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Sample records for early onset periodontitis

  1. Periodontal bone loss in Chinese subjects with untreated early-onset and adult periodontitis: a cross-sectional study using digital scanning radiographic image analysis.

    PubMed

    Hou, Guey-Lin; Hung, Chun-Cheng; Yang, Yi-Hsin; Chen, Yi-Ching; Tsai, Chi-Cheng; Shieh, Tien-Yu

    2002-10-01

    The purpose of this investigation was to evaluate the differences in radiographic alveolar bone loss (RABL) in Taiwanese subjects with early-onset periodontitis (EOP) and adult periodontitis (AP) using the digital scanning radiographic image analysis (DSRIA). A total of 4,262 teeth from 178 individuals (96 males and 82 females) were examined for RABL due to EOP and AP. The subjects with EOP and a comparison group with AP were identified from the Periodontal Clinic population (College of Dental Medicine, Kaohsiung Medical University). The following criteria were used to classify subjects with EOP and AP during the past 20 years. The RABL of teeth were calculated using a computer system equipped with Microstation 95 software, under 10 X magnification of the radiographs. Quantity assessment of RABL using the DSRIA showed that: (1) the means of RABL of maxillary and mandibular anterior teeth in the EOP group were significant greater than those in the AP group when the two sample t-test was used. (2) The greatest values of mean RABL of affected sites in the EOP group occurred most commonly in the first molars and mandibular incisors, whereas, in the AP group, the greatest values of mean RABL of affected sites occurred most commonly in the first and second molars. (3) Molars had the greatest mean RABL followed by incisors, premolars and canines. (4) The mean RABL increased with increasing age. We conclude that the features of naturally progressing alveolar bone loss at the molar and incisor sites in untreated subjects with the EOP and AP revealed that the mean RABL in the EOP group was faster and greater than that in the AP group. PMID:12517066

  2. Early-Onset Alzheimer's

    MedlinePLUS

    MENU Return to Web version Early-Onset Alzheimer’s What is early-onset Alzheimer’s disease? Early-onset Alzheimer’s disease is when Alzheimer’s affects a person younger than 65 years of age. People ...

  3. Early Onset Sepsis.

    PubMed

    Johnson, Kyrsten; Messier, Stephen

    2016-01-01

    Early onset sepsis (EOS) is a worrisome, life-threatening condition in newborns with onset during the first week of life. Evaluation can be challenging due to the dynamic nature of the condition as the infant transitions to life ex-utero. Symptoms/signs can be nonspecific, thus, a high index of suspicion is warranted for subtle changes in condition including poor feeding, respiratory distress, or decreased activity. Common risk factors include chorioamnionitis, maternal fever, group B strep (GBS) colonization and preterm delivery. Despite universal screening and intrapartum antibiotic prophylaxis (IAP), GBS remains the most frequent cause of EOS followed by Escherichia coli (E. coli). While the gold standard for diagnosis remains a positive blood culture, lab evaluation frequently involves complete blood count (CBC) with differential, c-reactive protein (CRP), and evaluation of spinal fluid if the infant is stable. Unfortunately, there is not a lab test that is rapidly diagnostic for sepsis, so treatment should be empirically started until it is clear that the infant is not infected. Treatment often includes ampicillin and gentamicin for coverage of the most frequent pathogens. There is much debate about timing of discontinuation of antibiotics. Frequently, antibiotics can be discontinued after 48 hours in well appearing, asymptomatic infants with negative blood cultures and either normal CBC analysis or normal CRP values. PMID:26882580

  4. Early onset sebaceous carcinoma

    PubMed Central

    2011-01-01

    Background Ocular sebaceous carcinoma can masquerade as benign lesions resulting in delay of diagnosis. Early recognition is even more difficult in young patients where the disease rarely occurs. Here, we provide a clinicopathological correlation of ocular sebaceous carcinoma in a young individual lacking history of hereditary cancer or immunosuppression. Findings A detailed histopathological study including p53 DNA sequencing was performed on an aggressive sebaceous carcinoma presenting in a healthy 32 year-old Caucasian woman. She had no history of retinoblastoma, evidence for a hereditary cancer syndrome, or radiation therapy. However, she potentially was at risk for excessive UV light exposure. A detailed review of the literature is also provided. A moderately well differentiated sebaceous carcinoma was established histopathologically arising from the meibomian gland of the upper eyelid. In most areas, the cytoplasm contained small but distinct Oil-red-O positive vacuoles. Direct sequencing of p53 identified a G:C?A:T mutation at a dipyrimidine site. The mutation results in substitution of arginine for the highly conserved glycine at residue 199 located at the p53 dimer-dimer interface. Energy minimization structural modeling predicts that G199R will neutralize negative charges contributed by nearby inter- and intramonomeric glutamate residues. Discussion This study points to the importance of recognizing that sebaceous carcinoma can occur in young patients with no evidence for hereditary cancer risk or radiation therapy. The G199R substitution is anticipated to alter the stability of the p53 tetrameric complex. The role of UV light in the etiology of sebaceous carcinoma deserves further study. Our findings, taken together with those of others, suggest that different environmental factors could lead to the development of sebaceous carcinoma in different patients. PMID:21892948

  5. Genetics Home Reference: Early-onset glaucoma

    MedlinePLUS

    ... literature OMIM Genetic disorder catalog Conditions > Early-onset glaucoma On this page: Description Genetic changes Inheritance Diagnosis ... definitions Reviewed February 2009 What is early-onset glaucoma? Glaucoma is a group of eye disorders in ...

  6. Serotonin in early-onset alcoholism.

    PubMed

    Virkkunen, M; Linnoila, M

    1997-01-01

    This chapter examines current, common schemes to subgroup alcoholics to arrive at relatively homogeneous groups of patients to facilitate psychobiological and molecular genetic studies. Early-onset, male-limited alcoholism is commonly associated with antisocial personality disorder or antisocial behavioral traits. It is often preceded by early-onset aggressiveness, which is followed by conduct disorder. Early-onset alcoholism among men is associated with low central serotonin turnover rate. The data concerning platelet MAO activity and serotonin uptake to platelets among early-onset alcoholics are conflicting. Recent molecular genetic and brain imaging studies on early-onset alcoholics are preliminary but appear very promising. PMID:9122495

  7. Early-Onset Neonatal Sepsis

    PubMed Central

    Simonsen, Kari A.; Anderson-Berry, Ann L.; Delair, Shirley F.

    2014-01-01

    SUMMARY Early-onset sepsis remains a common and serious problem for neonates, especially preterm infants. Group B streptococcus (GBS) is the most common etiologic agent, while Escherichia coli is the most common cause of mortality. Current efforts toward maternal intrapartum antimicrobial prophylaxis have significantly reduced the rates of GBS disease but have been associated with increased rates of Gram-negative infections, especially among very-low-birth-weight infants. The diagnosis of neonatal sepsis is based on a combination of clinical presentation; the use of nonspecific markers, including C-reactive protein and procalcitonin (where available); blood cultures; and the use of molecular methods, including PCR. Cytokines, including interleukin 6 (IL-6), interleukin 8 (IL-8), gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α), and cell surface antigens, including soluble intercellular adhesion molecule (sICAM) and CD64, are also being increasingly examined for use as nonspecific screening measures for neonatal sepsis. Viruses, in particular enteroviruses, parechoviruses, and herpes simplex virus (HSV), should be considered in the differential diagnosis. Empirical treatment should be based on local patterns of antimicrobial resistance but typically consists of the use of ampicillin and gentamicin, or ampicillin and cefotaxime if meningitis is suspected, until the etiologic agent has been identified. Current research is focused primarily on development of vaccines against GBS. PMID:24396135

  8. Salivary Antimicrobial Peptides in Early Detection of Periodontitis

    PubMed Central

    Güncü, Güliz N.; Yilmaz, Dogukan; Könönen, Eija; Gürsoy, Ulvi K.

    2015-01-01

    In the pathogenesis of periodontitis, an infection-induced inflammatory disease of the tooth-supporting tissues, there is a complex interaction between the subgingival microbiota and host tissues. A periodontal diagnostic tool for detecting the initiation and progression of the disease, monitoring the response to therapy, or measuring the degree of susceptibility to future disease progression has been of interest for a long time. The value of various enzymes, proteins, and immunoglobulins, which are abundant constituents of saliva, as potential biomarkers has been recognized and extensively investigated for periodontal diseases. Gingival defensins and cathelicidins are small cationic antimicrobial peptides that play an important role in innate immune response. However, their applicability as salivary biomarkers is still under debate. The present review focuses on proteomic biomarkers and antimicrobial peptides, in particular, to be used at early phases of periodontitis. PMID:26734583

  9. Predictors of Early Alcohol Drinking Onset

    ERIC Educational Resources Information Center

    Dooley, David; Prause, JoAnn

    2007-01-01

    Early alcohol drinking onset (ADO) has been implicated as a cause of adult alcohol disorder inviting interventions that target the causes of ADO. This study explores the precursors of early ADO using variables measured before drinking onset, reaching back to the mothers of the respondents. The sample consists of children of the women respondents

  10. Early- versus Late-Onset Systemic Sclerosis

    PubMed Central

    Alba, Marco A.; Velasco, Csar; Simen, Carmen Pilar; Fonollosa, Vicent; Trapiella, Luis; Egurbide, Mara Victoria; Sez, Luis; Castillo, Mara Jess; Callejas, Jos Luis; Camps, Mara Teresa; Tolosa, Carles; Ros, Juan Jos; Freire, Mayka; Vargas, Jos Antonio; Espinosa, Gerard

    2014-01-01

    Abstract Peak age at onset of systemic sclerosis (SSc) is between 20 and 50 years, although SSc is also described in both young and elderly patients. We conducted the present study to determine if age at disease onset modulates the clinical characteristics and outcome of SSc patients. The Spanish Scleroderma Study Group recruited 1037 patients with a mean follow-up of 5.2 6.8 years. Based on the mean 1 standard deviation (SD) of age at disease onset (45 15 yr) of the whole series, patients were classified into 3 groups: age ?30 years (early onset), age between 31 and 59 years (standard onset), and age ?60 years (late onset). We compared initial and cumulative manifestations, immunologic features, and death rates. The early-onset group included 195 patients; standard-onset group, 651; and late-onset, 191 patients. The early-onset group had a higher prevalence of esophageal involvement (72% in early-onset compared with 67% in standard-onset and 56% in late-onset; p = 0.004), and myositis (11%, 7.2%, and 2.9%, respectively; p = 0.009), but a lower prevalence of centromere antibodies (33%, 46%, and 47%, respectively; p = 0.007). In contrast, late-onset SSc was characterized by a lower prevalence of digital ulcers (54%, 41%, and 34%, respectively; p < 0.001) but higher rates of heart conduction system abnormalities (9%, 13%, and 21%, respectively; p = 0.004). Pulmonary hypertension was found in 25% of elderly patients and in 12% of the youngest patients (p = 0.010). After correction for the population effects of age and sex, standardized mortality ratio was shown to be higher in younger patients. The results of the present study confirm that age at disease onset is associated with differences in clinical presentation and outcome in SSc patients. PMID:24646463

  11. Periodontal Disease and Late-Onset Aortic Prosthetic Vascular Graft Infection

    PubMed Central

    Thomas, Stephanie; Ghosh, Jonathan; Porter, Johnathan; Cockcroft, Adele; Rautemaa-Richardson, Riina

    2015-01-01

    Prosthetic vascular graft infection (PVGI) is a rare but significant complication of arterial reconstructive surgery. Although the relative risk is low, the clinical consequences can be catastrophic. Microbiological data on causative bacteria are limited. We present four cases of late-onset PVGI. Using a culture-independent nucleic acid amplification method for analysis of intraoperative samples, the presence of bacteria highly suggestive of an oral source was reported. Examination by an oral health specialist confirmed the presence of chronic periodontal disease. We hypothesize that chronic oral infection may be a previously unreported risk factor for the development of late-onset PVGI. PMID:25685592

  12. Genetics Home Reference: Early-onset primary dystonia

    MedlinePLUS

    ... literature OMIM Genetic disorder catalog Conditions > Early-onset primary dystonia On this page: Description Genetic changes Inheritance ... definitions Reviewed May 2008 What is early-onset primary dystonia? Early-onset primary dystonia is a condition ...

  13. THE LINK BETWEEN EARLY ONSET DRINKING AND EARLY ONSET ALCOHOL-IMPAIRED DRIVING IN YOUNG MALES

    PubMed Central

    Zhang, Lening; Wieczorek, William F.; Welte, John W.

    2014-01-01

    Background Young drivers represent a disproportionate number of the individuals involved in alcohol-impaired driving. Although there is a known association between drinking and alcohol-impaired driving in young drivers, the link between early onset drinking and early onset alcohol-impaired driving has not been explored. Objectives The present study aimed to assess this link along with potentially confounding factors. Methods The assessment used a proportional hazards model with data collected from the Buffalo Longitudinal Study of Young Men, a population based sample of 625 males at ages of 1619 years old. Results Controlling for the effects of potentially relevant confounds, the early onset of drinking was the most influential factor in predicting the early onset of alcohol-impaired driving. Race and the early onset of other forms of delinquency also played a significant role in the early onset of alcohol-impaired driving. Conclusion Preventing an early start of drinking among adolescents may be the most critical factor to address in preventing an early start of alcohol-impaired driving. PMID:24766089

  14. Periodontitis

    MedlinePLUS

    ... brushing is always needed, even after professional tooth cleaning, to reduce your risk of gum disease. Your ... Patients with periodontitis should have a professional tooth cleaning every three months. Surgery may be necessary. Deep ...

  15. [Update on current care guidelines: prevention, early diagnosis and treatment of chronic periodontitis].

    PubMed

    2010-01-01

    Periodontitis is common in the adult Finnish population. Due to the lack of pain and other symptoms, affected patients seldom seek dental care but require attention through the health care system. A careful periodontal screening, including risk assessment, should form part of regular dental check-ups. Individual brushing and interdental cleaning instructions, as well as tobacco counselling, are important in both the prevention and treatment of periodontitis. When detecting early signs of periodontitis, periodontal treatment, including the necessary maintenance visits, is crucial in preventing the severe form of the disease and its harmful consequences for the patient's dentition and general health. PMID:21125755

  16. Unusual early-onset Huntingtons disease.

    PubMed

    Vargas, Antonio P; Carod-Artal, Francisco J; Bomfim, Denise; Vzquez-Cabrera, Carolina; Dantas-Barbosa, Carmela

    2003-06-01

    Huntington's disease is an autosomal dominant progressive neurodegenerative disorder characterized by involuntary movements, cognitive decline, and behavioral disorders leading to functional disability. In contrast to patients with adult onset, in which chorea is the major motor abnormality, children often present with spasticity, rigidity, and significant intellectual decline associated with a more rapidly progressive course. An unusual early-onset Huntington's disease case of an 11-year-old boy with severe hypokinetic/rigid syndrome appearing at the age of 2.5 years is presented. Clinical diagnosis was confirmed by polymerase chain reaction study of the expanded IT-15 allele with a compatible size of 102 cytosine-adenosine-guanosine repeats L-Dopa mildly ameliorated rigidity, bradykinesia, and dystonia. We conclude that Huntington's disease should be included in the differential diagnoses of regressive syndromes of early childhood. PMID:12886981

  17. [Brain imaging in early onset anorexia].

    PubMed

    Bargiacchi, A

    2014-05-01

    Structural and functional brain alterations in the structures involved in taste processing, emotions regulation and the reward system have been described in anorexia nervosa. The neurodevelopmental origin of this disorder has been recently discussed. In this article, brain-imaging data in early onset anorexia nervosa will be recalled and the relationship between clinical symptoms, normal brain maturation and brain imaging data in adolescents and adults will be discussed. PMID:24726667

  18. Genomic insights into early-onset obesity.

    PubMed

    Choquet, Hlne; Meyre, David

    2010-01-01

    The biological causes of childhood obesity are complex. Environmental factors, such as massive marketing campaigns for food leading to over-nutrition and snacking and the decline in physical activity, have undoubtedly contributed to the increased prevalence of overweight and obesity in children, but these cannot be considered as the only causes. Susceptibility to obesity is also determined to a great extent by genetic factors. Furthermore, molecular mechanisms involved in the regulation of gene expression, such as epigenetic mechanisms, can increase the risk of developing early-onset obesity. There is evidence that early-onset obesity is a heritable disorder, and a range of genetic factors have recently been shown to cause monogenic, syndromic and polygenic forms of obesity, in some cases interacting with environmental exposures. Modifications of the transcriptome can lead to increased adiposity, and the gut microbiome has recently been shown to be key to the genesis of obesity. These new genomic discoveries complement previous knowledge on the development of early-onset obesity and provide new perspectives for research on the complex molecular and physiological mechanisms involved in this disease. Personalized preventive strategies and genomic medicine may become possible in the near future. PMID:20587078

  19. Genetics Home Reference: Early-onset primary dystonia

    MedlinePLUS

    ... mutation in the TOR1A gene (also known as DYT1 ) is responsible for most cases of early-onset ... dystonia and may include treatment providers. Gene Review: DYT1 Early-Onset Primary Dystonia Genetic Testing Registry: Dystonia ...

  20. Early onset torsion dystonia (Oppenheim's dystonia)

    PubMed Central

    Kamm, Christoph

    2006-01-01

    Early onset torsion dystonia (EOTD) is a rare movement disorder characterized by involuntary, repetitive, sustained muscle contractions or postures involving one or more sites of the body. A US study estimated the prevalence at approximately 1 in 30,000. The estimated prevalence in the general population of Europe seems to be lower, ranging from 1 in 330,000 to 1 in 200,000, although precise numbers are currently not available. The estimated prevalence in the Ashkenazi Jewish population is approximately five to ten times higher, due to a founder mutation. Symptoms of EOTD typically develop first in an arm or leg in middle to late childhood and progress in approximately 30% of patients to other body regions (generalized dystonia) within about five years. Distribution and severity of symptoms vary widely between affected individuals. The majority of cases from various ethnic groups are caused by an autosomal dominantly inherited deletion of 3 bp (GAG) in the DYT1 gene on chromosome 9q34. This gene encodes a protein named torsinA, which is presumed to act as a chaperone protein associated with the endoplasmic reticulum and the nuclear envelope. It may interact with the dopamine transporter and participate in intracellular trafficking, although its precise function within the cell remains to be determined. Molecular genetic diagnostic and genetic counseling is recommended for individuals with age of onset below 26 years, and may also be considered in those with onset after 26 years having a relative with typical early onset dystonia. Treatment options include botulinum toxin injections for focal symptoms, pharmacological therapy such as anticholinergics (most commonly trihexiphenydil) for generalized dystonia and surgical approaches such as deep brain stimulation of the internal globus pallidus or intrathecal baclofen application in severe cases. All patients have normal cognitive function, and despite a high rate of generalization of dystonia, 75% of those patients are able to maintain ambulation and independence, and therefore a comparatively good quality of life, with modern treatment modalities. PMID:17129379

  1. Glucose metabolism in early onset versus late onset Alzheimer's disease: an SPM analysis of 120 patients.

    PubMed

    Kim, E J; Cho, S S; Jeong, Y; Park, K C; Kang, S J; Kang, E; Kim, S E; Lee, K H; Na, D L

    2005-08-01

    The aims of this cross-sectional study were (i) to compare the overall glucose metabolism between early onset and late onset Alzheimer's disease in a large sample of patients; and (ii) to investigate the pattern of glucose metabolism as a function of dementia severity in early onset versus late onset Alzheimer's disease, using a statistical parametric mapping (SPM) analysis. Subjects consisted of four groups: 74 patients with early onset Alzheimer's disease, 46 patients with late onset of the disease, and two control groups age matched to each patient group. All the subjects underwent 2-[(18)F]fluoro-2-deoxy-d-glucose (FDG)-PET under the same scanning conditions. Severity of dementia was rated with the Clincial Dementia Rating (CDR). Voxel-based SPM99 was used for statistical analyses. Overall glucose hypometabolism of early onset Alzheimer's disease patients was much greater in magnitude and extent than that of late onset patients, though both groups were similar in dementia severity: the early onset group showed more severe hypometabolism in parietal, frontal and subcortical (basal ganglia and thalamus) areas. When the decline of glucose metabolism was compared as a function of CDR stage, the slope was steeper in early onset than in late onset Alzheimer's disease. The rapid decline occurred at CDR 0.5-1 in the early onset group, whereas similar changes occurred at CDR 2-3 in the late onset group. The greater hypometabolism in early onset than in late onset patients is required to reach the same severity of dementia, probably reflecting greater functional reserve in younger than in older subjects. Alternatively, the metabolic decline curve suggests that the early onset patients may take a more rapid course in the reduction of glucose metabolism than the late onset patients. PMID:15888536

  2. Differences between early and late-onset Alzheimer's disease.

    PubMed

    Iversen, L L

    1987-01-01

    Alzheimer's disease of early onset versus that of late onset represent different syndromes, with distinct neuropathologies. Patients with early onset disease exhibit a more severe and more widespread loss of neurons from cortical and sub-cortical regions and the neurochemical changes involve not only the cholinergic system, but also neurons containing GABA, somatostatin and norepinephrine. PMID:3431630

  3. Obstetric Outcome in Early and Late Onset Gestational Diabetes Mellitus.

    PubMed

    Easmin, S; Chowdhury, T A; Islam, M R; Beg, A; Jahan, M K; Latif, T; Dhar, S; Alam, M N; Akhter, M

    2015-07-01

    Obstetric outcome in early onset and late onset GDM was compared in a prospective study conducted at the Department of Obstetrics & Gynecology in BIRDEM, Dhaka, Bangladesh. A total 120 pregnant women were recruited purposively for the study in which 60 were early onset GDM and 60 were late onset GDM during study period of January 2008 to December 2009. Patients were followed up in different periods of gestation, during delivery and early postpartum period & findings were compared between two groups. BMI & family history of diabetes were significantly higher in early GDM group (p<0.05). Evidence of increased glycaemia was observed in early GDM group & difference of glycaemic status was statistically significant (p<0.05). Insulin was needed in 85% of early onset GDM and 55% in late onset GDM. There was also significant difference (p<0.05). In this study, 23.3% of early onset GDM group developed pre-eclampsia while in late onset GDM it was 10% and was statistically significant (p<0.05). Regarding intrapartum & postpartum complications - perineal tear, PPH wound infection, puerperal sepsis were more in early onset than late onset GDM group with no significant difference. Regarding foetal outcome, 8.3% early GDM group delivered asphyxiated baby in comparison to 3.3% in late GDM group. Twenty percent (20%) of early onset GDM group had to admit their babies in neonatal unit while in late onset group it was 5%. There was significant difference between two groups (p<0.05). Neonatal hypoglycaemia was also statistically significantly (p<0.05) higher in early GDM group. Neonatal hyper-bilirubinaemia, RDS, perinatal death was more in early onset GDM subjects. Early onset GDM subjects are high risk subgroup & have significant deleterious effect on maternal and perinatal outcome than late GDM groups. PMID:26329938

  4. Early Onset Alzheimer's Disease and Oxidative Stress

    PubMed Central

    Meraz-Ríos, Marco Antonio; Franco-Bocanegra, Diana; Toral Rios, Danira; Campos-Peña, Victoria

    2014-01-01

    Alzheimer's disease (AD) is the most common cause of dementia in elderly adults. It is estimated that 10% of the world's population aged more than 60–65 years could currently be affected by AD, and that in the next 20 years, there could be more than 30 million people affected by this pathology. One of the great challenges in this regard is that AD is not just a scientific problem; it is associated with major psychosocial and ethical dilemmas and has a negative impact on national economies. The neurodegenerative process that occurs in AD involves a specific nervous cell dysfunction, which leads to neuronal death. Mutations in APP, PS1, and PS2 genes are causes for early onset AD. Several animal models have demonstrated that alterations in these proteins are able to induce oxidative damage, which in turn favors the development of AD. This paper provides a review of many, although not all, of the mutations present in patients with familial Alzheimer's disease and the association between some of these mutations with both oxidative damage and the development of the pathology. PMID:24669286

  5. [Early onset scoliosis. What are the options?].

    PubMed

    Farrington, D M; Tatay-Daz, A

    2013-01-01

    The prognosis of children with progressive early onset scoliosis has improved considerably due to recent advances in surgical and non-surgical techniques and the understanding of the importance of preserving the thoracic space. Improvements in existing techniques and development of new methods have considerably improved the management of this condition. Derotational casting can be considered in children with documented progression of a <60 curve without previous surgical treatment. Both single and dual growing rods are effective, but the latter seem to offer better results. Hybrid constructs may be a better option in children who require a low-profile proximal anchor. The vertical expandable prosthetic titanium rib (VEPTR()) appears to be beneficial for patients with congenital scoliosis and fused ribs, and thoracic Insufficiency Syndrome. Children with medical comorbidities who may not tolerate repeated lengthenings should be considered for Shilla or Luque Trolley technique. Growth modulation using shape memory alloy staples or other tethers seem promising for mild curves, although more research is required to define their precise indications. PMID:24071039

  6. Specific Intellectual Deficits in Children with Early Onset Diabetes Mellitus.

    ERIC Educational Resources Information Center

    Rovet, Joanne F.; And Others

    1988-01-01

    Compares 27 children with early onset diabetes (EOD) with 24 children with late onset diabetes (LOD) and 30 sibling controls in performance on tests of intellectual functioning and school achievement. Results revealed that duration of illness, age of onset, and hypoglycemic convulsions significantly predicted spatial ability. (Author/RWB)

  7. The Relationship between Early Disability Onset and Education and Employment

    ERIC Educational Resources Information Center

    Loprest, Pamela; Maag, Elaine

    2003-01-01

    The early onset of disability (at birth through young adulthood) can affect a person's employment outcomes in myriad ways. In addition to the direct effect of disability on employment, early onset of disability likely affects the acquisition of education and job skills (human capital). This reduced "investment" in human capital in turn may reduce

  8. The association of childhood adversities and early onset mental disorders with adult onset chronic physical conditions

    PubMed Central

    Scott, Kate M.; Von Korff, Michael; Angermeyer, Matthias C.; Benjet, Corina; Bruffaerts, Ronny; de Girolamo, Giovanni; Haro, Josep Maria; Lépine, Jean-Pierre; Ormel, Johan; Posada-Villa, José; Tachimori, Hisateru; Kessler, Ronald C.

    2012-01-01

    Context The physical health consequences of childhood psychosocial adversities may be as substantial as the mental health consequences but whether this is the case remains unclear because much prior research has involved unrepresentative samples and a selective focus on particular adversities or physical outcomes. The association between early onset mental disorders and subsequent poor physical health in adulthood has not been investigated. Objective To investigate whether childhood adversities and early onset mental disorders are independently associated with increased risk of a range of adult onset chronic physical conditions in culturally diverse samples spanning the full adult age range. Design Cross-sectional community surveys of adults in ten countries. Setting General population. Participants Adults (>= 18 years; n = 18,303), with diagnostic assessment and determination of age of onset of DSM-IV mental disorders; assessment of childhood familial adversities; and age of diagnosis/onset of chronic physical conditions. Main Outcome Measures Risk (hazard ratios) of adult onset (> age 20) heart disease, asthma, diabetes, arthritis, chronic spinal pain, and chronic headache as a function of specific childhood adversities and early onset (< age 21) DSM-IV depressive and anxiety disorders, with mutual adjustment. Results A history of three or more childhood adversities was independently associated with onset of all six physical conditions (hazard ratios from 1.44–2.19). Controlling for current mental disorder made little difference to these associations. Early onset mental disorders were independently associated with onset of five physical conditions (hazard ratios from 1.43–1.66). Conclusions These results are consistent with the hypothesis that childhood adversities and early onset mental disorders have independent, broad spectrum effects that increase risks of diverse chronic physical conditions in later life. They require confirmation in a prospective design. The long time course of these associations has theoretical and research implications. PMID:21810647

  9. Differences Between Early and Late Onset Adult Depression

    PubMed Central

    Bukh, Jens Drachmann; Bock, Camilla; Vinberg, Maj; Gether, Ulrik; Kessing, Lars Vedel

    2011-01-01

    Background: It is unclear, whether age-of-onset identifies subgroups of depression. Aim: To assess the clinical presentation of depression with onset in the early adult age (18-30 years) as compared to depression with later onset (31-70 years). Method: A total number of 301 patients with first episode depression were systematically recruited. Characteristics including psychiatric co-morbidity, personality disorders and traits, stressful life events prior to onset, family history, and treatment outcome were assessed by structured interviews and compared by chi-square tests for categorical data, t-tests for continuous parametric data and Mann-Whitney U-test for continuous nonparametric data. Logistic and multiple regression analyses were used to adjust the analyses for potentially confounding variables. Results: Patients with early onset of depression were characterised by a higher prevalence of co-morbid personality disorders, higher levels of neuroticism, and a lower prevalence of stressful life events preceding onset compared to patients with later age-of-onset. There were no differences in severity of the depressive episode, treatment outcome or family loading of psychiatric illness. Conclusion: Early adult onset of depression is associated with co-morbid personality deviances, whereas late onset is associated with environmental risk factors. PMID:21866230

  10. Early-onset colorectal cancer: A sporadic or inherited disease?

    PubMed Central

    Stigliano, Vittoria; Sanchez-Mete, Lupe; Martayan, Aline; Anti, Marcello

    2014-01-01

    Colorectal cancer is the third most common cancer diagnosed worldwide. Although epidemiology data show a marked variability around the world, its overall incidence rate shows a slow but steady decrease, mainly in developed countries. Conversely, early-onset colorectal cancer appears to display an opposite trend with an overall prevalence in United States and European Union ranging from 3.0% and 8.6%. Colorectal cancer has a substantial proportion of familial cases. In particular, early age at onset is especially suggestive of hereditary predisposition. The clinicopathological and molecular features of colorectal cancer cases show a marked heterogeneity not only between early- and late-onset cases but also within the early-onset group. Two distinct subtypes of early-onset colorectal cancers can be identified: a sporadic subtype, usually without family history, and an inherited subtype arising in the context of well defined hereditary syndromes. The pathogenesis of the early-onset disease is substantially well characterized in the inherited subtype, which is mainly associated to the Lynch syndrome and occasionally to other rare mendelian diseases, whereas in the sporadic subtype the origin of the disease may be attributed to the presence of various common/rare genetic variants, so far largely unidentified, displaying variable penetrance. These variants are thought to act cumulatively to increase the risk of colorectal cancer, and presumably to also anticipate its onset. Efforts are ongoing in the attempt to unravel the intricate genetic basis of this sporadic early-onset disease. A better knowledge of molecular entities and pathways may impact on family-tailored prevention and clinical management strategies. PMID:25253942

  11. Longitudinal Brain Changes in Early-Onset Psychosis

    PubMed Central

    Arango, Celso; Moreno, Carmen; Martínez, Salvador; Parellada, Mara; Desco, Manuel; Moreno, Dolores; Fraguas, David; Gogtay, Nitin; James, Anthony; Rapoport, Judith

    2008-01-01

    Progressive losses of cortical gray matter volumes and increases in ventricular volumes have been reported in patients with childhood-onset schizophrenia (COS) during adolescence. Longitudinal studies suggest that the rate of cortical loss seen in COS during adolescence plateaus during early adulthood. Patients with first-episode adolescent-onset schizophrenia show less marked progressive changes, although the number of studies in this population is small. Some studies show that, although less exaggerated, progressive changes are also present in nonschizophrenia early-onset psychosis. The greater loss of brain tissue seen in COS, even some years after the first episode, as compared to adolescent- or adult-onset schizophrenia may be due to variables such as sample bias (more severe, treatment refractory sample of childhood-onset patients studied), a process uniquely related to adolescent development in COS, differential brain effects of drug treatment in this population, clinical outcome, or interactions among these variables. Findings from both cross-sectional studies of first-episode patients and longitudinal studies in COS and adolescent onset support the concept of early-onset schizophrenia as a progressive neurodevelopmental disorder with both early and late developmental abnormalities. Future studies should look for correlates at a cellular level and for pathophysiological explanations of volume changes in these populations. The association of risk genes involved in circuitries associated with schizophrenia and their relationship to developmental trajectories is another promising area of future research. PMID:18234701

  12. Early- versus late-onset bipolar II disorder.

    PubMed Central

    Benazzi, F

    2000-01-01

    OBJECTIVE: To compare the clinical features and the outcome between patients with early- and late-onset bipolar II disorder. DESIGN: Case series. SETTING: Outpatient private practice. PATIENTS: One hundred and seventy-nine consecutive outpatients with bipolar II disorder presenting for treatment of a major depressive episode. OUTCOME MEASURES: Duration of illness, severity of depression, recurrences, psychosis, chronicity, atypical features and comorbidity. RESULTS: Patients with early-onset (before 20, 25 or 30 years of age) bipolar II disorder had a significantly longer duration of illness and more recurrences compared with patients with late-onset (after 20, 25 or 30 years of age) bipolar II disorder. All other variables were not significantly different between the 2 groups. CONCLUSIONS: Indicators of worse outcome (severity of depression, psychosis, chronicity, comorbidity) were not significantly different between patients with early- and late-onset bipolar II disorder. PMID:10721685

  13. [Early onset Parkinson's disease. Critical review of the literature].

    PubMed

    de Andrade, L A

    1996-12-01

    Since its original description Parkinson's disease has been considered as a clinical condition which affects older people. Nonetheless, since late in the last century, cases starting in very young age have been described. A great controversy has arisen concerning the real pathology in these cases and, consequently, how should they be named. Early or young onset parkinsonism, early or young onset Parkinson's disease, juvenile parkinsonism, all these terms have been used indistinguishable. There have been few pathological descriptions in early onset parkinsonism. Some show striking differences from the cases of older patients but others are very similar to what has been considered classical Parkinson's disease. Younger starting age usually corresponds to greater possibility of other family members being affected. Dyskinesias and fluctuations due to chronic levodopa treatment are an early and almost invariable complication in the course of young patients. Comments on several aspects based on an extensive literature review are presented. PMID:9201356

  14. Periodontitis as an early presentation of HIV infection.

    PubMed Central

    Tenenbaum, H C; Mock, D; Simor, A E

    1991-01-01

    OBJECTIVE: To determine whether the presence of rapidly progressive periodontitis (RPP) in people at high risk for acquired immunodeficiency syndrome (AIDS) may be the first symptom of previously unrecognized human immunodeficiency virus (HIV) infection. DESIGN: Case series. SETTING: Dental clinic. PATIENTS: Twenty patients who presented or were referred to the dental clinic over 6 months for the treatment of unexplained RPP and were at high risk for AIDS. OUTCOME MEASURES: Diagnosis of HIV infection: identification of candidal organisms in cytologic smears, determination of complete and differential blood counts and of ratio between T4 (helper) and T8 (suppressor) lymphocytes, and performance of HIV antibody assays. MAIN RESULTS: All of the patients were men, although sex was not an inclusion criterion. Sixteen (80%) of the 20 patients were found to have HIV infection. Four had been aware that they were HIV positive: two admitted it only when their T4:T8 ratio was known and the other two when the T4:T8 test was explained or requested. Fifteen of the patients were homosexual, three came from AIDS-endemic areas, and two had hemophilia. The RPP was responsible for alveolar bone loss in all of the patients. One patient lost bone in one site because of localized osteomyelitis. Only five patients had concurrent candidal overgrowth, and three had Kaposi's sarcoma. The mean T4:T8 ratio was 0.57 (standard deviation 0.52). CONCLUSIONS: These findings suggest that periodontal disease may be one of the first clinical presentations of previously undiagnosed HIV infection. Thus, patients at high risk for AIDS who present with aggressive periodontal disease should be investigated for possible HIV infection. However, further, prospective studies are required to confirm the contention that RPP is one of the first signs of HIV infection or AIDS. Images Fig. 1 Fig. 2 Fig. 3 PMID:2025822

  15. Early onset esophageal adenocarcinoma: a distinct molecular entity?

    PubMed Central

    van Nistelrooij, Anna M.J.; van Marion, Ronald; Biermann, Katharina; Spaander, Manon C.W.; van Lanschot, J. Jan B.; Wijnhoven, Bas P.L.; Dinjens, Winand N.M.

