoid hemorrhage.

PubMed

Marbacher, Serge; Andereggen, Lukas; Neuschmelting, Volker; Widmer, Hans Rudolf; von Gunten, Michael; Takala, Jukka; Jakob, Stephan M; Fandino, Javier

2012-07-15

Pathophysiological disturbances during subarachnoid hemorrhage (SAH) and within the first few days thereafter are responsible for significant brain damage. Early brain injury (EBI) after SAH has become the focus of current research activities. The purpose of the present study was to evaluate whether a novel rabbit SAH model provokes EBI by means of neuronal degeneration, brain tissue death, and apoptosis in cerebral vascular endothelial cells. SAH was performed using an extra-intracranial blood shunt. Intracranial pressure (ICP), cerebral perfusion pressure (CPP), and bilateral regional cerebral blood flow (rCBF) were continuously measured. Apoptosis and neurodegeneration were detected 24h post-SAH in basilar artery endothelial cells, bilateral basal cortex, and hippocampus (CA1 and CA3) using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Fluoro-jade B (FJB), respectively. ICP increase caused a CPP decrease to almost zero (8±5mmHg) and decreases in left and right rCBF to 23±8% and 19±9% of their baseline values. TUNEL- and FJB-stained sections revealed significant apoptosis and neurodegeneration in both basal cortex and hippocampal regions compared to sham-operated animals. The apoptotic index in basilar artery endothelial cells was 74%±11%. The blood shunt rabbit SAH model elicits acute physiological dearrangements and provokes marked and consistent early damage to the hippocampus, basal cortex, and cerebral vasculature 24h thereafter. These findings make the model a valid tool for investigation of pre-vasospasm pathophysiological mechanisms and novel treatment modalities. Copyright © 2012 Elsevier B.V. All rights reserved.

Discerning Apical and Basolateral Properties of HT-29/B6 and IPEC-J2 Cell Layers by Impedance Spectroscopy, Mathematical Modeling and Machine Learning

PubMed Central

Schmid, Thomas; Bogdan, Martin; Günzel, Dorothee

2013-01-01

Quantifying changes in partial resistances of epithelial barriers in vitro is a challenging and time-consuming task in physiology and pathophysiology. Here, we demonstrate that electrical properties of epithelial barriers can be estimated reliably by combining impedance spectroscopy measurements, mathematical modeling and machine learning algorithms. Conventional impedance spectroscopy is often used to estimate epithelial capacitance as well as epithelial and subepithelial resistance. Based on this, the more refined two-path impedance spectroscopy makes it possible to further distinguish transcellular and paracellular resistances. In a next step, transcellular properties may be further divided into their apical and basolateral components. The accuracy of these derived values, however, strongly depends on the accuracy of the initial estimates. To obtain adequate accuracy in estimating subepithelial and epithelial resistance, artificial neural networks were trained to estimate these parameters from model impedance spectra. Spectra that reflect behavior of either HT-29/B6 or IPEC-J2 cells as well as the data scatter intrinsic to the used experimental setup were created computationally. To prove the proposed approach, reliability of the estimations was assessed with both modeled and measured impedance spectra. Transcellular and paracellular resistances obtained by such neural network-enhanced two-path impedance spectroscopy are shown to be sufficiently reliable to derive the underlying apical and basolateral resistances and capacitances. As an exemplary perturbation of pathophysiological importance, the effect of forskolin on the apical resistance of HT-29/B6 cells was quantified. PMID:23840862

Alterations in primary motor cortex neurotransmission and gene expression in hemi-parkinsonian rats with drug-induced dyskinesia.

PubMed

Lindenbach, D; Conti, M M; Ostock, C Y; Dupre, K B; Bishop, C

2015-12-03

Treatment of Parkinson's disease (PD) with dopamine replacement relieves symptoms of poverty of movement, but often causes drug-induced dyskinesias. Accumulating clinical and pre-clinical evidence suggests that the primary motor cortex (M1) is involved in the pathophysiology of PD and that modulating cortical activity may be a therapeutic target in PD and dyskinesia. However, surprisingly little is known about how M1 neurotransmitter tone or gene expression is altered in PD, dyskinesia or associated animal models. The present study utilized the rat unilateral 6-hydroxydopamine (6-OHDA) model of PD/dyskinesia to characterize structural and functional changes taking place in M1 monoamine innervation and gene expression. 6-OHDA caused dopamine pathology in M1, although the lesion was less severe than in the striatum. Rats with 6-OHDA lesions showed a PD motor impairment and developed dyskinesia when given L-DOPA or the D1 receptor agonist, SKF81297. M1 expression of two immediate-early genes (c-Fos and ARC) was strongly enhanced by either L-DOPA or SKF81297. At the same time, expression of genes specifically involved in glutamate and GABA signaling were either modestly affected or unchanged by lesion and/or treatment. We conclude that M1 neurotransmission and signal transduction in the rat 6-OHDA model of PD/dyskinesia mirror features of human PD, supporting the utility of the model to study M1 dysfunction in PD and the elucidation of novel pathophysiological mechanisms and therapeutic targets. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Combined fetal inflammation and postnatal hypoxia causes myelin deficits and autism-like behavior in a rat model of diffuse white matter injury.

PubMed

van Tilborg, Erik; Achterberg, E J Marijke; van Kammen, Caren M; van der Toorn, Annette; Groenendaal, Floris; Dijkhuizen, Rick M; Heijnen, Cobi J; Vanderschuren, Louk J M J; Benders, Manon N J L; Nijboer, Cora H A

2018-01-01

Diffuse white matter injury (WMI) is a serious problem in extremely preterm infants, and is associated with adverse neurodevelopmental outcome, including cognitive impairments and an increased risk of autism-spectrum disorders. Important risk factors include fetal or perinatal inflammatory insults and fluctuating cerebral oxygenation. However, the exact mechanisms underlying diffuse WMI are not fully understood and no treatment options are currently available. The use of clinically relevant animal models is crucial to advance knowledge on the pathophysiology of diffuse WMI, allowing the definition of novel therapeutic targets. In the present study, we developed a multiple-hit animal model of diffuse WMI by combining fetal inflammation and postnatal hypoxia in rats. We characterized the effects on white matter development and functional outcome by immunohistochemistry, MRI and behavioral paradigms. Combined fetal inflammation and postnatal hypoxia resulted in delayed cortical myelination, microglia activation and astrogliosis at P18, together with long-term changes in oligodendrocyte maturation as observed in 10 week old animals. Furthermore, rats with WMI showed impaired motor performance, increased anxiety and signs of autism-like behavior, i.e. reduced social play behavior and increased repetitive grooming. In conclusion, the combination of fetal inflammation and postnatal hypoxia in rats induces a pattern of brain injury and functional impairments that closely resembles the clinical situation of diffuse WMI. This animal model provides the opportunity to elucidate pathophysiological mechanisms underlying WMI, and can be used to develop novel treatment options for diffuse WMI in preterm infants. © 2017 The Authors GLIA Published by Wiley Periodicals, Inc.

Effects of the dimeric PSD-95 inhibitor UCCB01-144 on functional recovery after fimbria-fornix transection in rats.

PubMed

Sommer, Jens Bak; Bach, Anders; Malá, Hana; Strømgaard, Kristian; Mogensen, Jesper; Pickering, Darryl S

2017-10-01

Pharmacological inhibition of PSD-95 is a promising therapeutic strategy in the treatment of stroke, and positive effects of monomeric and dimeric PSD-95 inhibitors have been reported in numerous studies. However, whether therapeutic effects will generalize to other types of acute brain injury such as traumatic brain injury (TBI), which has pathophysiological mechanisms in common with stroke, is currently uncertain. We have previously found a lack of neuroprotective effects of dimeric PSD-95 inhibitors in the controlled cortical impact model of TBI in rats. However, as no single animal model is currently able to mimic the complex and heterogeneous pathophysiology of TBI, it is necessary to assess treatment effects across a range of models. In this preliminary study we investigated the neuroprotective abilities of the dimeric PSD-95 inhibitor UCCB01-144 after fimbria-fornix (FF) transection in rats. UCCB01-144 or saline was injected into the lateral tail vein of rats immediately after sham surgery or FF-transection, and effects on spatial delayed alternation in a T-maze were assessed over a 28-day period. Task acquisition was significantly impaired in FF-transected animals, but there were no significant effects of UCCB01-144 on spatial delayed alternation after FF-transection or sham surgery, although decelerated learning curves were seen after treatment with UCCB01-144 in FF-transected animals. The results of the present study are consistent with previous research showing a lack of neuroprotective effects of PSD-95 inhibition in experimental models of TBI. Copyright © 2017 Elsevier Inc. All rights reserved.

Combined fetal inflammation and postnatal hypoxia causes myelin deficits and autism‐like behavior in a rat model of diffuse white matter injury

PubMed Central

van Tilborg, Erik; Achterberg, E. J. Marijke; van Kammen, Caren M.; van der Toorn, Annette; Groenendaal, Floris; Dijkhuizen, Rick M.; Heijnen, Cobi J.; Vanderschuren, Louk J. M. J.; Benders, Manon N. J. L.

2017-01-01

Abstract Diffuse white matter injury (WMI) is a serious problem in extremely preterm infants, and is associated with adverse neurodevelopmental outcome, including cognitive impairments and an increased risk of autism‐spectrum disorders. Important risk factors include fetal or perinatal inflammatory insults and fluctuating cerebral oxygenation. However, the exact mechanisms underlying diffuse WMI are not fully understood and no treatment options are currently available. The use of clinically relevant animal models is crucial to advance knowledge on the pathophysiology of diffuse WMI, allowing the definition of novel therapeutic targets. In the present study, we developed a multiple‐hit animal model of diffuse WMI by combining fetal inflammation and postnatal hypoxia in rats. We characterized the effects on white matter development and functional outcome by immunohistochemistry, MRI and behavioral paradigms. Combined fetal inflammation and postnatal hypoxia resulted in delayed cortical myelination, microglia activation and astrogliosis at P18, together with long‐term changes in oligodendrocyte maturation as observed in 10 week old animals. Furthermore, rats with WMI showed impaired motor performance, increased anxiety and signs of autism‐like behavior, i.e. reduced social play behavior and increased repetitive grooming. In conclusion, the combination of fetal inflammation and postnatal hypoxia in rats induces a pattern of brain injury and functional impairments that closely resembles the clinical situation of diffuse WMI. This animal model provides the opportunity to elucidate pathophysiological mechanisms underlying WMI, and can be used to develop novel treatment options for diffuse WMI in preterm infants. PMID:28925578

Stem cells for amyotrophic lateral sclerosis modeling and therapy: myth or fact?

PubMed

Coatti, G C; Beccari, M S; Olávio, T R; Mitne-Neto, M; Okamoto, O K; Zatz, M

2015-03-01

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose pathophysiology is poorly understood. Aiming to better understand the cause of motor neuron death, the use of experimental cell-based models increased significantly over the past years. In this scenario, much knowledge has been generated from the study of motor neurons derived from embryonic stem cells and induced pluripotent stem cells. These methods, however, have advantages and disadvantages, which must be balanced on experimental design. Preclinical studies provide valuable information, making it possible to combine diverse methods to build an expanded knowledge of ALS pathophysiology. In addition to using stem cells as experimental models for understanding disease mechanism, these cells had been quoted for therapy in ALS. Despite ethical issues involved in its use, cell therapy with neural stem cells stands out. A phase I clinical trial was recently completed and a phase II is on its way, attesting the method's safety. In another approach, mesenchymal stromal cells capable of releasing neuroregulatory and anti-inflammatory factors have also been listed as candidates for cell therapy for ALS, and have been admitted as safe in a phase I trial. Despite recent advances, application of stem cells as an actual therapy for ALS patients is still in debate. Here, we discuss how stem cells have been useful in modeling ALS and address critical topics concerning their therapeutic use, such as administration protocols, injection site, cell type to be administered, type of transplantation (autologous vs. allogeneic) among other issues with particular implications for ALS therapy. © 2015 International Society for Advancement of Cytometry.

Open questions in current models of antidepressant action

PubMed Central

Tanti, A; Belzung, C

2010-01-01

Research on depression and antidepressant drugs is necessary, as many patients display poor response to therapy. Different symptomatic and pathophysiological features have been proposed as end points of the depressive phenotype and of the antidepressant action, including anhedonia, depressed mood, alterations in morphology and activity of some brain areas (amygdala, nucleus accumbens, hippocampus, prefrontal cortex and cingulate cortex), modifications in the connectivity between brain structures, changes in neurotransmitters (serotonin, noradrenaline, glutamate and neuropeptides), brain plasticity (neurogenesis, neurotrophins) and abnormal function of the hypothalamic-pituitary adrenal axis. However, few models have been proposed to describe how these end points could induce the depressive phenotype and are involved in the mechanism of action of antidepressants. Here we propose a connectionist-inspired network of depression and antidepressant action, in which the different aetiological factors participating in the release of a depressive episode are represented by input nodes, the different symptomatic as well as pathophysiological end points are represented by an intermediate layer, and the onset of depression or of comorbid disease is represented by the output node. The occurrence of depression and the mechanism of the antidepressant action thus depend upon the weight of the interactions between the different end points, none of them being per se crucial to the onset of a depressive phenotype or to the antidepressant action. This model is heuristic to draw future lines of research concerning new antidepressant therapies, designing new animal models of depression and for a better understanding of the depressive pathology and of its comorbid pathology such as anxiety disorders. PMID:20132212

Cascading network failure across the Alzheimer’s disease spectrum

PubMed Central

Knopman, David S.; Gunter, Jeffrey L.; Graff-Radford, Jonathan; Vemuri, Prashanthi; Boeve, Bradley F.; Petersen, Ronald C.; Weiner, Michael W.; Jack, Clifford R.

2016-01-01

Abstract Complex biological systems are organized across various spatiotemporal scales with particular scientific disciplines dedicated to the study of each scale (e.g. genetics, molecular biology and cognitive neuroscience). When considering disease pathophysiology, one must contemplate the scale at which the disease process is being observed and how these processes impact other levels of organization. Historically Alzheimer’s disease has been viewed as a disease of abnormally aggregated proteins by pathologists and molecular biologists and a disease of clinical symptoms by neurologists and psychologists. Bridging the divide between these scales has been elusive, but the study of brain networks appears to be a pivotal inroad to accomplish this task. In this study, we were guided by an emerging systems-based conceptualization of Alzheimer’s disease and investigated changes in brain networks across the disease spectrum. The default mode network has distinct subsystems with unique functional-anatomic connectivity, cognitive associations, and responses to Alzheimer’s pathophysiology. These distinctions provide a window into the systems-level pathophysiology of Alzheimer’s disease. Using clinical phenotyping, metadata, and multimodal neuroimaging data from the Alzheimer’s Disease Neuroimaging Initiative, we characterized the pattern of default mode network subsystem connectivity changes across the entire disease spectrum (n = 128). The two main findings of this paper are (i) the posterior default mode network fails before measurable amyloid plaques and appears to initiate a connectivity cascade that continues throughout the disease spectrum; and (ii) high connectivity between the posterior default mode network and hubs of high connectivity (many located in the frontal lobe) is associated with amyloid accumulation. These findings support a system model best characterized by a cascading network failure—analogous to cascading failures seen in power grids triggered by local overloads proliferating to downstream nodes eventually leading to widespread power outages, or systems failures. The failure begins in the posterior default mode network, which then shifts processing burden to other systems containing prominent connectivity hubs. This model predicts a connectivity ‘overload’ that precedes structural and functional declines and recasts the interpretation of high connectivity from that of a positive compensatory phenomenon to that of a load-shifting process transiently serving a compensatory role. It is unknown whether this systems-level pathophysiology is the inciting event driving downstream molecular events related to synaptic activity embedded in these systems. Possible interpretations include that the molecular-level events drive the network failure, a pathological interaction between the network-level and the molecular-level, or other upstream factors are driving both. PMID:26586695

Animal models to guide clinical drug development in ADHD: lost in translation?

PubMed Central

Wickens, Jeffery R; Hyland, Brian I; Tripp, Gail

2011-01-01

We review strategies for developing animal models for examining and selecting compounds with potential therapeutic benefit in attention-deficit hyperactivity disorder (ADHD). ADHD is a behavioural disorder of unknown aetiology and pathophysiology. Current understanding suggests that genetic factors play an important role in the aetiology of ADHD. The involvement of dopaminergic and noradrenergic systems in the pathophysiology of ADHD is probable. We review the clinical features of ADHD including inattention, hyperactivity and impulsivity and how these are operationalized for laboratory study. Measures of temporal discounting (but not premature responding) appear to predict known drug effects well (treatment validity). Open-field measures of overactivity commonly used do not have treatment validity in human populations. A number of animal models have been proposed that simulate the symptoms of ADHD. The most commonly used are the spontaneously hypertensive rat (SHR) and the 6-hydroxydopamine-lesioned (6-OHDA) animals. To date, however, the SHR lacks treatment validity, and the effects of drugs on symptoms of impulsivity and inattention have not been studied extensively in 6-OHDA-lesioned animals. At the present stage of development, there are no in vivo models of proven effectiveness for examining and selecting compounds with potential therapeutic benefit in ADHD. However, temporal discounting is an emerging theme in theories of ADHD, and there is good evidence of increased value of delayed reward following treatment with stimulant drugs. Therefore, operant behaviour paradigms that measure the effects of drugs in situations of delayed reinforcement, whether in normal rats or selected models, show promise for the future. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21480864

Using thermal stress to model aspects of disease states.