    2016-01-01

    Esophageal adenocarcinoma (EAC) is typically diagnosed in elderly with a median age of 68 years. The incidence of EAC has been rising over the last decades, also among young adults. The aim of the study was to investigate whether early onset EAC is a distinct molecular entity. To identify early onset EACs, the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA) was searched. Twenty-eight tumors of patients aged ≤40 years were selected and matched with 27 tumors of patients aged ≥68 years. DNA was isolated from surgically resected specimen and sequenced on the Ion Torrent Personal Genome Machine with the Ion AmpliSeq Cancer Panel. No differences in mutational load between early onset and conventional EACs were observed (P=0.196). The most frequently mutated genes were TP53 (73%) and P16 (16%). Additional mutations in early onset EACs occurred exclusively in: APC, CDH1, CTNNB1, FGFR2, and STK11. In the conventional EACs additional mutations were exclusively identified in: ABL1, FBXW7, GNA11, GNAS, KRAS, MET, SMAD4, and VHL. Additional mutations besides TP53 and P16 seem to occur in different genes related to cell fate pathways for early onset EACs, while the additional mutations in conventional EACs are related to survival pathways. PMID:26973859

  16. Markers of neurodevelopmental impairments in early-onset psychosis

    PubMed Central

    Petruzzelli, Maria Giuseppina; Margari, Lucia; Craig, Francesco; Campa, Maria Gloria; Martinelli, Domenico; Pastore, Adriana; Simone, Marta; Margari, Francesco

    2015-01-01

    Background The aim of this study was to assess the association between the clinical and neurobiological markers of neurodevelopmental impairments and early-onset schizophrenia spectrum psychosis. Methods A sample of 36 patients with early-onset schizophrenia spectrum psychosis was compared to a control sample of 36 patients with migraine. We assessed early childhood neurodevelopmental milestones using a modified version of the General Developmental Scale, general intellectual ability using the Wechsler Intelligence Scale for Children–Revised or Leiter International Performance Scale–Revised for patients with speech and language abnormalities, and neurological soft signs with specific regard to subtle motor impairment. Results Subjects with early-onset psychosis had a higher rate of impaired social development (P=0.001), learning difficulties (P=0.04), enuresis (P=0.0008), a lower intelligence quotient (P<0.001), and subtle motor impairments (P=0.005) than control subjects. Conclusion We suggest that neurodevelopment in early-onset psychosis is characterized by a global impairment of functional and adaptive skills that manifests from early childhood, rather than a delay or limitation in language and motor development. The current evidence is based on a small sample and should be investigated in larger samples in future research. PMID:26229474

  17. Early-onset schizophrenia: a 15-year follow-up.

    PubMed

    Rpcke, Bernd; Eggers, Christian

    2005-09-01

    The study describes the psychopathological and social outcome of patients treated for schizophrenia in adolescence (mean age at onset 16.0 years/SD 1.52) after a mean follow-up period of 15.4 years (10.2-21.2 years). Out of 55 patients consecutively admitted to hospital, 47 (85 %) could be traced and 39 (71 %) could be re-examined. At follow-up, 33/39 patients (85 %) had had at least one readmission. Full remission of global psychopathological symptoms [Clinical Global Impression (CGI) onset (CGI: Beta=0.36, GAS: Beta=-0.37). A poor outcome was seen in 22 out of 25 cases with insidious onset. All predictors together explained 58% of the variance in the Positive and Negative Syndrome (PANSS) negative symptom ratings at follow-up. Gender, duration of first inpatient treatment and duration of untreated psychosis were of no predictive value for outcome. The nature of the diagnosis in the first episode strongly predicted the diagnosis given for the whole course after 15 years. In 26/37 cases (70 %), diagnosis at onset and overall diagnoses were the same. Our finding of an incidence of 61% insidious onset is similar to that in adult onset schizophrenia (AOS), but different to very early onset schizophrenia (VEOS), which shows a higher rate of insidious onset, cognitive impairment and poor outcome. Therefore, it seems that VEOS is a special group compared with early onset schizophrenia (EOS) and AOS. PMID:16220219

  18. Early and Late Onset Sepsis in Late Preterm Infants

    PubMed Central

    Cohen-Wolkowiez, Michael; Moran, Cassandra; Benjamin, Daniel K.; Cotten, C. Michael; Clark, Reese H.; Benjamin, Daniel K.; Smith, P. Brian

    2009-01-01

    Background Preterm birth is increasing worldwide, and late preterm births, which comprise more than 70% of all preterm births, account for much of the increase. Early and late onset sepsis results in significant mortality in extremely preterm infants, but little is known about sepsis outcomes in late preterm infants. Methods This is an observational cohort study of infants < 121 days of age (119,130 infants less than or equal to 3 days of life and 106,142 infants between 4 and 120 days of life) with estimated gestational age at birth between 34 and 36 weeks, admitted to 248 neonatal intensive care units in the United States between 1996 and 2007. Results During the study period, the cumulative incidence of early and late onset sepsis was 4.42 and 6.30 episodes per 1000 admissions, respectively. Gram-positive organisms caused the majority of early and late onset sepsis episodes. Infants with early onset sepsis caused by Gram-negative rods and infants with late onset sepsis were more likely to die than their peers with sterile blood cultures (OR 4.39, 95% CI 1.71–11.23, P=0.002; and OR 3.37, 95% CI 2.35–4.84, P<0.001, respectively). Conclusion Late preterm infants demonstrate specific infection rates, pathogen distribution, and mortality associated with early and late onset sepsis. The results of this study are generalizable to late preterm infants admitted to the special care nursery or neonatal intensive care unit. PMID:19953725

  19. Early onset marfan syndrome: Atypical clinical presentation of two cases

    PubMed Central

    Ozyurt, A; Baykan, A; Argun, M; Pamukcu, O; Halis, H; Korkut, S; Yuksel, Z; Gunes, T; Narin, N

    2015-01-01

    Early onset Marfan Syndrome (eoMFS) is a rare, severe form of Marfan Syndrome (MFS). The disease has a poor prognosis and most patients present with resistance to heart failure treatment during the newborn period. This report presents two cases of eoMFS with similar clinical features diagnosed in the newborn period and who died at an early age due to the complications related to the involvement of the cardiovascular system. PMID:26929908

  20. Neurocognition in Early-Onset Schizophrenia and Schizoaffective Disorders

    ERIC Educational Resources Information Center

    Hooper, Stephen R.; Giuliano, Anthony J.; Youngstrom, Eric A.; Breiger, David; Sikich, Linmarie; Frazier, Jean A.; Findling, Robert L.; McClellan, Jon; Hamer, Robert M.; Vitiello, Benedetto; Lieberman, Jeffrey A.

    2010-01-01

    Objective: We examined the neuropsychological functioning of youth enrolled in the NIMH funded trial, Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS). We compared the baseline neuropsychological functioning of youth with schizophrenia (SZ, n = 79) to those with schizoaffective disorder (SA, n = 40), and examined the relationship

  1. Early-Onset Psychosis in Youth with Intellectual Disability

    ERIC Educational Resources Information Center

    Friedlander, R. I.; Donnelly, T.

    2004-01-01

    Accurate diagnosis of psychotic disorders may be very difficult in youth with intellectual disabilities. The authors reviewed the assessment, treatment and follow-up of 21 youths with ID referred because of early onset of psychotic symptoms. Just over one half of the patients had a diagnosis of schizophrenia or schizo-affective disorder. One third

  2. Early-Onset Bipolar Spectrum Disorders: Diagnostic Issues

    ERIC Educational Resources Information Center

    Danner, Stephanie; Fristad, Mary A.; Arnold, L. Eugene; Youngstrom, Eric A.; Birmaher, Boris; Horwitz, Sarah M.; Demeter, Christine; Findling, Robert L.; Kowatch, Robert A.

    2009-01-01

    Since the mid 1990s, early-onset bipolar spectrum disorders (BPSDs) have received increased attention in both the popular press and scholarly press. Rates of diagnosis of BPSD in children and adolescents have increased in inpatient, outpatient, and primary care settings. BPSDs remain difficult to diagnose, particularly in youth. The current

  3. Early Onset Bipolar Spectrum Disorder: Psychopharmacological, Psychological, and Educational Management

    ERIC Educational Resources Information Center

    McIntosh, David E.; Trotter, Jeffrey S.

    2006-01-01

    Although published research continues to advocate medication as the first line of treatment for early onset bipolar spectrum disorder (EOBSD; N. Lofthouse & M.A. Fristad, 2004), preliminary research demonstrating the utility of cognitive, cognitive-behavioral, and psychoeducational therapies is promising. It appears as if future treatment of EOBSD

  4. Early-Onset Bipolar Spectrum Disorders: Diagnostic Issues

    ERIC Educational Resources Information Center

    Danner, Stephanie; Fristad, Mary A.; Arnold, L. Eugene; Youngstrom, Eric A.; Birmaher, Boris; Horwitz, Sarah M.; Demeter, Christine; Findling, Robert L.; Kowatch, Robert A.

    2009-01-01

    Since the mid 1990s, early-onset bipolar spectrum disorders (BPSDs) have received increased attention in both the popular press and scholarly press. Rates of diagnosis of BPSD in children and adolescents have increased in inpatient, outpatient, and primary care settings. BPSDs remain difficult to diagnose, particularly in youth. The current…

  5. Normal gastric antral myoelectrical activity in early onset anorexia nervosa.

    PubMed Central

    Ravelli, A M; Helps, B A; Devane, S P; Lask, B D; Milla, P J

    1993-01-01

    Anorexia, epigastric discomfort, nausea, and vomiting may result from disordered gastric motility and emptying. These features have been found in many adults with anorexia nervosa, but have never been investigated in early onset anorexia nervosa. In 14 patients with early onset anorexia nervosa (eight of whom had upper gastrointestinal tract symptoms), six children with other eating disorders, four children with non-ulcer dyspepsia, and 10 controls matched for age and sex, the non-invasive technique of surface electrogastrography was used to measure fasting and postprandial gastric antral electrical control activity, which underlies antral motility. The electrical signal was recorded by four bipolar silver/silver chloride electrodes attached to the upper abdomen, amplified and low pass filtered at 0.33 Hz before being displayed on a polygraph, digitised at 1 Hz, and stored on the hard disk of a personal computer for later offline analysis. Patients with non-ulcer dyspepsia had gastric antral dysrhythmias. No significant difference was found in the mean (SD) dominant frequency of the antral electrical control activity between patients with early onset anorexia nervosa (2.86 (0.35) cycles/minute (cpm)), patients with other eating disorders (3.14 (0.65) cpm), and controls (3.00 (0.46) cpm). The amplitude of electrical control activity increased postprandially in all but one subject and the fasting/postprandial amplitude ratio did not significantly differ between patients with early onset anorexia nervosa and controls, though patients with longer established disease had a smaller increase in amplitude. Gastric antral electrical dysrhythmias are not a feature of early onset anorexia nervosa and therefore do not induce or perpetuate food refusal in this disorder. PMID:8215543

  6. Acute, early thermal experience alters weaning onset in rats.

    PubMed

    Gerrish, C J; Onischak, C M; Alberts, J R

    1998-06-15

    We hypothesized that first ingestion of solid food (weaning onset) would be accelerated in young rats with advanced thermoregulatory development. To manipulate the pups' thermoregulatory development, we exposed rat pups, but not their dams, to a Cold (10 degrees C), Moderate (21 degrees C), or Warm (31 degrees C) ambience for 2 h/day from postnatal Day 2-14, expecting that early exposure to cooler temperatures would accelerate development of thermoregulatory capabilities and thus accelerate nest egression as well as onset of feeding. Contrary to expectation, cold exposure was associated with a profile of developmental delays in both growth and maturation. Pups in the Cold condition began feeding later than pups with Moderate or Warm thermal experiences. We then evaluated thermoregulatory status (mechanisms for heat production and temperature conservation) on Day 15-16 (just prior to weaning onset). Thermogenesis, measured by oxygen consumption, was unaltered by the thermal manipulation. In contrast, pelage development (insulation) was altered. Pups in the Warm condition had greater fur density and an increased frequency of longer hairs relative to pups in the Cold condition. Although the developmental response to early cold exposure was in the direction opposite to our predictions, the hypothesized relation of thermoregulatory development to weaning onset was supported: Thermoregulatory status correlated with weaning onset. PMID:9761220

  7. Early-onset dementia: frequency and causes compared to late-onset dementia.

    TOXLINE Toxicology Bibliographic Information

    McMurtray A; Clark DG; Christine D; Mendez MF

    2006-01-01

    BACKGROUND: Research on the epidemiology of dementia has focused on the elderly. Few investigations have studied differences in etiologic frequencies between early-onset dementia (EOD), with onset at an age of less than 65 years old, and the more common late-onset disorder.OBJECTIVES: To determine relative frequencies and characteristics of EOD versus late-onset dementia (LOD; age of onset > or =65 years) diagnosed in a large memory disorders program over a 4-year period.METHODS: We reviewed medical records, including an extensive neurobehavioral and neurological evaluation, of all patients seen at a large Veteran's Affairs Medical Center Memory Disorders clinic between 2001 and 2004 and assessed demographic variables, final diagnoses, presence of dementia, and differential diagnosis of dementing illnesses.RESULTS: Among 1,683 patients presenting for evaluation of an acquired decline in memory or cognition, 948 (56%) met established clinical criteria for a dementing illness. About 30% (n = 278) of these had an age of onset of <65 years, compared to 670 with LOD. Patients were predominantly male (98%). Compared to the late-onset group, the EOD patients were less severely impaired on presentation, but they did not differ in gender distribution or educational background. The EOD group had significantly more dementia attributed to traumatic brain injury, alcohol, human immunodeficiency virus (HIV), and frontotemporal lobar degeneration compared to the LOD patients. In contrast, the LOD group had significantly more Alzheimer's disease compared to the EOD group.CONCLUSIONS: This study, conducted at a Veterans Affairs Hospital, is the largest series to date on EOD, and found a previously unexpectedly large number of patients below the age of 65 with cognitive deficits and impaired functioning consequent to head trauma, alcohol abuse, and HIV. These findings highlight the differential distribution and importance of preventable causes of dementia in the young.

  8. Neonatal Septicemia in Nepal: Early-Onset versus Late-Onset

    PubMed Central

    Ansari, Shamshul; Nepal, Hari Prasad; Gautam, Rajendra; Shrestha, Sony; Neopane, Puja; Chapagain, Moti Lal

    2015-01-01

    Introduction. Neonatal septicemia is defined as infection in the first 28 days of life. Early-onset neonatal septicemia and late-onset neonatal septicemia are defined as illnesses appearing from birth to three days and from four to twenty-eight days postnatally, respectively. Methods. In this cross-sectional study, blood samples from the suspected infants were collected and processed in the bacteriology laboratory. The growth was identified by standard microbiological protocol and the antibiotic sensitivity testing was carried out by modified Kirby-Bauer disk diffusion method. Results. Among total suspected cases, the septicemia was confirmed in 116 (12.6%) neonates. Early-onset septicemia (EOS) was observed in 82 infants and late-onset septicemia (LOS) in 34 infants. Coagulase-negative staphylococcus (CoNS) (46.6%) was the predominant Gram-positive organism isolated from EOS as well as from LOS cases followed by Staphylococcus aureus (14.6%). Acinetobacter species (9.5%) was the predominant Gram-negative organism followed by Klebsiella pneumoniae (7.7%). Conclusions. The result of our study reveals that the CoNS, Staphylococcus aureus, Acinetobacter spp., and Klebsiella pneumoniae are the most common etiological agents of neonatal septicemia. In particular, since rate of CoNS causing sepsis is alarming, prompting concern to curb the excess burden of CoNS infection is necessary. PMID:26649057

  9. Association between Periodontitis and Alzheimer's Disease

    PubMed Central

    Abbayya, Keshava; Puthanakar, Nagraj Y; Naduwinmani, Sanjay; Chidambar, Y S

    2015-01-01

    Alzheimer's disease (AD) is a neurodegenerative disease which significantly increases with age. Its onset can be either early or late. AD is characterized by the salient inflammatory features, microglial activation, and increased levels of proinflammatory cytokines which contribute to the inflammatory status of the central nervous system (CNS). Whereas, periodontitis is a common oral infection associated with the gram negative anaerobic bacteria. Periodontitis can be marked as a low-grade systemic disease by release of proinflammatory cytokines into systemic circulation and elevation of C-reactive protein (CRP). Inflammation is known to play a pivotal role in both the disease process serving as a connecting link between periodontitis and AD. The present review throws a light on possible enigmatic link between AD and periodontitis. This review is designed by collecting data from PubMed database using key words like Alzheimer's disease, inflammation, periodontitis, and proinflammatory cytokines. PMID:26199919

  10. Association between Periodontitis and Alzheimer's Disease.

    PubMed

    Abbayya, Keshava; Puthanakar, Nagraj Y; Naduwinmani, Sanjay; Chidambar, Y S

    2015-06-01

    Alzheimer's disease (AD) is a neurodegenerative disease which significantly increases with age. Its onset can be either early or late. AD is characterized by the salient inflammatory features, microglial activation, and increased levels of proinflammatory cytokines which contribute to the inflammatory status of the central nervous system (CNS). Whereas, periodontitis is a common oral infection associated with the gram negative anaerobic bacteria. Periodontitis can be marked as a "low-grade systemic disease" by release of proinflammatory cytokines into systemic circulation and elevation of C-reactive protein (CRP). Inflammation is known to play a pivotal role in both the disease process serving as a connecting link between periodontitis and AD. The present review throws a light on possible enigmatic link between AD and periodontitis. This review is designed by collecting data from PubMed database using key words like "Alzheimer's disease", "inflammation", "periodontitis", and "proinflammatory cytokines". PMID:26199919

  11. Atypical antipsychotics in the treatment of early-onset schizophrenia

    PubMed Central

    Hrdlicka, Michal; Dudova, Iva

    2015-01-01

    Atypical antipsychotics (AAPs) have been successfully used in early-onset schizophrenia (EOS). This review summarizes the randomized, double-blind, controlled studies of AAPs in EOS, including clozapine, risperidone, olanzapine, aripiprazole, paliperidone, quetiapine, and ziprasidone. No significant differences in efficacy between AAPs were found, with the exception of clozapine and ziprasidone. Clozapine demonstrated superior efficacy in treatment-resistant patients with EOS, whereas ziprasidone failed to demonstrate efficacy in the treatment of EOS. Our review also focuses on the onset of action and weight gain associated with AAPs. The data on onset of action of AAPs in pediatric psychiatry are scanty and inconsistent. Olanzapine appears to cause the most significant weight gain in patients with EOS, while ziprasidone and aripiprazole seem to cause the least. PMID:25897226

  12. Early-onset dementias: diagnostic and etiological considerations

    PubMed Central

    2013-01-01

    This paper summarizes the body of literature about early-onset dementia (EOD) that led to recommendations from the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. A broader differential diagnosis is required for EOD compared with late-onset dementia. Delays in diagnosis are common, and the social impact of EOD requires special care teams. The etiologies underlying EOD syndromes should take into account family history and comorbid diseases, such as cerebrovascular risk factors, that may influence the clinical presentation and age at onset. For example, although many EODs are more likely to have Mendelian genetic and/or metabolic causes, the presence of comorbidities may drive the individual at risk for late-onset dementia to manifest the symptoms at an earlier age, which contributes further to the observed heterogeneity and may confound diagnostic investigation. A personalized medicine approach to diagnosis should therefore be considered depending on the age at onset, clinical presentation, and comorbidities. Genetic counseling and testing as well as specialized biochemical screening are often required, especially in those under the age of 40 and in those with a family history of autosomal dominant or recessive disease. Novel treatments in the drug development pipeline for EOD, such as genetic forms of Alzheimer's disease, should target the specific pathogenic cascade implicated by the mutation or biochemical defect. PMID:24565469

  13. Genetic Determinism of Primary Early-Onset Osteoarthritis.

    PubMed

    Aury-Landas, Juliette; Marcelli, Christian; Leclercq, Sylvain; Boumédiene, Karim; Baugé, Catherine

    2016-01-01

    Osteoarthritis (OA) is the most common joint disease worldwide. A minority of cases correspond to familial presentation characterized by early-onset forms which are genetically heterogeneous. This review brings a new point of view on the molecular basis of OA by focusing on gene mutations causing early-onset OA (EO-OA). Recently, thanks to whole-exome sequencing, a gain-of-function mutation in the TNFRSF11B gene was identified in two distant family members with EO-OA, opening new therapeutic perspectives for OA. Indeed, unraveling the molecular basis of rare Mendelian OA forms will improve our understanding of molecular processes involved in OA pathogenesis and will contribute to better patient diagnosis, management, and therapy. PMID:26691295

  14. Serotonin in early onset, male alcoholics with violent behaviour.

    PubMed

    Virkkunen, M; Linnoila, M

    1990-01-01

    Several lines of evidence suggest that abnormal brain serotonin metabolism may occur in early onset, type 2 alcoholism in men. Low cerebrospinal fluid 5-hydroxy-indoleacetic acid concentration has been found to be associated with a history of paternal alcoholism, and abnormal oral glucose tolerance tests (tendency to low blood glucose nadir) in subjects who are prone to exhibit impulsive, aggressive behaviour under the influence of alcohol. Moreover, a low ratio of the concentrations of tryptophan and other large neutral amino acids in plasma seems to correlate with early onset alcohol abuse and violent tendencies. More knowledge is required about neurochemical changes in homogenous subgroups of alcoholics such as the putative type 2 so as to understand which of the relationships are causative and to provide treatment strategies for alcoholism and its complications. PMID:2291840

  15. Early microbial succession in re-developing dental biofilms in periodontal health and disease

    PubMed Central

    TELES, F.R.; TELES, R.P.; UZEL, N.G.; SONG, X.Q.; TORRESYAP, G.; SOCRANSKY, S.S.; HAFFAJEE, A.D.

    2011-01-01

    Objective To determine the order of bacterial species succession in re-developing supra and subgingival biofilms. Methods Supra and subgingival plaque samples were taken separately from 28 teeth in 38 healthy and 17 periodontitis subjects immediately after professional cleaning. Samples were taken again from 7 teeth in randomly selected quadrants after 1, 2, 4 and 7 days of no oral hygiene and analyzed using checkerboard DNA-DNA hybridization. % DNA probe counts were averaged within subjects at each time point. Ecological succession was determined using a modified moving window analysis. Results Succession in supragingival biofilms from periodontitis and health was similar. At 1 day, Streptococcus mitis and Neisseria mucosa showed increased proportions, followed by Capnocytophaga gingivalis, Eikenella corrodens, Veillonella parvula and Streptococcus oralis at 14 days. At 47 days, Campylobacter rectus, Campylobacter showae, Prevotella melaninogenica and Prevotella nigrescens became elevated. Subgingival plaque redevelopment was slower and very different from supragingival. Increased proportions were first observed for S. mitis, followed by V. parvula and C. gingivalis and, at 7 days by Capnocytophaga sputigena and P. nigrescens. No significant increase in proportions of periodontal pathogens was observed in any of the clinical groups or locations. Conclusions There is a defined order in bacterial species succession in early supra and subgingival biofilm re-development after professional cleaning. PMID:21895662

  16. Susceptibility genetic variants associated with early-onset colorectal cancer.

    PubMed

    Girldez, Mara Dolores; Lpez-Driga, Adriana; Bujanda, Luis; Abul, Anna; Bessa, Xavier; Fernndez-Rozadilla, Ceres; Muoz, Jenifer; Cuatrecasas, Miriam; Jover, Rodrigo; Xicola, Rosa M; Llor, Xavier; Piqu, Josep M; Carracedo, Angel; Ruiz-Ponte, Clara; Cosme, Angel; Enrquez-Navascus, Jos Mara; Moreno, Victor; Andreu, Montserrat; Castells, Antoni; Balaguer, Francesc; Castellv-Bel, Sergi

    2012-03-01

    Colorectal cancer (CRC) is the second most common cancer in Western countries. Hereditary forms only correspond to 5% of CRC burden. Recently, genome-wide association studies have identified common low-penetrant CRC genetic susceptibility loci. Early-onset CRC (CRC<50 years old) is especially suggestive of hereditary predisposition although 85-90% of heritability still remains unidentified. CRC<50 patients (n = 191) were compared with a late-onset CRC group (CRC>65 years old) (n = 1264). CRC susceptibility variants at 8q23.3 (rs16892766), 8q24.21 (rs6983267), 10p14 (rs10795668), 11q23.1 (rs3802842), 15q13.3 (rs4779584), 18q21 (rs4939827), 14q22.2 (rs4444235), 16q22.1 (rs9929218), 19q13.1 (rs10411210) and 20p12.3 (rs961253) were genotyped in all DNA samples. A genotype-phenotype correlation with clinical and pathological characteristics in both groups was performed. Risk allele carriers for rs3802842 [Odds ratio (OR) = 1.5, 95% confidence interval (CI) 1.1-2.05, P = 0.0096, dominant model) and rs4779584 (OR = 1.39, 95% CI 1.02-1.9, P = 0.0396, dominant model) were more frequent in the CRC<50 group, whereas homozygotes for rs10795668 risk allele were also more frequent in the early-onset CRC (P = 0.02, codominant model). Regarding early-onset cases, 14q22 (rs4444235), 11q23 (rs3802842) and 20p12 (rs961253) variants were more associated with family history of CRC or tumors of the Lynch syndrome spectrum excluding CRC. In our entire cohort, sum of risk alleles was significantly higher in patients with a CRC family history (OR = 1.40, 95% CI 1.06-1.85, P = 0.01). In conclusion, variants at 10p14 (rs10795668), 11q23.1 (rs3802842) and 15q13.3 (rs4779584) may have a predominant role in predisposition to early-onset CRC. Association of CRC susceptibility variants with some patient's familiar and personal features could be relevant for screening and surveillance strategies in this high-risk group and it should be explored in further studies. PMID:22235025

  17. Childhood Risk Factors for Early-Onset Drinking*

    PubMed Central

    Donovan, John E.; Molina, Brooke S. G.

    2011-01-01

    Objective: There is relatively little research on the childhood antecedent predictors of early-onset alcohol use. This study examined an array of psychosocial variables assessed at age 10 and reflecting Problem Behavior Theory as potential antecedent risk factors for the initiation of alcohol use at age 14 or younger. Method: A sample of 452 children (238 girls) ages 8 or 10 and their families was drawn from Allegheny County, PA, using targeted-age directory sampling and random-digit dialing procedures. Children and parents were interviewed using computer-assisted interviews. Logistic regression analyses were used to examine the age-10 univariate and multivariate predictors of the initiation of alcohol use by age 14 or younger. Results: Twenty-five percent of the sample reported having more than a sip or a taste of alcohol in their life by age 14. Sex, race, and age cohort did not relate to early drinking status. Children with two parents were less likely to initiate drinking early. Early initiation of drinking related significantly to an array of antecedent risk factors (personality, social environment, and behavioral) assessed at age 10 that reflect psychosocial proneness for problem behavior. In the multivariate model, the variables most predictive of early-onset drinking were having a single parent, sipping or tasting alcohol by age 10, having parents who also started drinking at an early age, and parental drinking frequency. Conclusions: Initiation of alcohol use by age 14 reflects childhood psychosocial proneness to engage in problem behavior as measured by Problem Behavior Theory and having a family environment conducive to alcohol use. PMID:21906502

  18. Early Onset of Selective Serotonin Reuptake Inhibitor Antidepressant Action

    PubMed Central

    Taylor, Matthew J.; Freemantle, Nick; Geddes, John R.; Bhagwagar, Zubin

    2008-01-01

    Context: Selective serotonin reuptake inhibitors (SSRIs) are often described as having a delayed onset of effect in the treatment of depression. However, some trials have reported clinical improvement as early as the first week of treatment. Objective: To test the alternative hypotheses of delayed vs early onset of antidepressant action with SSRIs in patients with unipolar depression. Data Sources: Trials identified by searching CENTRAL, The Cochrane Collaboration database of controlled trials (2005), and the reference lists of identified trials and other systematic reviews. Study Selection: Randomized controlled trials of SSRIs vs placebo for the treatment of unipolar depression in adults that reported outcomes for at least 2 time points in the first 4 weeks of treatment (50 trials from >500 citations identified). Trials were excluded if limited to participants older than 65 years or specific comorbidities. Data Extraction: Data were extracted on trial design, participant characteristics, and outcomes by a single reviewer. Data Synthesis: Pooled estimates of treatment effect on depressive symptom rating scales were calculated for weeks 1 through 6 of treatment. In the primary analysis, the pattern of response seen was tested against alternative models of onset of response. The primary analysis incorporated data from 28 randomized controlled trials (n=5872). A model of early treatment response best fit the experimental data. Treatment with SSRIs rather than placebo was associated with clinical improvement by the end of the first week of use. A secondary analysis indicated an increased chance of achieving a 50% reduction in Hamilton Depression Rating Scale scores by 1 week (relative risk, 1.64; 95% confidence interval, 1.2-2.25) with SSRI treatment compared with placebo. Conclusions: Treatment with SSRIs is associated with symptomatic improvement in depression by the end of the first week of use, and the improvement continues at a decreasing rate for at least 6 weeks. PMID:17088502

  19. Late-onset systemic lupus erythematosus in Northwestern Spain: differences with early-onset systemic lupus erythematosus and literature review.

    PubMed

    Alonso, M D; Martinez-Vazquez, F; de Teran, T Diaz; Miranda-Filloy, J A; Dierssen, T; Blanco, R; Gonzalez-Juanatey, C; Llorca, J; Gonzalez-Gay, M A

    2012-09-01

    To further investigate into the epidaemiology of systemic lupus erythematosus (SLE) in Southern Europe, we have assessed the incidence, clinical spectrum and survival of patients diagnosed with late-onset SLE (age???50 years) according to the 1982 American College of Rheumatology (ACR) classification criteria at the single hospital for a well-defined population of Lugo, Northwestern (NW) Spain. Between January 1987 and December 2006, 51 (39.3%) of the 150 patients diagnosed as having SLE fulfilled definitions for late-onset SLE. The predominance of women among late-onset SLE (4:1) was reduced when compared with that observed in early-onset SLE (7:1). However, the incidence of late-onset SLE was significantly higher in women (4.2 [95% confidence interval (CI): 3.1-5.6] per 100,000 population) than in men (1.3 [95% CI: 0.6-2.2] per 100,000 population) (p?early-onset SLE, the most frequent clinical manifestation in patients with late-onset SLE was arthritis (71.2%). Renal disease was less common in late-onset SLE (13.5%) than in early-onset SLE (26.4%); p?=?0.07). In contrast, secondary Sjgren syndrome was more commonly found in the older age-group (27.1% versus 12.1%; p?=?0.03). A non-significantly increased incidence of serositis was also observed in late-onset SLE patients (33.9% versus 22.0%; p?=?0.13). Hypocomplementaemia (72.9% versus 91.2%) and positive results for anti-DNA and anti-Sm (49.2% and 6.8% versus 68.1% and 23.1, respectively) were significantly less common in late-onset SLE patients than in early-onset SLE. The probability of survival was reduced in late-onset SLE (p?onset SLE group and 96.3% and 91.0% in patients with early-onset SLE, respectively. In conclusion, our results confirm that in NW Spain SLE is not uncommon in individuals 50 years and older. In keeping with earlier studies, late-onset SLE patients from NW Spain have some clinical and laboratory differences with respect to those individuals with early-onset SLE. Our data support the claim of a reduced probability of survival in the older age-group of SLE patients. PMID:22652632

  20. Early onset neonatal septicaemia in a level II nursery.

    PubMed

    Malik, A S; Pennie, R A

    1994-03-01

    A prospective study of 486 high risk neonates admitted to a level II nursery in a relatively poor and rural area of Malaysia was carried out to determine the incidence, the spectrum of micro-organisms and predisposing factors in relation to early onset septicaemia. The incidence of proven or probable septicaemia was 57.61 per 1000 high risk newborns over 1.5 kg. The case fatality was 10.71 per cent. Coagulase negative staphylococci, Streptococcus Group B and Klebsiella species were the most commonly isolated organisms. Meconium staining of liquor was the most common risk factor for admission to the nursery, and prematurity was the most significant risk factor for early neonatal infection (P < 0.005) followed by small for gestational age (P < 0.04). Although the incidence of septicaemia was quite high in the level II nursery, the mortality rate was comparable to established figures. PMID:8057985

  1. Early-Onset Bipolar Spectrum Disorders: Diagnostic Issues

    PubMed Central

    Danner, Stephanie; Arnold, L. Eugene; Youngstrom, Eric A.; Birmaher, Boris; Horwitz, Sarah M.; Demeter, Christine; Findling, Robert L.; Kowatch, Robert A.