PubMed

Wilson, Thad E; Klabunde, Richard E; Monahan, Kevin D

2014-07-01

Exposure to acute heat or cold stress elicits numerous physiological responses aimed at maintaining body temperatures. Interestingly, many of the physiological responses, mediated by the cardiovascular and autonomic nervous systems, resemble aspects of, or responses to, certain disease states. The purpose of this Perspective is to highlight some of these areas in order to explore how they may help us better understand the pathophysiology underlying aspects of certain disease states. The benefits of using this human thermal stress approach are that (1) no adjustments for inherent comparative differences in animals are needed, (2) non-medicated healthy humans with no underlying co-morbidities can be studied in place of complex patients, and (3) more mechanistic perturbations can be safely employed without endangering potentially vulnerable populations. Cold stress can be used to induce stable elevations in blood pressure. Cold stress may also be used to model conditions where increases in myocardial oxygen demand are not met by anticipated increases in coronary blood flow, as occurs in older adults. Lower-body negative pressure has the capacity to model aspects of shock, and the further addition of heat stress improves and expands this model because passive-heat exposure lowers systemic vascular resistance at a time when central blood volume and left-ventricular filling pressure are reduced. Heat stress can model aspects of heat syncope and orthostatic intolerance as heat stress decreases cerebral blood flow and alters the Frank-Starling mechanism resulting in larger decreases in stroke volume for a given change in left-ventricular filling pressure. Combined, thermal perturbations may provide in vivo paradigms that can be employed to gain insights into pathophysiological aspects of certain disease states. Copyright © 2014 Elsevier Ltd. All rights reserved.

Pathophysiology, Evaluation, and Treatment of Bloating

PubMed Central

Gabbard, Scott L.; Crowell, Michael D.

2011-01-01

Abdominal bloating is commonly reported by men and women of all ages. Bloating occurs in nearly all patients with irritable bowel syndrome, and it also occurs in patients with other functional and organic disorders. Bloating is frequently disturbing to patients and frustrating to clinicians, as effective treatments are limited and are not universally successful. Although the terms bloating and abdominal distention are often used interchangeably, these symptoms likely involve different pathophysiologic processes, both of which are still not completely understood. The goal of this paper is to review the pathophysiology, evaluation, and treatment of bloating and abdominal distention. PMID:22298969

The role of autoantibodies in the pathophysiology of rheumatoid arthritis.

PubMed

Derksen, V F A M; Huizinga, T W J; van der Woude, D

2017-06-01

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation. The presence of autoantibodies in the sera of RA patients has provided many clues to the underlying disease pathophysiology. Based on the presence of several autoantibodies like rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), anti-carbamylated protein antibodies (anti-CarP), and more recently anti-acetylated protein antibodies RA can be subdivided into seropositive and seronegative disease. The formation of these autoantibodies is associated with both genetic and environmental risk factors for RA, like specific human leukocyte antigen (HLA) alleles and smoking. Autoantibodies can be detected many years before disease onset in a subset of patients, suggesting a sequence of events in which the first autoantibodies develop in predisposed hosts, before an inflammatory response ensues leading to clinically apparent arthritis. Research on the characteristics and effector functions of these autoantibodies might provide more insight in pathophysiological processes underlying arthritis in RA. Recent data suggests that ACPA might play a role in perpetuating inflammation once it has developed. Furthermore, pathophysiological mechanisms have been discovered supporting a direct link between the presence of ACPA and both bone erosions and pain in RA patients. In conclusion, investigating the possible pathogenic potential of autoantibodies might lead to improved understanding of the underlying pathophysiological processes in rheumatoid arthritis.

The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease

PubMed Central

Shin, Rick; Kobayashi, Katsunori; Hagihara, Hideo; Kogan, Jeffrey H; Miyake, Shinichi; Tajinda, Katsunori; Walton, Noah M; Gross, Adam K; Heusner, Carrie L; Chen, Qian; Tamura, Kouichi; Miyakawa, Tsuyoshi; Matsumoto, Mitsuyuki

2013-01-01

Objectives There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in patients has recently been reported, represents a common phenotype of both diseases. Methods Behaviors of calcium/calmodulin-dependent protein kinase II alpha (α-CaMKII) heterozygous knock-out (KO) mice, which are a representative bipolar disorder/schizophrenia model displaying iDG, and pilocarpine-treated mice, which are a representative epilepsy model, were tested followed by quantitative polymerase chain reaction (qPCR)/immunohistochemistry for mRNA/protein expression associated with an iDG phenotype. In vitro electrophysiology of dentate gyrus granule cells (DG GCs) was examined in pilocarpine-treated epileptic mice. Results The two disease models demonstrated similar behavioral deficits, such as hyperactivity, poor working memory performance, and social withdrawal. Significant reductions in mRNA expression and immunoreactivity of the mature neuronal marker calbindin and concomitant increases in mRNA expression and immunoreactivity of the immature neuronal marker calretinin represent iDG signatures that are present in both mice models. Electrophysiologically, we have confirmed that DG GCs from pilocarpine-treated mice represent an immature state. A significant decrease in hippocampal α-CaMKII protein levels was also found in both models. Conclusions Our data have shown iDG signatures from mouse models of both bipolar disorder/schizophrenia and epilepsy. The evidence suggests that the iDG may, in part, be responsible for the abnormal behavioral phenotype, and that the underlying pathophysiologies in epilepsy and bipolar disorder/schizophrenia are strikingly similar. PMID:23560889

The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease.

PubMed

Shin, Rick; Kobayashi, Katsunori; Hagihara, Hideo; Kogan, Jeffrey H; Miyake, Shinichi; Tajinda, Katsunori; Walton, Noah M; Gross, Adam K; Heusner, Carrie L; Chen, Qian; Tamura, Kouichi; Miyakawa, Tsuyoshi; Matsumoto, Mitsuyuki

2013-06-01

There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in patients has recently been reported, represents a common phenotype of both diseases. Behaviors of calcium/calmodulin-dependent protein kinase II alpha (α-CaMKII) heterozygous knock-out (KO) mice, which are a representative bipolar disorder/schizophrenia model displaying iDG, and pilocarpine-treated mice, which are a representative epilepsy model, were tested followed by quantitative polymerase chain reaction (qPCR)/immunohistochemistry for mRNA/protein expression associated with an iDG phenotype. In vitro electrophysiology of dentate gyrus granule cells (DG GCs) was examined in pilocarpine-treated epileptic mice. The two disease models demonstrated similar behavioral deficits, such as hyperactivity, poor working memory performance, and social withdrawal. Significant reductions in mRNA expression and immunoreactivity of the mature neuronal marker calbindin and concomitant increases in mRNA expression and immunoreactivity of the immature neuronal marker calretinin represent iDG signatures that are present in both mice models. Electrophysiologically, we have confirmed that DG GCs from pilocarpine-treated mice represent an immature state. A significant decrease in hippocampal α-CaMKII protein levels was also found in both models. Our data have shown iDG signatures from mouse models of both bipolar disorder/schizophrenia and epilepsy. The evidence suggests that the iDG may, in part, be responsible for the abnormal behavioral phenotype, and that the underlying pathophysiologies in epilepsy and bipolar disorder/schizophrenia are strikingly similar. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Yin-yang of space travel: lessons from the ground-based models of microgravity and their applications to disease and health for life on Earth

NASA Astrophysics Data System (ADS)

Kulkarni, A.; Yamauchi, K.; Hales, N.; Sundaresan, A.; Pellis, N.; Yamamoto, S.; Andrassy, R.

Space flight environment has numerous clinical effects on human physiology; however, the advances made in physical and biological sciences have benefited humans on Earth. Space flight induces adverse effects on bone, muscle, cardiovascular, neurovestibular, gastrointestinal, and immune function. Similar pathophysiologic changes are also observed in aging with debilitating consequences. Anti-orthostatic tail-suspension (AOS) of rodents is an in vivo model to study many of these effects induced by the microgravity environment of space travel. Over the years AOS has been used by several researchers to study bone demineralization, muscle atrophy, neurovestibular and stress related effects. ecently we employed the AOS model in parallel with in vitro cell culture microgravity analog (Bioreactor) to document the decrease in immune function and its reversal by a nutritional countermeasure. We have modified the rodent model to study nutrient effects and benefits in a short period of time, usually within one to two weeks, in contrast to conventional aging research models which take several weeks to months to get the same results. This model has a potential for further development to study the role of nutrition in other pathophysiologies in an expedited manner. Using this model it is possible to evaluate the response of space travelers of various ages to microgravity stressors for long-term space travel. Hence this modified model will have significant impact on time and financial research budget. For the first time our group has documented a true potential immunonutritional countermeasure for the space flight induced effects on immune system (Clinical Nutrition 2002). Based on our nutritional and immunological studies we propose application of these microgravity analogs and its benefits and utility for nutritional effects on other physiologic parameters especially in aging. (Supported by NASA NCC8-168 grant, ADK)

Adult Mouse Venous Hypertension Model: Common Carotid Artery to External Jugular Vein Anastomosis.

PubMed Central

Yang, Shun-Tai; Rodriguez-Hernandez, Ana; Walker, Espen J.; Young, William L.; Su, Hua; Lawton, Michael T.

2015-01-01

The understanding of the pathophysiology of brain arteriovenous malformations and arteriovenous fistulas has improved thanks to animal models. A rat model creating an artificial fistula between the common carotid artery (CCA) and the external jugular vein (EJV) has been widely described and proved technically feasible. This construct provokes a consistent cerebral venous hypertension (CVH), and therefore has helped studying the contribution of venous hypertension to formation, clinical symptoms, and prognosis of brain AVMs and dural AVFs. Equivalent mice models have been only scarcely described and have shown trouble with stenosis of the fistula. An established murine model would allow the study of not only pathophysiology but also potential genetic therapies for these cerebrovascular diseases. We present a model of arteriovenous fistula that produces a durable intracranial venous hypertension in the mouse. Microsurgical anastomosis of the murine CCA and EJV can be difficult due to diminutive anatomy and frequently result in a non-patent fistula. In this step-by-step protocol we address all the important challenges encountered during this procedure. Avoiding excessive retraction of the vein during the exposure, using 11-0 sutures instead of 10-0, and making a carefully planned end-to-side anastomosis are some of the critical steps. Although this method requires advanced microsurgical skills and a longer learning curve that the equivalent in the rat, it can be consistently developed. This novel model has been designed to integrate transgenic mouse techniques with a previously well-established experimental system that has proved useful to study brain AVMs and dural AVFs. By opening the possibility of using transgenic mice, a broader spectrum of valid models can be achieved and genetic treatments can also be tested. The experimental construct could also be further adapted to the study of other cerebrovascular diseases related with venous hypertension such as migraine, transient global amnesia, transient monocular blindness, etc. PMID:25650793

3D tissue-engineered bone marrow as a novel model to study pathophysiology and drug resistance in multiple myeloma

PubMed Central

de la Puente, Pilar; Muz, Barbara; Gilson, Rebecca C; Azab, Feda; Luderer, Micah; King, Justin; Achilefu, Samuel; Vij, Ravi; Azab, Abdel Kareem

2016-01-01

Purpose Multiple myeloma (MM) is the second most prevalent hematological malignancy and it remains incurable despite the introduction of several novel drugs. The discrepancy between preclinical and clinical outcomes can be attributed to the failure of classic two-dimensional (2D) culture models to accurately recapitulate the complex biology of MM and drug responses observed in patients. Experimental design We developed 3D tissue engineered bone marrow (3DTEBM) cultures derived from the BM supernatant of MM patients to incorporate different BM components including MM cells, stromal cells, and endothelial cells. Distribution and growth were analyzed by confocal imaging, and cell proliferation of cell lines and primary MM cells was tested by flow cytometry. Oxygen and drug gradients were evaluated by immunohistochemistry and flow cytometry, and drug resistance was studied by flow cytometry. Results 3DTEBM cultures allowed proliferation of MM cells, recapitulated their interaction with the microenvironment, recreated 3D aspects observed in the bone marrow niche (such as oxygen and drug gradients), and induced drug resistance in MM cells more than 2D or commercial 3D tissue culture systems. Conclusions 3DTEBM cultures not only provide a better model for investigating the pathophysiology of MM, but also serve as a tool for drug development and screening in MM. In the future, we will use the 3DTEBM cultures for developing personalized therapeutic strategies for individual MM patients. PMID:26402156

Comparative proteomics of cerebrospinal fluid reveals a predictive model for differential diagnosis of pneumococcal, meningococcal, and enteroviral meningitis, and novel putative therapeutic targets

PubMed Central

2015-01-01

Background Meningitis is the inflammation of the meninges in response to infection or chemical agents. While aseptic meningitis, most frequently caused by enteroviruses, is usually benign with a self-limiting course, bacterial meningitis remains associated with high morbidity and mortality rates, despite advances in antimicrobial therapy and intensive care. Fast and accurate differential diagnosis is crucial for assertive choice of the appropriate therapeutic approach for each form of meningitis. Methods We used 2D-PAGE and mass spectrometry to identify the cerebrospinal fluid proteome specifically related to the host response to pneumococcal, meningococcal, and enteroviral meningitis. The disease-specific proteome signatures were inspected by pathway analysis. Results Unique cerebrospinal fluid proteome signatures were found to the three aetiological forms of meningitis investigated, and a qualitative predictive model with four protein markers was developed for the differential diagnosis of these diseases. Nevertheless, pathway analysis of the disease-specific proteomes unveiled that Kallikrein-kinin system may play a crucial role in the pathophysiological mechanisms leading to brain damage in bacterial meningitis. Proteins taking part in this cellular process are proposed as putative targets to novel adjunctive therapies. Conclusions Comparative proteomics of cerebrospinal fluid disclosed candidate biomarkers, which were combined in a qualitative and sequential predictive model with potential to improve the differential diagnosis of pneumococcal, meningococcal and enteroviral meningitis. Moreover, we present the first evidence of the possible implication of Kallikrein-kinin system in the pathophysiology of bacterial meningitis. PMID:26040285

Comparative proteomics of cerebrospinal fluid reveals a predictive model for differential diagnosis of pneumococcal, meningococcal, and enteroviral meningitis, and novel putative therapeutic targets.

PubMed

Cordeiro, Ana Paula; Silva Pereira, Rosiane Aparecida; Chapeaurouge, Alex; Coimbra, Clarice Semião; Perales, Jonas; Oliveira, Guilherme; Sanchez Candiani, Talitah Michel; Coimbra, Roney Santos

2015-01-01

Meningitis is the inflammation of the meninges in response to infection or chemical agents. While aseptic meningitis, most frequently caused by enteroviruses, is usually benign with a self-limiting course, bacterial meningitis remains associated with high morbidity and mortality rates, despite advances in antimicrobial therapy and intensive care. Fast and accurate differential diagnosis is crucial for assertive choice of the appropriate therapeutic approach for each form of meningitis. We used 2D-PAGE and mass spectrometry to identify the cerebrospinal fluid proteome specifically related to the host response to pneumococcal, meningococcal, and enteroviral meningitis. The disease-specific proteome signatures were inspected by pathway analysis. Unique cerebrospinal fluid proteome signatures were found to the three aetiological forms of meningitis investigated, and a qualitative predictive model with four protein markers was developed for the differential diagnosis of these diseases. Nevertheless, pathway analysis of the disease-specific proteomes unveiled that Kallikrein-kinin system may play a crucial role in the pathophysiological mechanisms leading to brain damage in bacterial meningitis. Proteins taking part in this cellular process are proposed as putative targets to novel adjunctive therapies. Comparative proteomics of cerebrospinal fluid disclosed candidate biomarkers, which were combined in a qualitative and sequential predictive model with potential to improve the differential diagnosis of pneumococcal, meningococcal and enteroviral meningitis. Moreover, we present the first evidence of the possible implication of Kallikrein-kinin system in the pathophysiology of bacterial meningitis.

The 6-hydroxydopamine model and parkinsonian pathophysiology: Novel findings in an older model.

PubMed

Hernandez-Baltazar, D; Zavala-Flores, L M; Villanueva-Olivo, A

2017-10-01

The neurotoxin 6-hydroxydopamine (6-OHDA) is widely used to induce models of Parkinson's disease (PD). We now know that the model induced by 6-OHDA does not include all PD symptoms, although it does reproduce the main cellular processes involved in PD, such as oxidative stress, neurodegeneration, neuroinflammation, and neuronal death by apoptosis. In this review we analyse the factors affecting the vulnerability of dopaminergic neurons as well as the close relationships between neuroinflammation, neurodegeneration, and apoptosis in the 6-OHDA model. Knowledge of the mechanisms involved in neurodegeneration and cell death in this model is the key to identifying potential therapeutic targets for PD. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Identification and Treatment of Pathophysiological Comorbidities of Autism Spectrum Disorder to Achieve Optimal Outcomes

PubMed Central

Frye, Richard E.; Rossignol, Daniel A.