    2013-01-01

    Since the mid 1990s, early-onset bipolar spectrum disorders (BPSDs) have received increased attention in both the popular press and scholarly press. Rates of diagnosis of BPSD in children and adolescents have increased in inpatient, outpatient, and primary care settings. BPSDs remain difficult to diagnose, particularly in youth. The current diagnostic system makes few modifications to accommodate children and adolescents. Researchers in this area have developed specific BPSD definitions that affect the generalizability of their findings to all youth with BPSD. Despite knowledge gains from the research, BPSDs are still difficult to diagnose because clinicians must: (1) consider the impact of the child’s developmental level on symptom presentation (e.g., normative behavior prevalence, environmental limitations on youth behavior, pubertal status, irritability, symptom duration); (2) weigh associated impairment and course of illness (e.g., neurocognitive functioning, failing to meet full DSM criteria, future impairment); and (3) make decisions about appropriate assessment (differentiating BPSD from medical illnesses, medications, drug use, or other psychiatric diagnoses that might better account for symptoms; comorbid disorders; informant characteristics and assessment measures to use). Research findings concerning these challenges and relevant recommendations are offered. Areas for further research to guide clinicians’ assessment of children with early-onset BPSD are highlighted. PMID:19466543

  2. The External Limiting Membrane in Early-Onset Stargardt Disease

    PubMed Central

    Lee, Winston; Nupuu, Kalev; Oll, Maris; Duncker, Tobias; Burke, Tomas; Zernant, Jana; Bearelly, Srilaxmi; Tsang, Stephen H.; Sparrow, Janet R.; Allikmets, Rando

    2014-01-01

    Purpose. To describe pathologic changes of the external limiting membrane (ELM) in young patients with early-onset Stargardt (STGD1) disease. Methods. Twenty-six STGD1 patients aged younger than 20 years with confirmed disease-causing adenosine triphosphatebinding cassette, subfamily A, member 4 (ABCA4) alleles and 30 age-matched unaffected individuals were studied. Spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (AF), and color fundus photography (CFP) images, as well as full-field electroretinograms were obtained and analyzed for one to four visits in each patient. Results. The ELM in all patients exhibited a distinct thickening that was not observed in unaffected individuals. In addition, accumulations of reflective deposits were noted in the outer nuclear layer in every patient. Four patients exhibited a concave protuberance or bulging of a thickened and hyperreflective ELM band within the fovea containing preserved photoreceptors. Longitudinal SD-OCT data in several patients revealed the persistence of this ELM abnormality over a period of time (14 years). Furthermore, the edges of the inner segment ellipsoid band appeared to recede earlier than the ELM band in active lesions. Conclusions. Structural changes seen in the ELM of this cohort may reflect a gliotic response to cellular stress at the photoreceptor level in early-onset STGD1. PMID:25139735

  3. Early onset cardiomyopathy in females with Danon disease.

    PubMed

    Hedberg Oldfors, Carola; Mth, Gyngyvr; Thomson, Kate; Tulinius, Mar; Karason, Kristjan; stman-Smith, Ingegerd; Oldfors, Anders

    2015-06-01

    Danon disease is caused by mutations in the lysosome-associated membrane protein-2 gene, LAMP2, located on the X chromosome. Female carriers with LAMP2 mutations most often present with late onset cardiomyopathy and slow disease progress; however, there are unusual cases that emerge early and show a more severe disease course. We investigated the explanted heart and skeletal muscle biopsies in two girls, aged ten and thirteen years, who underwent cardiac transplantation because of hypertrophic cardiomyopathy secondary to LAMP2 mutations and a 41-year old female with late-onset familial LAMP2 cardiomyopathy with more typical clinical phenotype. The two girls in contrast had clinical features that mimicked severe primary hypertrophic cardiomyopathy caused by mutations in genes encoding sarcomeric proteins. Immunohistochemistry in cardiac muscles showed a remarkable pattern with lack of LAMP2 protein in large regions including thousands of cardiomyocytes that also showed myocyte hypertrophy, lysosomal enlargement and disarray. In other equally large regions there were preserved LAMP2 expression and nearly normal histology. The skeletal muscle biopsy revealed no pathological changes. An uneven distribution of LAMP2 protein may cause deleterious effects depending on which regions of the myocardium are lacking LAMP2 protein in spite of an overall moderate reduction of LAMP2 protein. This may be a more common mechanism behind early aggressive disease in females than an overall skewed X-chromosome inactivation in the tissue. PMID:25900304

  4. Genetic segregation analysis of early-onset recurrent unipolar depression.

    PubMed Central

    Marazita, M L; Neiswanger, K; Cooper, M; Zubenko, G S; Giles, D E; Frank, E; Kupfer, D J; Kaplan, B B

    1997-01-01

    Major depression is a relatively common psychiatric disorder that can be quite debilitating. Family, twin, and adoption studies indicate that unipolar depression has both genetic and environmental components. Early age at onset and recurrent episodes in the proband each increase the familiarity of the illness. To investigate the potential genetic underpinnings of the disease, we have performed a complex segregation analysis on 832 individuals from 50 multigenerational families ascertained through a proband with early-onset recurrent unipolar major depression. The analysis was conducted by use of regressive models, to test a variety of hypotheses to explain the familial aggregation of recurrent unipolar depression. Analyses were conducted under two alternative definitions of affection status for the relatives of probands: (1) "narrow," in which relatives were assumed to be affected only if they were diagnosed with recurrent unipolar depression; and (2) "broad," in which relatives were assumed to be affected if diagnosed with any major affective illness. Under the narrow-definition assumption, the model that best explains these family data is a transmitted (although non-Mendelian) recessive major effect with significant residual parental effects on affection status. Under the broad-definition assumption, the best-fitting model is a Mendelian codominant major locus with significant residual parental and spousal effects. PMID:9399885

  5. Assessing Racial/Ethnic Differences in the Social Consequences of Early-Onset Psychiatric Disorder

    PubMed Central

    L Cook, Benjamin; Carson, Nicholas; Alegria, Margarita

    2010-01-01

    Individuals with early onset of psychiatric disorder have worse social outcomes than individuals with adult onset. It is unknown whether this association varies by racial/ethnic group. Identifying groups at risk for poor social outcomes is important for improving clinical and policy interventions. We compared unemployment, high school dropout, arrest, and welfare participation by race/ethnicity and time of onset using a nationally representative sample of Whites, Blacks, Asians, and Latinos with lifetime psychiatric disorder. Early onset was associated with worse social outcomes than adult onset. Significant Black-White and Latino-White differences in social outcomes were identified. The association between early onset and negative social outcomes was similar across Whites, Latinos, and Blacks. For Asians, the association between unemployment and early onset was opposite that of Whites. Increasing early detection and treatment of psychiatric illness should be prioritized. Further study will clarify the association between onset and social outcomes among sub-ethnic populations. PMID:20453376

  6. Gaze holding deficits discriminate early from late onset cerebellar degeneration.

    PubMed

    Tarnutzer, Alexander A; Weber, K P; Schuknecht, B; Straumann, D; Marti, S; Bertolini, G

    2015-08-01

    The vestibulo-cerebellum calibrates the output of the inherently leaky brainstem neural velocity-to-position integrator to provide stable gaze holding. In healthy humans small-amplitude centrifugal nystagmus is present at extreme gaze-angles, with a non-linear relationship between eye-drift velocity and eye eccentricity. In cerebellar degeneration this calibration is impaired, resulting in pathological gaze-evoked nystagmus (GEN). For cerebellar dysfunction, increased eye drift may be present at any gaze angle (reflecting pure scaling of eye drift found in controls) or restricted to far-lateral gaze (reflecting changes in shape of the non-linear relationship) and resulting eyed-drift patterns could be related to specific disorders. We recorded horizontal eye positions in 21 patients with cerebellar neurodegeneration (gaze-angle=40) and clinically confirmed GEN. Eye-drift velocity, linearity and symmetry of drift were determined. MR-images were assessed for cerebellar atrophy. In our patients, the relation between eye-drift velocity and gaze eccentricity was non-linear, yielding (compared to controls) significant GEN at gaze-eccentricities?20. Pure scaling was most frequently observed (n=10/18), followed by pure shape-changing (n=4/18) and a mixed pattern (n=4/18). Pure shape-changing patients were significantly (p=0.001) younger at disease-onset compared to pure scaling patients. Atrophy centered around the superior/dorsal vermis, flocculus/paraflocculus and dentate nucleus and did not correlate with the specific drift behaviors observed. Eye drift in cerebellar degeneration varies in magnitude; however, it retains its non-linear properties. With different drift patterns being linked to age at disease-onset, we propose that the gaze-holding pattern (scaling vs. shape-changing) may discriminate early- from late-onset cerebellar degeneration. Whether this allows a distinction among specific cerebellar disorders remains to be determined. PMID:25980905

  7. Severe early-onset colitis revealing mevalonate kinase deficiency.

    PubMed

    Levy, Michael; Arion, Alina; Berrebi, Dominique; Cuisset, Laurence; Jeanne-Pasquier, Corinne; Bader-Meunier, Brigitte; Jung, Camille

    2013-09-01

    Hyperimmunoglobulinemia D is the less severe form of mevalonate kinase deficiency (MKD) caused by recessive inherited mutation in the mevalonate kinase gene. Hyperimmunoglobulinemia D is characterized by febrile attacks, often associated with transient digestive manifestations, such as abdominal pain, diarrhea, and vomiting. Here we report for the first time 2 patients with MKD revealed by severe neonatal colitis. Both patients had chronic bloody diarrhea and failure to thrive; 1 patient since the age of 1 month and the other since the age of 12 days. Total parenteral nutrition was required. A marked elevation of acute phase reactants was present, and no evidence of infection was found. In patient 1, ileocolonoscopy revealed ulcerative colitis at the age of 5 months. Patient 2 suffered from enterocolitis and shock, associated with multiple bowel adhesions at age 5 weeks; the rectosigmoidoscopy showed aphtoid lesions of the sigmoid colon. Pathologic findings of colonic biopsies revealed a dense polymorph inflammatory infiltrate associated with deep ulcerations. Febrile attacks occurred 2 months after the onset of digestive symptoms in patient 1, and at onset of disease in patient 2. Genomic sequencing of the mevalonate kinase gene revealed compound heterozygous mutations in both patients. Anti-interleukin-1 agent produced long-term remission of all digestive features and laboratory parameters. This report emphasizes that MKD may be the cause of severe early-onset inflammatory colitis, and must be considered by physicians, even in the absence of fever, after ruling out infections. Anti-interleukin-1 therapy may result in a dramatic improvement of MKD-related inflammatory bowel disease. PMID:23979089

  8. Early Onset Recurrent Subtype of Adolescent Depression: Clinical and Psychosocial Correlates

    ERIC Educational Resources Information Center

    Hammen, Constance; Brennan, Patricia A.; Keenan-Miller, Danielle; Herr, Nathaniel R.

    2008-01-01

    Background: Evaluated trajectories of adolescent depression and their correlates in a longitudinal study of a community sample: early onset (by age 15) with major depression (MDE) recurrence between 15 and 20; early onset with no recurrence; later onset of major depression after age 15 with and without recurrence by 20; and never-depressed.

  9. The onset of galactic winds in early-type galaxies

    NASA Technical Reports Server (NTRS)

    Forman, W.; Jones, C.; Tucker, W.; David, L. P.

    1990-01-01

    Researchers report on a program using Einstein x ray observations of the x ray spectra and surface brightness profiles (or extents) of a large sample of early-type (elliptical and SO) galaxies for which the goal is to determine the critical optical luminosity for which galactic winds are important. For galaxies in which the x ray emission is dominated by hydrostatic coronae, the x ray spectra will be relatively soft (characterized by a temperature of approx. 10 to the 7th power K), while for galaxies with a galactic wind, the emission will be dominated by the spectrally harder discrete sources (since the x ray emission from the wind is essentially negligible). In this new sample of 180 galaxies, there are 28 early type galaxies with sufficient counts to obtain a spectrum with the Einstein Image Proportional Counter (IPC). This sample more than doubles the total number of early-type galaxies in earlier compilations (Forman, Jones, and Tucker 1985; Canizares et al. 1987). The new spectral observations will help determine the critical optical luminosity for the onset of galactic winds which is important for understanding the chemical evolution of galaxies and of the intergalactic medium. The implications of galactic winds for the heavy element enrichment and energy content of the intracluster medium are discussed.

  10. Clinical Characteristics and Prognostic Factors in Early-Onset Alopecia Totalis and Alopecia Universalis

    PubMed Central

    Cho, Hyun Hee; Jo, Seong Jin; Paik, Seung Hwan; Jeon, Hye Chan; Kim, Kyu Han; Eun, Hee Chul

    2012-01-01

    Alopecia totalis (AT) and alopecia universalis (AU), severe forms of alopecia areata (AA), show distinguishable clinical characteristics from those of patch AA. In this study, we investigated the clinical characteristics of AT/AU according to the onset age. Based on the onset age around adolescence (< or ? 13 yr), 108 patients were classified in an early-onset group and the other 179 patients in a late-onset group. We found that more patients in the early-onset group had a family history of AA, nail dystrophy, and history of atopic dermatitis than those in the late-onset group. These clinical differences were more prominent in patients with AU than in those with AT. In addition, significantly more patients with concomitant medical disorders, especially allergic diseases were found in the early-onset group (45.8%) than in the late-onset group (31.2%). All treatment modalities failed to show any association with the present hair condition of patients. In the early-onset group, patients with AU or a family history of AA showed worse prognosis, whereas this trend was not observed in the late-onset group. Systemic evaluations might be needed in early-onset patients due to the higher incidence of comorbid diseases. It is suggested that patients with AU or family history of AA make worse progress in the early-onset group than in the late-onset group. PMID:22787378

  11. Clinical characteristics and prognostic factors in early-onset alopecia totalis and alopecia universalis.

    PubMed

    Cho, Hyun Hee; Jo, Seong Jin; Paik, Seung Hwan; Jeon, Hye Chan; Kim, Kyu Han; Eun, Hee Chul; Kwon, Oh Sang

    2012-07-01

    Alopecia totalis (AT) and alopecia universalis (AU), severe forms of alopecia areata (AA), show distinguishable clinical characteristics from those of patch AA. In this study, we investigated the clinical characteristics of AT/AU according to the onset age. Based on the onset age around adolescence (< or ? 13 yr), 108 patients were classified in an early-onset group and the other 179 patients in a late-onset group. We found that more patients in the early-onset group had a family history of AA, nail dystrophy, and history of atopic dermatitis than those in the late-onset group. These clinical differences were more prominent in patients with AU than in those with AT. In addition, significantly more patients with concomitant medical disorders, especially allergic diseases were found in the early-onset group (45.8%) than in the late-onset group (31.2%). All treatment modalities failed to show any association with the present hair condition of patients. In the early-onset group, patients with AU or a family history of AA showed worse prognosis, whereas this trend was not observed in the late-onset group. Systemic evaluations might be needed in early-onset patients due to the higher incidence of comorbid diseases. It is suggested that patients with AU or family history of AA make worse progress in the early-onset group than in the late-onset group. PMID:22787378

  12. Clinical features associated with an early onset in chronic tic disorders.

    PubMed

    Richer, Francois; Daghfal, Roula; Rouleau, Guy A; Lespérance, Paul; Chouinard, Sylvain

    2015-12-30

    In chronic tic disorders such as Tourette syndrome (TS), tics often appear between 4 and 8 years but they can also appear in early childhood, a period in which symptom expression may be affected by early brain development. The present study examined whether symptom expression in early-onset TS was distinct from that observed in TS with a later onset. We compared the clinical characteristics in children with TS who developed tics before age 4 or after age 6. Early-onset TS was significantly associated with an increased rate of stuttering and other speech disfluencies as well as an increased rate of oppositional defiant disorder, symptoms that often appear before age 4. Early-onset TS was also linked to maternal transmission of tics. Early-onset TS was not significantly associated with tic severity, obsessive-compulsive behavior or attention-deficit hyperactivity disorder. The results suggest that an early onset affects symptom expression in tic disorders. PMID:26596364

  13. Early onset Alzheimer's disease is associated with a distinct neuropsychological profile.

    PubMed

    Smits, Lieke L; Pijnenburg, Yolande A L; Koedam, Esther L G E; van der Vlies, Annelies E; Reuling, Ilona E W; Koene, Teddy; Teunissen, Charlotte E; Scheltens, Philip; van der Flier, Wiesje M

    2012-01-01

    Alzheimer's disease (AD) in younger patients is associated with a higher prevalence of atypical symptoms. We examined neuropsychological performance according to age-at-onset. We assessed cognition in 172 patients with AD (81 early and 91 late onset) in five cognitive domains (memory, language, visuo-spatial functioning, executive functioning, attention). Dementia severity was assessed using the Mini-Mental State Examination (MMSE) and global cognitive decline using Cambridge Cognitive Examination (CAMCOG). Analyses of variance were performed with age-at-onset as between-subjects factor, and gender and education as covariates. Analysis was repeated after stratification for dementia severity (based on median MMSE). In early onset AD, age (mean SD) was 60 4 years; 44 (54%) were female. In late onset AD, age was 72 5 years; 47 (52%) were female. Dementia severity and global cognitive decline did not differ between groups (early onset: MMSE: 20 5, CAMCOG: 69 15, late onset: MMSE: 21 5, CAMCOG: 70 15; p > 0.05). Early onset patients performed worse than late onset patients on visuo-spatial functioning (p < 0.01), executive functioning (p < 0.001), and attention (p < 0.01). Late onset patients performed worse on memory, although not significantly (p = 0.11). Stratification for dementia severity showed that in mildly demented early onset patients, memory function was remarkably preserved compared to late onset patients (p < 0.01). In moderate AD, differences in memory function disappeared, but early onset patients performed worse on visuo-spatial functioning (p < 0.01), executive functioning (p < 0.001), and attention (p < 0.01) than late onset patients. Adjustment for APOE left results unchanged. In conclusion, early onset AD presents with a different cognitive profile and the disease course seems different. Relative sparing of memory function in early stages stresses the need to adequately test other cognitive domains. PMID:22366769

  14. Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS): Rationale, Design, and Methods

    ERIC Educational Resources Information Center

    McClellan, Jon; Sikich, Linmarie; Findling, Robert L.; Frazier, Jean A.; Vitiello, Benedetto; Hlastala, Stefanie A.; Williams, Emily; Ambler, Denisse; Hunt-Harrison, Tyehimba; Maloney, Ann E.; Ritz, Louise; Anderson, Robert; Hamer, Robert M.; Lieberman, Jeffrey A.

    2007-01-01

    Objective: The Treatment of Early Onset Schizophrenia Spectrum Disorders Study is a publicly funded clinical trial designed to compare the therapeutic benefits, safety, and tolerability of risperidone, olanzapine, and molindone in youths with early-onset schizophrenia spectrum disorders. The rationale, design, and methods of the Treatment of Early

  15. Pharmacotherapy of early-onset depression. Update and new directions.

    PubMed

    Martin, A; Kaufman, J; Charney, D

    2000-01-01

    Although an increased recognition of depressive disorders in youth represents a positive conceptual change over the past decades, there still is a very limited amount of research on useful treatment interventions. The paucity of data is particularly keen for the use of psychotropic drugs. For example, by applying the criteria suggested by the International Psychopharmacology Algorithm Project, there barely are enough first-grade ("Level A," meaning at least two RCTs) data supporting the short-term efficacy of antidepressants (the SSRIs) in the treatment of juvenile depression. And yet, limited data have not translated into limited use in routine clinical practice. In fact, the use of antidepressant medications has increased exponentially over the last decade, a change that is especially conspicuous for individuals less than 18 years of age. The perceived safety of the SSRIs and other novel antidepressants is partly at the root of their increased popularity. Data regarding their safety are likewise quite limited, however, and essentially are nonexistent for longer-term use. Based on the reviewed data, a medication algorithm for the treatment of early-onset depression can be suggested (Fig. 1). The algorithm underscores the need for adequate evaluation and diagnostic assessment, with particular attention to comorbid conditions (such as a bipolar diathesis) that may dictate alternative treatment strategies. In general, psychotherapy is the initial approach to juvenile MDD, with medication use reserved for more severe cases or those not responding to psychotherapy alone. Given that only two types of psychotherapy and two SSRIs have adequate controlled short-term efficacy data, all but the initial steps must be undertaken guided by clinical judgment and an individualized risk-benefit analysis. An algorithm such as this one, based on the very limited efficacy and safety data available, may be viewed as setting priorities for a comprehensive research agenda, more than dictating rigid treatment guidelines. In closing, it can be suggested that future research on the pharmacotherapy of early-onset depressive disorder pay particular attention to the following three aspects: 1. Too many drugs, too few data: Rapid advances in drug development have led to a plethora of available antidepressant agents. It is clear that there are many more agents available than can be adequately studied at present. Because many such agents are mechanistically similar, if not identical, it may be wise to focus research efforts on truly novel agents, particularly those (such as the CRH receptor antagonists, or those affecting neurosteroidogenesis) whose action is based on preclinical and clinical pathophysiologic disease paradigms. 2. Longitudinal follow-up and maintenance studies: Essentially all reviewed treatment studies have been short-term trials. There is a marked paucity of longer-term follow-up data, or of naturalistic and "real-world" effectiveness studies. For example, one of the few studies addressing maintenance pharmacotherapy for early-onset depression has demonstrated surprisingly high recurrence rates, even for those subjects actively on maintenance medication. 3. Long-term safety: Clinicians and parents alike often face difficult decisions regarding the long-term exposure of antidepressant drugs on the developing brain. Although no definitive long-term safety data are likely to become available anytime soon, real risks, such as suicide, and potential sequelae of long-term exposure to the underlying illness itself need all to be part of any decision-making process. Preclinical studies have shown that brain-derived neurotrophic factor (BDNF) levels can be upregulated by antidepressants, and low BDNF factors have been associated with atrophic brain changes in recurrent forms of adult MDD. Although these observations require specific application to juvenile forms of the disorder, they raise the exciting prospect that the natural course of the illne PMID:10674194

  16. Early-onset versus late-onset Alzheimer's disease: the case of the missing APOE ?4 allele.

    PubMed

    van der Flier, Wiesje M; Pijnenburg, Yolande Al; Fox, Nick C; Scheltens, Philip

    2011-03-01

    Some patients with early-onset Alzheimer's disease (AD) present with a distinct phenotype. Typically, the first and most salient characteristic of AD is episodic memory impairment. A few patients, however, present with focal cortical, non-memory symptoms, such as difficulties with language, visuospatial, or executive functions. These presentations are associated with specific patterns of atrophy and frequently with a young age at onset. Age is not, however, the only determinant of phenotype; underlying factors, especially genetic factors, seem also to affect phenotype and predispose patients to younger or older age at onset. Importantly, patients with atypical early-onset disease seldom carry the APOE ?4 allele, which is the most important risk factor for lowering the age of onset in patients with AD. Additionally, theAPOE ?4 genotype seems to predispose patients to vulnerability in the medial temporal areas, which leads to memory loss. Conversely, patients negative for the APOE ?4 allele and with early-onset AD are more likely to be predisposed to vulnerability of cerebral networks beyond the medial temporal lobes. Other factors are probably involved in determining the pattern of atrophy, but these are currently unknown. PMID:21185234

  17. Early onset of ghrelin production in a marsupial.

    PubMed

    Menzies, Brandon R; Shaw, Geoff; Fletcher, Terry P; Renfree, Marilyn B

    2009-02-27

    Ghrelin regulates appetite in mammals and can stimulate growth hormone (GH) release from the pituitary. In rats and humans, ghrelin cells appear in the stomach during late fetal life. Nevertheless, the role of ghrelin in early mammalian development is not well understood. Marsupials deliver highly altricial young that weigh less than 1g so they must feed and digest milk at a comparatively immature stage of development. Since they complete their growth and differentiation while in the pouch, they are accessible models in which to determine the time course of ghrelin production during development. We examined the distribution of gastric ghrelin cells, plasma ghrelin concentrations and pituitary expression of the ghrelin receptor (ghsr-1alpha) and GH in the tammar wallaby, Macropus eugenii. There were ghrelin immunopositive cells in the developing mesenchyme of the stomach from day 10 post partum (pp) to day 150pp. Subsequently ghrelin protein in the fore-stomach declined and was absent by day 250pp but remained in the gastric cells of the hind-stomach. Ghrelin was detected in the developing pancreas from day 10pp but was absent by day 150pp and in the adult. Pituitary ghsr-1alpha expression and plasma concentrations of ghrelin increased significantly up to day 70-120pp while GH expression was also elevated, declining with GH to reach adult levels by day 180pp. These results demonstrate an early onset of gastric ghrelin expression in the tammar in concert with a functional stomach at a relatively earlier stage than that of developmentally more mature eutherian young. PMID:19026714

  18. Clinicopathological and genetic study of early-onset demyelinating neuropathy.

    PubMed

    Parman, Yesim; Battaloglu, Esra; Baris, Ibrahim; Bilir, Birdal; Poyraz, Mürüvvet; Bissar-Tadmouri, Nisrine; Williams, Anna; Ammar, Nadia; Nelis, Eva; Timmerman, Vincent; De Jonghe, Peter; Najafov, Ayaz; Necefov, Ayaz; Deymeer, Feza; Serdaroglu, Piraye; Brophy, Peter J; Said, G

    2004-11-01

    Autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT4), Dejerine-Sottas disease and congenital hypomyelinating neuropathy are variants of hereditary demyelinating neuropathy of infancy, a genetically heterogeneous group of disorders. To explore the spectrum of early-onset demyelinating neuropathies further, we studied the clinicopathological and genetic aspects of 20 patients born to unaffected parents. In 19 families out of 20, consanguinity between the parents or presence of an affected sib suggested autosomal recessive transmission. Screening of various genes known to be involved in CMT4 revealed six mutations of which five are novel. Four of these novel mutations occurred in the homozygous state and include: one in GDAP1, one in MTMR2, one in PRX and one in KIAA1985. One patient was heterozygous for a novel MTMR2 mutation and still another was homozygous for the founder mutation, R148X, in NDRG1. All patients tested negative for mutations in EGR2. Histopathological examination of nerve biopsy specimens showed a severe, chronic demyelinating neuropathy, with onion bulb formation, extensive demyelination of isolated fibres and axon loss. We did not discern a specific pattern of histopathology that could be correlated to mutations in a particular gene. PMID:15469949

  19. Periodontal Health in Women with Early Stage Postmenopausal Breast Cancer Newly on Aromatase Inhibitors: A Pilot Study

    PubMed Central

    Taichman, LS; Inglehart, MR; Giannobile, W; Braun, T; Kolenic, G; Van Poznak, C

    2015-01-01

    Background Aromatase inhibitor (AI) use results in low estrogen levels which in turn affect bone mineral density (BMD). Periodontitis, alveolar bone loss, and tooth loss are associated with low BMD. The goal of this study was to assess the prevalence of periodontitis, perceived oral health, and evaluate salivary biomarkers in postmenopausal women who are early stage (I-IIIA) breast cancer (BCa) survivors and receive adjuvant AI therapy. Methods Participants included 58 postmenopausal women; 29 with BCa on AIs and 29 controls without BCa diagnoses. Baseline periodontal status was assessed with: (1) periodontal pocket depth (PD); (2) bleeding on probing (BOP); and (3) attachment loss (AL). Demographic and dental utilization information was gathered by questionnaire. Linear regression modeling was used to analyze the outcomes. Results No differences in mean PD or the number of teeth were found. The AI group had significantly more sites with BOP (27.8 vs. 16.7; p = 0.02), higher worst-site AL (5.2 mm vs. 4.0 mm; p < 0.01) and more sites with dental calculus than did controls (18.2 vs. 6.4; p < 0.001). Linear regression adjusted for income, tobacco use, and dental insurance, and previous radiation and chemotherapy exposure demonstrated AI use increased CAL over 2 mm (95% CI: 0.46 -3.92). Median salivary osteocalcin and Tumor Necrosis Factor levels were significantly higher in the BCa group than the control group. Conclusions This first investigation of the periodontal status of women initiating adjuvant AI therapy identifies this population as having an increased risk for periodontitis (NCT1272570). PMID:25672657

  20. Evidence for apolipoprotein E {epsilon}4 association in early-onset Alzheimer`s patients with late-onset relatives

    SciTech Connect

    Perez-Tur, J.; Delacourte, A.; Chartier-Harlin, M.C.

    1995-12-18

    Recently several reports have extended the apolipoprotein E (APOE) {epsilon}4 association found in late-onset Alzheimer`s disease (LOAD) patients to early-onset (EO) AD patients. We have studied this question in a large population of 119 EOAD patients (onset {<=}60 years) in which family history was carefully assessed and in 109 controls. We show that the APOE {epsilon}A allele frequency is increased only in the subset of patients who belong to families where LOAD secondary cases are present. Our sampling scheme permits us to demonstrate that, for an individual, bearing at least one {epsilon}4 allele increases both the risk of AD before age 60 and the probability of belonging to a family with late-onset affected subjects. Our results suggest that a subset of EOAD cases shares a common determinism with LOAD cases. 19 refs., 3 tabs.

  1. Role of the NK Cell-Activating Receptor CRACC in Periodontitis

    PubMed Central

    Krämer, Benjamin; Kebschull, Moritz; Nowak, Michael; Demmer, Ryan T.; Haupt, Manuela; Körner, Christian; Perner, Sven; Jepsen, Søren

    2013-01-01

    Periodontitis is a highly prevalent, biofilm-mediated chronic inflammatory disease that results in the loss of the tooth-supporting tissues. It features two major clinical entities: chronic periodontitis, which is more common, and aggressive periodontitis, which usually has an early onset and a rapid progression. Natural killer (NK) cells are a distinct subgroup of lymphocytes that play a major role in the ability of the innate immune system to steer immune responses. NK cells are abundant in periodontitis lesions, and NK cell activation has been causally linked to periodontal tissue destruction. However, the exact mechanisms of their activation and their role in the pathophysiology of periodontitis are elusive. Here, we show that the predominant NK cell-activating molecule in periodontitis is CD2-like receptor activating cytotoxic cells (CRACC). We show that CRACC induction was significantly more pronounced in aggressive than chronic periodontitis and correlated positively with periodontal disease severity, subgingival levels of specific periodontal pathogens, and NK cell activation in vivo. We delineate how Aggregatibacter actinomycetemcomitans, an oral pathogen that is causally associated with aggressive periodontitis, indirectly induces CRACC on NK cells via activation of dendritic cells and subsequent interleukin 12 (IL-12) signaling. In contrast, we demonstrate that fimbriae from Porphyromonas gingivalis, a principal pathogen in chronic periodontitis, actively attenuate CRACC induction on NK cells. Our data suggest an involvement of CRACC-mediated NK cell activation in periodontal tissue destruction and point to a plausible distinction in the pathobiology of aggressive and chronic periodontitis that may help explain the accelerated tissue destruction in aggressive periodontitis. PMID:23250953

  2. Role of the NK cell-activating receptor CRACC in periodontitis.

    PubMed

    Krmer, Benjamin; Kebschull, Moritz; Nowak, Michael; Demmer, Ryan T; Haupt, Manuela; Krner, Christian; Perner, Sven; Jepsen, Sren; Nattermann, Jacob; Papapanou, Panos N

    2013-03-01

    Periodontitis is a highly prevalent, biofilm-mediated chronic inflammatory disease that results in the loss of the tooth-supporting tissues. It features two major clinical entities: chronic periodontitis, which is more common, and aggressive periodontitis, which usually has an early onset and a rapid progression. Natural killer (NK) cells are a distinct subgroup of lymphocytes that play a major role in the ability of the innate immune system to steer immune responses. NK cells are abundant in periodontitis lesions, and NK cell activation has been causally linked to periodontal tissue destruction. However, the exact mechanisms of their activation and their role in the pathophysiology of periodontitis are elusive. Here, we show that the predominant NK cell-activating molecule in periodontitis is CD2-like receptor activating cytotoxic cells (CRACC). We show that CRACC induction was significantly more pronounced in aggressive than chronic periodontitis and correlated positively with periodontal disease severity, subgingival levels of specific periodontal pathogens, and NK cell activation in vivo. We delineate how Aggregatibacter actinomycetemcomitans, an oral pathogen that is causally associated with aggressive periodontitis, indirectly induces CRACC on NK cells via activation of dendritic cells and subsequent interleukin 12 (IL-12) signaling. In contrast, we demonstrate that fimbriae from Porphyromonas gingivalis, a principal pathogen in chronic periodontitis, actively attenuate CRACC induction on NK cells. Our data suggest an involvement of CRACC-mediated NK cell activation in periodontal tissue destruction and point to a plausible distinction in the pathobiology of aggressive and chronic periodontitis that may help explain the accelerated tissue destruction in aggressive periodontitis. PMID:23250953

  3. Distributional Cues and the Onset Bias in Early Word Segmentation

    ERIC Educational Resources Information Center

    Babineau, Mireille; Shi, Rushen

    2014-01-01

    In previous infant studies on statistics-based word segmentation, the unit of statistical computation was always aligned with the syllabic edge, which had a consonant onset. The current study addressed whether the learning system imposes a constraint that favors word forms beginning with a consonant onset over those beginning with an onsetless

  4. Characterization of early and late onset psoriasis in the Korean population.

    PubMed

    Youn, J I; Park, B S; Park, S B; Kim, S D; Suh, D H

    1999-10-01

    It has been proposed that two types of psoriasis can be characterized based upon age of onset. The purpose of our study was to investigate the characteristics of early and late onset psoriasis in the Korean population. A total of 986 psoriasis patients were included in this study, and the age of onset frequency proved to be bimodal. Family history in the first-degree relatives was significantly higher in the early onset group (< 40 years old) when compared with the late onset group (> or = 40 years old). A series of statistical analyses concerning the correlation between the extent of involvement and age of onset showed that earlier onset is related to more extensive involvement. A questionnaire survey concerning the influence of various external factors upon their psoriasis was given to a subgroup of 800 psoriasis patients. Multiple logistic regression analysis, controlled for confounding factors such as current age, sex and extent of involvement, revealed that early onset psoriasis patients showed significantly increased tendencies to worsen at times of psychological stress and in winter, and to improve in summer, compared with late onset psoriasis patients. In conclusion, distribution of the age of onset revealed two peaks in Korean psoriasis patients, and psoriasis with an onset prior to the age of 40 years was associated with increased inheritability, greater susceptibility to seasonal changes and more psychological stress than psoriasis with later onset. PMID:10554430

  5. Deficits in Facial Expression Recognition in Male Adolescents with Early-Onset or Adolescence-Onset Conduct Disorder

    ERIC Educational Resources Information Center

    Fairchild, Graeme; Van Goozen, Stephanie H. M.; Calder, Andrew J.; Stollery, Sarah J.; Goodyer, Ian M.

    2009-01-01

    Background: We examined whether conduct disorder (CD) is associated with deficits in facial expression recognition and, if so, whether these deficits are specific to the early-onset form of CD, which emerges in childhood. The findings could potentially inform the developmental taxonomic theory of antisocial behaviour, which suggests that

  6. Early onset versus late onset peripherally inserted central venous catheter infections: an analysis of risk factors and microbiology.

    PubMed

    Chittick, Paul; Azhar, Sobia; Movva, Kalyani; Keller, Paula; Boura, Judith A; Band, Jeffrey

    2013-09-01

    The risks and microbiology for peripherally inserted central catheters (PICCs) are less well described than those for traditional central catheters, particularly as they pertain to duration of catheterization. We compared patients with early- and late-onset PICC bloodstream infections at our institution and found significant differences in microbiologic etiologies. PMID:23917915

  7. Child and Adolescent (Early Onset) Schizophrenia: A Review in Light of DSM-III-R.

    ERIC Educational Resources Information Center

    Werry, John S.

    1992-01-01

    This review of studies of early onset schizophrenia examines the nosological similarity between adult and early onset schizophrenia, differential diagnosis, treatment, and the extent to which children and adolescents diagnosed as having schizophrenia using adult criteria have the characteristic adult correlates. The paper discusses gender…

  8. Child and Adolescent (Early Onset) Schizophrenia: A Review in Light of DSM-III-R.

    ERIC Educational Resources Information Center

    Werry, John S.

    1992-01-01

    This review of studies of early onset schizophrenia examines the nosological similarity between adult and early onset schizophrenia, differential diagnosis, treatment, and the extent to which children and adolescents diagnosed as having schizophrenia using adult criteria have the characteristic adult correlates. The paper discusses gender

  9. Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS): Rationale, Design, and Methods

    ERIC Educational Resources Information Center

    McClellan, Jon; Sikich, Linmarie; Findling, Robert L.; Frazier, Jean A.; Vitiello, Benedetto; Hlastala, Stefanie A.; Williams, Emily; Ambler, Denisse; Hunt-Harrison, Tyehimba; Maloney, Ann E.; Ritz, Louise; Anderson, Robert; Hamer, Robert M.; Lieberman, Jeffrey A.