2016-01-01

Despite the fact that the prevalence of autism spectrum disorder (ASD) continues to rise, no effective medical treatments have become standard of care. In this paper we review some of the pathophysiological abnormalities associated with ASD and their potential associated treatments. Overall, there is evidence for some children with ASD being affected by seizure and epilepsy, neurotransmitter dysfunction, sleep disorders, metabolic abnormalities, including abnormalities in folate, cobalamin, tetrahydrobiopterin, carnitine, redox and mitochondrial metabolism, and immune and gastrointestinal disorders. Although evidence for an association between these pathophysiological abnormalities and ASD exists, the exact relationship to the etiology of ASD and its associated symptoms remains to be further defined in many cases. Despite these limitations, treatments targeting some of these pathophysiological abnormalities have been studied in some cases with high-quality studies, whereas treatments for other pathophysiological abnormalities have not been well studied in many cases. There are some areas of more promising treatments specific for ASD including neurotransmitter abnormalities, particularly imbalances in glutamate and acetylcholine, sleep onset disorder (with behavioral therapy and melatonin), and metabolic abnormalities in folate, cobalamin, tetrahydrobiopterin, carnitine, and redox pathways. There is some evidence for treatments of epilepsy and seizures, mitochondrial and immune disorders, and gastrointestinal abnormalities, particularly imbalances in the enteric microbiome, but further clinical studies are needed in these areas to better define treatments specific to children with ASD. Clearly, there are some promising areas of ASD research that could lead to novel treatments that could become standard of care in the future, but more research is needed to better define subgroups of children with ASD who are affected by specific pathophysiological abnormalities and the optimal treatments for these abnormalities. PMID:27330338

Advancing the understanding of autism disease mechanisms through genetics

PubMed Central

de la Torre-Ubieta, Luis; Won, Hyejung; Stein, Jason L; Geschwind, Daniel H

2016-01-01

Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies. PMID:27050589

Computational Psychiatry and the Challenge of Schizophrenia.

PubMed

Krystal, John H; Murray, John D; Chekroud, Adam M; Corlett, Philip R; Yang, Genevieve; Wang, Xiao-Jing; Anticevic, Alan

2017-05-01

Schizophrenia research is plagued by enormous challenges in integrating and analyzing large datasets and difficulties developing formal theories related to the etiology, pathophysiology, and treatment of this disorder. Computational psychiatry provides a path to enhance analyses of these large and complex datasets and to promote the development and refinement of formal models for features of this disorder. This presentation introduces the reader to the notion of computational psychiatry and describes discovery-oriented and theory-driven applications to schizophrenia involving machine learning, reinforcement learning theory, and biophysically-informed neural circuit models. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2017.

Modeling Neuropsychiatric and Neurodegenerative Diseases With Induced Pluripotent Stem Cells.

PubMed

LaMarca, Elizabeth A; Powell, Samuel K; Akbarian, Schahram; Brennand, Kristen J

2018-01-01

Human-induced pluripotent stem cells (hiPSCs) have revolutionized our ability to model neuropsychiatric and neurodegenerative diseases, and recent progress in the field is paving the way for improved therapeutics. In this review, we discuss major advances in generating hiPSC-derived neural cells and cutting-edge techniques that are transforming hiPSC technology, such as three-dimensional "mini-brains" and clustered, regularly interspersed short palindromic repeats (CRISPR)-Cas systems. We examine specific examples of how hiPSC-derived neural cells are being used to uncover the pathophysiology of schizophrenia and Parkinson's disease, and consider the future of this groundbreaking research.

Primary Blast Injury Criteria for Animal/Human TBI Models using Field Validated Shock Tubes

DTIC Science & Technology

2017-09-01

differential pathological response, which depends on the local tissue composition, and the response is to insult depends upon the cell type. regions...Neuroinflammation A single blast induces cell-type dependent increase in NADPH oxidase isoforms We have performed characterization of the spatial variations and...uniformly distribute and affect the whole brain. However, pathophysiological outcomes (e.g., NOX changes) in response to bTBI depend on the differential

Small-molecule WNK inhibition regulates cardiovascular and renal function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamada, Ken; Park, Hyi-Man; Rigel, Dean F.

The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.

Screening for Cerebroprotective Agents Using an In Vivo Model of Cerebral Reversible Depolarization in Awake Rats

DTIC Science & Technology

2001-01-01

next millennium. Roach RC, Wagner pathophysiology and therapy . Neurosci Biobehav Res 1987; 11: PD, Hackett PH, eds. New York: Kluwer Academic/Plenum 287...Medical 43. Anonymous. Neuroprotection as initial therapy in acute Publishers, 1989. stroke. Third report of an ad hoc consensus group meeting. The 19...metabolism during electroconvulsive treatment in relaxation. rotoxicity risk assessment. In: Neuroprotective agents, vol. 825. EEG-EMG Zeitschrift fur

Experimental study of /sup 99m/Tc pertechnetate abdominal scans in jejunal intussusception: preliminary results

DOE Office of Scientific and Technical Information (OSTI.GOV)

James, A.E. Jr.; Strecker, E.P.; Miller, F.J. Jr.

1975-07-01

Recent communications have related the diagnosis of small bowel intussusceptions to abnormal accumulations of the radiopharmaceutical /sup 99m/Tc pertechnetate on abdominal scans. Considering the pathophysiological alterations attendant to intussusceptions, we have attempted an experimental model to examine these changes in temporal sequence. This study was initiated to understand the etiology better and to characterize the abnormalities noted on the /sup 99m/Tc pertechnetate abdominal scans.

Teaching Differential Diagnosis by Computer: A Pathophysiological Approach

ERIC Educational Resources Information Center

Goroll, Allan H.; And Others

1977-01-01

An interactive, computer-based teaching exercise in diagnosis that emphasizes pathophysiology in the analysis of clinical data is described. Called the Jaundice Program, its objective is to simplify the pattern recognition problem by relating clinical findings to diagnosis via reference to disease mechanisms. (LBH)

Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes

PubMed Central

Makris, Konstantinos; Spanou, Loukia

2016-01-01

Acute kidney injury (AKI) is a clinical syndrome that complicates the course and worsens the outcome in a significant number of hospitalised patients. Recent advances in clinical and basic research will help with a more accurate definition of this syndrome and in the elucidation of its pathogenesis. With this knowledge we will be able to conduct more accurate epidemiologic studies in an effort to gain a better understanding of the impact of this syndrome. AKI is a syndrome that rarely has a sole and distinct pathophysiology. Recent evidence, in both basic science and clinical research, is beginning to change our view for AKI from a single organ failure syndrome to a syndrome where the kidney plays an active role in the progress of multi-organ dysfunction. Accurate and prompt recognition of AKI and better understanding of the pathophysiologic mechanisms underlying the various clinical phenotypes are of great importance to research for effective therapeutic interventions. In this review we provide the most recent updates in the definition, epidemiology and pathophysiology of AKI. PMID:28303073

Intracranial and Intraocular Pressure at the Lamina Cribrosa: Gradient Effects.

PubMed

Jóhannesson, Gauti; Eklund, Anders; Lindén, Christina

2018-04-12

A pressure difference between the intraocular and intracranial compartments at the site of the lamina cribrosa has been hypothesized to have a pathophysiological role in several optic nerve head diseases. This paper reviews the current literature on the translamina cribrosa pressure difference (TLCPD), the associated pressure gradient, and its potential pathophysiological role, as well as the methodology to assess TLCPD. For normal-tension glaucoma (NTG), initial studies indicated low intracranial pressure (ICP) while recent findings indicate that a reduced ICP is not mandatory. Data from studies on the elevated TLCPD as a pathophysiological factor of NTG are equivocal. From the identification of potential postural effects on the cerebrospinal fluid (CSF) communication between the intracranial and retrolaminar space, we hypothesize that the missing link could be a dysfunction of an occlusion mechanism of the optic nerve sheath around the optic nerve. In upright posture, this could cause an elevated TLCPD even with normal ICP and we suggest that this should be investigated as a pathophysiological component in NTG patients.

Blended Learning Versus Traditional Lecture in Introductory Nursing Pathophysiology Courses.

PubMed

Blissitt, Andrea Marie

2016-04-01

Currently, many undergraduate nursing courses use blended-learning course formats with success; however, little evidence exists that supports the use of blended formats in introductory pathophysiology courses. The purpose of this study was to compare the scores on pre- and posttests and course satisfaction between traditional and blended course formats in an introductory nursing pathophysiology course. This study used a quantitative, quasi-experimental, nonrandomized control group, pretest-posttest design. Analysis of covariance compared pre- and posttest scores, and a t test for independent samples compared students' reported course satisfaction of the traditional and blended course formats. Results indicated that the differences in posttest scores were not statistically significant between groups. Students in the traditional group reported statistically significantly higher satisfaction ratings than students in the blended group. The results of this study support the need for further research of using blended learning in introductory pathophysiology courses in undergraduate baccalaureate nursing programs. Further investigation into how satisfaction is affected by course formats is needed. Copyright 2016, SLACK Incorporated.

Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes.

PubMed

Makris, Konstantinos; Spanou, Loukia

2016-05-01

Acute kidney injury (AKI) is a clinical syndrome that complicates the course and worsens the outcome in a significant number of hospitalised patients. Recent advances in clinical and basic research will help with a more accurate definition of this syndrome and in the elucidation of its pathogenesis. With this knowledge we will be able to conduct more accurate epidemiologic studies in an effort to gain a better understanding of the impact of this syndrome. AKI is a syndrome that rarely has a sole and distinct pathophysiology. Recent evidence, in both basic science and clinical research, is beginning to change our view for AKI from a single organ failure syndrome to a syndrome where the kidney plays an active role in the progress of multi-organ dysfunction. Accurate and prompt recognition of AKI and better understanding of the pathophysiologic mechanisms underlying the various clinical phenotypes are of great importance to research for effective therapeutic interventions. In this review we provide the most recent updates in the definition, epidemiology and pathophysiology of AKI.

TGF-β1 in Vascular Wall Pathology: Unraveling Chronic Venous Insufficiency Pathophysiology.

PubMed

Serralheiro, Pedro; Soares, Andreia; Costa Almeida, Carlos M; Verde, Ignacio

2017-11-26

Chronic venous insufficiency and varicose veins occur commonly in affluent countries and are a socioeconomic burden. However, there remains a relative lack of knowledge about venous pathophysiology. Various theories have been suggested, yet the molecular sequence of events is poorly understood. Transforming growth factor-beta one (TGF-β1) is a highly complex polypeptide with multifunctional properties that has an active role during embryonic development, in adult organ physiology and in the pathophysiology of major diseases, including cancer and various autoimmune, fibrotic and cardiovascular diseases. Therefore, an emphasis on understanding its signaling pathways (and possible disruptions) will be an essential requirement for a better comprehension and management of specific diseases. This review aims at shedding more light on venous pathophysiology by describing the TGF-β1 structure, function, activation and signaling, and providing an overview of how this growth factor and disturbances in its signaling pathway may contribute to specific pathological processes concerning the vessel wall which, in turn, may have a role in chronic venous insufficiency.

The endothelin B receptor plays a crucial role in the adhesion of neutrophils to the endothelium in sickle cell disease

PubMed Central

Koehl, Bérengère; Nivoit, Pierre; El Nemer, Wassim; Lenoir, Olivia; Hermand, Patricia; Pereira, Catia; Brousse, Valentine; Guyonnet, Léa; Ghinatti, Giulia; Benkerrou, Malika; Colin, Yves; Le Van Kim, Caroline; Tharaux, Pierre-Louis

2017-01-01

Although the primary origin of sickle cell disease is a hemoglobin disorder, many types of cells contribute considerably to the pathophysiology of the disease. The adhesion of neutrophils to activated endothelium is critical in the pathophysiology of sickle cell disease and targeting neutrophils and their interactions with endothelium represents an important opportunity for the development of new therapeutics. We focused on endothelin-1, a mediator involved in neutrophil activation and recruitment in tissues, and investigated the involvement of the endothelin receptors in the interaction of neutrophils with endothelial cells. We used fluorescence intravital microscopy analyses of the microcirculation in sickle mice and quantitative microfluidic fluorescence microscopy of human blood. Both experiments on the mouse model and patients indicate that blocking endothelin receptors, particularly ETB receptor, strongly influences neutrophil recruitment under inflammatory conditions in sickle cell disease. We show that human neutrophils have functional ETB receptors with calcium signaling capability, leading to increased adhesion to the endothelium through effects on both endothelial cells and neutrophils. Intact ETB function was found to be required for tumor necrosis factor α-dependent upregulation of CD11b on neutrophils. Furthermore, we confirmed that human neutrophils synthesize endothelin-1, which may be involved in autocrine and paracrine pathophysiological actions. Thus, the endothelin-ETB axis should be considered as a cytokine-like potent pro-inflammatory pathway in sickle cell disease. Blockade of endothelin receptors, including ETB, may provide major benefits for preventing or treating vaso-occlusive crises in sickle cell patients. PMID:28385784

Pathophysiology of motor dysfunction in a childhood motor neuron disease caused by mutations in the riboflavin transporter.

PubMed

Menezes, Manoj P; Farrar, Michelle A; Webster, Richard; Antony, Jayne; O'Brien, Katherine; Ouvrier, Robert; Kiernan, Matthew C; Burns, Joshua; Vucic, Steve

2016-01-01

Brown-Vialetto-Van Laere (BVVL) syndrome is a progressive motor and sensory neuronopathy secondary to mutations in SLC52A2 encoding the riboflavin transporter type 2 (RFVT2). The phenotype is characterized by early childhood onset hearing loss and sensory ataxia followed by progressive upper limb weakness, optic atrophy, bulbar weakness and respiratory failure. To gain further insight into disease pathophysiology and response to riboflavin supplementation, the present study investigated whether axonal ion channel or membrane abnormalities were a feature of BVVL. Axonal excitability studies and clinical assessments were prospectively undertaken on six patients with BVVL secondary to riboflavin transporter deficiency type 2 (age range 10-21 years) at baseline and after 12 months of riboflavin (1000 mg daily) therapy. At baseline, depolarizing and hyperpolarizing threshold electrotonus was 'fanned out' and superexcitability was increased, while the resting current-threshold gradient and refractoriness were significantly reduced in BVVL patients when compared to controls. Mathematical modeling suggested that functional alterations of myelin underlay these findings with an increase in myelin permeability. Riboflavin therapy resulted in partial normalization of the axonal excitability findings, paralleled by maintenance of muscle strength. The present study established that abnormalities in myelin permeability at the paranode was a feature of BVVL and were partially normalized with riboflavin therapy. This study reveals a novel pathophysiological process for motor nerve dysfunction in BVVL. It also indicates that nerve excitability studies may be further developed in larger cohorts as a potential biomarker to identify treatment response for BVVL patients. Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.

A model for diagnosing and explaining multiple disorders.

PubMed

Jamieson, P W

1991-08-01

The ability to diagnose multiple interacting disorders and explain them in a coherent causal framework has only partially been achieved in medical expert systems. This paper proposes a causal model for diagnosing and explaining multiple disorders whose key elements are: physician-directed hypotheses generation, object-oriented knowledge representation, and novel explanation heuristics. The heuristics modify and link the explanations to make the physician aware of diagnostic complexities. A computer program incorporating the model currently is in use for diagnosing peripheral nerve and muscle disorders. The program successfully diagnoses and explains interactions between diseases in terms of underlying pathophysiologic concepts. The model offers a new architecture for medical domains where reasoning from first principles is difficult but explanation of disease interactions is crucial for the system's operation.

FROM REINFORCEMENT LEARNING MODELS OF THE BASAL GANGLIA TO THE PATHOPHYSIOLOGY OF PSYCHIATRIC AND NEUROLOGICAL DISORDERS

PubMed Central

Maia, Tiago V.; Frank, Michael J.

2013-01-01

Over the last decade and a half, reinforcement learning models have fostered an increasingly sophisticated understanding of the functions of dopamine and cortico-basal ganglia-thalamo-cortical (CBGTC) circuits. More recently, these models, and the insights that they afford, have started to be used to understand key aspects of several psychiatric and neurological disorders that involve disturbances of the dopaminergic system and CBGTC circuits. We review this approach and its existing and potential applications to Parkinson’s disease, Tourette’s syndrome, attention-deficit/hyperactivity disorder, addiction, schizophrenia, and preclinical animal models used to screen novel antipsychotic drugs. The approach’s proven explanatory and predictive power bodes well for the continued growth of computational psychiatry and computational neurology. PMID:21270784

Learned helplessness: unique features and translational value of a cognitive depression model.

PubMed

Vollmayr, Barbara; Gass, Peter

2013-10-01

The concept of learned helplessness defines an escape or avoidance deficit after uncontrollable stress and is regarded as a depression-like coping deficit in aversive but avoidable situations. Based on a psychological construct, it ideally complements other stress-induced or genetic animal models for major depression. Because of excellent face, construct, and predictive validity, it has contributed to the elaboration of several pathophysiological concepts and has brought forward new treatment targets. Whereas learned helplessness can be modeled not only in a broad variety of mammals, but also in fish and Drosophila, we will focus here on the use of this model in rats and mice, which are today the most common species for preclinical in vivo research in psychiatry.