    2007-01-01

    Objective: The Treatment of Early Onset Schizophrenia Spectrum Disorders Study is a publicly funded clinical trial designed to compare the therapeutic benefits, safety, and tolerability of risperidone, olanzapine, and molindone in youths with early-onset schizophrenia spectrum disorders. The rationale, design, and methods of the Treatment of Early…

  10. Verbal and Academic Skills in Children with Early-Onset Type 1 Diabetes

    ERIC Educational Resources Information Center

    Hannonen, Riitta; Komulainen, Jorma; Eklund, Kenneth; Tolvanen, Asko; Riikonen, Raili; Ahonen, Timo

    2010-01-01

    Aim: Basic verbal and academic skills can be adversely affected by early-onset diabetes, although these skills have been studied less than other cognitive functions. This study aimed to explore the mechanism of learning deficits in children with diabetes by assessing basic verbal and academic skills in children with early-onset diabetes and in

  11. Internalizing and Externalizing Behaviors as Predictors of Sexual Onset in Early Adolescence

    ERIC Educational Resources Information Center

    Boislard, Marie-Aude P.; Dussault, Frdric; Brendgen, Mara; Vitaro, Frank

    2013-01-01

    This study had three goals: (a) assessing the predictive association of externalizing and internalizing behaviors during childhood with sexual onset during early adolescence; (b) examining the interactive link of externalizing and internalizing behaviors with early sexual onset; and (c) investigating the moderating effect of gender in this

  12. Family Functioning and Early Onset of Sexual Intercourse in Latino Adolescents

    ERIC Educational Resources Information Center

    Velez-Pastrana, Maria C.; Gonzalez-Rodriguez, Rafael A.; Borges-Hernandez, Adalisse

    2005-01-01

    The purpose of this study was to identify factors associated with early onset of sexual intercourse. Within an ecological system's conceptual framework, familial factors associated with early onset of sexual activity were identified in a sample of 425 adolescents from San Juan metro area schools. Measures included questions about sexual activity,…

  13. Verbal and Academic Skills in Children with Early-Onset Type 1 Diabetes

    ERIC Educational Resources Information Center

    Hannonen, Riitta; Komulainen, Jorma; Eklund, Kenneth; Tolvanen, Asko; Riikonen, Raili; Ahonen, Timo

    2010-01-01

    Aim: Basic verbal and academic skills can be adversely affected by early-onset diabetes, although these skills have been studied less than other cognitive functions. This study aimed to explore the mechanism of learning deficits in children with diabetes by assessing basic verbal and academic skills in children with early-onset diabetes and in…

  14. Children with Very Early Onset Obsessive-Compulsive Disorder: Clinical Features and Treatment Outcome

    ERIC Educational Resources Information Center

    Nakatani, Eriko; Krebs, Georgina; Micali, Nadia; Turner, Cynthia; Heyman, Isobel; Mataix-Cols, David

    2011-01-01

    Background: There is emerging evidence that early onset obsessive-compulsive disorder (OCD) may be a phenomenologically distinct subtype of the disorder. Previous research has shown that individuals who report an early onset display greater severity and persistence of symptoms, and they may be less responsive to treatment. To date, this question…

  15. Children with Very Early Onset Obsessive-Compulsive Disorder: Clinical Features and Treatment Outcome

    ERIC Educational Resources Information Center

    Nakatani, Eriko; Krebs, Georgina; Micali, Nadia; Turner, Cynthia; Heyman, Isobel; Mataix-Cols, David

    2011-01-01

    Background: There is emerging evidence that early onset obsessive-compulsive disorder (OCD) may be a phenomenologically distinct subtype of the disorder. Previous research has shown that individuals who report an early onset display greater severity and persistence of symptoms, and they may be less responsive to treatment. To date, this question

  16. Early- versus late-onset systemic sclerosis: differences in clinical presentation and outcome in 1037 patients.

    PubMed

    Alba, Marco A; Velasco, Csar; Simen, Carmen Pilar; Fonollosa, Vicent; Trapiella, Luis; Egurbide, Mara Victoria; Sez, Luis; Castillo, Mara Jess; Callejas, Jos Luis; Camps, Mara Teresa; Tolosa, Carles; Ros, Juan Jos; Freire, Mayka; Vargas, Jos Antonio; Espinosa, Gerard

    2014-03-01

    Peak age at onset of systemic sclerosis (SSc) is between 20 and 50 years, although SSc is also described in both young and elderly patients. We conducted the present study to determine if age at disease onset modulates the clinical characteristics and outcome of SSc patients. The Spanish Scleroderma Study Group recruited 1037 patients with a mean follow-up of 5.2 6.8 years. Based on the mean 1 standard deviation (SD) of age at disease onset (45 15 yr) of the whole series, patients were classified into 3 groups: age ? 30 years (early onset), age between 31 and 59 years (standard onset), and age ? 60 years (late onset). We compared initial and cumulative manifestations, immunologic features, and death rates. The early-onset group included 195 patients; standard-onset group, 651; and late-onset, 191 patients. The early-onset group had a higher prevalence of esophageal involvement (72% in early-onset compared with 67% in standard-onset and 56% in late-onset; p = 0.004), and myositis (11%, 7.2%, and 2.9%, respectively; p = 0.009), but a lower prevalence of centromere antibodies (33%, 46%, and 47%, respectively; p = 0.007). In contrast, late-onset SSc was characterized by a lower prevalence of digital ulcers (54%, 41%, and 34%, respectively; p < 0.001) but higher rates of heart conduction system abnormalities (9%, 13%, and 21%, respectively; p = 0.004). Pulmonary hypertension was found in 25% of elderly patients and in 12% of the youngest patients (p = 0.010). After correction for the population effects of age and sex, standardized mortality ratio was shown to be higher in younger patients. The results of the present study confirm that age at disease onset is associated with differences in clinical presentation and outcome in SSc patients. PMID:24646463

  17. Sildenafil citrate therapy for severe early-onset intrauterine growth restriction.

    PubMed

    von Dadelszen, P; Dwinnell, S; Magee, L A; Carleton, B C; Gruslin, A; Lee, B; Lim, K I; Liston, R M; Miller, S P; Rurak, D; Sherlock, R L; Skoll, M A; Wareing, M M; Baker, P N

    2011-04-01

    Sildenafil citrate therapy for severe early-onset intrauterine growth restriction. BJOG 2011;118:624-628. Currently, there is no effective therapy for severe early-onset intrauterine growth restriction (IUGR). Sildenafil citrate vasodilates the myometrial arteries isolated from women with IUGR-complicated pregnancies. Women were offered Sildenafil (25 mg three times daily until delivery) if their pregnancy was complicated by early-onset IUGR [abdominal circumference (AC)< 5th percentile] and either the gestational age was <25(+0) weeks or an estimate of the fetal weight was <600 g (excluding known fetal anomaly/syndrome and/or planned termination). Sildenafil treatment was associated with increased fetal AC growth [odds ratio, 12.9; 95% confidence interval (CI), 1.3, 126; compared with institutional Sildenafil-naive early-onset IUGR controls]. Randomised controlled trial data are required to determine whether Sildenafil improves perinatal outcomes for early-onset IUGR-complicated pregnancies. PMID:21392225

  18. Neuropsychological profile in early Parkinson's disease: Comparison between patients with right side onset versus left side onset of motor symptoms

    PubMed Central

    Adwani, Sikandar; Yadav, Ravi; Kumar, Keshav; Chandra, S. R.; Pal, Pramod Kumar

    2016-01-01

    Aims: Though impaired cognition in Parkinson's disease (PD) is well known, data in early PD is sparse. This study was designed to assess the cognitive profile in patients with early PD (motor symptoms <5 years and Hoehn and Yahr stage <2), and to compare the cognitive profile between these patients with right versus left side onset of motor symptoms. Materials and Methods: National Institute of National Health and Neurosciences (NIMHANS) neuropsychological battery was used to assess the cognitive profile in 50 patients with early PD and compared with 50 age-, education-, and gender-matched healthy controls. Within the PD group, the cognitive profile was also compared between patients with right side onset motor symptoms (RPD) versus those with left side onset (LPD). The neuropsychological tests assessed the executive functions, memory, attention, visuospatial functions, and psychomotor speed. Results: Among the 50 patients, 25 each were RPD and LPD. The two subgroups were matched for age, gender, education, age at disease onset, disease duration, and degree of motor disability. There was no significant difference between the groups on Hoehn and Yahr staging or Unified Parkinson Disease Rating Scale (UPDRS) motor score. Patients with early PD performed significantly worse in the tasks involving memory, executive functions, and attention compared to controls. However, there was no difference in the cognitive profile between RPD and LPD subgroups. Conclusions: Patients with early PD have cognitive dysfunction with predominant involvement of frontal and temporal lobes. Side of onset of motor symptoms probably does not have significant role in future development or profile of cognitive dysfunction in PD. PMID:27011633

  19. Early results of a remotely-operated magnetic growth rod in early-onset scoliosis.

    PubMed

    Dannawi, Z; Altaf, F; Harshavardhana, N S; El Sebaie, H; Noordeen, H

    2013-01-01

    Conventional growing rods are the most commonly used distraction-based devices in the treatment of progressive early-onset scoliosis. This technique requires repeated lengthenings with the patient anaesthetised in the operating theatre. We describe the outcomes and complications of using a non-invasive magnetically controlled growing rod (MCGR) in children with early-onset scoliosis. Lengthening is performed on an outpatient basis using an external remote control with the patient awake.Between November 2009 and March 2011, 34 children with a mean age of eight years (5 to 12) underwent treatment. The mean length of follow-up was 15 months (12 to 18). In total, 22 children were treated with dual rod constructs and 12 with a single rod. The mean number of distractions per patient was 4.8 (3 to 6). The mean pre-operative Cobb angle was 69° (46° to 108°); this was corrected to a mean 47° (28° to 91°) post-operatively. The mean Cobb angle at final review was 41° (27° to 86°). The mean pre-operative distance from T1 to S1 was 304 mm (243 to 380) and increased to 335 mm (253 to 400) in the immediate post-operative period. At final review the mean distance from T1 to S1 had increased to 348 mm (260 to 420).Two patients developed a superficial wound infection and a further two patients in the single rod group developed a loss of distraction. In the dual rod group, one patient had pull-out of a hook and one developed prominent metalwork. Two patients had a rod breakage; one patient in the single rod group and one patient in the dual rod group. Our early results show that the MCGR is safe and effective in the treatment of progressive early-onset scoliosis with the avoidance of repeated surgical lengthenings. PMID:23307677

  20. Early-onset obsessive-compulsive disorder and personality disorders in adulthood.

    PubMed

    Maina, Giuseppe; Albert, Umberto; Salvi, Virginio; Pessina, Enrico; Bogetto, Filippo

    2008-03-15

    Obsessive-compulsive disorder (OCD) often emerges in childhood or adolescence. The aim of the present study was to evaluate whether adult patients with prepuberal onset differ from subjects with later onset in terms of personality disorder comorbidity. The Structured Clinical Interview for DSM-IV Axis II Disorders was used to assess 148 patients with a principal diagnosis of OCD according to the Structured Clinical Interview for DSM-IV Axis I Disorders. The following two subgroups of subjects were selected according to the age at onset of symptomatology: patients with an early-onset (< or =10 years), and patients with a later onset (> or =17 years). Of the 148 patients screened for the present study, 33 (22.3%) had an early onset and 1369 (46.6%) had a later onset. With regard to personality disorders, early-onset patients showed more OC personality disorders (OCPD) than later onset patients. Our finding suggests that OCD in childhood increases the risk for developing OCPD in adulthood, or that early-onset OCD and OCPD share a common pathogenesis. PMID:18237785

  1. Actinobacillus actinomycetemcomitans serotype e--biotypes, genetic diversity and distribution in relation to periodontal status.

    PubMed

    Doğan, B; Saarela, M H; Jousimies-Somer, H; Alaluusua, S; Asikainen, S

    1999-04-01

    Actinobacillus actinomycetemcomitans isolates from 356 individuals were screened for identification of serotype e in order to investigate its distribution in relation to periodontal status. From subjects with serotype e, 1-6 isolates per subject (n = 61) were genotyped using arbitrarily primed-polymerase chain reaction (AP-PCR) and apaH gene polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) analysis to determine the genetic heterogeneity within the serotype. Furthermore, one serotype e strain per subject was tested for fermentation of 8 carbohydrates for biotyping. Among patients with adult periodontitis (n = 219), localized juvenile periodontitis (n = 55) and other forms of early-onset periodontitis (n = 18) serotypes b, a and c, respectively, were the most frequently detected serotypes. Non-periodontitis subjects (n = 64) were predominantly colonized with serotype c. Serotype e was found in 30 (14%) adult periodontitis patients, 2 (11%) early-onset periodontitis patients and in 5 (8%) non-periodontitis individuals, but in none of the 55 localized juvenile periodontitis patients. AP-PCR distinguished 3 and apaH gene PCR-RFLP analysis 2 genotypes among the 61 A. actinomycetemcomitans serotype e isolates, one genotype per subject. The AP-PCR genotypes 1 and 3 represented the apaH genotype 1 and the AP-PCR genotype 2 the apaH genotype 2. On the basis of variable fermentation of galactose and xylose, 3 biotypes among A. actinomycetemcomitans serotype e were established. Contrary to the absence of A. actinomycetemcomitans serotype e in localized juvenile periodontitis patients, its detection frequency was comparable among other forms of periodontitis and periodontal health. Clinical serotype e isolates form at least 2 genetic types and 3 biotypes. PMID:10219168

  2. Early-versus late-onset Alzheimer's disease: more than age alone.

    PubMed

    Koedam, Esther L G E; Lauffer, Vivian; van der Vlies, Annelies E; van der Flier, Wiesje M; Scheltens, Philip; Pijnenburg, Yolande A L

    2010-01-01

    Alzheimer's disease (AD) is the most common cause of dementia at older age. Although less prevalent before the age of 65 years, it is still the most frequent cause of early-onset dementia followed by frontotemporal dementia. The typical presentation of AD is memory dysfunction, however, presentations with prominent cognitive impairment in other domains besides memory, like prominent apraxia, language problems, or executive dysfunction, may occur and are relatively more common in early-onset AD. In this retrospective descriptive study, we determined the prevalence of non-memory presentations in a large sample of early-onset AD patients compared to late-onset AD. The clinical files of 270 patients with AD starting before the age of 65 years and 90 patients with late-onset AD ( 65 years) were reviewed to assess clinical characteristics. Patients were classified as memory presentation and non-memory presentation according to their clinical presentation. The mean age of the early-onset group was 56 +/- 5 years and 74 +/- 6 years for the late-onset group. A third of the early-onset AD group presented with non-memory symptoms compared to only 6% in the late-onset group (p < 0.001). Within the group with non-memory presentations, apraxia/visuospatial dysfunction was the most prevalent presenting symptom (12%). Patients with early-onset AD often present with a non-memory phenotype, of which apraxia/visuospatial dysfunction is the most common presenting symptom. Atypical presentations of AD should be considered in the clinical differential diagnosis of early-onset dementia. PMID:20061618

  3. Benefits of Early Systemic Antibiotics in Localized Aggressive Periodontitis. A Retrospective Study

    PubMed Central

    Beliveau, Dennis; Magnusson, Ingvar; Bidwell, John A.; Zapert, Edward F.; Aukhil, Ikramuddin; Wallet, Shannon M.; Shaddox, Luciana M.

    2012-01-01

    Treatment of localized aggressive periodontitis (LAP) may include systemic antibiotics, yet it is unclear at what stage of treatment planning antibiotics are most effective. Aim This retrospective analysis compared immediate vs. delayed antibiotic therapy on clinical parameters and gingival crevicular fluid (GCF) inflammatory mediators. Material and Methods At baseline, 3 and 6 months after treatment, clinical parameters [probing depth (PD), attachment level (CAL), bleeding on probing (BoP), and plaque] and GCF were collected from LAP participants, who received a 7-day antibiotic regimen immediately (ImA) or 3 months following (DelA) mechanical therapy. Results While both groups presented significant CAL reductions at 6 months, only ImA resulted in a reduction in mean PD at both 3 and 6 months, along with reductions in CAL and BoP at 3 months following therapy. In addition, GCF mediators were higher in DelA group at 3 months post-mechanical treatment, but were significantly reduced 6 months following antibiotic therapy. Conclusions ImA and DelA regimens were both effective in improving CAL by 6 months post-therapy. However, ImA allowed for better improvement in overall clinical parameters early in the course of treatment, concomitant with lower levels of inflammatory mediators within the GCF. PMID:22931240

  4. Increased Genetic Vulnerability to Smoking at CHRNA5 in Early-Onset Smokers

    PubMed Central

    Hartz, Sarah M.; Short, Susan E.; Saccone, Nancy L.; Culverhouse, Robert; Chen, LiShiun; Schwantes-An, Tae-Hwi; Coon, Hilary; Han, Younghun; Stephens, Sarah H.; Sun, Juzhong; Chen, Xiangning; Ducci, Francesca; Dueker, Nicole; Franceschini, Nora; Frank, Josef; Geller, Frank; Gu?bjartsson, Daniel; Hansel, Nadia N.; Jiang, Chenhui; Keskitalo-Vuokko, Kaisu; Liu, Zhen; Lyytikinen, Leo-Pekka; Michel, Martha; Rawal, Rajesh; Hum, Sc; Rosenberger, Albert; Scheet, Paul; Shaffer, John R.; Teumer, Alexander; Thompson, John R.; Vink, Jacqueline M.; Vogelzangs, Nicole; Wenzlaff, Angela S.; Wheeler, William; Xiao, Xiangjun; Yang, Bao-Zhu; Aggen, Steven H.; Balmforth, Anthony J.; Baumeister, Sebastian E.; Beaty, Terri; Bennett, Siiri; Bergen, Andrew W.; Boyd, Heather A.; Broms, Ulla; Campbell, Harry; Chatterjee, Nilanjan; Chen, Jingchun; Cheng, Yu-Ching; Cichon, Sven; Couper, David; Cucca, Francesco; Dick, Danielle M.; Foroud, Tatiana; Furberg, Helena; Giegling, Ina; Gu, Fangyi; Hall, Alistair S.; Hllfors, Jenni; Han, Shizhong; Hartmann, Annette M.; Hayward, Caroline; Heikkil, Kauko; Lic, Phil; Hewitt, John K.; Hottenga, Jouke Jan; Jensen, Majken K.; Jousilahti, Pekka; Kaakinen, Marika; Kittner, Steven J.; Konte, Bettina; Korhonen, Tellervo; Landi, Maria-Teresa; Laatikainen, Tiina; Leppert, Mark; Levy, Steven M.; Mathias, Rasika A.; McNeil, Daniel W.; Medland, Sarah E.; Montgomery, Grant W.; Muley, Thomas; Murray, Tanda; Nauck, Matthias; North, Kari; Pergadia, Michele; Polasek, Ozren; Ramos, Erin M.; Ripatti, Samuli; Risch, Angela; Ruczinski, Ingo; Rudan, Igor; Salomaa, Veikko; Schlessinger, David; Styrkrsdttir, Unnur; Terracciano, Antonio; Uda, Manuela; Willemsen, Gonneke; Wu, Xifeng; Abecasis, Goncalo; Barnes, Kathleen; Bickebller, Heike; Boerwinkle, Eric; Boomsma, Dorret I.; Caporaso, Neil; Duan, Jubao; Edenberg, Howard J.; Francks, Clyde; Gejman, Pablo V.; Gelernter, Joel; Grabe, Hans Jrgen; Hops, Hyman; Jarvelin, Marjo-Riitta; Viikari, Jorma; Khnen, Mika; Kendler, Kenneth S.; Lehtimki, Terho; Levinson, Douglas F.; Marazita, Mary L.; Marchini, Jonathan; Melbye, Mads; Mitchell, Braxton D.; Murray, Jeffrey C.; Nthen, Markus M.; Penninx, Brenda W.; Raitakari, Olli; Rietschel, Marcella; Rujescu, Dan; Samani, Nilesh J.; Sanders, Alan R.; Schwartz, Ann G.; Shete, Sanjay; Shi, Jianxin; Spitz, Margaret; Stefansson, Kari; Swan, Gary E.; Thorgeirsson, Thorgeir; Vlzke, Henry; Wei, Qingyi; Wichmann, H.-Erich; Amos, Christopher I.; Breslau, Naomi; Cannon, Dale S.; Ehringer, Marissa; Grucza, Richard; Hatsukami, Dorothy; Heath, Andrew; Johnson, Eric O.; Kaprio, Jaakko; Madden, Pamela; Martin, Nicholas G.; Stevens, Victoria L.; Stitzel, Jerry A.; Weiss, Robert B.; Kraft, Peter; Bierut, Laura J.

    2012-01-01

    Context Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. Objective To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. Data Sources Primary data. Study Selection Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. Data Extraction Uniform statistical analysis scripts were run locally. Starting with 94 050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ?10) with age-at-onset information, reducing the sample size to 33 348. Each study was stratified into early-onset smokers (age at onset ?16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. Data Synthesis Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR]=1.45; 95% CI, 1.361.55; n=13 843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.211.33, n = 19 505) (P = .01). Conclusion These results highlight an increased genetic vulnerability to smoking in early-onset smokers. PMID:22868939

  5. Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping

    PubMed Central

    Prahalad, Sampath; Walters, Thomas; Guthery, Stephen L.; Dubinsky, Marla; Baldassano, Robert; Crandall, Wallace V.; Rosh, Joel; Markowitz, James; Stephens, Michael; Kellermayer, Richard; Pfefferkorn, Marian; Heyman, Melvin B.; LeLeiko, Neal; Mack, David; Moulton, Dedrick; Kappelman, Michael D.; Kumar, Archana; Prince, Jarod; Bose, Promita; Mondal, Kajari; Ramachandran, Dhanya; Bohnsack, John F.; Griffiths, Anne M.; Haberman, Yael; Essers, Jonah; Thompson, Susan D.; Aronow, Bruce; Keljo, David J.; Hyams, Jeffrey S.; Denson, Lee A.; Kugathasan, Subra

    2015-01-01

    Background The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent. Methods We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohns disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohns disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases. Conclusions The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD. PMID:26098103

  6. Does early-onset Alzheimer disease constitute a distinct subtype? The contribution of molecular genetics.

    PubMed

    Harvey, R J; Rossor, M N

    1995-01-01

    Alzheimer disease (AD) is a clinical and pathologic diagnosis and refers to the findings of neurofibrillary tangles and amyloid plaques in the brain of a patient with dementia. Clinically it is recognized that there are familial and sporadic forms, with further division into those with presenile and senile onset. Clinical, neuroimaging, neuropathological, and neurochemical studies have attempted to identify differences between cases with an earlier and later onset, but have not identified a categorical biologic difference between the two groups. Recent advances in the molecular genetics of familial Alzheimer disease (FAD) and the discovery of defined genetic abnormalities have provided a robust approach to distinguishing between early- and late-onset cases within the group of autosomal dominant FAD. The precise biologic classification made possible by molecular genetic analysis of FAD provides a benchmark against which phenotypic differences can be assessed. This article argues that future studies will be able to contrast early-onset familial versus late-onset familial disease, and early-onset familial versus early-onset sporadic disease. Previous reports of phenotypic differences within AD may have been the result of including FAD within early-onset groups, though this remains to be established. PMID:7546599

  7. Immediate, Early, and Conventional Implant Placement in a Patient with History of Periodontitis

    PubMed Central

    Lanza, Alessandro; Scognamiglio, Fabio; Femiano, Felice; Lanza, Michele

    2015-01-01

    The aim of this paper is to describe a case of implant-prosthetic rehabilitation in a patient with periodontitis, focusing on the different timing of implant placement. After initial periodontal treatment, teeth with advanced mobility degree and severe bone resorption were extracted. At different healing time oral implants were placed in a prosthetic-guided position. After osseointegration period the implants were loaded and the results at one year of follow-up are presented. PMID:25949833

  8. Recurrent papilloedema and early onset optic atrophy in Behet's syndrome.

    PubMed Central

    Teh, L S; O'Connor, G M; O'Sullivan, M M; Pandit, J C; Beck, L; Williams, B D

    1990-01-01

    Two patients with Behet's syndrome and intracranial hypertension are reported. One developed a recurrence of papilloedema while receiving treatment but eventually made a full recovery, whereas the other developed optic atrophy within three months of onset despite treatment. Images PMID:2383068

  9. Social Anxiety and Onset of Drinking in Early Adolescence

    ERIC Educational Resources Information Center

    Tomlinson, Kristin L.; Cummins, Kevin M.; Brown, Sandra A.

    2013-01-01

    The present study examines several types of social anxiety that may be associated with the onset of alcohol use in middle school students, and whether the relationship differs by sex and grade. Students in the seventh and eighth grades (N = 2,621) completed the Social Anxiety Scale for Adolescents and a measure of lifetime drinking via schoolwide

  10. Early-Onset Obsessive-Compulsive Disorder: A Subgroup with a Specific Clinical and Familial Pattern?

    ERIC Educational Resources Information Center

    Chabane, Nadia; Delorme, Richard; Millet, Bruno; Mouren, Marie-Christine; Leboyer, Marion; Pauls, David

    2005-01-01

    Background: The familial nature of obsessive-compulsive disorder (OCD) has been previously demonstrated. The identification of candidate symptoms such as age at onset may help to disentangle the clinical and genetic heterogeneity of the disorder. In this study, the specificity of early-onset OCD was investigated, focusing on the effect of gender,…

  11. Alcohol Abuse and the Elderly: Comparison of Early & Late-Life Onset.

    ERIC Educational Resources Information Center

    Schonfeld, Lawrence; And Others

    Two types of elderly alcohol abusers are described. Early onset or long-term alcohol abusers are abusers with long-standing behavioral problems considered well known to the social service delivery system. Late-life onset elderly alcohol abusers are those whose drinking problems began in the later years, after age 50, often in response to stresses

  12. Early-Onset Obsessive-Compulsive Disorder: A Subgroup with a Specific Clinical and Familial Pattern?

    ERIC Educational Resources Information Center

    Chabane, Nadia; Delorme, Richard; Millet, Bruno; Mouren, Marie-Christine; Leboyer, Marion; Pauls, David

    2005-01-01

    Background: The familial nature of obsessive-compulsive disorder (OCD) has been previously demonstrated. The identification of candidate symptoms such as age at onset may help to disentangle the clinical and genetic heterogeneity of the disorder. In this study, the specificity of early-onset OCD was investigated, focusing on the effect of gender,

  13. White Matter Abnormalities in Early-Onset Schizophrenia: A Voxel-Based Diffusion Tensor Imaging Study

    ERIC Educational Resources Information Center

    Kumra, Sanjiv; Ashtari, Manzar; Cervellione, Kelly L.; Henderson, Inika; Kester, Hana; Roofeh, David; Wu, Jinghui; Clarke, Tana; Thaden, Emily; Kane, John M.; Rhinewine, Joseph; Lencz, Todd; Diamond, Alan; Ardekani, Babak A.; Szeszko, Philip R.

    2005-01-01

    Objective: To investigate abnormalities in the structural integrity of brain white matter as suggested by diffusion tensor imaging in adolescents with early-onset schizophrenia (onset of psychosis by age 18). Method: Twenty-six patients with schizophrenia and 34 age- and gender-matched healthy volunteers received diffusion tensor imaging and

  14. Global and Temporal Cortical Folding in Patients with Early-Onset Schizophrenia

    ERIC Educational Resources Information Center

    Penttila, Jani; Paillere-Martinot, Marie-Laure; Martinot, Jean-Luc; Mangin, Jean-Francois; Burke, Lisa; Corrigall, Richard; Frangou, Sophia; Cachia, Arnaud

    2008-01-01

    Disturbances in the temporal lobes and alterations in cortical folding in adult on-set schizophrenia are studied using magnetic resonance T1 images of 51 patients. The study showed that patients with early on-set schizophrenia had lower global sulcal indices in both hemispheres and the left collateral sulcus has a lower sulcal index irrespective…

  15. Global and Temporal Cortical Folding in Patients with Early-Onset Schizophrenia

    ERIC Educational Resources Information Center

    Penttila, Jani; Paillere-Martinot, Marie-Laure; Martinot, Jean-Luc; Mangin, Jean-Francois; Burke, Lisa; Corrigall, Richard; Frangou, Sophia; Cachia, Arnaud

    2008-01-01

    Disturbances in the temporal lobes and alterations in cortical folding in adult on-set schizophrenia are studied using magnetic resonance T1 images of 51 patients. The study showed that patients with early on-set schizophrenia had lower global sulcal indices in both hemispheres and the left collateral sulcus has a lower sulcal index irrespective

  16. White Matter Abnormalities in Early-Onset Schizophrenia: A Voxel-Based Diffusion Tensor Imaging Study

    ERIC Educational Resources Information Center

    Kumra, Sanjiv; Ashtari, Manzar; Cervellione, Kelly L.; Henderson, Inika; Kester, Hana; Roofeh, David; Wu, Jinghui; Clarke, Tana; Thaden, Emily; Kane, John M.; Rhinewine, Joseph; Lencz, Todd; Diamond, Alan; Ardekani, Babak A.; Szeszko, Philip R.

    2005-01-01

    Objective: To investigate abnormalities in the structural integrity of brain white matter as suggested by diffusion tensor imaging in adolescents with early-onset schizophrenia (onset of psychosis by age 18). Method: Twenty-six patients with schizophrenia and 34 age- and gender-matched healthy volunteers received diffusion tensor imaging and…

  17. Early-Onset, Regular Cannabis Use Is Linked to IQ Decline

    MedlinePLUS

    ... Is Linked to IQ Decline Early-Onset, Regular Cannabis Use Is Linked to IQ Decline Email Facebook ... that cannabis use may harm the developing brain. Cannabis Use Correlates With Cognitive Decline The study participants ...

  18. Treatment of Early Onset Schizophrenia: Recent Trends, Challenges and Future Considerations

    PubMed Central

    Vyas, Nora S.; Gogtay, Nitin

    2012-01-01

    Early onset schizophrenia (onset before adulthood) is a rare, severe, and chronic form of schizophrenia. The clinical presentation of schizophrenia at this unusually early age of onset has been associated with premorbid developmental abnormalities, poor response to neuroleptic treatment, greater admission rates, and poor prognosis. This is a brief, condensed review of current treatment strategies for the early onset population highlighting the need for novel treatment strategies for these generally treatment-refractory cases. Based on the current literature, second-generation antipsychotics remain the mainstay of treatment, although current medications provide suboptimal response at best. Based on the adult literature, combining antipsychotic treatment with psychotherapeutic intervention may be a more comprehensive treatment strategy. Indeed, early detection, identification of relevant biomarkers, coupled with advancing knowledge of the neurochemical and neuroanatomic pathways may help design informed and novel treatment strategies. PMID:22485097

  19. Substance abuse treatment patients with early onset cocaine use respond as well to contingency management interventions as those with later onset cocaine use.

    PubMed

    Weiss, Lindsay M; Petry, Nancy M

    2014-08-01

    Early onset drug use is associated with increased risk of developing substance use disorders, but relatively little is known about the correlates of early drug use among adults receiving treatment. A retrospective analysis of a randomized study of contingency management treatment compared cocaine-dependent patients who reported initial cocaine use at age 14 or younger (n = 41) to those who began using after age 14 (n = 387). Patients with early onset cocaine use had more legal and psychiatric problems than those who initiated cocaine use later. Patients with early-onset cocaine use also dropped out of treatment sooner and achieved less sustained abstinence than those who began using at older ages, but the interaction between age of first use and treatment condition was not significant. Early-onset cocaine use is associated with persistent psychosocial problems and an overall poor response to treatment. However, contingency management is efficacious in improving outcomes in early onset cocaine users. PMID:24865619

  20. The solved and unsolved mysteries of the genetics of early-onset Alzheimer's disease.

    PubMed

    Rogaeva, Ekaterina

    2002-01-01

    Approximately half of the Alzheimer's disease (AD) cases that are associated with early onset appear to be transmitted as a pure genetic, autosomal dominant trait. Genetic analyses of these pedigrees have found three causal genes: betaAPP, presenilin 1 (PS1), and presenilin 2 (PS2). This review provides an update on the pathological consequences of mutations in early-onset AD genes, the phenotypic heterogeneity of those cases, and future directions for research and clinical practice. PMID:12230301

  1. Aggressive and acute periodontal diseases.

    PubMed

    Albandar, Jasim M

    2014-06-01

    Inflammatory periodontal diseases are highly prevalent, although most of these diseases develop and progress slowly, often unnoticed by the affected individual. However, a subgroup of these diseases include aggressive and acute forms that have a relatively low prevalence but show a rapid-course, high rate of progression leading to severe destruction of the periodontal tissues, or cause systemic symptoms that often require urgent attention from healthcare providers. Aggressive periodontitis is an early-onset, destructive disease that shows a high rate of periodontal progression and distinctive clinical features. A contemporary case definition of this disease is presented. Population studies show that the disease is more prevalent in certain geographic regions and ethnic groups. Aggressive periodontitis is an infectious disease, and recent data show that in affected subjects the subgingival microbiota is composed of a mixed microbial infection, with a wide heterogeneity in the types and proportions of microorganisms recovered. Furthermore, there are significant differences in the microbiota of the disease among different geographic regions and ethnicities. There is also evidence that the Aggregatibacter actinomycetemycomitans-JP2 clone may play an important role in the development of the disease in certain populations. The host response plays an important role in the susceptibility to aggressive periodontitis, where the immune response may be complex and involve multiple mechanisms. Also, genetic factors seem to play an important role in the pathogenesis of this disease, but the mechanisms of increased susceptibility are complex and not yet fully understood. The available data suggest that aggressive periodontitis is caused by mutations either in a few major genes or in multiple small-effect genes, and there is also evidence of gene-gene and gene-environment interaction effects. Diagnostic methods for this disease, based on a specific microbiologic, immunologic or genetic profile, currently do not exist. Genetic markers have the potential to be implemented as screening tools to identify subjects at risk. This approach may significantly enhance treatment outcome through the early detection and treatment of affected subjects, as well as using future approaches based on gene therapy. At present, the treatment of this disease is directed toward elimination of the subgingival bacterial load and other local risk factors. Adjunctive use of appropriate systemic antibiotics is recommended and may contribute to a longer suppression of the microbial infection. Other aggressive forms of periodontal diseases occur in patients who are affected with certain systemic diseases, including the leukocyte adhesion deficiency syndrome, Papillon-Lefvre syndrome, Chediak-Higashi syndrome and Down syndrome. Management of the periodontal component of these diseases is very challenging. Acute gingival and periodontal lesions include a group of disorders that range from nondestructive to destructive forms, and these lesions are usually associated with pain and are a common reason for emergency dental consultations. Some of these lesions may cause a rapid and severe destruction of the periodontal tissues and loss of teeth. Oral infections, particularly acute infections, can spread to extra-oral sites and cause serious medical complications, and even death. Hence, prompt diagnosis and treatment are paramount. PMID:24738583

  2. Episodic and semantic memory in early versus late onset Alzheimer's disease.

    PubMed

    Grosse, D A; Gilley, D W; Wilson, R S

    1991-11-01

    The aim of this study was to replicate and extend previous work demonstrating selective impairment of semantic, but not episodic, memory in late versus early onset Alzheimer's disease (AD). Measures of episodic and semantic memory were administered to 12 pairs of patients; early (less than or equal to 62) and late (greater than or equal to 68) onset pairs were matched on dementia severity and education. As hypothesized, the groups did not differ on the three episodic memory measures but did on two of three semantic memory measures. In conjunction with prior research, these findings indicate that late onset AD is characterized by more profound impairment on measures of semantic processing. PMID:1777810

  3. Management of neonates with suspected or proven early-onset bacterial sepsis.

    PubMed

    Polin, Richard A

    2012-05-01

    With improved obstetrical management and evidence-based use of intrapartum antimicrobial therapy, early-onset neonatal sepsis is becoming less frequent. However, early-onset sepsis remains one of the most common causes of neonatal morbidity and mortality in the preterm population. The identification of neonates at risk for early-onset sepsis is frequently based on a constellation of perinatal risk factors that are neither sensitive nor specific. Furthermore, diagnostic tests for neonatal sepsis have a poor positive predictive accuracy. As a result, clinicians often treat well-appearing infants for extended periods of time, even when bacterial cultures are negative. The optimal treatment of infants with suspected early-onset sepsis is broad-spectrum antimicrobial agents (ampicillin and an aminoglycoside). Once a pathogen is identified, antimicrobial therapy should be narrowed (unless synergism is needed). Recent data suggest an association between prolonged empirical treatment of preterm infants (?5 days) with broad-spectrum antibiotics and higher risks of late onset sepsis, necrotizing enterocolitis, and mortality. To reduce these risks, antimicrobial therapy should be discontinued at 48 hours in clinical situations in which the probability of sepsis is low. The purpose of this clinical report is to provide a practical and, when possible, evidence-based approach to the management of infants with suspected or proven early-onset sepsis. PMID:22547779

  4. Different cellular and molecular mechanisms for early and late-onset myelin protein zero mutations.

    PubMed

    Grandis, Marina; Vigo, Tiziana; Passalacqua, Mario; Jain, Manisha; Scazzola, Sara; La Padula, Veronica; Brucal, Michelle; Benvenuto, Federica; Nobbio, Lucilla; Cadoni, Angela; Mancardi, Gian Luigi; Kamholz, John; Shy, Michael E; Schenone, Angelo

    2008-07-01

    Mutations in the gene MPZ, encoding myelin protein zero (MPZ), cause inherited neuropathies collectively called Charcot-Marie-Tooth type 1B (CMT1B). Based on the age of onset, clinical and pathological features, most MPZ mutations are separable into two groups: one causing a severe, early-onset, demyelinating neuropathy and a second, causing a late-onset neuropathy with prominent axonal loss. To investigate potential pathomechanisms underlying the two phenotypes, we transiently transfected HeLa cells with two late-onset (T95M, H10P) and two early-onset (H52R, S22_W28 deletion) mutations and analyzed their effects on intracellular protein trafficking, glycosylation, cell viability and intercellular adhesion. We found that the two late-onset mutations were both transported to the cell membrane and moderately reduced MPZ-mediated intercellular adhesion. The two early-onset mutations caused two distinct abnormalities. H52R was correctly glycosylated and trafficked to the plasma membrane, but strongly affected intercellular adhesion. When co-expressed with wild-type MPZ (wtMPZ), a functional dominant negative effect was observed. Alternatively, S22_W28 deletion was retained within the cytoplasm and reduced both adhesion caused by wtMPZ and cellular viability. Since the same trafficking patterns were observed in transfected murine Schwann cells, they are not an artifact of heterologous cell expression. Our results suggest that at least some late-onset mutations cause a partial loss of function in the transfected cells, whereas multiple abnormal gain of function pathways can result in early-onset neuropathy. Further characterization of these pathways will lead to a better understanding of the pathogenesis of CMT1B and a rational basis for treating these debilitating inherited neuropathies. PMID:18337304

  5. Predictors of Early-Onset Permanent Hearing Loss in Malnourished Infants in Sub-Saharan Africa

    ERIC Educational Resources Information Center

    Olusanya, Bolajoko O.

    2011-01-01

    The objective of this study was to determine the predictors of early-onset permanent hearing loss (EPHL) among undernourished infants in a low-income country where routine screening for developmental disabilities in early childhood is currently unattainable. All infants attending four community-based clinics for routine immunization who met the

  6. Depression and Anxiety Symptoms: Onset, Developmental Course and Risk Factors during Early Childhood

    ERIC Educational Resources Information Center

    Cote, Sylvana M.; Boivin, Michel; Liu, Xuecheng; Nagin, Daniel S.; Zoccolillo, Mark; Tremblay, Richard E.

    2009-01-01

    Background: Depressive and anxiety disorders are among the top ten leading causes of disabilities. We know little, however, about the onset, developmental course and early risk factors for depressive and anxiety symptoms (DAS). Objective: Model the developmental trajectories of DAS during early childhood and to identify risk factors for atypically

  7. Predictors of Early-Onset Permanent Hearing Loss in Malnourished Infants in Sub-Saharan Africa

    ERIC Educational Resources Information Center

    Olusanya, Bolajoko O.

    2011-01-01

    The objective of this study was to determine the predictors of early-onset permanent hearing loss (EPHL) among undernourished infants in a low-income country where routine screening for developmental disabilities in early childhood is currently unattainable. All infants attending four community-based clinics for routine immunization who met the…

  8. Depression and Anxiety Symptoms: Onset, Developmental Course and Risk Factors during Early Childhood

    ERIC Educational Resources Information Center

    Cote, Sylvana M.; Boivin, Michel; Liu, Xuecheng; Nagin, Daniel S.; Zoccolillo, Mark; Tremblay, Richard E.