Histaminergic Receptors Modulate Spinal Cord Injury-Induced Neuronal Nitric Oxide Synthase Upregulation and Cord Pathology: New Roles of Nanowired Drug Delivery for Neuroprotection.

PubMed

Sharma, Hari S; Patnaik, Ranjana; Muresanu, Dafin F; Lafuente, José V; Ozkizilcik, Asya; Tian, Z Ryan; Nozari, Ala; Sharma, Aruna

2017-01-01

The possibility that histamine influences the spinal cord pathophysiology following trauma through specific receptor-mediated upregulation of neuronal nitric oxide synthase (nNOS) was examined in a rat model. A focal spinal cord injury (SCI) was inflicted by a longitudinal incision into the right dorsal horn of the T10-11 segments. The animals were allowed to survive 5h. The SCI significantly induced breakdown of the blood-spinal cord barrier to protein tracers, reduced the spinal cord blood flow at 5h, and increased the edema formation and massive upregulation of nNOS expression. Pretreatment with histamine H1 receptor antagonist mepyramine (1mg, 5mg, and 10mg/kg, i.p., 30min before injury) failed to attenuate nNOS expression and spinal cord pathology following SCI. On the other hand, blockade of histamine H2 receptors with cimetidine or ranitidine (1mg, 5mg, or 10mg/kg) significantly reduced these early pathophysiological events and attenuated nNOS expression in a dose-dependent manner. Interestingly, TiO 2 -naowire delivery of cimetidine or ranitidine (5mg doses) exerted superior neuroprotective effects on SCI-induced nNOS expression and cord pathology. It appears that effects of ranitidine were far superior than cimetidine at identical doses in SCI. On the other hand, pretreatment with histamine H3 receptor agonist α-methylhistamine (1mg, 2mg, or 5mg/kg, i.p.) that inhibits histamine synthesis and release in the central nervous system thwarted the spinal cord pathophysiology and nNOS expression when used in lower doses. Interestingly, histamine H3 receptor antagonist thioperamide (1mg, 2mg, or 5mg/kg, i.p.) exacerbated nNOS expression and cord pathology after SCI. These novel observations suggest that blockade of histamine H2 receptors or stimulation of histamine H3 receptors attenuates nNOS expression and induces neuroprotection in SCI. Taken together, our results are the first to demonstrate that histamine-induced pathophysiology of SCI is mediated via nNOS expression involving specific histamine receptors. © 2017 Elsevier Inc. All rights reserved.

Protocol for the specialist supervised individualised multifactorial treatment of new clinically diagnosed type 2 diabetes in general practice (IDA): a prospective controlled multicentre open-label intervention study

PubMed Central

Stidsen, Jacob Volmer; Nielsen, Jens Steen; Henriksen, Jan Erik; Friborg, Søren Gunnar; Olesen, Thomas Bastholm; Olsen, Michael Hecht; Beck-Nielsen, Henning

2017-01-01

Introduction We present the protocol for a multifactorial intervention study designed to test whether individualised treatment, based on pathophysiological phenotyping and individualised treatment goals, improves type 2 diabetes (T2D) outcomes. Methods and analysis We will conduct a prospective controlled multicentre open-label intervention study, drawing on the longitudinal cohort of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2). New clinically diagnosed patients with T2D in the intervention group will be assigned to receive individualised treatment by their general practitioner. Intervention patients will be compared with a matched control cohort of DD2 patients receiving routine clinical care. Among intervention patients, we will first do pathophysiological phenotyping to classify patients into WHO-defined T2D or other specific types of diabetes (monogenic diabetes, secondary diabetes etc). Patients with WHO-defined T2D will then be further subcharacterised by their beta-cell function (BCF) and insulin sensitivity (IS), using the revised homeostatic assessment model, as having either insulinopaenic T2D (high IS and low BCF), classical T2D (low IS and low BCF) or hyperinsulinaemic T2D (low IS and high BCF). For each subtype, a specific treatment algorithm will target the primary pathophysiological defect. Similarly, antihypertensive treatment will be targeted at the specific underlying pathophysiology, characterised by impedance cardiography (relative importance of vascular resistance, intravascular volume and cardiac inotropy). All treatment goals will be based on individual patient assessment of expected positive versus adverse effects. Web-based and face-to-face individualised lifestyle intervention will also be implemented to empower patients to make a sustainable improvement in daily physical activity and to change to a low-carbohydrate diet. Ethics and dissemination The study will use well-known pharmacological agents according to their labels; patient safety is therefore considered high. Study results will be published in international peer-reviewed journals. Trial registration number NCT02015130; Pre-results. PMID:29229652

Pathophysiology, treatment, and animal and cellular models of human ischemic stroke

PubMed Central

2011-01-01

Stroke is the world's second leading cause of mortality, with a high incidence of severe morbidity in surviving victims. There are currently relatively few treatment options available to minimize tissue death following a stroke. As such, there is a pressing need to explore, at a molecular, cellular, tissue, and whole body level, the mechanisms leading to damage and death of CNS tissue following an ischemic brain event. This review explores the etiology and pathogenesis of ischemic stroke, and provides a general model of such. The pathophysiology of cerebral ischemic injury is explained, and experimental animal models of global and focal ischemic stroke, and in vitro cellular stroke models, are described in detail along with experimental strategies to analyze the injuries. In particular, the technical aspects of these stroke models are assessed and critically evaluated, along with detailed descriptions of the current best-practice murine models of ischemic stroke. Finally, we review preclinical studies using different strategies in experimental models, followed by an evaluation of results of recent, and failed attempts of neuroprotection in human clinical trials. We also explore new and emerging approaches for the prevention and treatment of stroke. In this regard, we note that single-target drug therapies for stroke therapy, have thus far universally failed in clinical trials. The need to investigate new targets for stroke treatments, which have pleiotropic therapeutic effects in the brain, is explored as an alternate strategy, and some such possible targets are elaborated. Developing therapeutic treatments for ischemic stroke is an intrinsically difficult endeavour. The heterogeneity of the causes, the anatomical complexity of the brain, and the practicalities of the victim receiving both timely and effective treatment, conspire against developing effective drug therapies. This should in no way be a disincentive to research, but instead, a clarion call to intensify efforts to ameliorate suffering and death from this common health catastrophe. This review aims to summarize both the present experimental and clinical state-of-the art, and to guide future research directions. PMID:21266064

Translational Animal Models of Atopic Dermatitis for Preclinical Studies



PubMed Central

Martel, Britta C.; Lovato, Paola; Bäumer, Wolfgang; Olivry, Thierry

2017-01-01

There is a medical need to develop new treatments for patients suffering from atopic dermatitis (AD). To improve the discovery and testing of novel treatments, relevant animal models for AD are needed. Generally, these animal models mimic different aspects of the pathophysiology of human AD, such as skin barrier defects and Th2 immune bias with additional Th1 and Th22, and in some populations Th17, activation. However, the pathomechanistic characterization and pharmacological validation of these animal models are generally incomplete. In this paper, we review animal models of AD in the context of preclinical use and their possible translation to the human disease. Most of these models use mice, but we will also critically evaluate dog models of AD, as increasing information on disease mechanism show their likely relevance for the human disease. PMID:28955179

Multiphysics and multiscale modelling, data-model fusion and integration of organ physiology in the clinic: ventricular cardiac mechanics.

PubMed

Chabiniok, Radomir; Wang, Vicky Y; Hadjicharalambous, Myrianthi; Asner, Liya; Lee, Jack; Sermesant, Maxime; Kuhl, Ellen; Young, Alistair A; Moireau, Philippe; Nash, Martyn P; Chapelle, Dominique; Nordsletten, David A

2016-04-06

With heart and cardiovascular diseases continually challenging healthcare systems worldwide, translating basic research on cardiac (patho)physiology into clinical care is essential. Exacerbating this already extensive challenge is the complexity of the heart, relying on its hierarchical structure and function to maintain cardiovascular flow. Computational modelling has been proposed and actively pursued as a tool for accelerating research and translation. Allowing exploration of the relationships between physics, multiscale mechanisms and function, computational modelling provides a platform for improving our understanding of the heart. Further integration of experimental and clinical data through data assimilation and parameter estimation techniques is bringing computational models closer to use in routine clinical practice. This article reviews developments in computational cardiac modelling and how their integration with medical imaging data is providing new pathways for translational cardiac modelling.

The role of nitric oxide in the physiology and pathophysiology of the exocrine pancreas.

PubMed

Hegyi, Péter; Rakonczay, Zoltán

2011-11-15

Nitric oxide (NO), a ubiquitous gaseous signaling molecule, contributes to both pancreatic physiology and pathophysiology. The present review provides a general overview of NO synthesis, signaling, and function. Further, it specifically discusses NO metabolism and its effects in the exocrine pancreas and focuses on the role of NO in the pathogenesis of acute pancreatitis and pancreatic ischemia/reperfusion injury. Unfortunately, the role of NO in pancreatic physiology and pathophysiology remains controversial in numerous areas. Many questions regarding the messenger molecule still remain unanswered. Probably the least is known about the downstream targets of NO, which need to be identified, especially at the molecular level.