    2009-01-01

    Background: Depressive and anxiety disorders are among the top ten leading causes of disabilities. We know little, however, about the onset, developmental course and early risk factors for depressive and anxiety symptoms (DAS). Objective: Model the developmental trajectories of DAS during early childhood and to identify risk factors for atypically…

  9. Early-onset colorectal cancer: A separate subset of colorectal cancer

    PubMed Central

    Silla, Irene Osorio; Rueda, Daniel; Rodrguez, Yolanda; Garca, Juan Luis; de la Cruz Vigo, Felipe; Perea, Jos

    2014-01-01

    Colorectal cancer (CRC) has a great impact on the world population. With increasing frequency, CRC is described according to the presenting phenotype, based on its molecular characteristics. Classification of CRC tumors according to their genetic and/or epigenetic alterations is not only important for establishing the molecular bases of the disease, but also for predicting patient outcomes and developing more individualized treatments. Early-onset CRC is a heterogeneous disease, with a strong familial component, although the disease is sporadic in an important proportion of cases. Different molecular alterations appear to contribute to the apparent heterogeneity of the early-onset population and subgroups can be distinguished with distinct histopathologic and familial characteristics. Moreover, compared with late-onset CRC, there are characteristics that suggest that early-onset CRC may have a different molecular basis. The purpose of this review was to analyze the current state of knowledge about early-onset CRC with respect to clinicopathologic, familial and molecular features. Together, these features make it increasingly clear that this subset of CRC may be a separate disease, although it has much in common with late-onset CRC. PMID:25516639

  10. Common variants at five new loci associated with early-onset inflammatory bowel disease.

    PubMed

    Imielinski, Marcin; Baldassano, Robert N; Griffiths, Anne; Russell, Richard K; Annese, Vito; Dubinsky, Marla; Kugathasan, Subra; Bradfield, Jonathan P; Walters, Thomas D; Sleiman, Patrick; Kim, Cecilia E; Muise, Aleixo; Wang, Kai; Glessner, Joseph T; Saeed, Shehzad; Zhang, Haitao; Frackelton, Edward C; Hou, Cuiping; Flory, James H; Otieno, George; Chiavacci, Rosetta M; Grundmeier, Robert; Castro, Massimo; Latiano, Anna; Dallapiccola, Bruno; Stempak, Joanne; Abrams, Debra J; Taylor, Kent; McGovern, Dermot; Silber, Gary; Wrobel, Iwona; Quiros, Antonio; Barrett, Jeffrey C; Hansoul, Sarah; Nicolae, Dan L; Cho, Judy H; Duerr, Richard H; Rioux, John D; Brant, Steven R; Silverberg, Mark S; Taylor, Kent D; Barmuda, M Michael; Bitton, Alain; Dassopoulos, Themistocles; Datta, Lisa Wu; Green, Todd; Griffiths, Anne M; Kistner, Emily O; Murtha, Michael T; Regueiro, Miguel D; Rotter, Jerome I; Schumm, L Philip; Steinhart, A Hillary; Targan, Stephen R; Xavier, Ramnik J; Libioulle, Ccile; Sandor, Cynthia; Lathrop, Mark; Belaiche, Jacques; Dewit, Olivier; Gut, Ivo; Heath, Simon; Laukens, Debby; Mni, Myriam; Rutgeerts, Paul; Van Gossum, Andr; Zelenika, Diana; Franchimont, Denis; Hugot, J P; de Vos, Martine; Vermeire, Severine; Louis, Edouard; Cardon, Lon R; Anderson, Carl A; Drummond, Hazel; Nimmo, Elaine; Ahmad, Tariq; Prescott, Natalie J; Onnie, Clive M; Fisher, Sheila A; Marchini, Jonathan; Ghori, Jilur; Bumpstead, Suzannah; Gwillam, Rhian; Tremelling, Mark; Delukas, Panos; Mansfield, John; Jewell, Derek; Satsangi, Jack; Mathew, Christopher G; Parkes, Miles; Georges, Michel; Daly, Mark J; Heyman, Melvin B; Ferry, George D; Kirschner, Barbara; Lee, Jessica; Essers, Jonah; Grand, Richard; Stephens, Michael; Levine, Arie; Piccoli, David; Van Limbergen, John; Cucchiara, Salvatore; Monos, Dimitri S; Guthery, Stephen L; Denson, Lee; Wilson, David C; Grant, Straun F A; Daly, Mark; Silverberg, Mark S; Satsangi, Jack; Hakonarson, Hakon

    2009-12-01

    The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD. PMID:19915574

  11. Early onset type 2 diabetes: risk factors, clinical impact and management

    PubMed Central

    Idris, Iskandar

    2014-01-01

    Early onset type 2 diabetes mellitus (T2DM) is increasingly prevalent with a significant impact on the individual, healthcare service delivery and planning. The individuals are likely to be obese, lead a sedentary lifestyle, have a strong family history of T2DM, be of black and minority ethnic (BME) origin and come from a less affluent socioeconomic group. They have a heightened risk of developing microvascular and macrovascular complications, often at an earlier stage and with greater frequency than seen in type 1 diabetes. As such, early and aggressive risk factor management is warranted. Early onset T2DM is complex and impacts on service delivery with a need for multidisciplinary care of complications and comorbidities’, in addition to adequate educational and psychological support. This review on the impact of early onset T2DM provides the latest insights into this emerging epidemic. PMID:25364491

  12. Early Onset of Laying and Bumblefoot Favor Keel Bone Fractures.

    PubMed

    Gebhardt-Henrich, Sabine G; Fröhlich, Ernst K F

    2015-01-01

    Numerous studies have demonstrated influences of hybrid, feed, and housing on prevalence of keel bone fractures, but influences of behavior and production on an individual level are less known. In this longitudinal study, 80 white and brown laying hens were regularly checked for keel bone deviations and fractures while egg production was individually monitored using Radio Frequency Identification (RFID) from production until depopulation at 65 weeks of age. These focal birds were kept in eight pens with 20 hens per pen in total. About 62% of the hens had broken keel bones at depopulation. The occurrence of new fractures was temporally linked to egg laying: more new fractures occurred during the time when laying rates were highest. Hens with fractured keel bones at depopulation had laid their first egg earlier than hens with intact keel bones. However, the total number of eggs was neither correlated with the onset of egg laying nor with keel bone fractures. All birds with bumblefoot on both feet had a fracture at depopulation. Hens stayed in the nest for a longer time during egg laying during the ten days after the fracture than during the ten days before the fracture. In conclusion, a relationship between laying rates and keel bone fractures seems likely. PMID:26633520

  13. Early-onset hypoparathyroidism and chronic keratitis revealing APECED

    PubMed Central

    Mezgueldi, Ellia; Bertholet-Thomas, Aurlia; Milazzo, Solange; Morris, Michael; Bacchetta, Justine; Fabien, Nicole; Cochat, Pierre; Weetman, Anthony P; Kemp, Elizabeth Helen; Belot, Alexandre

    2015-01-01

    Key Clinical Message Early diagnosis of potentially life-threatening autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is crucial, but is often delayed due to the clinical heterogeneity of the disorder. Even in the absence of the classic disease triad of chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical insufficiency, a diagnosis of APECED should be considered in children who have hypoparathyroidism and chronic keratitis, with a past medical history showing a mild and transient Candida infection. PMID:26509012

  14. Prevention of Early-onset Neonatal Group B Streptococcal Disease

    PubMed Central

    Marió, M. J. Soto; Valenzuela, I; Vásquez, A. E; Illanes, S. E

    2013-01-01

    Streptococcus agalactiae, also known as Group B Streptococcus (GBS), is an opportunistic pathogen that colonizes the gastrointestinal and genitourinary tracts of up to 50% of healthy adults and newborns; it is responsible for significant morbidity and mortality. Early detection can be used to establish the use of antibiotic prophylaxis to significantly reduce neonatal sepsis. This article reviews methods of detection and prevention of GBS infection in the neonate. PMID:24358406

  15. Early onset parkinsonism in dementia lacking distinct histopathological features.

    PubMed

    Bergareche, A; Martí-Massó, J F; Linacasoro, G; Arrinda, J M; De Arce, A

    2006-01-01

    Dementia lacking distinct histopathological features (DLDHF) belongs to the frontotemporal dementia syndromes. Behavioral, cognitive and motor symptoms are its usual clinical manifestations. However, considerable heterogeneity exists and no evident clinicopathological correlations can be performed. We report a patient who presented with a very unusual combination of behavioral abnormalities and prominent early parkinsonism progressing to a severe dementia. Pathological studies confirmed DLDHF with severe frontal and striatal neuronal loss and gliosis. PMID:16465769

  16. Early Onset of Laying and Bumblefoot Favor Keel Bone Fractures

    PubMed Central

    Gebhardt-Henrich, Sabine G.; Frhlich, Ernst K. F.

    2015-01-01

    Simple Summary Numerous studies have documented a high prevalence of keel bone fractures in laying hens. In this longitudinal study, 80 white and brown laying hens were regularly checked for keel bone deviations and fractures while egg production was individually monitored. About 62% of the hens had broken keel bones at depopulation. More new fractures occurred during the time when laying rates were highest. Hens with broken keel bones at depopulation had laid their first egg earlier than hens with intact keel bones. All birds with bumblefoot on both feet had a fracture at depopulation. Abstract Numerous studies have demonstrated influences of hybrid, feed, and housing on prevalence of keel bone fractures, but influences of behavior and production on an individual level are less known. In this longitudinal study, 80 white and brown laying hens were regularly checked for keel bone deviations and fractures while egg production was individually monitored using Radio Frequency Identification (RFID) from production until depopulation at 65 weeks of age. These focal birds were kept in eight pens with 20 hens per pen in total. About 62% of the hens had broken keel bones at depopulation. The occurrence of new fractures was temporally linked to egg laying: more new fractures occurred during the time when laying rates were highest. Hens with fractured keel bones at depopulation had laid their first egg earlier than hens with intact keel bones. However, the total number of eggs was neither correlated with the onset of egg laying nor with keel bone fractures. All birds with bumblefoot on both feet had a fracture at depopulation. Hens stayed in the nest for a longer time during egg laying during the ten days after the fracture than during the ten days before the fracture. In conclusion, a relationship between laying rates and keel bone fractures seems likely. PMID:26633520

  17. Brain Structure Changes Visualized in Early- and Late-Onset Blind Subjects

    PubMed Central

    Lepor, Natasha; Voss, Patrice; Lepore, Franco; Chou, Yi-Yu; Fortin, Madeleine; Gougoux, Frdric; Lee, Agatha D.; Brun, Caroline; Lassonde, Maryse; Madsen, Sarah K.; Toga, Arthur W.; Thompson, Paul M.

    2009-01-01

    We examine 3D patterns of volume differences in the brain associated with blindness, in subjects grouped according to early and late onset. Using tensor-based morphometry, we map volume reductions and gains in 16 early-onset (EB) and 16 late-onset (LB) blind adults (onset <5 and >14 years old, respectively) relative to 16 matched sighted controls. Each subjects structural MRI was fluidly registered to a common template. Anatomical differences between groups were mapped based on statistical analysis of the resulting deformation fields revealing profound deficits in primary and secondary visual cortices for both blind groups. Regions outside the occipital lobe showed significant hypertrophy, suggesting widespread compensatory adaptations. EBs but not LBs showed deficits in the splenium and hypertrophy in the isthmus. Gains in the isthmus and non-occipital white matter were more widespread in the EBs. These differences may reflect regional alterations in late neurodevelopmental processes, such as myelination, that continue into adulthood. PMID:19643183

  18. WT1 gene mutations in Chinese children with early onset nephrotic syndrome.

    PubMed

    Li, Jianguo; Ding, Jie; Zhao, Dan; Yu, Zihua; Fan, Qingfeng; Chen, Yan; Zhang, Hongwen; Zhong, Xuhui; Huang, Jianping; Yao, Yong; Xiao, Huijie

    2010-08-01

    In Chinese children with steroid-resistant nephrotic syndrome (SRNS), it was reported that NPHS2 mutation was detected in 4.3%, which was lower than that in Caucasians (10-30%). However, there were no data on WT1 mutation in nephrotic syndrome (NS), especially in early-onset NS of Chinese children. Thus, a study, which enrolled 36 Chinese children with early-onset (before 3 y old) NS and steroid resistance if failing steroid therapy (early-group), was conducted. As control, 35 children with SRNS and with disease onset age after 3 y old were also analyzed (control-group). WT1 gene was examined by PCR and direct sequencing. The result showed that in the early-group 6/36 (16.7%) were detected with WT1 mutations. Further analysis according to different onset age revealed that the mutation detection rates of WT1 were 26.3% (5/19), 6.3% (1/16), and 0 (0/1) in children younger than 1 y, 1-2 y, and 2-3 y, respectively. In control-group, no WT1 (0/35) mutation was detected. WT1 mutation combined with NPHS2 variant was detected in a girl. In conclusion, WT1 mutations seemed more common in Chinese children with early-onset NS. PMID:20442690

  19. The Use of Cannabis as a Predictor of Early Onset of Bipolar Disorder and Suicide Attempts

    PubMed Central

    Leite, Rafaela Torres Portugal; Nogueira, Sarah de Oliveira; do Nascimento, João Paulo Rodrigues; de Lima, Laisa Soares; da Nóbrega, Taís Bastos; Virgínio, Mariana da Silva; Moreno, Lucas Monte da Costa; Sampaio, Bruno Henrique Barbosa; Souza, Fábio Gomes de Matos e

    2015-01-01

    Introduction. Bipolar disorder (BD) implies risk of suicide. The age at onset (AAO) of BD carries prognostic significance. Substance abuse may precede the onset of BD and cannabis is the most common illicit drug used. The main goal of this study is to review the association of cannabis use as a risk factor for early onset of BD and for suicide attempts. Materials and Methods. PubMed database was searched for articles using key words “bipolar disorder,” “suicide attempts,” “cannabis,” “marijuana,” “early age at onset,” and “early onset.” Results. The following percentages in bipolar patients were found: suicide attempts 3.6–42%; suicide attempts and substance use 5–60%; suicide attempts and cannabis use 15–42%. An early AAO was associated with cannabis misuse. The mean age of the first manic episode in individuals with and without BD and cannabis use disorder (CUD) was 19.5 and 25.1 years, respectively. The first depressive episode was at 18.5 and 24.4 years, respectively. Individuals misusing cannabis showed increased risk of suicide. Discussion. Cannabis use is associated with increased risk of suicide attempts and with early AAO. However, the effect of cannabis at the AAO and suicide attempts is not clear. PMID:26097750

  20. Responses of early and late onset phrenic motoneurons to lung inflation.

    PubMed

    Donnelly, D F; Cohen, M I; Sica, A L; Zhang, H

    1985-07-01

    In anesthetized or decerebrate cats that were paralyzed and ventilated with a cycle-triggered pump, we produced changes in activity of the whole phrenic nerve and of individual phrenic motoneurons (fibers or cells in the spinal cord) by withholding lung inflation during the inspiratory (I) phase. The neurons were classified into early- and late-onset types (discharge onset less or greater than 80 msec, respectively, after whole phrenic onset). Both unit and whole phrenic activity exhibited a variety of responses to inflation (excitation, depression, or no effect); but there were no consistent differences between responses of early- and late-onset neurons. The distribution of responses was quite different from that of dorsal respiratory group (DRG) I neurons (Cohen and Feldman, 1984); in particular there was no group of phrenic neurons corresponding to the late-onset I-beta neurons (I neurons excited by inflation). We conclude that the inputs to late-onset phrenic neurons are not predominantly or exclusively from late-onset DRG neurons. PMID:4035116

  1. Early-onset unilateral electric cataract: a rare clinical entity.

    PubMed

    Mutlu, Fatih Mehmet; Duman, Haluk; Cil, Yakup

    2004-01-01

    Electrical injury may result in cataracts, which usually occur bilaterally. In this report, we present a rare complication of such an injury presenting as a unilateral cataract in a 33-year-old woman with a painless but gradual worsening of vision in her left eye 3 weeks after sustaining a high-voltage electrical injury. A cataract did not develop in the right eye during 26 months of follow-up. The patient underwent successful cataract surgery with an excellent return of vision. Electrical injuries may result in the formation of a unilateral cataract and therefore an ophthalmic examination should be performed regularly in the early recovery period of such injuries. Cataract surgery with intraocular lens implantation results in an excellent return of vision in patients with electrical cataract who do not have any other ocular damage. PMID:15247836

  2. Very early-onset inflammatory bowel disease: gaining insight through focused discovery.

    PubMed

    Moran, Christopher J; Klein, Christoph; Muise, Aleixo M; Snapper, Scott B

    2015-05-01

    The pathogenesis of pediatric inflammatory bowel disease (IBD) is only partially understood. Strong evidence implicates a strong genetic component including high monozygotic twin concordance and familial disease phenotype concordance rates. Genome-wide association studies have identified associations between >160 genetic loci and the risk for developing IBD. The roles of implicated genes are largely immune-mediated, although other functions include cellular migration, oxidative stress, and carbohydrate metabolism. Additionally, growing literature describes monogenic causes of IBD that frequently present as infantile or very early-onset IBD. The interplay between IBD risk single nucleotide polymorphisms and rare genetic variants has yet to be determined. Studying patients with very early-onset IBD may elicit genetic factors that could be applied to broader populations of IBD. This review describes what is known about the genetic causes of very early-onset IBD and genetic strategies that may unravel more of the genetic causes of IBD. PMID:25895007

  3. Systematic search for rare variants in Finnish early-onset colorectal cancer patients.

    PubMed

    Tanskanen, Tomas; Gylfe, Alexandra E; Katainen, Riku; Taipale, Minna; Renkonen-Sinisalo, Laura; Jrvinen, Heikki; Mecklin, Jukka-Pekka; Bhm, Jan; Kilpivaara, Outi; Pitknen, Esa; Palin, Kimmo; Vahteristo, Pia; Tuupanen, Sari; Aaltonen, Lauri A

    2015-01-01

    The heritability of colorectal cancer (CRC) is incompletely understood, and the contribution of undiscovered rare variants may be important. In search of rare disease-causing variants, we exome sequenced 22 CRC patients who were diagnosed before the age of 40 years. Exome sequencing data from 95 familial CRC patients were available as a validation set. Cases with known CRC syndromes were excluded. All patients were from Finland, a country known for its genetically homogenous population. We searched for rare nonsynonymous variants with allele frequencies below 0.1% in 3,374 Finnish and 58,112 non-Finnish controls. In addition, homozygous and compound heterozygous variants were studied. No genes with rare loss-of-function variants were present in more than one early-onset CRC patient. Three genes (ADAMTS4, CYTL1, and SYNE1) harbored rare loss-of-function variants in both early-onset and familial CRC cases. Five genes with homozygous variants in early-onset CRC cases were found (MCTP2, ARHGAP12, ATM, DONSON, and ROS1), including one gene (MCTP2) with a homozygous splice site variant. All discovered homozygous variants were exclusive to one early-onset CRC case. Independent replication is required to associate the discovered variants with CRC. These findings, together with a lack of family history in 19 of 22 (86%) early-onset patients, suggest genetic heterogeneity in unexplained early-onset CRC patients, thus emphasizing the requirement for large sample sizes and careful study designs to elucidate the role of rare variants in CRC susceptibility. PMID:25749350

  4. Classifying onset durations of early VLF events: Scattered field analysis and new insights

    NASA Astrophysics Data System (ADS)

    Kotovsky, D. A.; Moore, R. C.

    2015-08-01

    The physical processes responsible for a variety of early VLF scattering events have not yet been satisfactorily identified. Properly categorizing the early VLF event type is imperative to understand the causative physical processes involved. In this paper, the onset durations of 26 exceptionally high signal-to-noise ratio early VLF scattering events are analyzed, using scattered fields to classify events. New observations of events that exhibit "slow" amplitude changes, but "fast" scattered field changes are presented, which call into question previous analyses of early/slow events. We separately identify and analyze three early VLF events that definitively exhibit slow scattered field behavior. Additionally, we identify a significant number of events which have onset durations between the current definitions of fast and slow. Four events are observed which unambiguously exhibit a rapid initial rotation of the scattered field phasor during the first few seconds of the recovery stage. Possible physical mechanisms are discussed.

  5. Tissue engineered periodontal products.

    PubMed

    Bartold, P M; Gronthos, S; Ivanovski, S; Fisher, A; Hutmacher, D W

    2016-02-01

    Attainment of periodontal regeneration is a significant clinical goal in the management of advanced periodontal defects arising from periodontitis. Over the past 30 years numerous techniques and materials have been introduced and evaluated clinically and have included guided tissue regeneration, bone grafting materials, growth and other biological factors and gene therapy. With the exception of gene therapy, all have undergone evaluation in humans. All of the products have shown efficacy in promoting periodontal regeneration in animal models but the results in humans remain variable and equivocal concerning attaining complete biological regeneration of damaged periodontal structures. In the early 2000s, the concept of tissue engineering was proposed as a new paradigm for periodontal regeneration based on molecular and cell biology. At this time, tissue engineering was a new and emerging field. Now, 14 years later we revisit the concept of tissue engineering for the periodontium and assess how far we have come, where we are currently situated and what needs to be done in the future to make this concept a reality. In this review, we cover some of the precursor products, which led to our current position in periodontal tissue engineering. The basic concepts of tissue engineering with special emphasis on periodontal tissue engineering products is discussed including the use of mesenchymal stem cells in bioscaffolds and the emerging field of cell sheet technology. Finally, we look into the future to consider what CAD/CAM technology and nanotechnology will have to offer. PMID:25900048

  6. Genetic variability in SQSTM1 and risk of early-onset Alzheimer dementia: a European early-onset dementia consortium study.

    PubMed

    Cuyvers, Elise; van der Zee, Julie; Bettens, Karolien; Engelborghs, Sebastiaan; Vandenbulcke, Mathieu; Robberecht, Caroline; Dillen, Lubina; Merlin, Cline; Geerts, Nathalie; Graff, Caroline; Thonberg, Hkan; Chiang, Huei-Hsin; Pastor, Pau; Ortega-Cubero, Sara; Pastor, Maria A; Diehl-Schmid, Janine; Alexopoulos, Panagiotis; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Nacmias, Benedetta; Sorbi, Sandro; Sanchez-Valle, Raquel; Llad, Albert; Gelpi, Ellen; Almeida, Maria Rosrio; Santana, Isabel; Clarimon, Jordi; Lle, Alberto; Fortea, Juan; de Mendona, Alexandre; Martins, Madalena; Borroni, Barbara; Padovani, Alessandro; Mat?j, Radoslav; Rohan, Zdenek; Ruiz, Agustn; Frisoni, Giovanni B; Fabrizi, Gian Maria; Vandenberghe, Rik; De Deyn, Peter P; Van Broeckhoven, Christine; Sleegers, Kristel

    2015-05-01

    Meta-analysis of existing genome-wide association studies on Alzheimer's disease (AD) showed subgenome-wide association of an intronic variant in the sequestosome 1 (SQSTM1) gene with AD. We performed targeted resequencing of SQSTM1 in Flanders-Belgian AD patients selected to be enriched for a genetic background (n= 435) and geographically matched nonaffected individuals (n= 872) to investigate the role of both common and rare SQSTM1 variants. Results were extended to the European early-onset dementia cohorts (926 early-onset Alzheimer's disease [EOAD] patients and 1476 nonaffected individuals). Of the 61 detected exonic variants in SQSTM1, the majority were rare (n= 57). Rare variant (minor allele frequency <0.01) burden analysis did not reveal an increased frequency of rare variants in EOAD patients in any of the separate study populations nor when meta-analyzing all cohorts. Common variants p.D292= and p.R312= showed nominal association with AD (odds ratiop.D292== 1.11 [95% confidence interval= 1-1.22], p= 0.04), only when including the Flanders-Belgian cohort in the meta-analysis. We cannot exclude a role of SQSTM1 genetic variability in late-onset AD, but our data indicate that SQSTM1 does not play a major role in the etiology of EOAD. PMID:25796131

  7. Melatonin can induce early onset of the breeding season in ewes.

    PubMed

    Arendt, J; Symons, A M; Laud, C A; Pryde, S J

    1983-06-01

    Patterns of plasma melatonin, similar in the duration of high levels to those found in winter, were induced in Suffolk-cross ewes kept in summer light (16 h light: 8 h darkness) by daily oral administration of melatonin (3 mg/13 mumol). The onset of oestrous cycles in these sheep occurred in August, 2-8 weeks before the onset of oestrous cycles in untreated ewes kept in natural light. The onset of oestrous cycles in a further group of ewes kept in winter light (8 h light: 16 h darkness) from mid-June was indistinguishable from that of the melatonin-treated ewes. Rams were excluded from the premises. These data indicate that melatonin alone in physiological quantities is sufficient to induce early onset of the breeding season in the ewe, and provide strong evidence for a hormonal role of melatonin in a short-day breeder. PMID:6683298

  8. Assessment of Systemic Inflammatory Markers in Patients with Aggressive Periodontitis

    PubMed Central

    Iqbal, P Safar; Khan, S Nubesh; Haris, Mohamed; Narayanan, Mahesh; Laju, S; Kumar, Swaminathan Senthil

    2015-01-01

    Background: Aggressive periodontitis (AgP) is a destructive disease characterized by the following: The involvement of multiple teeth with a distinctive pattern of periodontal tissue loss; a high rate of disease progression; an early age of onset; and the absence of systemic diseases. Chronic low-level bacteremia and systemic inflammatory response have been suggested as a pathogenic link between periodontal disease and systemic disease. The present study was aimed to assess the levels of systemic inflammatory markers in patients with AgP. Methods: A sample of 50 systemically healthy patients comprised two groups, based on full mouth periodontal examination: Group I healthy individuals, includes 25 periodontally healthy subjects with fully functioning dentition. Group II includes 25 patients diagnosed clinically as AgP. Laboratory blood investigation included white blood cell (WBC) count, neutrophil count, lymphocyte count, and platelet count. Serum protein parameters included total protein (TP), albumin (ALB), and globulin (GLB). Periodontal clinical parameters including plaque index, gingival index, probing pocket depth, and clinical attachment level were recorded. Results: Data analysis shows an increase in WBC, neutrophil, lymphocyte, and platelet count and a decrease in TP, ALB, and GLB in AgP patients when compared to healthy individuals. Conclusion: Results of the present study shows an increase in blood parameters and decrease in serum protein parameters in AgP. Hence, AgP could be considered as one of the risk factors associated with the cardiovascular diseases as assessed by changes in the level of systemic inflammatory markers observed. PMID:26668481

  9. Topical and systemic antibiotics in the management of periodontal diseases.

    PubMed

    Mombelli, Andrea; Samaranayake, Lakshman P

    2004-02-01

    Both systemic and topical antibiotics are increasingly used in the management of periodontal infections. Whilst these drugs are used mostly on an empirical basis, some contend that rational use of antibiotics should be the norm due to their wide abuse and consequential global emergence of antibiotic resistance organisms. Here we review the rationale and principles of antimicrobial therapy, treatment goals, drug delivery routes and various antibiotics that are used in the management of periodontal diseases. The pros and cons of systemic and local antibiotic therapy are described together with practical guidelines for their delivery. The available data indicate, in general, that mechanical periodontal treatment alone is adequate to ameliorate or resolve the clinical condition in most cases, but adjunctive antimicrobial agents, delivered either locally or systemically, can enhance the effect of therapy in specific situations. This is particularly true for aggressive (early onset) periodontitis, in patients with generalised systemic disease that may affect host resistance and in case of poor response to conventional mechanical therapy. Locally delivered antibiotics together with mechanical debridement are indicated for non-responding sites of focal infection or in localised recurrent disease. After resolution of the periodontal infection, the patient should be placed on an individually tailored maintenance care programme. Optimal plaque control by the patient is of paramount importance for a favourable clinical and microbiological response to any form of periodontal therapy. PMID:15005467

  10. Differences in Comorbidity Profiles between Early-Onset and Late-Onset Alopecia Areata Patients: A Retrospective Study of 871 Korean Patients

    PubMed Central

    Lee, Noo Ri; Kim, Bo-Kyung; Yoon, Na Young; Lee, Sung-yul; Ahn, Seok-Yong

    2014-01-01

    Background Alopecia areata (AA) is a common dermatologic condition with a broad spectrum of clinical features and age of onset, classically characterized by nonscarring patches of hair loss. In the past, early-onset (before adolescence) AA has been associated with various autoimmune diseases, especially atopic diseases and lupus erythematosus and demonstrates a worse prognosis compared with late onset AA. Objective To evaluate the differences in the comorbidity profile of AA with regard to age at onset. Methods We completed a retrospective study of 871 Korean AA patients seen at our department within the last 10 years. After these patients were subdivided according to onset before or after age 13 years, the two groups were compared on the basis of their comorbid disorders, family history of AA, and hematologic test results. Results Our results demonstrate that significantly more patients in the early-onset group had a personal history of atopic dermatitis or family history of AA. These findings are consistent with previous reports associating early-onset AA with autoimmune diseases and a family history of AA in different ethnic populations. Most of the serologic test values showed no significant differences between the groups and the results were considerably affected by age. Conclusion This study is significant because it is a large group study in Korean AA patients, and Korean AA patients with an onset age before adolescence show similar clinical manifestations to other ethnic populations. PMID:25473224

  11. Very early onset and greater vulnerability in schizophrenia: A clinical and neuroimaging study

    PubMed Central

    Margari, Francesco; Presicci, Anna; Petruzzelli, Maria Giuseppina; Ventura, Patrizia; Di Cuonzo, Franca; Palma, Michele; Margari, Lucia

    2008-01-01

    Although schizophrenia has been diagnosed in children, this group of disorders has received too little attention in the clinical and research literature. Preliminary data suggest that early onset schizophrenia (EOS) and very early onset schizophrenia (VEOS) tend to have a worse outcome than adult onset schizophrenia, and seem to be related to a greater familial vulnerability, due to genetic, psychosocial, and environmental factors. Recently, advanced neuroimaging techniques have revealed structural and functional brain abnormalities in some cerebral areas. This paper reports on a case diagnosed as VEOS, with premorbid year-long psychopathological history. The patient showed atypical proton magnetic resonance spectroscopy findings, and normal brain and spine computer tomography and brain magnetic resonance images. PMID:19043525

  12. Very early onset and greater vulnerability in schizophrenia: A clinical and neuroimaging study.

    PubMed

    Margari, Francesco; Presicci, Anna; Petruzzelli, Maria Giuseppina; Ventura, Patrizia; Di Cuonzo, Franca; Palma, Michele; Margari, Lucia

    2008-08-01

    Although schizophrenia has been diagnosed in children, this group of disorders has received too little attention in the clinical and research literature. Preliminary data suggest that early onset schizophrenia (EOS) and very early onset schizophrenia (VEOS) tend to have a worse outcome than adult onset schizophrenia, and seem to be related to a greater familial vulnerability, due to genetic, psychosocial, and environmental factors. Recently, advanced neuroimaging techniques have revealed structural and functional brain abnormalities in some cerebral areas. This paper reports on a case diagnosed as VEOS, with premorbid year-long psychopathological history. The patient showed atypical proton magnetic resonance spectroscopy findings, and normal brain and spine computer tomography and brain magnetic resonance images. PMID:19043525

  13. Allelic association at the D14S43 locus in early onset Alzheimer`s disease

    SciTech Connect

    Brice, A.; Tardieu, S.; Campion, D.; Martinez, M.

    1995-04-24

    The D14S43 marker is closely linked to the major gene for early onset autosomal dominant Alzheimer`s disease on chromosome 14. Allelic frequencies at the D14S43 locus were compared in 113 familial and isolated cases of early onset Alzheimer`s disease (<60 years of age at onset) (EOAD) and 109 unaffected individuals of the same geographic origin. Allele 7 was significantly (P = 0.033) more frequent in type 1 EOAD patients (13.2%), defined by the presence of at least another first degree relative with EOAD, than in controls (4.1%). Since an autosomal dominant gene is probably responsible for type 1 patients, allelic association may reflect linkage disequilibrium at the D14S43 locus. This would mean that some patients share a common ancestral mutation. However, since multiple tests were carried out, this result must be interpreted with caution, and needs confirmation in an independent sample. 16 refs., 2 tabs.

  14. Reconceptualizing Early- and Late-Onset: A Life Course Analysis of Older Heroin Users

    PubMed Central

    Boeri, Miriam Williams; Sterk, Claire E.; Elifson, Kirk W.

    2013-01-01

    Purpose Our knowledge regarding older users of illicit drugs is limited despite their increasing numbers. In this paper we apply a life course perspective to gain a further understanding of older adult drug use, specifically contrasting early- and late-onset heroin users. Design and Methods Qualitative data were collected from 29 older heroin users. Life course analysis focused on the users’ experiences across the life span. Results The findings suggest that those aging-into heroin use (late-onset) are disadvantaged compared to those who are maturing-in (early-onset) except in areas of health. Implications We propose that conceptualizing the use of heroin and other illicit drugs among older adults based on their life course trajectory will provide insights for social and health services, including drug treatment. PMID:18981280

  15. Early Onset Ageing and Service Preparation in People with Intellectual Disabilities: Institutional Managers' Perspective

    ERIC Educational Resources Information Center

    Lin, Jin-Ding; Wu, Chia-Ling; Lin, Pei-Ying; Lin, Lan-Ping; Chu, Cordia M.

    2011-01-01

    Although longevity among older adults with intellectual disabilities is increasing, there is limited information on their premature aging related health characteristics and how it may change with increasing age. The present paper provides information of the institutional manager's perception on early onset aging and service preparation for this

  16. Memory in Early Onset Bipolar Disorder and Attention-Deficit/Hyperactivity Disorder: Similarities and Differences

    ERIC Educational Resources Information Center

    Udal, Anne H.; Oygarden, Bjorg; Egeland, Jens; Malt, Ulrik F.; Groholt, Berit

    2012-01-01

    Differentiating between early-onset bipolar disorder (BD) and attention-deficit/hyperactivity disorder (ADHD) can be difficult. Memory problems are commonly reported in BD, and forgetfulness is among the diagnostic criteria for ADHD. We compared children and adolescents with BD (n = 23), ADHD combined type (ADHD-C; n = 26), BD + ADHD-C (n = 15),

  17. Two-Year Diagnostic Stability in Early-Onset First-Episode Psychosis

    ERIC Educational Resources Information Center

    Castro-Fornieles, Josefina; Baeza, Immaculada; de la Serna, Elena; Gonzalez-Pinto, Ana; Parellada, Mara; Graell, Montserrat; Moreno, Dolores; Otero, Soraya; Arango, Celso

    2011-01-01

    Background: Only one study has used a prospective method to analyze the diagnostic stability of first psychotic episodes in children and adolescents. The Child and Adolescent First-Episode Psychosis Study (CAFEPS) is a 2-year, prospective longitudinal study of early-onset first episodes of psychosis (EO-FEP). Aim: To describe diagnostic stability

  18. Psychosocial Interventions for Children with Early-Onset Bipolar Spectrum Disorder

    ERIC Educational Resources Information Center

    Lofthouse, Nicholas; Fristad, Mary A.

    2004-01-01

    Once considered virtually nonexistent, bipolar disorder in children has recently received a great deal of attention from mental health professionals and the general public. This paper provides a current review of literature pertaining to the psychosocial treatment of children with early-onset bipolar spectrum disorder (EOBPSD). Commencing with

  19. Neurocognitive Outcomes in the Treatment of Early-Onset Schizophrenia Spectrum Disorders Study

    ERIC Educational Resources Information Center

    Frazier, Jean A.; Giuliano, Anthony J.; Johnson, Jacqueline L.; Yakutis, Lauren; Youngstrom, Eric A.; Breiger, David; Sikich, Linmarie; Findling, Robert L.; McClellan, Jon; Hamer, Robert M.; Vitiello, Benedetto; Lieberman, Jeffrey A.; Hooper, Stephen R.

    2012-01-01

    Objective: To assess neurocognitive outcomes following antipsychotic intervention in youth enrolled in the National Institute of Mental Health (NIMH)-funded Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS). Method: Neurocognitive functioning of youth (ages 8 to 19 years) with schizophrenia or schizoaffective disorder was evaluated

  20. Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS): Demographic and Clinical Characteristics

    ERIC Educational Resources Information Center

    Frazier, Jean A.; McClellan, Jon; Findling, Robert L.; Vitiello, Benedetto; Anderson, Robert; Zablotsky, Benjamin; Williams, Emily; McNamara, Nora K.; Jackson, Joseph A.; Ritz, Louise; Hlastala, Stefanie A.; Pierson, Leslie; Varley, Jennifer A.; Puglia, Madeline; Maloney, Ann E.; Ambler, Denisse; Hunt-Harrison, Tyehimba; Hamer, Robert M.; Noyes, Nancy; Lieberman, Jeffrey A.; Sikich, Linmarie

    2007-01-01

    Objective: We examined baseline demographic and clinical profiles of youths enrolled from 2001 to 2006 in the publicly funded multicenter, randomized controlled trial Treatment of Early-Onset Schizophrenia Spectrum Disorders. Method: Youths (8-19 years) with schizophrenia (SZ) and schizoaffective disorder were recruited at four academic sites.

  1. The Effects of Childhood ADHD Symptoms on Early-Onset Substance Use: A Swedish Twin Study

    ERIC Educational Resources Information Center

    Chang, Zheng; Lichtenstein, Paul; Larsson, Henrik

    2012-01-01

    Research has documented that children and adolescents with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of substance use problems. Few studies, however, have focused on early-onset substance use. This study therefore investigated how the two symptom dimensions of ADHD (hyperactivity/impulsivity and inattention) are…

  2. Reconceptualizing Early and Late Onset: A Life Course Analysis of Older Heroin Users

    ERIC Educational Resources Information Center

    Boeri, Miriam Williams; Sterk, Claire E.; Elifson, Kirk W.

    2008-01-01

    Purpose: Researchers' knowledge regarding older users of illicit drugs is limited despite the increasing numbers of users. In this article, we apply a life course perspective to gain a further understanding of older adult drug use, specifically contrasting early- and late-onset heroin users. Design and Methods: We collected qualitative data from…

  3. Functional Connectivity of the Amygdala in Early-Childhood-Onset Depression

    ERIC Educational Resources Information Center

    Luking, Katherine R.; Repovs, Grega; Belden, Andy C.; Gaffrey, Michael S.; Botteron, Kelly N.; Luby, Joan L.; Barch, Deanna M.

    2011-01-01

    Objective: Adult major depressive disorder (MDD) is associated with reduced cortico-limbic functional connectivity thought to indicate decreased top-down control of emotion. However, it is unclear whether such connectivity alterations are also present in early-childhood-onset MDD. Method: A total of 51 children 7 through 11 years of age who had…

  4. Reconceptualizing Early and Late Onset: A Life Course Analysis of Older Heroin Users

    ERIC Educational Resources Information Center

    Boeri, Miriam Williams; Sterk, Claire E.; Elifson, Kirk W.

    2008-01-01

    Purpose: Researchers' knowledge regarding older users of illicit drugs is limited despite the increasing numbers of users. In this article, we apply a life course perspective to gain a further understanding of older adult drug use, specifically contrasting early- and late-onset heroin users. Design and Methods: We collected qualitative data from

  5. Functional Connectivity of the Amygdala in Early-Childhood-Onset Depression

    ERIC Educational Resources Information Center

    Luking, Katherine R.; Repovs, Grega; Belden, Andy C.; Gaffrey, Michael S.; Botteron, Kelly N.; Luby, Joan L.; Barch, Deanna M.

    2011-01-01

    Objective: Adult major depressive disorder (MDD) is associated with reduced cortico-limbic functional connectivity thought to indicate decreased top-down control of emotion. However, it is unclear whether such connectivity alterations are also present in early-childhood-onset MDD. Method: A total of 51 children 7 through 11 years of age who had

  6. Early-Onset Neutropenia Induced by Rituximab in a Patient with Lupus Nephritis and Hemolytic Anemia

    PubMed Central

    Arroyo-Ávila, Mariangelí; Fred-Jiménez, Ruth M.; Vilá, Luis M.

    2015-01-01

    Rituximab is an anti-CD20 monoclonal antibody that has been used to treat several complications of systemic lupus erythematosus (SLE) including nephritis, cerebritis, and hematological disorders. Neutropenia is among the adverse events associated with rituximab; this usually occurs several weeks after therapy. However, early-onset neutropenia has been reported only in a few cases. Herein, we describe a 36-year-old Hispanic SLE woman who developed severe early-onset neutropenia (0.3 × 109/L) after the second weekly rituximab infusion (375 mg/m2 weekly × 4) given for nephritis and hemolytic anemia. She also had early-onset thrombocytopenia after rituximab therapy. Both hematological disorders resolved 12 days after the fourth and final dose. This case, together with few others, suggests that early-onset neutropenia may occur during rituximab therapy. Even though rituximab-induced neutropenia seems to be transient, it may predispose SLE patients to severe complications such as infections. PMID:25767732

  7. The Effects of Childhood ADHD Symptoms on Early-Onset Substance Use: A Swedish Twin Study

    ERIC Educational Resources Information Center

    Chang, Zheng; Lichtenstein, Paul; Larsson, Henrik

    2012-01-01

    Research has documented that children and adolescents with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of substance use problems. Few studies, however, have focused on early-onset substance use. This study therefore investigated how the two symptom dimensions of ADHD (hyperactivity/impulsivity and inattention) are

  8. Developmental Trends and L1 Effects in Early L2 Learners' Onset Cluster Production

    ERIC Educational Resources Information Center

    Tessier, Anne-Michelle; Duncan, Tamara Sorenson; Paradis, Johanne

    2013-01-01

    This study focuses on English onset cluster production in spontaneous speech samples of 10 children aged 5;04-6;09 from Chinese and Hindi/Punjabi first language (L1) backgrounds, each with less than a year of exposure to English. The results suggest commonalities between early second language (L2) learners and both monolingual and adult L2

  9. Developmental Trends and L1 Effects in Early L2 Learners' Onset Cluster Production

    ERIC Educational Resources Information Center

    Tessier, Anne-Michelle; Duncan, Tamara Sorenson; Paradis, Johanne

    2013-01-01

    This study focuses on English onset cluster production in spontaneous speech samples of 10 children aged 5;04-6;09 from Chinese and Hindi/Punjabi first language (L1) backgrounds, each with less than a year of exposure to English. The results suggest commonalities between early second language (L2) learners and both monolingual and adult L2…

  10. Neurocognitive Outcomes in the Treatment of Early-Onset Schizophrenia Spectrum Disorders Study

    ERIC Educational Resources Information Center

    Frazier, Jean A.; Giuliano, Anthony J.; Johnson, Jacqueline L.; Yakutis, Lauren; Youngstrom, Eric A.; Breiger, David; Sikich, Linmarie; Findling, Robert L.; McClellan, Jon; Hamer, Robert M.; Vitiello, Benedetto; Lieberman, Jeffrey A.; Hooper, Stephen R.

    2012-01-01

    Objective: To assess neurocognitive outcomes following antipsychotic intervention in youth enrolled in the National Institute of Mental Health (NIMH)-funded Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS). Method: Neurocognitive functioning of youth (ages 8 to 19 years) with schizophrenia or schizoaffective disorder was evaluated…

  11. Two-Year Diagnostic Stability in Early-Onset First-Episode Psychosis

    ERIC Educational Resources Information Center

    Castro-Fornieles, Josefina; Baeza, Immaculada; de la Serna, Elena; Gonzalez-Pinto, Ana; Parellada, Mara; Graell, Montserrat; Moreno, Dolores; Otero, Soraya; Arango, Celso

    2011-01-01

    Background: Only one study has used a prospective method to analyze the diagnostic stability of first psychotic episodes in children and adolescents. The Child and Adolescent First-Episode Psychosis Study (CAFEPS) is a 2-year, prospective longitudinal study of early-onset first episodes of psychosis (EO-FEP). Aim: To describe diagnostic stability…

  12. Memory in Early Onset Bipolar Disorder and Attention-Deficit/Hyperactivity Disorder: Similarities and Differences

    ERIC Educational Resources Information Center

    Udal, Anne H.; Oygarden, Bjorg; Egeland, Jens; Malt, Ulrik F.; Groholt, Berit

    2012-01-01

    Differentiating between early-onset bipolar disorder (BD) and attention-deficit/hyperactivity disorder (ADHD) can be difficult. Memory problems are commonly reported in BD, and forgetfulness is among the diagnostic criteria for ADHD. We compared children and adolescents with BD (n = 23), ADHD combined type (ADHD-C; n = 26), BD + ADHD-C (n = 15),…

  13. Exploring the genetic basis of early-onset chronic kidney disease.

    PubMed

    Vivante, Asaf; Hildebrandt, Friedhelm

    2016-03-01

    The primary causes of chronic kidney disease (CKD) in children differ from those of CKD in adults. In the USA the most common diagnostic groups of renal disease that manifest before the age of 25 years are congenital anomalies of the kidneys and urinary tract, steroid-resistant nephrotic syndrome, chronic glomerulonephritis and renal cystic ciliopathies, which together encompass >70% of early-onset CKD diagnoses. Findings from the past decade suggest that early-onset CKD is caused by mutations in any one of over 200 different monogenic genes. Developments in high-throughput sequencing in the past few years has rendered identification of causative mutations in this high number of genes feasible. Use of genetic analyses in patients with early onset-CKD will provide patients and their families with a molecular genetic diagnosis, generate new insights into disease mechanisms, facilitate aetiology-based classifications of patient cohorts for clinical studies, and might have consequences for personalized approaches to the prevention and treatment of CKD. In this Review, we discuss the implications of next-generation sequencing in clinical genetic diagnostics and the discovery of novel genes in early-onset CKD. We also delineate the resulting opportunities for deciphering disease mechanisms and the therapeutic implications of these findings. PMID:26750453

  14. Prelabor cesarean delivery and early-onset acute childhood leukemia risk.

    PubMed

    Thomopoulos, Thomas P; Skalkidou, Alkistis; Dessypris, Nick; Chrousos, George; Karalexi, Maria A; Karavasilis, Theodoros G; Baka, Margarita; Hatzipantelis, Emmanuel; Kourti, Maria; Polychronopoulou, Sophia; Sidi, Vasiliki; Stiakaki, Eftichia; Moschovi, Maria; Loutradis, Dimitrios; Petridou, Eleni Th

    2016-03-01

    The long-term impact of cesarean delivery (CD) on the health of the offspring is being explored methodically. We sought to investigate the effect of birth by (a) prelabor and (b) during-labor CD on the risk of early-onset (≤3 years) acute lymphoblastic leukemia (ALL), specifically of its prevailing precursor B (B-ALL) subtype. A total of 1099 incident cases of ALL (957 B-ALL), 131 of acute myeloid leukemia (AML), and their 1 : 1 age-matched and sex-matched controls, derived from the Nationwide Registry for Childhood Hematological Malignancies (1996-2013), were analyzed using multivariate regression models. A null association was found between prelabor and/or during labor CD and either ALL (B-ALL) or AML in the 0-14 age range. By contrast, birth by CD increased significantly the risk of early-onset ALL [odds ratioCD (ORCD)=1.57, 95% confidence interval (CI): 1.10-2.24] mainly on account of prelabor CD (ORprelaborCD=1.66, 95% CI: 1.13-2.43). The respective figures were even higher for the early-onset precursor B-ALL (ORCD=1.66, 95% CI: 1.15-2.40 and ORprelaborCD=1.79, 95% CI: 1.21-2.66), whereas no association emerged for early-onset AML. Prelabor CD, which deprives exposure of the fetus/infant to the presumably beneficial effect of stress hormones released in both vaginal labor and during labor CD, was associated exclusively with an increased risk of early-onset ALL, particularly the precursor B-ALL subtype. If confirmed, these adverse long-term outcomes of CD may point to re-evaluation of prelabor CD practices and prompt scientific discussion on the best ways to simulate the effects of vaginal delivery, such as a precesarean induction of labor. PMID:25793919

  15. Exome sequencing identified null mutations in LOXL3 associated with early-onset high myopia

    PubMed Central

    Li, Jiali; Gao, Bei; Xiao, Xueshan; Li, Shiqiang; Jia, Xiaoyun; Sun, Wenmin; Guo, Xiangming

    2016-01-01

    Purpose To identify null mutations in novel genes associated with early-onset high myopia using whole exome sequencing. Methods Null mutations, including homozygous and compound heterozygous truncations, were selected from whole exome sequencing data for 298 probands with early-onset high myopia. These data were compared with those of 507 probands with other forms of eye diseases. Null mutations specific to early-onset high myopia were considered potential candidates. Candidate mutations were confirmed with Sanger sequencing and were subsequently evaluated in available family members and 480 healthy controls. Results A homozygous frameshift mutation (c.39dup; p.L14Afs*21) and a compound heterozygous frameshift mutation (c.39dup; p.L14Afs*21 and c.594delG; p.Q199Kfs*35) in LOXL3 were separately identified in two of the 298 probands with early-onset high myopia. These mutations were confirmed with Sanger sequencing and were not detected in 1,974 alleles of the controls from the same region (507 individuals with other conditions and 480 healthy control individuals). These two probands were singleton cases, and their parents had only heterozygous mutations. A homozygous missense mutation in LOXL3 was recently reported in a consanguineous family with Stickler syndrome. Conclusions Our results suggest that null mutations in LOXL3 are likely associated with autosomal recessive early-onset high myopia. LOXL3 is a potential candidate gene for high myopia, but this possibility should be confirmed in additional studies. LOXL3 null mutations in human beings are not lethal, providing a phenotype contrary to that in mice. PMID:26957899

  16. Distinct breast cancer subtypes in women with early-onset disease across races

    PubMed Central

    Singh, Mandeep; Ding, Yi; Zhang, Li-Ying; Song, Dong; Gong, Yun; Adams, Sylvia; Ross, Dara S; Wang, Jin-Hua; Grover, Shruti; Doval, Dinesh Chandra; Shao, Charles; He, Zi-Li; Chang, Victor; Chin, Warren W; Deng, Fang-Ming; Singh, Baljit; Zhang, David; Xu, Ru-Liang; Lee, Peng

    2014-01-01

    Background: Racial disparities among breast cancer (BCa) patients are known but not well studied in early-onset BCa. We analyzed molecular subtypes in early-onset BCa across five major races. Methods: A total of 2120 cases were included from non-Hispanic White (NHW), African American (AA) and Hispanic, Chinese and Indian. Based on ER, PR and HER-2 status, BCa was classified into 4 intrinsic subtypes as Luminal A, Luminal B, HER2/neu overexpression and Triple negative BCa (TNBC) subtypes. Data was stratified according to race and age as younger/early-onset group (40-years and younger) and older group (50-years and older). Results: In early-onset BCa, incidence of TNBC was significantly higher (p = 0.0369) in Indian women followed by AA, Hispanic, NHW and Chinese women. Incidence of Her2 over-expression subtype also was highest in Indian women, followed by Hispanic, Chinese, AA and NHW women. In contrast, Luminal B subtype was most significantly higher in AA women (p = 0.0000) followed by NHW (p = 0.0002), Chinese (p = 0.0003), Hispanic (0.0128) and Indian (p = 0.0468) women. Luminal A subtype was most significantly reduced in Indian women (p = 0.0113) followed by Hispanic, AA, NHW and Chinese women. These results were based on statistical analysis with the mean of older group populations. Conclusions: These results show significant disparities in receptor subtypes across races. This study will contribute in developing optimal clinical trial protocols and personalized management strategies for early-onset BCa patients. PMID:25057437

  17. Blood Culture Proven Early Onset Sepsis and Late Onset Sepsis in Very-Low-Birth-Weight Infants in Korea

    PubMed Central

    Lee, Soon Min; Chang, Meayoung

    2015-01-01

    Neonatal sepsis remains one of the most important causes of death and co-morbidity in very-low-birth-weight (VLBW) infants. The aim of this study was to determine the current incidences of early-onset sepsis (EOS) and late-onset sepsis (LOS), the distribution of pathogens, and the impact of infection on co-morbidities in VLBW infants. We analyzed the data including sepsis episode from 2,386 VLBW infants enrolled in Korean Neonatal Network from January 2013 to June 2014. We defined EOS as a positive blood culture occurring between birth and 7 days of life and LOS after 7 days of life. Sepsis was found in 21.1% of VLBW infants. The risk of sepsis was inversely related to birth weight and gestational age. EOS was found in only 3.6% of VLBW infants, however the mortality rate was as high as 34.1%. EOS was associated with the increased odds for bronchopulmonary dysplasia and intraventricular hemorrhage. The vast majority of EOS was caused by Gram-positive organisms, particularly coagulase-negative staphylococci (30.6%). LOS developed in 19.4% of VLBW infants with a 16.1% mortality rate. Pathogens in LOS were dominated by coagulase-negative staphylococci (38.3%). Twenty-five percent and fifty percent of first LOS episode occurred after 12 days and 20 days from birth, respectively. Younger and smaller VLBW infants showed the earlier occurrence day for the 25% of first LOS episode. This study provides a recent nationwide epidemiology of sepsis in VLBW infants in Korea. Based on this study, successful strategies to reduce infections would improve survival and reduce morbidity. PMID:26566360

  18. Early-onset and late-onset Alzheimer's disease are associated with distinct patterns of memory impairment.

    PubMed

    Joubert, Sven; Gour, Natalina; Guedj, Eric; Didic, Mira; Guriot, Claude; Koric, Lejla; Ranjeva, Jean-Philippe; Felician, Olivier; Guye, Maxime; Ceccaldi, Mathieu

    2016-01-01

    The goal of this study was to investigate the specific patterns of memory breakdown in patients suffering from early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD). Twenty EOAD patients, twenty LOAD patients, twenty matched younger controls, and twenty matched older controls participated in this study. All participants underwent a detailed neuropsychological assessment, an MRI scan, an FDG-PET scan, and AD patients had biomarkers as supporting evidence of both amylodopathy and neuronal injury. Results of the neuropsychological assessment showed that both EOAD and LOAD groups were impaired in the domains of memory, executive functions, language, praxis, and visuoconstructional abilities, when compared to their respective control groups. EOAD and LOAD groups, however, showed distinct patterns of memory impairment. Even though both groups were similarly affected on measures of episodic, short term and working memory, in contrast semantic memory was significantly more impaired in LOAD than in EOAD patients. The EOAD group was not more affected than the LOAD group in any memory domain. EOAD patients, however, showed significantly poorer performance in other cognitive domains including executive functions and visuoconstructional abilities. A more detailed analysis of the pattern of semantic memory performance among patient groups revealed that the LOAD was more profoundly impaired, in tasks of both spontaneous recall and semantic recognition. Voxel-Based Morphometry (VBM) analyses showed that impaired semantic performance in patients was associated with reduced gray matter volume in the anterior temporal lobe (ATL) region, while PET-FDG analyses revealed that poorer semantic performance was associated with greater hypometabolism in the left temporoparietal region, both areas reflecting key regions of the semantic network. Results of this study indicate that EOAD and LOAD patients present with distinct patterns of memory impairment, and that a genuine semantic impairment may represent one of the clinical hallmarks of LOAD. PMID:26694580

  19. Two Novel De Novo GARS Mutations Cause Early-Onset Axonal Charcot-Marie-Tooth Disease

    PubMed Central

    Liao, Yi-Chu; Liu, Yo-Tsen; Tsai, Pei-Chien; Chang, Chia-Ching; Huang, Yen-Hua; Soong, Bing-Wen; Lee, Yi-Chung

    2015-01-01

    Background Mutations in the GARS gene have been identified in a small number of patients with Charcot-Marie-Tooth disease (CMT) type 2D or distal spinal muscular atrophy type V, for whom disease onset typically occurs during adolescence or young adulthood, initially manifesting as weakness and atrophy of the hand muscles. The role of GARS mutations in patients with inherited neuropathies in Taiwan remains elusive. Methodology and Principal Findings Mutational analyses of the coding regions of GARS were performed using targeted sequencing of 54 patients with molecularly unassigned axonal CMT, who were selected from 340 unrelated CMT patients. Two heterozygous mutations in GARS, p.Asp146Tyr and p.Met238Arg, were identified; one in each patient. Both are novel de novo mutations. The p.Asp146Tyr mutation is associated with a severe infantile-onset neuropathy and the p.Met238Arg mutation results in childhood-onset disability. Conclusion GARS mutations are an uncommon cause of CMT in Taiwan. The p.Asp146Tyr and p.Met238Arg mutations are associated with early-onset axonal CMT. These findings broaden the mutational spectrum of GARS and also highlight the importance of considering GARS mutations as a disease cause in patients with early-onset neuropathies. PMID:26244500

  20. Premorbid Risk Factors for Major Depressive Disorder: Are They Associated With Early Onset and Recurrent Course?

    PubMed Central

    Wilson, Sylia; Vaidyanathan, Uma; Miller, Michael B.; McGue, Matt; Iacono, William G.

    2014-01-01

    Premorbid risk for major depressive disorder (MDD) and predictors of an earlier onset and recurrent course were examined in two studies in a large, community-based sample of parents and offspring, prospectively assessed from late childhood into adulthood. In Study 1 (N = 2,764 offspring and their parents), parental psychiatric status, offspring personality at age 11, and age-11 offspring internalizing and externalizing symptoms predicted the subsequent development of MDD, as did poor quality parent-child relationships, poor academic functioning, early pubertal development, and childhood maltreatment by age 11. Parental MDD and adult antisocial behavior, offspring negative emotionality and disconstraint, externalizing symptoms, and childhood maltreatment predicted an earlier onset of MDD, after accounting for course; lower positive emotionality, trait anxiety, and childhood maltreatment predicted recurrent MDD, after accounting for age of onset. In Study 2 (N = 7,146), we examined molecular genetic risk for MDD by extending recent reports of associations with glutamatergic system genes. We failed to confirm associations with MDD using either individual SNP-based tests or gene-based analyses. Overall, results speak to the pervasiveness of risk for MDD, as well as specific risk for early-onset MDD; risk for recurrent MDD appears to be largely a function of its often earlier onset. PMID:25422974

  1. Premorbid risk factors for major depressive disorder: are they associated with early onset and recurrent course?

    PubMed

    Wilson, Sylia; Vaidyanathan, Uma; Miller, Michael B; McGue, Matt; Iacono, William G

    2014-11-01

    Premorbid risk for major depressive disorder (MDD) and predictors of an earlier onset and recurrent course were examined in two studies in a large, community-based sample of parents and offspring, prospectively assessed from late childhood into adulthood. In Study 1 (N = 2,764 offspring and their parents), parental psychiatric status, offspring personality at age 11, and age 11 offspring internalizing and externalizing symptoms predicted the subsequent development of MDD, as did poor quality parent-child relationships, poor academic functioning, early pubertal development, and childhood maltreatment by age 11. Parental MDD and adult antisocial behavior, offspring negative emotionality and disconstraint, externalizing symptoms, and childhood maltreatment predicted an earlier onset of MDD, after accounting for course; lower positive emotionality, trait anxiety, and childhood maltreatment predicted recurrent MDD, after accounting for age of onset. In Study 2 (N = 7,146), we examined molecular genetic risk for MDD by extending recent reports of associations with glutamatergic system genes. We failed to confirm associations with MDD using either individual single nucleotide polymorphism based tests or gene-based analyses. Overall, results speak to the pervasiveness of risk for MDD, as well as specific risk for early onset MDD; risk for recurrent MDD appears to be largely a function of its often earlier onset. PMID:25422974

  2. Differences between Early and Late-Onset Alzheimer’s Disease in Neuropsychological Tests

    PubMed Central

    Sá, Francisca; Pinto, Paula; Cunha, Catarina; Lemos, Raquel; Letra, Liliana; Simões, Mário; Santana, Isabel

    2012-01-01

    Although patients with Alzheimer disease (AD) share clinical and histological features regardless of age of onset, the hypothesis that early onset AD constitutes a distinct subgroup prevails. Some authors suggest that early attention or language impairment constitute patterns of differentiation in terms of neuropsychological profile, between these groups. However, investigations are not consensual in terms of cognitive domains affected in each group. Aim: To investigate whether there is early neuropsychological difference between two types of AD using the conventional dividing line of 65 years. Methods: We evaluated the results obtained in the Mini-Mental State Examination (MMSE) and in a comprehensive neuropsychological battery – Battery of Lisbon for the Assessment of Dementia (BLAD), at a Dementia clinic in the University Hospital of Coimbra and a Memory Clinic. The study was developed in consecutive patients with a clinical probable diagnosis of mild to moderate AD, using standard criteria (DSMIV and NINCDS-ADRDA). Statistical analysis was performed using Qui-square and U-Mann–Whitney, for categorical and non-categorical variables. The degree of relation between variables, was measured using the coefficient of correlation rs de Spearman. Results: The total sample included 280 patients: 109 with early onset AD and 171 with a late-onset form. Groups were comparable in terms of gender, education or severity of disease, and MMSE. In BLAD, for univariate analysis the early onset group had lower scores in Naming (p = 0.025), Right–Left Orientation (p = 0.029) and Praxis (p = 0.001), and better performances in Orientation (p = 0.001) and Visual Memory (p = 0.022). After application of Bonferroni correction for multiple comparisons only Praxis and Orientation could differentiate the two groups. No significant differences were found in other tests or functions. Discussion: The results are suggestive of dissociated profiles between early and late-onset AD. Younger patients have a major impairment in Praxis and a tendency for a great impairment in neocortical temporal functions. AD patients with late-onset forms had a tendency for worse performances in Visual Memory and Orientation, suggesting a more localized disease to the limbic structures. PMID:22593755

  3. Characteristics of familial aggregation in early-onset Alzheimer`s disease: Evidence of subgroups

    SciTech Connect

    Campion, D.; Martinez, M.; Babron, M.C.

    1995-06-19

    Characteristics of familial aggregation of Alzheimer`s Disease were studied in 92 families ascertained through a clinically diagnosed proband with an onset below age 60 years. In each family data were systematically collected on the sibships of the proband, of his father, and of his mother. A total of 926 relatives were included and 81% of the living relatives (i.e., 251 individuals) were directly examined. The estimated cumulative risk among first degree relatives was equal to 35% by age 89 years (95% confidence interval 22 to 47%). This result does not support the hypothesis that an autosomal dominant gene, fully penetrant by age 90 years, is segregating within all these pedigrees. Despite the fact that all probands were selected for an onset before age 60 years it was shown that two types of families could be delineated with respect to age at onset among affected relatives: all secondary cases with an onset below age 60 years were contributed by a particular group of families (type 1 families), whereas all secondary cases with an onset after age 60 years were contributed by another group of families (type 2 families). Although genetic interpretation of these findings is not straightforward, they support the hypothesis of etiologic heterogeneity in the determinism of early-onset Alzheimer`s disease. 58 refs., 5 figs., 2 tabs.

  4. Novel presenilin mutations within Moroccan patients with Early-Onset Alzheimer's Disease.

    PubMed

    El Kadmiri, N; Zaid, N; Zaid, Y; Tadevosyan, A; Hachem, A; Dub, M-P; Hamzi, K; El Moutawakil, B; Slassi, I; Nadifi, S

    2014-06-01

    Alzheimer's disease (AD) is a progressive brain disorder that causes gradual and irreversible loss of higher brain functions and is the most common cause of dementia in the elderly, as assessed by autopsy and clinical series. Furthermore, it has an annual incidence of approximately 3% in the 65-74-year-old age group. This incidence rate doubles with every increment of 5 years above the age of 65. In Morocco, AD affects almost 30,000 individuals and this number will possibly increase to 75,000 by 2020 (projections of the World Health Organization (WHO)). Genetically, AD is caused by a mutation in one of at least 3 genes: presenilin 1 (PS1), presenilin 2 (PS2) and the amyloid precursor protein (APP). Most cases are late onset and apparently sporadic, most likely as a result of a combination of environmental and non-dominant genetic factors. In Morocco, the genes predisposing individuals to AD and predicting disease incidence remain elusive. The purpose of the present study was to evaluate the genetic contribution of mutations in PS1 and PS2 genes to familial early-onset AD cases and sporadic late-onset AD cases. Seventeen sporadic late-onset AD cases and eight familial early-onset AD cases were seen at the memory clinic of the University of Casablanca Neurology Department. These patients underwent standard somatic neurological examination, cognitive function assessment, brain imaging and laboratory tests. Direct sequencing of each exon in PS1 and PS2 genes was performed on genomic DNA of AD patients. Further, we identified 1 novel frameshift mutation in the PS1 gene and 2 novel frameshift mutations in the PS2 gene. Our mutational analysis reports a correlation between clinical symptoms and genetic factors in our cases of Early-Onset Alzheimer's Disease (EOAD). These putative mutations cosegregate with affected family members suggesting a direct mutagenic effect. PMID:24704512

  5. Complement Split Products in Amniotic Fluid in Pregnancies Subsequently Developing Early-Onset Preeclampsia

    PubMed Central

    Banadakoppa, Manu; Vidaeff, Alex C.; Yallampalli, Uma; Ramin, Susan M.; Belfort, Michael A.; Yallampalli, Chandra

    2015-01-01

    Objective. To determine the second-trimester amniotic fluid concentrations of complement split products in pregnancies subsequently affected by early-onset preeclampsia. Study Design. Cohort of 731 women with singleton pregnancies undergoing second-trimester genetic amniocentesis followed up to delivery and analyzed as a nested case-control study. Cases of preeclampsia developing before 34 weeks' gestation (n = 15) were compared with 47 uncomplicated term controls. Amniotic fluid collected at amniocentesis was tested for complement split products Bb, C4a, C3a, and C5a. Results. Women who developed early-onset preeclampsia as compared with the term pregnant controls had significantly higher (P = 0.04) median amniotic fluid C3a levels (318.7?ng/mL versus 254.5?ng/mL). Median amniotic fluid Bb levels were also significantly higher (P = 0.03) in preeclamptic women than in normal pregnant women (1127?ng/mL versus 749?ng/mL). Median levels of C4a and C5a were not significantly different between the groups. Conclusion. Our data suggest that complement activation in early pregnancy is associated with early-onset preeclampsia. We believe this to be the first prospective study to link complement activation in amniotic fluid in early pregnancy and later development of preeclampsia. Our findings provide evidence that immune dysregulation may precede the clinical manifestations of preeclampsia and that the alternative complement pathway is principally involved. PMID:26556948

  6. DRD3 variation associates with early-onset heroin dependence, but not specific personality traits.

    PubMed

    Kuo, Shin-Chang; Yeh, Yi-Wei; Chen, Chun-Yen; Huang, Chang-Chih; Chang, Hsin-An; Yen, Che-Hung; Ho, Pei-Shen; Liang, Chih-Sung; Chou, Han-Wei; Lu, Ru-Band; Huang, San-Yuan

    2014-06-01

    Dopamine D3 receptor-mediated pathways are involved in the mechanism of addiction, and genetic factors play a role in the vulnerability to heroin dependence. The aim of this study was to examine whether the corresponding gene, DRD3, is associated with the development of heroin dependence and specific personality traits in HD patients. Eight polymorphisms in DRD3 were analyzed in 1067 unrelated Han Chinese subjects (566 heroin dependence patients and 501 controls). All participants were screened using the same assessment tool and all patients met the criteria for heroin dependence. A Tridimensional Personality Questionnaire was used to assess personality traits in 276 heroin dependence patients. In addition, heroin dependence patients were divided into 4 clinical subgroups based on age-of-onset and family history of substance abuse, to reduce the clinical heterogeneity. The rs6280 and rs9825563 variants showed association with the development of early-onset heroin dependence. The GTA haplotype frequency in the block (rs324029, rs6280, rs9825563) was significantly associated with early-onset heroin dependence (p=0.003). However, these significant associations were weaker after Bonferroni's correction. In addition, these DRD3 polymorphisms did not influence novelty seeking and harm avoidance scores in HD patients. DRD3 is possibly a genetic factor in the development of early-onset heroin dependence, but is not associated with specific personality traits in these patients among the Han Chinese population. PMID:24398431

  7. Identification of Novel Candidate Genes for Early-Onset Colorectal Cancer Susceptibility

    PubMed Central

    Weren, Robbert D. A.; Mensenkamp, Arjen R.; Gilissen, Christian; van Zelst-Stams, Wendy A.; Spruijt, Liesbeth; Kets, C. Marleen; Zhang, Junxiao; Venselaar, Hanka; Vreede, Lilian; Schubert, Nil; Tychon, Marloes; Derks, Ronny; Schackert, Hans K.; Geurts van Kessel, Ad; Hoogerbrugge, Nicoline; Ligtenberg, Marjolijn J. L.; Kuiper, Roland P.

    2016-01-01

    Approximately 25–30% of colorectal cancer (CRC) cases are expected to result from a genetic predisposition, but in only 5–10% of these cases highly penetrant germline mutations are found. The remaining CRC heritability is still unexplained, and may be caused by a hitherto-undefined set of rare variants with a moderately penetrant risk. Here we aimed to identify novel risk factors for early-onset CRC using whole-exome sequencing, which was performed on a cohort of CRC individuals (n = 55) with a disease onset before 45 years of age. We searched for genes that were recurrently affected by rare variants (minor allele frequency ≤0.001) with potentially damaging effects and, subsequently, re-sequenced the candidate genes in a replication cohort of 174 early-onset or familial CRC individuals. Two functionally relevant genes with low frequency variants with potentially damaging effects, PTPN12 and LRP6, were found in at least three individuals. The protein tyrosine phosphatase PTP-PEST, encoded by PTPN12, is a regulator of cell motility and LRP6 is a component of the WNT-FZD-LRP5-LRP6 complex that triggers WNT signaling. All variants in LRP6 were identified in individuals with an extremely early-onset of the disease (≤30 years of age), and two of the three variants showed increased WNT signaling activity in vitro. In conclusion, we present PTPN12 and LRP6 as novel candidates contributing to the heterogeneous susceptibility to CRC. PMID:26901136

  8. Early onset type 2 diabetes in Jamaica and in Mexico. Opportunities derived from an interethnic study.

    PubMed

    Irving, Rachael; Tusié-Luna, Ma Teresa; Mills, James; Wright-Pascoe, Rosemarie; McLaughlin, Wayne; Aguilar-Salinas, Carlos A

    2011-01-01

    Populations with Amerindian or African heritages are the one with the highest prevalence of diabetes worldwide. A large percentage of these individuals survived famine. However, the survival effect has become detrimental to their descendents living in an environment of caloric surplus. In countries, like Mexico and Jamaica, in which diabetes is highly prevalent, the onset of the disease happens at earlier ages. Our objective is to summarize diabetes data from Mexico and Jamaica and to discuss the opportunities that can result from an interethnic study. On one hand, the prevalence of diabetes in Jamaica is 17.9% in the 15+ age group. Jamaican researchers have built a cohort of families with early onset type 2 diabetes. In this population, this form of the disease is unrelated to MODY genes. On the other hand, the prevalence of diabetes in adult Mexicans is 14.4%. The group in which the greater percentual changes have occurred is the adults who are below the age of 40. More than two thirds of the early onset cases studied have a body mass index that is >25 kg/m2 and the clinical characteristics of metabolic syndrome. A minority of them has mutations in the MODY genes. The joint study of Mexican and Jamaican cohorts of early onset type 2 diabetes cases will be useful to identify new genetic and environmental players in the pathogenesis of this entity. PMID:21714438

  9. DJ1 analysis in a large cohort of Italian early onset Parkinson Disease patients.

    PubMed

    Sironi, Francesca; Primignani, Paola; Ricca, Sara; Tunesi, Sara; Zini, Michela; Tesei, Silvana; Cilia, Roberto; Pezzoli, Gianni; Seia, Manuela; Goldwurm, Stefano

    2013-12-17

    We analyzed the DJ1 gene in a large consecutive series (N=163) of Italian unrelated Early Onset Parkinson Disease (EOPD: onset ?40 years of age) patients and 100 healthy controls (mean age 64 7 years). No homozygous or compound heterozygous mutations with an obvious pathogenic effect were found. Several variants were identified, some of which were novels. All variants had similar frequency in patients and in controls. Our data suggest that DJ1 mutations are very rare in Italian EOPD. Other genes and risk factors for PD are still to be identified. PMID:24176883

  10. Clinical features of early onset, familial Alzheimer`s disease linked to chromosome 14

    SciTech Connect

    Mullan, M.; Bennett, C.; Figueredo, C.; Crawford, F.

    1995-02-27

    Early onset familial Alzheimer`s disease (AD) has an autosomal dominant mode of inheritance. Two genes are responsible for the majority of cases of this subtype of AD. Mutations in the {beta}-amyloid precursor protein ({beta}APP) gene on chromosome 21 have been shown to completely cosegregate with the disease. We and others have previously described the clinical features of families with {beta}APP mutations at the codon 717 locus in an attempt to define the phenotype associated with a valine to isoleucine (Val {r_arrow} Ile) or a valine to glycine (Val {r_arrow} Gly) change. More recently, a second locus for very early onset disease has been localized to chromosome 14. The results of linkage studies in some families suggesting linkage to both chromosomes have been explained by the suggestion of a second (centromeric) locus on chromosome 21. Here we report the clinical features and genetic analysis of a British pedigree (F74) with early onset AD in which neither the {beta}APP locus nor any other chromosome 21 locus segregates with the disease, but in which good evidence is seen for linkage on the long arm of chromosome 14. In particular we report marker data suggesting that the chromosome 14 disease locus is close to D14S43 and D14S77. Given the likelihood that F74 represents a chromosome 14 linked family, we describe the clinical features and make a limited clinical comparison with the {beta}APP717 Val {r_arrow} Ile and {beta}APP717 Val {r_arrow} Gly encoded families that have been previously described. We conclude that although several previously reported clinical features occur to excess in early onset familial AD, no single clinical feature demarcates either the chromosome 14 or {beta}APP codon 717 mutated families except mean age of onset. 52 refs., 2 figs., 5 tabs.