Cognitive impairment in Epilepsy: The Role of Network Abnormalities

PubMed Central

Holmes, Gregory L.

2015-01-01

The challenges to individuals with epilepsy extend far beyond the seizures. Co-morbidities in epilepsy are very common and are often more problematic to individuals than the seizures themselves. In this review, the pathophysiological mechanisms of cognitive impairment are discussed. While etiology of the epilepsy has a significant influence on cognition there is increasing evidence that prolonged or recurrent seizures can cause or exacerbate cognitive impairment. Alterations in signaling pathways and neuronal network function play a major role in both the pathophysiology of epilepsy and the epilepsy comorbidities. However, the biological underpinnings of cognitive impairment can be distinct from the pathophysiological processes that cause seizures. PMID:25905906

Azelaic acid gel 15%: clinical versatility in the treatment of rosacea.

PubMed

Del Rosso, James Q; Baum, Eric W; Draelos, Zoe Diana; Elewski, Boni E; Fleischer, Alan B; Kakita, Lenore S; Thiboutot, Diane

2006-11-01

There are numerous proposed but contested components involved in the pathophysiology of rosacea, including inflammatory mediators, reactive oxygen species (ROS) released by neutrophils, and microbial components. Ideal comprehensive rosacea management should address these components. Azelaic acid (AzA), a naturally occurring substance, has many proposed mechanisms of action--antimicrobial, anti-inflammatory/antioxidant, and keratinolytic--that address the proposed components of rosacea pathophysiology and has demonstrated efficacy in subtype 2 rosacea. In a roundtable discussion, information leaders discussed the pathophysiology of rosacea and other issues of importance to successful rosacea management, such as skin care regimens, quality of life (QOL), and compliance.

A narrative review on the difficulties associated with fibromyalgia diagnosis

PubMed Central

Kumbhare, Dinesh; Ahmed, Sara; Watter, Scott

2017-01-01

Fibromyalgia presents a clinical enigma as its pathophysiology is not well understood and its symptoms are nonspecific and overlap with many disorders, making its diagnosis a challenge for clinicians and researchers. Efforts have been made to develop a set of diagnostic criteria for this disorder. However, these criteria rely heavily on expert clinician opinion and produce a large heterogeneity within the diagnosed population. With no present specific technique reflecting the underlying pathophysiology of fibromyalgia, a definitive diagnosis of fibromyalgia remains elusive. This review discusses some problems and challenges associated with fibromyalgia diagnosis and presents some novel findings on the pathophysiological nature of fibromyalgia. PMID:29290763

Exploring the influence of students' attributions for success on their self-regulation in pathophysiology.

PubMed

Dunn, Karee E; Osborne, Cara; Link, Hope J

2012-06-01

Pathophysiology is a difficult course both for students to take and for instructors to teach. However, little research has explored learner characteristics that teachers may address through targeted instruction to make both the teaching and learning experience better. This study examined the influence of students' causal attributions for success on their self-regulated learning, which is strongly associated with positive learning outcomes. Results indicated that ability, effort, and luck attributions for success collectively influenced Pathophysiology students' self-regulated learning and that ability was the most potent influence. The findings and the implication for teaching are discussed. Copyright 2012, SLACK Incorporated.

Zebrafish heart failure models: opportunities and challenges.

PubMed

Shi, Xingjuan; Chen, Ru; Zhang, Yu; Yun, Junghwa; Brand-Arzamendi, Koroboshka; Liu, Xiangdong; Wen, Xiao-Yan

2018-05-03

Heart failure is a complex pathophysiological syndrome of pumping functional failure that results from injury, infection or toxin-induced damage on the myocardium, as well as genetic influence. Gene mutations associated with cardiomyopathies can lead to various pathologies of heart failure. In recent years, zebrafish, Danio rerio, has emerged as an excellent model to study human cardiovascular diseases such as congenital heart defects, cardiomyopathy, and preclinical development of drugs targeting these diseases. In this review, we will first summarize zebrafish genetic models of heart failure arose from cardiomyopathy, which is caused by mutations in sarcomere, calcium or mitochondrial-associated genes. Moreover, we outline zebrafish heart failure models triggered by chemical compounds. Elucidation of these models will improve the understanding of the mechanism of pathogenesis and provide potential targets for novel therapies.

A Murine Model to Study Epilepsy and SUDEP Induced by Malaria Infection

PubMed Central

Ssentongo, Paddy; Robuccio, Anna E.; Thuku, Godfrey; Sim, Derek G.; Nabi, Ali; Bahari, Fatemeh; Shanmugasundaram, Balaji; Billard, Myles W.; Geronimo, Andrew; Short, Kurt W.; Drew, Patrick J.; Baccon, Jennifer; Weinstein, Steven L.; Gilliam, Frank G.; Stoute, José A.; Chinchilli, Vernon M.; Read, Andrew F.; Gluckman, Bruce J.; Schiff, Steven J.

2017-01-01

One of the largest single sources of epilepsy in the world is produced as a neurological sequela in survivors of cerebral malaria. Nevertheless, the pathophysiological mechanisms of such epileptogenesis remain unknown and no adjunctive therapy during cerebral malaria has been shown to reduce the rate of subsequent epilepsy. There is no existing animal model of postmalarial epilepsy. In this technical report we demonstrate the first such animal models. These models were created from multiple mouse and parasite strain combinations, so that the epilepsy observed retained universality with respect to genetic background. We also discovered spontaneous sudden unexpected death in epilepsy (SUDEP) in two of our strain combinations. These models offer a platform to enable new preclinical research into mechanisms and prevention of epilepsy and SUDEP. PMID:28272506

Early-life stress origins of gastrointestinal disease: animal models, intestinal pathophysiology, and translational implications

PubMed Central

Pohl, Calvin S.; Medland, Julia E.

2015-01-01

Early-life stress and adversity are major risk factors in the onset and severity of gastrointestinal (GI) disease in humans later in life. The mechanisms by which early-life stress leads to increased GI disease susceptibility in adult life remain poorly understood. Animal models of early-life stress have provided a foundation from which to gain a more fundamental understanding of this important GI disease paradigm. This review focuses on animal models of early-life stress-induced GI disease, with a specific emphasis on translational aspects of each model to specific human GI disease states. Early postnatal development of major GI systems and the consequences of stress on their development are discussed in detail. Relevant translational differences between species and models are highlighted. PMID:26451004

Poststroke Seizures and Epilepsy: Clinical Studies and Animal Models

PubMed Central

Kelly, Kevin M.

2002-01-01

Poststroke seizures and epilepsy have been described in numerous clinical studies for many years. Most studies are retrospective in design, include relatively small numbers of patients, have limited periods of follow-up, and report a diversity of findings. Well-designed clinical trials and population studies in the recent past addressed several critical clinical issues and generated important findings regarding the occurrence of poststroke seizures and epilepsy. In contrast, the pathophysiologic events of injured brain that establish poststroke epileptogenesis are not well understood, and animal modeling has had limited development. Reviews of several important clinical studies and animal models that hold promise for a better understanding of poststroke epileptogenesis are presented. PMID:15309107

Depressive Disorder, Anxiety Disorder and Chronic Pain: Multiple Manifestations of a Common Clinical and Pathophysiological Core.

PubMed

Arango-Dávila, Cesar A; Rincón-Hoyos, Hernán G

A high proportion of depressive disorders are accompanied by anxious manifestations, just as depression and anxiety often present with many painful manifestations, or conversely, painful manifestations cause or worsen depressive and anxious expressions. There is increasingly more evidence of the pathophysiological, and neurophysiological and technical imaging similarity of pain and depression. Narrative review of the pathophysiological and clinical aspects of depression and chronic pain comorbidity. Research articles are included that emphasise the most relevant elements related to understanding the pathophysiology of both manifestations. The pathological origin, physiology and clinical approach to these disorders have been more clearly established with the latest advances in biochemical and cellular techniques, as well as the advent of imaging technologies. This information is systematised with comprehensive images and clinical pictures. The recognition that the polymorphism of inflammation-related genes generates susceptibility to depressive manifestations and may modify the response to antidepressant treatments establishes that the inflammatory response is not only an aetiopathogenic component of pain, but also of stress and depression. Likewise, the similarity in approach with images corroborates not only the structural, but the functional and pathophysiological analogy between depression and chronic pain. Knowledge of depression-anxiety-chronic pain comorbidity is essential in the search for effective therapeutic interventions. Copyright © 2016 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.