  11. Extent of Spine Deformity Predicts Lung Growth and Function in Rabbit Model of Early Onset Scoliosis

    PubMed Central

    Olson, J. Casey; Takahashi, Ayuko; Glotzbecker, Michael P.; Snyder, Brian D.

    2015-01-01

    Early onset deformity of the spine and chest wall (initiated <8 years of age) is associated with increased morbidity at adulthood relative to adolescent onset deformity of comparable severity. Presumably, inhibition of thoracic growth during late stage alveolarization leads to an irreversible loss of pulmonary growth and thoracic function; however the natural history of this disease from onset to adulthood has not been well characterized. In this study we establish a rabbit model of early onset scoliosis to establish the extent that thoracic deformity affects structural and functional respiratory development. Using a surgical right unilateral rib-tethering procedure, rib fusion with early onset scoliosis was induced in 10 young New Zealand white rabbits (3 weeks old). Progression of spine deformity, functional residual capacity, total lung capacity, and lung mass was tracked through longitudinal breath-hold computed tomography imaging up to skeletal maturity (28 weeks old). Additionally at maturity forced vital capacity and regional specific volume were calculated as functional measurements and histo-morphometry performed with the radial alveolar count as a measure of acinar complexity. Data from tethered rib rabbits were compared to age matched healthy control rabbits (N = 8). Results show unilateral rib-tethering created a progressive spinal deformity ranging from 30° to 120° curvature, the severity of which was strongly associated with pulmonary growth and functional outcomes. At maturity rabbits with deformity greater than the median (55°) had decreased body weight (89%), right (59%) and left (86%) lung mass, right (74%) and left (69%) radial alveolar count, right lung volume at total lung capacity (60%), and forced vital capacity (75%). Early treatment of spinal deformity in children may prevent pulmonary complications in adulthood and these results provide a basis for the prediction of pulmonary development from thoracic structure. This model may also have future use as a platform to evaluate treatment effectiveness. PMID:26317230

  12. Onset to First Alcohol Use in Early Adolescence: A Network Diffusion Model

    PubMed Central

    Light, John M.; Greenan, Charlotte C.; Rusby, Julie C.; Nies, Kimberley M.; Snijders, Tom A.B.

    2013-01-01

    A novel version of Snijderss stochastic actor-based modeling (SABM) framework is applied to model the diffusion of first alcohol use through middle school-wide longitudinal networks of early adolescents, aged approximately 1114 years. Models couple a standard SABM for friendship network evolution with a proportional hazard model for first alcohol use. Meta-analysis of individual models for 12 schools found significant effects for friendship selection based on the same alcohol use status, and for an increased rate of onset to first use based on exposure to already-onset peers. Onset rate was greater at higher grades and among participants who spent more unsupervised time with friends. Neither selection nor exposure effects interacted with grade, adult supervision, or gender. PMID:24039379

  13. Modified areal cartography in auditory cortex following early- and late-onset deafness.

    PubMed

    Wong, Carmen; Chabot, Nicole; Kok, Melanie A; Lomber, Stephen G

    2014-07-01

    Cross-modal plasticity following peripheral sensory loss enables deprived cortex to provide enhanced abilities in remaining sensory systems. These functional adaptations have been demonstrated in cat auditory cortex following early-onset deafness in electrophysiological and psychophysical studies. However, little information is available concerning any accompanying structural compensations. To examine the influence of sound experience on areal cartography, auditory cytoarchitecture was examined in hearing cats, early-deaf cats, and cats with late-onset deafness. Cats were deafened shortly after hearing onset or in adulthood. Cerebral cytoarchitecture was revealed immunohistochemically using SMI-32, a monoclonal antibody used to distinguish auditory areas in many species. Auditory areas were delineated in coronal sections and their volumes measured. Staining profiles observed in hearing cats were conserved in early- and late-deaf cats. In all deaf cats, dorsal auditory areas were the most mutable. Early-deaf cats showed further modifications, with significant expansions in second auditory cortex and ventral auditory field. Borders between dorsal auditory areas and adjacent visual and somatosensory areas were shifted ventrally, suggesting expanded visual and somatosensory cortical representation. Overall, this study shows the influence of acoustic experience in cortical development, and suggests that the age of auditory deprivation may significantly affect auditory areal cartography. PMID:23413302

  14. Neurological and cytogenetic study in early-onset ataxia-telangiectasia patients.

    PubMed

    Leuzzi, V; Elli, R; Antonelli, A; Chessa, L; Cardona, F; Marcucci, L; Petrinelli, P

    1993-07-01

    The clinical diagnosis of ataxia-telangiectasia (AT) is difficult before the age of 4 years. We report clinical and cytogenetic data on three early-onset, early-diagnosed AT patients at the age of 12, 18 and 22 months, respectively. Postural instability of the trunk, characterized by motor impersistence, was the earliest neurological sign detected as early as 1 year of life. Dystonic movements and postures of arms and trunk and a subtle disorder of eye movement (blinking before gaze changing, increased latency and dysmetry of saccades) were observed during the 2nd year of life. All patients exhibited an unusual temper tantrum. We also observed an increased bleomycin-induced chromosomal instability in patient's cells in the early stages of the disease before all the clinical hallmarks were apparent. Our data suggest that detection of clinical indications, leading to early laboratory confirmation of AT, can reduce the age at diagnosis. PMID:7689057

  15. MRI-based diagnostic biomarkers for early onset pediatric multiple sclerosis

    PubMed Central

    Weygandt, Martin; Hummel, Hannah-Maria; Schregel, Katharina; Ritter, Kerstin; Allefeld, Carsten; Dommes, Esther; Huppke, Peter; Haynes, JohnDylan; Wuerfel, Jens; Grtner, Jutta

    2014-01-01

    Currently, it is unclear whether pediatric multiple sclerosis (PMS) is a pathoetiologically homogeneous disease phenotype due to clinical and epidemiological differences between early and late onset PMS (EOPMS and LOPMS). Consequently, the question was raised whether diagnostic guidelines need to be complemented by specific EOPMS markers. To search for such markers, we analyzed cerebral MRI images acquired with standard protocols using computer-based classification techniques. Specifically, we applied classification algorithms to gray (GM) and white matter (WM) tissue probability parameters of small brain regions derived from T2-weighted MRI images of EOPMS patients (onset <12years), LOPMS patients (onset ?12years), and healthy controls (HC). This was done for PMS subgroups matched for disease duration and participant age independently. As expected, maximal diagnostic information for distinguishing PMS patients and HC was found in a periventricular WM area containing lesions (87.1% accuracy, p<2.2נ10?5). MRI-based biomarkers specific for EOPMS were identified in prefrontal cortex. Specifically, a coordinate in middle frontal gyrus contained maximal diagnostic information (77.3%, p=1.8נ10?4). Taken together, we were able to identify biomarkers reflecting pathognomonic processes specific for MS patients with very early onset. Especially GM involvement in the separation between PMS subgroups suggests that conventional MRI contains a richer set of diagnostically informative features than previously assumed. PMID:25685704

  16. Maturation, Peer Context, and Indigenous Girls' Early-Onset Substance Use

    PubMed Central

    Walls, Melissa L.; Whitbeck, Les B.

    2011-01-01

    This paper examines a biosocial model of the impact of puberty on Indigenous girls' early-onset substance use by considering the potential mediating role of peer context (i.e. mixed-sex peer groups and substance use prototypes) on the puberty and substance use relationship. Data include responses from 360 girls of a common Indigenous cultural group residing on reservations/reserves in the upper Midwest and Canada. Results of structural equation modeling revealed that the statistically significant relationship between girls' pubertal development and early-onset substance use was mediated by both mixed-sex/romantic peer groups and favorable social definitions of substance use. Implications for substance use prevention work include addressing the multiple and overlapping effects of peer influence from culturally-relevant perspectives. PMID:22228919

  17. Neonatal infected subgaleal hematoma: an unusual complication of early-onset E. coli sepsis.

    PubMed

    Chang, Hung-Yang; Cheng, Kun-Shan; Liu, Yu-Peng; Hung, Hsiao-Fang; Fu, Hua-Wen

    2015-04-01

    Subgaleal hematoma (SGH) is an uncommon but potentially lethal medical emergency in newborns. Delay in diagnosis may lead to mortality and morbidity. Infection of an SGH is extremely rare. We report an infected SGH with abscess formation as a complication of early-onset Escherichia coli sepsis in a term neonate. The patient was discovered to have SGH soon after birth. Early-onset E. coli sepsis developed on Day 3 of life. The SGH became infected, with abscess formation 1 week later. The infected SGH was probably due to direct hematogenous spreading of sepsis. The patient was successfully treated without complications. Clinicians should be aware that SGH is a potential site of infection and infection may be caused either by direct hematogenous extension or from traumatic scalp lesions. Appropriate antibiotic treatment and surgical debridement are necessary when an infected SGH occurs. PMID:23597516

  18. Does Diagnostic Classification of Early-Onset Psychosis Change over Follow-Up?

    ERIC Educational Resources Information Center

    Fraguas, David; de Castro, Maria J.; Medina, Oscar; Parellada, Mara; Moreno, Dolores; Graell, Montserrat; Merchan-Naranjo, Jessica; Arango, Celso

    2008-01-01

    Objective: To examine the diagnostic stability and the functional outcome of patients with early-onset psychosis (EOP) over a 2-year follow-up period. Methods: A total of 24 patients (18 males (75%) and 6 females (25%), mean age [plus or minus] SD: 15.7 [plus or minus] 1.6 years) with a first episode of EOP formed the sample. Psychotic symptoms

  19. Association between Interleukin-10 gene polymorphisms and risk of early-onset preeclampsia

    PubMed Central

    Song, Limeng; Zhong, Mei

    2015-01-01

    We conducted a case-control study to investigate the role of IL-10 -1082A/G (rs1800896), -819T/C (rs1800871), and -592A/C (rs1800872) polymorphisms in the development of early-onset preeclampsia. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay was applied to assess the polymorphisms of IL-10 -1082A/G (rs1800896), -819T/C (rs1800871), and -592A/C (rs1800872). The genotype distributions of IL-10 -1082A/G (rs1800896), -819T/C (rs1800871), and -592A/C (rs1800872) confirmed with HWE in the controls, and the P value for HWE was 0.41, 0.38 and 0.26, respectively. The results of the multivariate logistic regression analysis revealed that the association of individuals expressing the CC genotype and AC+CC of IL-10 -592A/C (rs1800872) with a significantly increased risk of early-onset preeclampsia in co-dominant and dominant models, compared to the AA genotype; the OR (95% CI) for these individuals was determined to be 2.09 (1.12-3.90) and 1.66 (1.03-2.71), respectively. In the recessive model, we found that CC genotype of IL-10 -592A/C (rs1800872) was associated with the increased risk of early-onset preeclampsia when compared with AA+AC genotype (OR = 1.67; 95% CI = 1.01-2.92). In conclusion, our study has indicated that IL-10 -592A/C (rs1800872) polymorphism was associated with an increased risk of early-onset preeclampsia in a Chinese population. PMID:26617906

  20. Advanced magnetic resonance neuroimaging in bulbar and limb onset early amyotrophic lateral sclerosis

    PubMed Central

    Vora, Maulik; Kumar, Suresh; Sharma, Sanjiv; Sharma, Sudhir; Makhaik, Sushma; Sood, R. G.

    2016-01-01

    Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal and most common motor neuron disease, caused by progressive loss of motor neurons. Diffusion tensor imaging (DTI) and magnetic resonance spectroscopic (MRS) studies detect pathological changes in neuronal fibers in vivo. We evaluated the role of DTI and MRS in early course of the disease, which may prove beneficial in the early diagnosis and better management. Materials and Methods: Twenty-one patients with ALS and 13 age-matched controls received 1.5T DTI and three-dimensional multi-voxel MRS. Fractional anisotropy (FA), apparent diffusion coefficient, N-acetyl aspartate (NAA)/Creatine (Cr), and NAA/Choline (Ch) ratios were analyzed in various regions of the brain and compared with healthy controls. ALS patients were classified as definite, possible, and probable category, and patients were also studied in limb versus bulbar onset. Results: Decreased FA and increase mean diffusivity values in regions of corticospinal tract (CST) and corpus callosum (CC) was consistent finding in definite and probable disease category (P < 0.05). In possible disease, CC involvement was not significant. NAA/Cr and NAA/Ch ratios were lower in CC and regions of CST. However, in possible disease, CC involvement was not significant, while regions of CST were showing significant reduction in NAA/Cr and NAA/Ch ratios (P < 0.05). Conclusion: DTI and MRS detect changes associated with ALS even in the early phase of the disease. Bulbar onset and limb onset ALS patients show different pattern of involvement. Extramotor involvement suggested by CC involvement is a feature seen in bulbar onset patient and can suggest poor outcome in such patients. The present findings may be helpful for designing further studies in the direction of more early diagnosis of disease and its management.

  1. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.

    PubMed

    Flanagan, Sarah E; Haapaniemi, Emma; Russell, Mark A; Caswell, Richard; Lango Allen, Hana; De Franco, Elisa; McDonald, Timothy J; Rajala, Hanna; Ramelius, Anita; Barton, John; Heiskanen, Kaarina; Heiskanen-Kosma, Tarja; Kajosaari, Merja; Murphy, Nuala P; Milenkovic, Tatjana; Seppnen, Mikko; Lernmark, ke; Mustjoki, Satu; Otonkoski, Timo; Kere, Juha; Morgan, Noel G; Ellard, Sian; Hattersley, Andrew T

    2014-08-01

    Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome. PMID:25038750

  2. Alcohol intake and early-onset basal cell carcinoma in a case-control study

    PubMed Central

    Zhang, Y; Ferrucci, L.M.; Cartmel, B.; Molinaro, A.M.; Leffell, D.J.; Bale, A.E.; Mayne, S.T.

    2014-01-01

    Background Previous epidemiologic studies of overall alcohol intake and basal cell carcinoma (BCC) are inconsistent, with some evidence for differences by type of alcoholic beverage. While alcohol may enhance the carcinogenicity of ultraviolet (UV) light, this has not been evaluated in existing epidemiologic studies. Objective To evaluate alcohol intake in relation to early-onset BCC, and explore potential interactions with UV exposure. Methods BCC cases (n=380) and controls with benign skin conditions (n=390) under age 40 were identified through Yale Dermatopathology. Participants provided information on lifetime alcohol intake, including type of beverage during an in-person interview. Self-report data on indoor tanning and outdoor sunbathing were used to categorize UV exposure. We calculated odds ratios (OR) and 95% confidence intervals (CI) using unconditional multivariate logistic regression in the full sample and in women only. Results There was no statistically significant association between lifetime alcohol intake and early-onset BCC overall (above median intake vs. no regular alcohol intake OR 1.10, 95% CI 0.69-1.73) or in women only (OR 1.21, 95% CI 0.73-2.01). Similarly, intake of red wine, white wine, beer or hard liquor and mixed drinks was not associated with early-onset BCC. In exploratory analyses, we saw limited evidence for an interaction (pinteraction=0.003), with highest risk for high alcohol and high UV exposures, especially in women, but subgroup risk estimates had wide and overlapping confidence intervals. Conclusions Overall, we did not observe any clear association between lifetime alcohol intake and early-onset BCC. PMID:25059635

  3. Executive Abilities as Reflected by Clock Hand Placement: Frontotemporal Dementia Versus Early-Onset Alzheimer Disease.

    PubMed

    Barrows, Robin J; Barsuglia, Joseph; Paholpak, Pongsatorn; Eknoyan, Donald; Sabodash, Valeriy; Lee, Grace J; Mendez, Mario F

    2015-12-01

    The clock-drawing test (CDT) is widely used in clinical practice to diagnose and distinguish patients with dementia. It remains unclear, however, whether the CDT can distinguish among the early-onset dementias. Accordingly, we examined the ability of both quantitative and qualitative CDT analyses to distinguish behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer disease (eAD), the 2 most common neurodegenerative dementias with onset <65 years of age. We hypothesized that executive aspects of the CDT would discriminate between these 2 disorders. The study compared 15 patients with bvFTD and 16 patients with eAD on the CDT using 2 different scales and correlated the findings with neuropsychological testing and magnetic resonance imaging. The total CDT scores did not discriminate bvFTD and eAD; however, specific analysis of executive hand placement items successfully distinguished the groups, with eAD exhibiting greater errors than bvFTD. The performance on those executive hand placement items correlated with measures of naming as well as visuospatial and executive function. On tensor-based morphometry of the magnetic resonance images, executive hand placement correlated with right frontal volume. These findings suggest that lower performance on executive hand placement items occurs with involvement of the right dorsolateral frontal-parietal network for executive control in eAD, a network disproportionately affected in AD of early onset. Rather than the total performance on the clock task, the analysis of specific errors, such as executive hand placement, may be useful for early differentiation of eAD, bvFTD, and other conditions. PMID:26251109

  4. S-Nitrosoglutathione improves haemodynamics in early-onset pre-eclampsia

    PubMed Central

    Everett, Thomas R; Wilkinson, Ian B; Mahendru, Amita A; McEniery, Carmel M; Garner, Stephen F; Goodall, Alison H; Lees, Christoph C

    2014-01-01

    Aims To determine the effects of in vivo S-nitrosoglutathione (GSNO) infusion on cardiovascular function, platelet function, proteinuria and biomarker parameters in early-onset pre-eclampsia. Methods We performed an open-label dose-ranging study of GSNO in early-onset pre-eclampsia. Six women underwent GSNO infusion whilst receiving standard therapy. The dose of GSNO was increased incrementally to 100 ?g min?1 whilst maintaining blood pressure of >140/80 mmHg. Aortic augmentation index, aortic pulse wave velocity, blood pressure and maternalfetal Doppler parameters were measured at each dose. Platelet P-selectin, protein-to-creatinine ratio and soluble anti-angiogenic factors were measured pre- and postinfusion. Results Augmentation index fell at 30 ?g min?1 S-nitrosoglutathione (?6%, 95% confidence interval 0.6 to 13%), a dose that did not affect blood pressure. Platelet P-selectin expression was reduced [mean (interquartile range), 6.3 (4.97.6) vs. 4.1 (3.15.7)% positive, P = 0.03]. Soluble endoglin levels showed borderline reduction (P = 0.06). There was a borderline significant change in pre-to-postinfusion protein-to-creatinine ratio [mean (interquartile range), 0.37 (0.090.82) vs. 0.23 (0.070.49) g mmol?1, P = 0.06]. Maternal uterine and fetal Doppler pulsatility indices were unchanged. Conclusions In early-onset pre-eclampsia, GSNO reduces augmentation index, a biomarker of small vessel tone and pulse wave reflection, prior to affecting blood pressure. Proteinuria and platelet activation are improved at doses that affect blood pressure minimally. These effects of GSNO may be of therapeutic potential in pre-eclampsia, a condition for which no specific treatment exists. Clinical studies of GSNO in early-onset pre-eclampsia will determine whether these findings translate to improvement in maternal and/or fetal outcome. PMID:24627995

  5. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease

    PubMed Central

    Caswell, Richard; Allen, Hana Lango; De Franco, Elisa; McDonald, Timothy J.; Rajala, Hanna; Ramelius, Anita; Barton, John; Heiskanen, Kaarina; Heiskanen-Kosma, Tarja; Kajosaari, Merja; Murphy, Nuala P.; Milenkovic, Tatjana; Seppnen, Mikko; Lernmark, ke; Mustjoki, Satu; Otonkoski, Timo; Kere, Juha; Morgan, Noel G.; Ellard, Sian; Hattersley, Andrew T.

    2014-01-01

    Monogenic causes of autoimmunity give key insights to the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in 5 individuals with a spectrum of early-onset autoimmune disease including type 1 diabetes. These findings emphasise the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in Hyper IgE syndrome. PMID:25038750

  6. Early onset of vegetation growth vs. rapid green-up: impacts on juvenile mountain ungulates.

    PubMed

    Pettorelli, Nathalie; Pelletier, Fanie; Von Hardenberg, Achaz; Festa-Bianchet, Marco; Ct, Steeve D

    2007-02-01

    Seasonal patterns of climate and vegetation growth are expected to be altered by global warming. In alpine environments, the reproduction of birds and mammals is tightly linked to seasonality; therefore such alterations may have strong repercussions on recruitment. We used the normalized difference vegetation index (NDVI), a satellite-based measurement that correlates strongly with aboveground net primary productivity, to explore how annual variations in the timing of vegetation onset and in the rate of change in primary production during green-up affected juvenile growth and survival of bighorn sheep (Ovis canadensis), Alpine ibex (Capra ibex), and mountain goats (Oreamnos americanus) in four different populations in two continents. We indexed timing of onset of vegetation growth by the integrated NDVI (INDVI) in May. The rate of change in primary production during green-up (early May to early July) was estimated as (1) the maximal slope between any two successive bimonthly NDVI values during this period and (2) the slope in NDVI between early May and early July. The maximal slope in NDVI was negatively correlated with lamb growth and survival in both populations of bighorn sheep, growth of mountain goat kids, and survival of Alpine ibex kids, but not with survival of mountain goat kids. There was no effect of INDVI in May and of the slope in NDVI between early May and early July on juvenile growth and survival for any species. Although rapid changes in NDVI during the green-up period could translate into higher plant productivity, they may also lead to a shorter period of availability of high-quality forage over a large spatial scale, decreasing the opportunity for mountain ungulates to exploit high-quality forage. Our results suggest that attempts to forecast how warmer winters and springs will affect animal population dynamics and life histories in alpine environments should consider factors influencing the rate of changes in primary production during green-up and the timing of vegetation onset. PMID:17479756

  7. Modeling early-onset post-ischemic seizures in aging mice.

    PubMed

    Wu, Chiping; Wang, Justin; Peng, Jessie; Patel, Nisarg; Huang, Yayi; Gao, Xiaoxing; Aljarallah, Salman; Eubanks, James H; McDonald, Robert; Zhang, Liang

    2015-09-01

    Stroke is the leading cause of seizures and epilepsy in the aged population, with post-stroke seizures being a poor prognostic factor. The pathological processes underlying post-stroke seizures are not well understood and studies of these seizures in aging/aged animals remain scarce. Therefore, our primary objective was to model post-stroke seizures in aging mice (C57 black strain, 16-20 months-old), with a focus on early-onset, convulsive seizures that occur within 24-hours of brain ischemia. We utilized a middle cerebral artery occlusion model and examined seizure activity and brain injury using combined behavioral and electroencephalographic monitoring and histological assessments. Aging mice exhibited vigorous convulsive seizures within hours of the middle cerebral artery occlusion. These seizures manifested with jumping, rapid running, barrel-rolling and/or falling all in the absence of hippocampal-cortical electrographic discharges. Seizure development was closely associated with severe brain injury and acute mortality. Anticonvulsive treatments after seizure occurrence offered temporary seizure control but failed to improve animal survival. A separate cohort of adult mice (6-8 months-old) exhibited analogous early-onset convulsive seizures following the middle cerebral artery occlusion but had better survival outcomes following anticonvulsive treatment. Collectively, our data suggest that early-onset convulsive seizures are a result of severe brain ischemia in aging animals. PMID:25943585

  8. A novel homozygous mutation at the GAA gene in Mexicans with early-onset Pompe disease.

    PubMed

    Esmer, Carmen; Becerra-Becerra, Rosario; Peña-Zepeda, Claudia; Bravo-Oro, Antonio

    2013-10-01

    Glycogen-storage disease type II, also named Pompe disease, is caused by the deficiency of the enzyme acid alpha-glucosidase, which originates lysosomal glycogen accumulation leading to progressive neuromuscular damage. Early-onset Pompe disease shows a debilitating and frequently fulminating course. To date, more than 300 mutations have been described; the majority of them are unique to each affected individual. Most early-onset phenotypes are associated with frameshift mutations leading to a truncated alpha-glucosidase protein with loss of function. Founder effects are responsible from many cases from few highprevalence world regions. Herein we described two apparently unrelated cases affected with classical early-onset Pompe disease, both pertaining to a small region from Central Mexico (the State of San Luis Potosí), the same novel homozygous frameshift mutation at gene GAA (c.1987delC) was demonstrated in both cases. This GAA gene deletion implies a change of glutamine to serine at codon 663, and a new reading frame that ends after 33 base pairs, which leads to the translation of a truncated protein. This report contributes to widen the knowledge on the effect of pathogenic mutations in Pompe disease. Here we postulate the existence of a founder effect. PMID:24399866

  9. Modeling early-onset post-ischemic seizures in aging mice

    PubMed Central

    Wu, Chiping; Wang, Justin; Peng, Jessie; Patel, Nisarg; Huang, Yayi; Gao, Xiaoxing; Aljarallah, Salman; Eubanks, James H; McDonald, Robert; Zhang, Liang

    2016-01-01

    Stroke is the leading cause of seizures and epilepsy in the aged population, with post-stroke seizures being a poor prognostic factor. The pathological processes underlying post-stroke seizures are not well understood and studies of these seizures in aging/aged animals remain scarce. Therefore, our primary objective was to model post-stroke seizures in aging mice (C57 black strain, 16–20 month-old), with a focus on early-onset, convulsive seizures that occur within 24-hours of brain ischemia. We utilized a middle cerebral artery occlusion model and examined seizure activity and brain injury using combined behavioral and electroencephalographic monitoring and histological assessments. Aging mice exhibited vigorous convulsive seizures within hours of the middle cerebral artery occlusion. These seizures manifested with jumping, rapid running, barrel-rolling and/or falling all in the absence of hippocampal-cortical electrographic discharges. Seizure development was closely associated with severe brain injury and acute mortality. Anticonvulsive treatments after seizure occurrence offered temporary seizure control but failed to improve animal survival. A separate cohort of adult mice (6–8 months-old) exhibited analogous early-onset convulsive seizures following the middle cerebral artery occlusion but had better survival outcomes following anticonvulsive treatment. Collectively, our data suggest that early-onset convulsive seizures are a result of severe brain ischemia in aging animals. PMID:25943585

  10. Recessive mutations in PCBD1 cause a new type of early-onset diabetes.

    PubMed

    Simaite, Deimante; Kofent, Julia; Gong, Maolian; Rschendorf, Franz; Jia, Shiqi; Arn, Pamela; Bentler, Kristi; Ellaway, Carolyn; Khnen, Peter; Hoffmann, Georg F; Blau, Nenad; Spagnoli, Francesca M; Hbner, Norbert; Raile, Klemens

    2014-10-01

    Mutations in several genes cause nonautoimmune diabetes, but numerous patients still have unclear genetic defects, hampering our understanding of the development of the disease and preventing pathogenesis-oriented treatment. We used whole-genome sequencing with linkage analysis to study a consanguineous family with early-onset antibody-negative diabetes and identified a novel deletion in PCBD1 (pterin-4 ?-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 ?), a gene that was recently proposed as a likely cause of diabetes. A subsequent reevaluation of patients with mild neonatal hyperphenylalaninemia due to mutations in PCBD1 from the BIODEF database identified three additional patients who had developed HNF1A-like diabetes in puberty, indicating early ?-cell failure. We found that Pcbd1 is expressed in the developing pancreas of both mouse and Xenopus embryos from early specification onward showing colocalization with insulin. Importantly, a morpholino-mediated knockdown in Xenopus revealed that pcbd1 activity is required for the proper establishment of early pancreatic fate within the endoderm. We provide the first genetic evidence that PCBD1 mutations can cause early-onset nonautoimmune diabetes with features similar to dominantly inherited HNF1A-diabetes. This condition responds to and can be treated with oral drugs instead of insulin, which is important clinical information for these patients. Finally, patients at risk can be detected through a newborn screening for phenylketonuria. PMID:24848070

  11. Early impact basins and the onset of plate tectonics. Ph.D. Thesis - Maryland Univ.

    NASA Technical Reports Server (NTRS)

    Frey, H.

    1977-01-01

    The fundamental crustal dichotomy of the Earth (high and low density crust) was established nearly 4 billion years ago. Therefore, subductable crust was concentrated at the surface of the Earth very early in its history, making possible an early onset for plate tectonics. Simple thermal history calculations spanning 1 billion years show that the basin forming impact thins the lithosphere by at least 25%, and increases the sublithosphere thermal gradients by roughly 20%. The corresponding increase in convective heat transport, combined with the highly fractured nature of the thinned basin lithosphere, suggest that lithospheric breakup or rifting occurred shortly after the formation of the basins. Conditions appropriate for early rifting persisted from some 100,000,000 years following impact. We suggest a very early stage of high temperature, fast spreading "microplate" tectonics, originating before 3.5 billion years ago, and gradually stabilizing over the Archaean into more modern large plate or Wilson Cycle tectonics.

  12. Delineation of Early and Later Adult Onset Depression by Diffusion Tensor Imaging

    PubMed Central

    Yu, Hongjun; Nie, Binbin; Li, Na; Luo, Chunrong; Li, Haijun; Liu, Fang; Bai, Yan; Shan, Baoci; Xu, Lin; Xu, Xiufeng

    2014-01-01

    Background Due to a lack of evidence, there is no consistent age of onset to define early onset (EO) versus later onset (LO) major depressive disorder (MDD). Fractional anisotropy (FA), derived from diffusion tensor imaging (DTI), has been widely used to study neuropsychiatric disorders by providing information about the brain circuitry, abnormalities of which might facilitate the delineation of EO versus LO MDD. Method In this study, 61 pairs of untreated, non-elderly, first-episode MDD patients and healthy controls (HCs) aged 1845 years old received DTI scans. The voxel-based analysis method (VBM), classification analysis, using the Statistical Package for the Social Sciences (SPSS), and regression analyses were used to determine abnormal FA clusters and their correlations with age of onset and clinical symptoms. Results Classification analysis suggested in the best model that there were two subgroups of MDD patients, delineated by an age of onset of 30 years old, by which MDD patients could be divided into EO (1829 years old) and LO (3045 years old) groups. LO MDD was characterized by decreased FA, especially in the white matter (WM) of the fronto-occipital fasciculus and posterior limb of internal capsule, with a negative correlation with the severity of depressive symptoms; in marked contrast, EO MDD showed increased FA, especially in the WM of the corpus callosum, corticospinal midbrain and inferior fronto-occipital fasciculus, while FA of the WM near the midbrain had a positive correlation with the severity of depressive symptoms. Conclusion Specific abnormalities of the brain circuitry in EO vs. LO MDD were delineated by an age of onset of 30 years old, as demonstrated by distinct abnormal FA clusters with opposite correlations with clinical symptoms. This DTI study supported the evidence of an exact age for the delineation of MDD, which could have broad multidisciplinary importance. Trial Registration ClinicalTrials.gov NCT00703742 PMID:25393297

  13. Early-onset acute kidney injury is a poor prognostic sign for allogeneic SCT recipients.

    PubMed

    Shingai, N; Morito, T; Najima, Y; Kobayashi, T; Doki, N; Kakihana, K; Ohashi, K; Ando, M

    2015-12-01

    Acute kidney injury (AKI) following stem-cell transplantation (SCT) contributes to a poor prognosis, yet its impact may vary depending on the timing of AKI onset. A prospective cohort study was performed to understand the significance of the onset timing in 103 allogeneic SCT (allo-SCT) recipients. AKI prior to stem-cell engraftment was defined as early AKI and subsequently occurring AKI as late AKI. Propensity score (PS) for early AKI was calculated using a logistic regression model to reduce confounding effects related to differences in clinical background between the early and late AKI groups. The cumulative incidences of early and late AKI were 22.3% and 54.9%, respectively. Non-relapse mortality (NRM) was 39.1% and 7.0%, and overall survival (OS) was 56.5% and 90.9% in early and late AKI at 100 days after AKI, respectively (P<0.001). The cumulative incidence of chronic kidney disease (CKD) over 2 years after SCT was 41.5% and 19.1% in early and late AKI, respectively (P=0.048). Logistic regression analysis adjusted for the PS showed that early AKI was significantly associated with OS (odds ratio (95% confidence interval); 4.63 (1.15-21.4), P=0.031) but with neither NRM (1.25 (0.28-5.33), P=0.766) nor CKD (1.85 (0.41-8.60), P=0.422). In conclusion, early AKI may portend a poor survival for allo-SCT recipients. PMID:26301965

  14. Association between Polymorphisms in Cancer-Related Genes and Early Onset of Esophageal Adenocarcinoma123

    PubMed Central

    Wu, I-Chen; Zhao, Yang; Zhai, Rihong; Liu, Geoffrey; Ter-Minassian, Monica; Asomaning, Kofi; Su, Li; Liu, Chen-yu; Chen, Feng; Kulke, Matthew H; Heist, Rebecca S; Christiani, David C

    2011-01-01

    There is an increasing incidence of esophageal adenocarcinoma (EA) among younger people in the western populations. However, the association between genetic polymorphisms and the age of EA onset is unclear. In this study, 1330 functional/tagging single-nucleotide polymorphisms (SNPs) from 354 cancer-related genes were genotyped in 335 white EA patients. Twenty important SNPs that have the highest importance scores and lowest classification error rate were identified by the random forest algorithm to be associated with early onset of EA (age ? 55 years). Subsequent logistic regression analysis indicated that 10 SNPs (rs2070744 of NOS3, rs720321 of BCL2, rs17757541 of BCL2, rs11775256 of TNFRSF10A, rs1035142 of CASP8, rs2236302 of MMP14, rs4740363 of ABL1, rs696217 of GHRL, rs2445762 of CYP19A1, and rs11941492 of VEGFR2/KDR) were significantly associated with early onset of EA (?55 vs >55 years, all P < .05 after adjusting for co-variates and false discovery rate). Among them, five SNPs in the NOS3, BCL2, TNFRSF10A, and CASP8 genes were known to be involved in apoptosis processes. In Kaplan-Meier analyses, rs2070744 of NOS3, rs720321 of BCL2, and rs1035142 of CASP8 were also significantly associated with early onset of EA. Moreover, there was a higher risk of developing EA at a younger age when one had more risk genotypes. In conclusion, polymorphisms in cancer-related genes, especially those in the apoptotic pathway, play an important role in the development of younger-aged EA in a dose-response manner. PMID:21472143

  15. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy

    PubMed Central

    Fehr, Stephanie; Wilson, Meredith; Downs, Jenny; Williams, Simon; Murgia, Alessandra; Sartori, Stefano; Vecchi, Marilena; Ho, Gladys; Polli, Roberta; Psoni, Stavroula; Bao, Xinhua; de Klerk, Nick; Leonard, Helen; Christodoulou, John

    2013-01-01

    The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Available photographs of CDKL5 patients were examined for dysmorphic features. The proportion of CDKL5 patients meeting the recent Neul criteria for atypical RTT was determined. Logistic regression and time-to-event analyses were used to compare the occurrence of Rett-like features in those with MECP2 and CDKL5 mutations. Most individuals with CDKL5 mutations had severe developmental delay from birth, seizure onset before the age of 3 months and similar non-dysmorphic features. Less than one-quarter met the criteria for early-onset seizure variant RTT. Seizures and sleep disturbances were more common than in those with MECP2 mutations whereas features of regression and spinal curvature were less common. The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies. Although mutations in the CDKL5 gene have been described in association with the early-onset variant of RTT, in our study the majority did not meet these criteria. Therefore, the CDKL5 disorder should be considered separate to RTT, rather than another variant. PMID:22872100

  16. Long-term efficacy of microbiology-driven periodontal laser-assisted therapy.

    PubMed

    Martelli, F S; Fanti, E; Rosati, C; Martelli, M; Bacci, G; Martelli, M L; Medico, E

    2016-03-01

    Periodontitis represents a highly prevalent health problem, causing severe functional impairment, reduced quality of life and increased risk of systemic disorders, including respiratory, cardiovascular and osteoarticular diseases, diabetes and fertility problems. It is a typical example of a multifactorial disease, where a polymicrobial infection inducing chronic inflammation of periodontal tissues is favoured by environmental factors, life style and genetic background. Since periodontal pathogens can colonise poorly vascularised niches, antiseptics and antibiotics are typically associated with local treatments to manage the defects, with unstable outcomes especially in early-onset cases. Here, the results of a retrospective study are reported, evaluating the efficacy of a protocol (Periodontal Biological Laser-Assisted Therapy, Perioblast™) by which microbial profiling of periodontal pockets is used to determine the extent and duration of local neodymium-doped yttrium aluminium garnet (Nd:YAG) laser irradiation plus conventional treatment. The protocol was applied multicentrically on 2683 patients, and found to produce a significant and enduring improvement of all clinical and bacteriological parameters, even in aggressive cases. Microbiome sequencing of selected pockets revealed major population shifts after treatment, as well as strains potentially associated with periodontitis in the absence of known pathogens. This study, conducted for the first time on such a large series, clearly demonstrates long-term efficacy of microbiology-driven non-invasive treatment of periodontal disease. PMID:26740323

  17. Evidence of early onset of antidepressant effect in randomized controlled trials.

    PubMed

    Stahl, S M; Nierenberg, A A; Gorman, J M

    2001-01-01

    Although antidepressant medications are effective in approximately 70% of patients with major depressive disorder, they have a delayed onset of therapeutic effect. This latency is problematic in that it prolongs the impairments associated with depression, leaves patients vulnerable to an increased risk of suicide, increases the likelihood that a patient will prematurely discontinue therapy, and increases medical costs associated with severe depression. No adequately designed prospective trials have been conducted to evaluate comparative time to onset of antidepressant effect. However, evidence suggests that some antidepressant agents may begin to work faster than others. Citalopram, venlafaxine, and mirtazapine each have exhibited statistically significant differences in some measures of antidepressant action within the first 2 weeks of treatment, both in placebo-controlled trials and in head-to-head comparisons with other antidepressants. This article reviews the data that hint at these drug-specific differences in time to onset of action. Given the potential benefits of early-acting antidepressant treatments, the possibility of superior speed of onset of citalopram, venlafaxine, and mirtazapine presented here merits further study in adequately designed, prospective clinical trials. PMID:11229783

  18. Selenoprotein N muscular dystrophy: differential diagnosis for early-onset limited mobility of the spine.

    PubMed

    Sponholz, Stefanie; von der Hagen, Maja; Hahn, Gabriele; Seifert, Jens; Richard, Pascale; Stoltenburg-Didinger, Gisela; Ferreiro, Ana; Kaindl, Angela M

    2006-04-01

    Early spinal rigidity is a nonspecific feature reported in diseases such as neuromuscular and central movement disorders. We present a male patient with rigid spine muscular dystrophy caused by newly identified compound heterozygote mutations of the selenoprotein N gene and discuss this disease as a possible differential diagnosis for early-onset reduced spine mobility. Rigid spine muscular dystrophy is a rare myopathy presenting in childhood with a typical combination of stable or slowly progressive mild to moderate muscle weakness, limitation in flexion of the spine, and progressive restrictive ventilatory disorder. The clinical features of our patient include early-onset rigidity of his spine, scoliosis, mild muscular weakness predominantly of neck and trunk flexors, and restrictive ventilatory disorder. Biopsy of the biceps muscle revealed nonspecific myopathic changes, and molecular analysis confirmed the diagnosis of rigid spine muscular dystrophy. Thus, neuromuscular diseases such as muscular dystrophy must be considered in all patients presenting with early spinal rigidity, and genetic determination is a possible way to determine the diagnosis. PMID:16900928

  19. Diagnostic Approach to Genetic Causes of Early-Onset Epileptic Encephalopathy.

    PubMed

    Grsoy, Semra; Eral, Derya

    2016-03-01

    Epileptic encephalopathies are characterized by recurrent clinical seizures and prominent interictal epileptiform discharges seen during the early infantile period. Although epileptic encephalopathies are mostly associated with structural brain defects and inherited metabolic disorders, pathogenic gene mutations may also be involved in the development of epileptic encephalopathies even when no clear genetic inheritance patterns or consanguinity exist. The most common epileptic encephalopathies are Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, West syndrome and Dravet syndrome, which are usually unresponsive to traditional antiepileptic medication. Many of the diagnoses describe the phenotype of these electroclinical syndromes, but not the underlying causes. To date, approximately 265 genes have been defined in epilepsy and several genes including STXBP1, ARX, SLC25A22, KCNQ2, CDKL5, SCN1A, and PCDH19 have been found to be associated with early-onset epileptic encephalopathies. In this review, we aimed to present a diagnostic approach to primary genetic causes of early-onset epileptic encephalopathies. PMID:26271793

  20. Familial liability, obstetric complications and childhood development abnormalities in early onset schizophrenia: a case control study

    PubMed Central

    2011-01-01

    Background Genetic and environmental risk factors and gene-environment interactions are linked to higher likelihood of developing schizophrenia in accordance with the neurodevelopmental model of disease; little is known about risk factors and early development in early-onset schizophrenia (EOS) and very early-onset schizophrenia (VEOS). Methods We present a case-control study of a sample of 21 patients with EOS/VEOS and a control group of 21 patients with migraine, recruited from the Child Neuropsychiatry Unit, Department of Neurologic and Psychiatric Science, University of Bari, Italy. The aim was to assess the statistical association between VEOS/EOS and family history for psychiatric disorders, obstetric complications and childhood developmental abnormalities using 2 × 2 tables and a Chi Squared or Fisher test. Results The results show a statistical association between EOS/VEOS and schizophrenia and related disorders (P = 0.02) and personality disorders (P = 0.003) in relatives, and between EOS/VEOS and developmental abnormalities of early relational skills (P = 0.008) and learning (P = 0.04); there is not a statistically relevant difference between cases and controls (P > 0.05) for any obstetric complications (pre, peri and postpartum). Conclusions This study confirms the significant role of familial liability but not of obstetric complications in the pathogenesis of VEOS/EOS; the association between childhood developmental abnormalities and EOS/VEOS supports the neurodevelopmental model of disease. PMID:21492438

  1. Herlyn-Werner-Wunderlich syndrome: An "early" onset case report and review of Literature.

    PubMed

    Angotti, R; Molinaro, F; Bulotta, A L; Bindi, E; Cerchia, E; Sica, M; Messina, M

    2015-01-01

    Herlyn-Werner-Wunderlich syndrome (HWWS) is a rare congenital mullerian anomaly consisting of uterus didelphys, hemivaginal septum, and unilateral renal agenesis [1,2]. Most authors reported cases of Herlyn-Werner-Wunderlich syndrome with prepuberal or postpuberal onset with cyclical abdominal pain and a vaginal mass (3-8). Only six cases are reported in Literature with early onset of this syndrome under 5 years (9-14). Our case is about 3 years old girl, with all the features of this syndrome who came to our attention for lower abdominal mass. The aim of this article is to share our experience and focus the attention on the importance of high level of suspicion of HWWS in neonatal period to early diagnosis and treatment. The possible early presentation of this syndrome should be suspected in all neonates (females) with renal agenesia confirmed postnatally or with prenatal diagnosis. It is common, in fact, an error of evaluation with planning of removal of mass, that can damage patients in term of chance for a successful reproductive outcome. For all these reasons, our team consider HWWS as differential diagnosis in newborn with prenatal ultrasonography of a cystic mass behind the urinary bladder in the absence of a kidney and plan a pelvic ultrasound (with aim to identify an uterus, normal or dydhelfus, and presence or absence of pelvic mass), an examination under anesthesia and cystoscopy and vaginoscopy, if it is necessary. A high level of suspicion, indeed, is the key to early diagnosis. PMID:25932973

  2. Linkage of early-onset osteoarthritis and chondrocalcinosis to human chromosome 8q

    SciTech Connect

    Baldwin, C.T.; Farrer, L.A.; Adair, R.; Dharmavaram, R.; Jimenez, S.; Anderson, L.

    1995-03-01

    Calcium pyrophosphate-deposition disease (CPDD), also called {open_quotes}chondrocalcinosis{close_quotes} or {open_quotes}pseudogout{close_quotes}, is a disorder characterized by the deposition of calcium-containing crystals in joint tissue, which leads to arthritis-like symptoms. The presence of these crystals in joint tissue is a common finding in the elderly, and, in this population, there is a poor correlation with joint pain. In contrast, early-onset CPDD has been described in several large families in which the disease progresses to severe degenerative osteoarthritis (OA). In these families, an autosomal dominant mode of inheritance is observed, with an age at onset between the 2nd and 5th decades of life. In this report, we describe a large New England family with early-onset CPDD and severe degenerative OA. We found genetic linkage between the disease in this family and chromosome 8q, with a multipoint lod score of 4.06. These results suggest that a defective gene at this location causes the disease in this family. 29 refs., 2 figs., 1 tab.

  3. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families.

    PubMed

    1995-10-01

    Genetic linkage studies place a gene causing early onset familial Alzheimer's disease (FAD) on chromosome 14q24.3 (refs 1-4). Five mutations within the S182 (Presenilin 1: PS-1) gene, which maps to this region, have recently been reported in several early onset FAD kindreds. We have localized the PS-1 gene to a 75 kb region and present the structure of this gene, evidence for alternative splicing and describe six novel mutations in early onset FAD pedigrees all of which alter residues conserved in the STM2 (Presenilin 2: PS-2) gene. PMID:7550356

  4. A Unified Hypothesis of Early- and Late-Onset Alzheimer's Disease Pathogenesis.

    PubMed

    Atwood, Craig S; Bowen, Richard L

    2015-01-01

    Early-onset familial Alzheimer's disease (EOFAD) and late-onset sporadic AD (LOSAD) both follow a similar pathological and biochemical course that includes: neuron and synapse loss and dysfunction, microvascular damage, microgliosis, extracellular amyloid-β deposition, tau phosphorylation, formation of intracellular neurofibrillary tangles, endoreduplication and related cell cycle events in affected brain regions. Any mechanistic explanation of AD must accommodate these biochemical and neuropathological features for both forms of the disease. In this insight paper we provide a unifying hypothesis for EOFAD and LOSAD that proposes that the aberrant re-entry of terminally differentiated, post-mitotic neurons into the cell division cycle is a common pathway that explains both early and late-onset forms of AD. Cell cycle abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles, and explain the biochemical (e.g. tau phosphorylation), neuropathological (e.g. neuron hypertrophy; polypoidy) and cognitive changes observed in EOFAD and LOSAD. Genetic mutations in AβPP, PSEN1, and PSEN2 that alter amyloid-β precursor protein and Notch processing drive reactivation of the cell cycle in EOFAD, while age-related reproductive endocrine dyscrasia that upregulates mitogenic TNF signaling and AβPP processing toward the amyloidogenic pathway drives reactivation of the cell cycle in LOSAD. In essence, AβPP and presenilin mutations initiate early, what endocrine dyscrasia initiates later: aberrant cell cycle re-entry of post-mitotic neurons leading to neurodegeneration and cognitive decline in AD. Inhibition of cell cycle re-entry in post-mitotic neurons may be a useful therapeutic strategy to prevent, slow or halt disease progression. PMID:26402752

  5. Time since onset of walking predicts tibial bone strength in early childhood.

    PubMed

    Ireland, Alex; Rittweger, Jrn; Schnau, Eckhard; Lamberg-Allardt, Christel; Viljakainen, Heli

    2014-11-01

    Bone strength in adulthood is known to be affected by health at birth and early childhood. Habitual bone loading is a primary determinant of bone strength in later childhood and adulthood. However, the effects of physical activity in early childhood (e.g. crawling, standing and walking) on bone strength are unknown. Fifty-three children (twenty-seven males) were included in a longitudinal study in their early infancy. Shortly after birth (0.30.3months), details of mass and height were obtained along with a pQCT scan at 20% distal-proximal tibia length. At 14.80.5months of age the same data were collected, along with details of age at onset of standing, crawling, supported and unsupported walking. Time since onset of walking unsupported was associated with greater bone mass, cortical bone area, pericortical circumference and polar moment of inertia of both total and cortical bone (all P<0.05). There were no significant associations between other physical activity timepoints and bone measures. Age at onset of walking was not significantly related to mass, length or bone measures at birth. The results suggest that time since attainment of independent walking - representing exposure of the tibia to the large reaction and muscular forces associated with locomotion - is a primary determinant of bone strength in early childhood. This finding raises the possible opportunity of physical activity interventions at young age in paediatric populations associated with low childhood bone strength and late walking (e.g. low birth weight, cerebral palsy and Down's Syndrome, etc.). PMID:25132490

  6. An insight into early onset of scoliosis: new update information - a review.

    PubMed

    Alsiddiky, A M

    2015-08-01

    Early-onset scoliosis is an onerous challenge to physicians. These patients are young with significant remaining growth potential. Thus, patients are likely to develop progressive deformities, cosmetic disfigurement and cardiopulmonary consequences warrant early intervention in many cases. The purpose of this review is to provide the readers with brief description of the disease, therapeutic modalities available and their indications and use. Publications and abstracts related to EOS in the last decade were carried out and synthesized into a review "an insight into early onset of scoliosis." A comprehensive understanding of the scoliosis, its impact on the thoracic development may guide in treatment, which is often required at a young age in these children to prevent irreversible pulmonary insufficiency. Current treatment techniques are based on multiple factors may include non-surgical strategies, such as Derotational body cast or brace in younger patients with curve <50 degrees. Surgical treatment of spinal deformity should be considered when nonoperative measures are failed to arrest curve progression. Growing rods have been the mainstay treatment of early-onset scoliosis which require repeated surgeries for distraction and are associated with exponential increase in complications. The vertical expandable prosthetic titanium rib may be beneficial for those patients with congenital scoliosis and fused ribs and thoracic insufficiency syndrome. Shilla technique is an alternative to growing rods that avoids the morbidity of repeated lengthening. Growth modulation using staples or tethers shows promise for milder curvatures, but further follow-up is needed to define their use. Although new technologies have improved the treatment of children with EOS but it continues to be challenging with high complication rates. PMID:26241527

  7. Comparison of Clock Test Deficits Between Elderly Patients With Early and Late Onset Depression.

    PubMed

    Klein, Lisa; Saur, Ralf; Mller, Stephan; Leyhe, Thomas

    2015-12-01

    To compare clock test deficits in elderly patients with early onset depression (EOD) and late onset depression (LOD), we assessed 32 elderly healthy controls (HCs), 26 patients with EOD, and 27 patients with LOD with the clock drawing test (CDT), clock setting test, clock reading test, and the Tbingen Clock Questionnaire testing semantic memory about clock times. There was no significant difference in depression severity between patients with EOD and LOD. Patients with LOD had significantly lower scores on the CDT than patients with EOD and HCs. Semantic memory impairment concerning minute hand functionality was highly correlated with CDT performance and was significantly different between the EOD and the LOD groups. It can be suggested that significant differences in cognitive impairment severity between patients with EOD and LOD can be detected with CDT. Semantic memory impairment concerning minute hand functionality might affect CDT test results in elderly patients with depression. PMID:26047634

  8. Early-onset pneumonia after out-of-hospital cardiac arrest.

    PubMed

    Kakavas, S; Mongardon, N; Cariou, A; Gulati, A; Xanthos, T

    2015-06-01

    Early-onset pneumonia (EOP) is a common complication after successful cardiopulmonary resuscitation. Currently, EOP diagnosis is difficult because usual diagnostic tools are blunted by the features of post-cardiac arrest syndrome and therapeutic hypothermia itself. When the diagnosis of EOP is suspected, empiric antimicrobial therapy should be considered following bronchopulmonary sampling. The onset of EOP increases the length of mechanical ventilation duration and intensive care unit stay, but its influence on survival and neurological outcome seems marginal. Therapeutic hypothermia has been recognized as an independent risk factor for this infectious complication. All together, these observations underline the need for future prospective clinical trials to better delineate pathogens and risk factors associated with EOP. In addition, there is a need for diagnostic approaches serving the accurate diagnosis of EOP. PMID:25644317

  9. Differences in anxiety among patients with early- versus late-onset Alzheimer's disease.

    PubMed

    Kaiser, Natalie C; Liang, Li-Jung; Melrose, Rebecca J; Wilkins, Stacy S; Sultzer, David L; Mendez, Mario F

    2014-01-01

    The authors sought to evaluate the incidence and correlates of anxiety in early-onset Alzheimer's disease (EOAD) versus the more typical late-onset AD (LOAD). A group of 23 EOAD and 22 LOAD patients were compared by the Neuropsychiatric Inventory Anxiety subscale. Demographic and disease-related relationships with anxiety were evaluated, as well as types of anxiety symptoms that were endorsed. EOAD patients had significantly more anxiety symptoms than LOAD patients. Among those with EOAD, anxiety was associated with male gender, higher Mini-Mental State Exam score, and separation from caregivers. Among LOAD patients, anxiety was associated with psychotic and activating psychiatric symptoms. These results have implications for the management and alleviation of anxiety in AD. PMID:24515678

  10. PhenotypeGenotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy

    PubMed Central

    Tan, Dandan; Yang, Haipo; Yuan, Yun; Bonnemann, Carsten; Chang, Xingzhi; Wang, Shuang; Wu, Yuchen; Wu, Xiru; Xiong, Hui

    2015-01-01

    This study aimed to analyze the correlation between the phenotype and genotype of Chinese patients with early-onset lamin A (LMNA)-related muscular dystrophy (MD). The clinical and myopathological data of 21 Chinese pediatric patients with early-onset LMNA-related MD were collected and analyzed. LMNA gene mutation analysis was performed by direct sequencing of genomic DNA. Sublocalization of wild-type and mutant proteins were observed by immunofluorescence using cultured fibroblasts and human embryonic kidney 293 (HEK 293) cell. Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD). Four biopsy specimens from the L-CMD cases exhibited inflammatory changes. Abnormal nuclear morphology was observed with both transmission electron microscopy and lamin A/C staining. We identified 10 novel and nine known LMNA gene mutations in the 21 patients. Some mutations (c.91G>A, c.94_96delAAG, c.116A>G, c.745C>T, c.746G>A, and c.1580G>C) were well correlated with EDMD or L-CMD. LMNA-related MD has a common symptom triad of muscle weakness, joint contractures, and cardiac involvement, but the severity of symptoms and disease progression differ greatly. Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD. Phenotypegenotype analysis determines that some mutations are well correlated with LMNA-related MD. PMID:26098624

  11. Early-onset restrictive eating disturbances in primary school boys and girls.

    PubMed

    Kurz, Susanne; van Dyck, Zoé; Dremmel, Daniela; Munsch, Simone; Hilbert, Anja

    2015-07-01

    This study sought to determine the distribution of early-onset restrictive eating disturbances characteristic of the new DSM-5 diagnosis, avoidant/restrictive food intake disorder (ARFID) in middle childhood, as well as to evaluate the screening instrument, Eating Disturbances in Youth-Questionnaire (EDY-Q). A total of 1,444 8- to 13-year-old children were screened in regular schools (3rd to 6th grade) in Switzerland using the self-report measure EDY-Q, consisting of 12 items based on the DSM-5 criteria for ARFID. 46 children (3.2%) reported features of ARFID in the self-rating. Group differences were found for body mass index, with underweight children reporting features of ARFID more often than normal and overweight children. The EDY-Q revealed good psychometric properties, including adequate discriminant and convergent validity. Early-onset restrictive eating disturbances are commonly reported in middle childhood. Because of possible negative short- and long-term impact, early detection is essential. Further studies with structured interviews and parent reports are needed to confirm this study's findings. PMID:25296563

  12. Early-Onset Scoliosis: A Review of History, Current Treatment, and Future Directions.

    PubMed

    Yang, Scott; Andras, Lindsay M; Redding, Gregory J; Skaggs, David L

    2016-01-01

    Early-onset scoliosis (EOS) is defined as curvature of the spine in children >10 with onset before age 10 years. Young children with EOS are at risk for impaired pulmonary function because of the high risk of progressive spinal deformity and thoracic constraints during a critical time of lung development. The treatment of EOS is very challenging because the population is inhomogeneous, often medically complex, and often needs multiple surgeries. In the past, early spinal fusion was performed in children with severe progressive EOS, which corrected scoliosis but limited spine and thoracic growth and resulted in poor pulmonary outcomes. The current goal in treatment of EOS is to maximize growth of the spine and thorax by controlling the spinal deformity, with the aim of promoting normal lung development and pulmonary function. Bracing and casting may improve on the natural history of progression of spinal deformity and are often used to delay surgical intervention or in some cases obviate surgery. Recent advances in surgical implants and techniques have led to the development of growth-friendly implants, which have replaced early spine fusion as the surgical treatment of choice. Treatment with growth-friendly implants usually requires multiple surgeries and is associated with frequent complications. However, growth-friendly spine surgery has been shown to correct spinal deformity while allowing growth of the spine and subsequently lung growth. PMID:26644484

  13. Internalizing and Externalizing Psychopathology as Predictors of Cannabis Use Disorder Onset during Adolescence and Early Adulthood

    PubMed Central

    Farmer, Richard F.; Seeley, John R.; Kosty, Derek B.; Gau, Jeff M.; Duncan, Susan C.; Lynskey, Michael T.; Lewinsohn, Peter M.

    2015-01-01

    Risk-related liabilities associated with the development of cannabis use disorders (CUDs) during adolescence and early adulthood are thought to be established well before the emergence of the index episode. In this study, internalizing and externalizing psychopathology from earlier developmental periods were evaluated as risk factors for CUDs during adolescence and early adulthood. Participants (N = 816) completed four diagnostic assessments between the ages 16 and 30, during which current and past CUDs were assessed as well as a full range of psychiatric disorders associated with internalizing and externalizing psychopathology domains. In unadjusted and adjusted time-to-event analyses, externalizing but not internalizing psychopathology from proximal developmental periods predicted subsequent CUD onset. A large proportion of adolescent and early adult cases, however, did not manifest any externalizing or internalizing psychopathology during developmental periods prior to CUD onset. Findings are consistent with the emerging view that externalizing disorders from proximal developmental periods are robust risk factors for CUDs. Although the identification of externalizing liabilities may aid in the identification of individuals at risk for embarking on developmental pathways that culminate in CUDs, such liabilities are an incomplete indication of overall risk. PMID:25799438

  14. Committee Opinion Summary No. 638: First-Trimester Risk Assessment for Early-Onset Preeclampsia.

    PubMed

    2015-09-01

    Hypertensive disorders with adverse sequelae (including preterm birth, maternal morbidity and mortality, and long-term risk of maternal cardiovascular disease) complicate 5-10% of pregnancies. Early identification of pregnant women at risk of developing early-onset preeclampsia would theoretically allow referral for more intensive surveillance or application of preventive therapies to reduce the risk of severe disease. In practice, however, the effectiveness of such triage would be hindered by the low positive predictive value for early-onset preeclampsia reported in the literature. In spite of the modest predictive value of first-trimester preeclampsia risk assessment and the lack of data demonstrating improved clinical outcomes, commercial tests are being marketed for the prediction of preeclampsia in the first trimester. Taking a detailed medical history to evaluate for risk factors is currently the best and only recommended screening approach for preeclampsia; it should remain the method of screening for preeclampsia until studies show that aspirin or other interventions reduce the incidence of preeclampsia for women at high risk based on first-trimester predictive tests. PMID:26287782

  15. Evidence for possible non-canonical pathway(s) driven early-onset colorectal cancer in India.

    PubMed

    Raman, Ratheesh; Kotapalli, Viswakalyan; Adduri, Raju; Gowrishankar, Swarnalata; Bashyam, Leena; Chaudhary, Ajay; Vamsy, Mohana; Patnaik, Sujith; Srinivasulu, Mukta; Sastry, Regulagadda; Rao, Subramanyeshwar; Vasala, Anjayneyulu; Kalidindi, NarasimhaRaju; Pollack, Jonathan; Murthy, Sudha; Bashyam, Murali

    2014-02-01

    Two genetic instability pathways viz. chromosomal instability, driven primarily by APC mutation induced deregulated Wnt signaling, and microsatellite instability (MSI) caused by mismatch repair (MMR) inactivation, together account for >90% of late-onset colorectal cancer (CRC). Our understanding of early-onset sporadic CRC is however comparatively limited. In addition, most seminal studies have been performed in the western population and analyses of tumorigenesis pathway(s) causing CRC in developing nations have been rare. We performed a comparative analysis of early and late-onset CRC from India with respect to common genetic aberrations including Wnt, KRAS, and p53 (constituting the classical CRC progression sequence) in addition to MSI. Our results revealed the absence of Wnt and MSI in a significant proportion of early-onset as against late-onset CRC in India. In addition, KRAS mutation frequency was significantly lower in early-onset CRC indicating that a significant proportion of CRC in India may follow tumorigenesis pathways distinct from the classical CRC progression sequence. Our study has therefore revealed the possible existence of non-canonical tumorigenesis pathways in early-onset CRC in India. PMID:23168910

  16. A Unified Hypothesis of Early- and Late-Onset Alzheimer’s Disease Pathogenesis

    PubMed Central

    Atwood, Craig S.; Bowen, Richard L.

    2016-01-01

    Early-onset familial Alzheimer’s disease (EOFAD) and late-onset sporadic AD (LOSAD) both follow a similar pathological and biochemical course that includes: neuron and synapse loss and dysfunction, microvascular damage, microgliosis, extracellular amyloid-β deposition (Aβ), and the deposition of phosphorylated tau protein in the form of intracellular neurofibrillary tangles in affected brain regions. Any mechanistic explanation of AD must accommodate these biochemical and neuropathological features for both forms of the disease. Cell cycle abnormalities represent another major biochemical and neuropathological feature common to both EOFAD and LOSAD, and 1) appear very early in the disease process, prior to the appearance of plaques and tangles, and 2) explain the biochemical (e.g., tau phosphorylation), neuropathological (e.g., neuron hypertrophy) and cognitive changes observed in EOFAD and LOSAD. Since neurogenesis after the formation of a memory is sufficient to induce forgetting, any stimulus that promotes cell cycle re-entry will be a negative event for memory. In this insight paper, we propose that aberrant re-entry of terminally differentiated, post-mitotic neurons into the cell cycle is a common pathway that explains both early and late-onset forms of AD. In the case of EOFAD, mutations in APP, PSEN1, and PSEN2 that alter AβPP and Notch processing drive reactivation of the cell cycle, while in LOSAD, age-related reproductive endocrine dyscrasia that upregulates mitogenic TNF signaling, AβPP processing toward the amyloidogenic pathway and tau phosphorylation drives reactivation of the cell cycle. Inhibition of cell cycle reentry of post-mitotic neurons may be a useful therapeutic strategy to prevent or halt disease progression. PMID:26402752

  17. Common and Rare Variant Analysis in Early-Onset Bipolar Disorder Vulnerability

    PubMed Central

    Jamain, Stéphane; Cichon, Sven; Etain, Bruno; Mühleisen, Thomas W.; Georgi, Alexander; Zidane, Nora; Chevallier, Lucie; Deshommes, Jasmine; Nicolas, Aude; Henrion, Annabelle; Degenhardt, Franziska; Mattheisen, Manuel; Priebe, Lutz; Mathieu, Flavie; Kahn, Jean-Pierre; Henry, Chantal; Boland, Anne; Zelenika, Diana; Gut, Ivo; Heath, Simon; Lathrop, Mark; Maier, Wolfgang; Albus, Margot; Rietschel, Marcella; Schulze, Thomas G.; McMahon, Francis J.; Kelsoe, John R.; Hamshere, Marian; Craddock, Nicholas; Nöthen, Markus M.; Bellivier, Frank; Leboyer, Marion

    2014-01-01

    Bipolar disorder is one of the most common and devastating psychiatric disorders whose mechanisms remain largely unknown. Despite a strong genetic contribution demonstrated by twin and adoption studies, a polygenic background influences this multifactorial and heterogeneous psychiatric disorder. To identify susceptibility genes on a severe and more familial sub-form of the disease, we conducted a genome-wide association study focused on 211 patients of French origin with an early age at onset and 1,719 controls, and then replicated our data on a German sample of 159 patients with early-onset bipolar disorder and 998 controls. Replication study and subsequent meta-analysis revealed two genes encoding proteins involved in phosphoinositide signalling pathway (PLEKHA5 and PLCXD3). We performed additional replication studies in two datasets from the WTCCC (764 patients and 2,938 controls) and the GAIN-TGen cohorts (1,524 patients and 1,436 controls) and found nominal P-values both in the PLCXD3 and PLEKHA5 loci with the WTCCC sample. In addition, we identified in the French cohort one affected individual with a deletion at the PLCXD3 locus and another one carrying a missense variation in PLCXD3 (p.R93H), both supporting a role of the phosphatidylinositol pathway in early-onset bipolar disorder vulnerability. Although the current nominally significant findings should be interpreted with caution and need replication in independent cohorts, this study supports the strategy to combine genetic approaches to determine the molecular mechanisms underlying bipolar disorder. PMID:25111785

  18. Candidate colorectal cancer predisposing gene variants in Chinese early-onset and familial cases

    PubMed Central

    Zhang, Jun-Xiao; Fu, Lei; de Voer, Richarda M; Hahn, Marc-Manuel; Jin, Peng; Lv, Chen-Xi; Verwiel, Eugène TP; Ligtenberg, Marjolijn JL; Hoogerbrugge, Nicoline; Kuiper, Roland P; Sheng, Jian-Qiu; Geurts van Kessel, Ad

    2015-01-01

    AIM: To investigate whether whole-exome sequencing may serve as an efficient method to identify known or novel colorectal cancer (CRC) predisposing genes in early-onset or familial CRC cases. METHODS: We performed whole-exome sequencing in 23 Chinese patients from 21 families with non-polyposis CRC diagnosed at ≤ 40 years of age, or from multiple affected CRC families with at least 1 first-degree relative diagnosed with CRC at ≤ 55 years of age. Genomic DNA from blood was enriched for exome sequences using the SureSelect Human All Exon Kit, version 2 (Agilent Technologies) and sequencing was performed on an Illumina HiSeq 2000 platform. Data were processed through an analytical pipeline to search for rare germline variants in known or novel CRC predisposing genes. RESULTS: In total, 32 germline variants in 23 genes were identified and confirmed by Sanger sequencing. In 6 of the 21 families (29%), we identified 7 mutations in 3 known CRC predisposing genes including MLH1 (5 patients), MSH2 (1 patient), and MUTYH (biallelic, 1 patient), five of which were reported as pathogenic. In the remaining 15 families, we identified 20 rare and novel potentially deleterious variants in 19 genes, six of which were truncating mutations. One previously unreported variant identified in a conserved region of EIF2AK4 (p.Glu738_Asp739insArgArg) was found to represent a local Chinese variant, which was significantly enriched in our early-onset CRC patient cohort compared to a control cohort of 100 healthy Chinese individuals scored negative by colonoscopy (33.3% vs 7%, P < 0.001). CONCLUSION: Whole-exome sequencing of early-onset or familial CRC cases serves as an efficient method to identify known and potential pathogenic variants in established and novel candidate CRC predisposing genes. PMID:25892863

  19. Late mortality among 5-year survivors of early onset cancer: a population-based register study.

    PubMed

    Kero, Andreina E; Järvelä, Liisa S; Arola, Mikko; Malila, Nea; Madanat-Harjuoja, Laura M; Matomäki, Jaakko; Lähteenmäki, Päivi M

    2015-04-01

    To date, only few studies have been published documenting late mortality among early onset cancer survivors, especially regarding young adulthood (YA) malignancies. Our nation-wide population-based registry study provides information concerning cause-specific long-term mortality among 16,769 5-year survivors of early onset cancer (aged 0-34 years at diagnosis), with follow-up for death extending from 1971 through 2012. A sibling cohort and population data were used as reference. The overall standardized mortality ratio (SMR) of cancer patients was 4.6-fold, (95% CI 4.4-4.8). Highest SMRs were found for malignancies (12.8, 95% CI 12.3-13.3), infectious (4.8, 95%CI 2.9-6.7) and cardiovascular diseases (1.9, 95% CI 1.7-2.1). Malignancies and cardiovascular diseases accounted for the largest number of deaths. Childhood and YA cancer survivors with the same primary cancer site had a similarly elevated overall SMR with the exception of markedly higher SMRs after childhood Hodgkin lymphoma. The highest cumulative non-malignancy-related mortality was due to cardiovascular disease with a steady rise throughout the follow-up, but strongly dependent on the primary cancer site and age at diagnosis. In childhood cancer survivors, the cumulative cardiovascular mortality did not reduce over time. However, overall and malignancy-related mortality showed a declining tendency towards the most recent periods after both, childhood and YA cancer. Our findings on non-malignancy-related mortality stress the need to set up long-term individual follow-up with a focus on cardiovascular late effects for early onset cancer survivors, especially for YA cancer survivors still lacking those. PMID:25110999

  20. Identification of inherited genetic variations influencing prognosis in early-onset breast cancer.

    PubMed

    Rafiq, Sajjad; Tapper, William; Collins, Andrew; Khan, Sofia; Politopoulos, Ioannis; Gerty, Sue; Blomqvist, Carl; Couch, Fergus J; Nevanlinna, Heli; Liu, Jianjun; Eccles, Diana

    2013-03-15

    Genome-Wide Association Studies (GWAS) have begun to investigate associations between inherited genetic variations and breast cancer prognosis. Here, we report our findings from a GWAS conducted in 536 patients with early-onset breast cancer aged 40 or less at diagnosis and with a mean follow-up period of 4.1 years (SD = 1.96). Patients were selected from the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer. A Bonferroni correction for multiple testing determined that a P value of 1.0 10(-7) was a statistically significant association signal. Following quality control, we identified 487,496 single nucleotide polymorphisms (SNP) for association tests in stage 1. In stage 2, 35 SNPs with the most significant associations were genotyped in 1,516 independent cases from the same early-onset cohort. In stage 2, 11 SNPs remained associated in the same direction (P ? 0.05). Fixed effects meta-analysis models identified one SNP associated at close to genome wide level of significance 556 kb upstream of the ARRDC3 locus [HR = 1.61; 95% confidence interval (CI), 1.33-1.96; P = 9.5 10(-7)]. Four further associations at or close to the PBX1, ROR?, NTN1, and SYT6 loci also came close to genome-wide significance levels (P = 10(-6)). In the first ever GWAS for the identification of SNPs associated with prognosis in patients with early-onset breast cancer, we report a SNP upstream of the ARRDC3 locus as potentially associated with prognosis (median follow-up time for genotypes: CC = 4 years, CT = 3 years, and TT = 2.7 years; Wilcoxon rank-sum test CC vs. CT, P = 4 10(-4) and CT vs. TT, P = 0.76). Four further loci may also be associated with prognosis. PMID:23319801

  1. A genomewide scan for early-onset coronary artery disease in 438 families: the GENECARD Study.

    PubMed

    Hauser, Elizabeth R; Crossman, David C; Granger, Christopher B; Haines, Jonathan L; Jones, Christopher J H; Mooser, Vincent; McAdam, Brendan; Winkelmann, Bernhard R; Wiseman, Alan H; Muhlestein, J Brent; Bartel, Alan G; Dennis, Charles A; Dowdy, Elaine; Estabrooks, Susan; Eggleston, Karen; Francis, Sheila; Roche, Kath; Clevenger, Paula W; Huang, Liling; Pedersen, Bonnie; Shah, Svati; Schmidt, Silke; Haynes, Carol; West, Sandra; Asper, Donny; Booze, Michael; Sharma, Sanjay; Sundseth, Scott; Middleton, Lefkos; Roses, Allen D; Hauser, Michael A; Vance, Jeffery M; Pericak-Vance, Margaret A; Kraus, William E

    2004-09-01

    A family history of coronary artery disease (CAD), especially when the disease occurs at a young age, is a potent risk factor for CAD. DNA collection in families in which two or more siblings are affected at an early age allows identification of genetic factors for CAD by linkage analysis. We performed a genomewide scan in 1,168 individuals from 438 families, including 493 affected sibling pairs with documented onset of CAD before 51 years of age in men and before 56 years of age in women. We prospectively defined three phenotypic subsets of families: (1) acute coronary syndrome in two or more siblings; (2) absence of type 2 diabetes in all affected siblings; and (3) atherogenic dyslipidemia in any one sibling. Genotypes were analyzed for 395 microsatellite markers. Regions were defined as providing evidence for linkage if they provided parametric two-point LOD scores >1.5, together with nonparametric multipoint LOD scores >1.0. Regions on chromosomes 3q13 (multipoint LOD = 3.3; empirical P value <.001) and 5q31 (multipoint LOD = 1.4; empirical P value <.081) met these criteria in the entire data set, and regions on chromosomes 1q25, 3q13, 7p14, and 19p13 met these criteria in one or more of the subsets. Two regions, 3q13 and 1q25, met the criteria for genomewide significance. We have identified a region on chromosome 3q13 that is linked to early-onset CAD, as well as additional regions of interest that will require further analysis. These data provide initial areas of the human genome where further investigation may reveal susceptibility genes for early-onset CAD. PMID:15272420

  2. Internet-Delivered, Family-Based Treatment for Early-Onset OCD: A Preliminary Case Series

    PubMed Central

    Comer, Jonathan S.; Furr, Jami M.; Cooper-Vince, Christine E.; Kerns, Caroline E.; Chan, Priscilla T.; Edson, Aubrey L.; Khanna, Muniya; Franklin, Martin E.; Garcia, Abbe M.; Freeman, Jennifer B.

    2014-01-01

    Given the burdens of early-onset obsessive-compulsive disorder (OCD), limitations in the broad availability and accessibility of evidence-based care for affected youth present serious public health concerns. The growing potential for technological innovations to transform care for the most traditionally remote and underserved families holds enormous promise. This article presents the rationale, key considerations, and a preliminary case series for a promising behavioral telehealth innovation in the evidence-based treatment of early-onset OCD. We developed an Internet-based format for the delivery of family-based treatment for early-onset OCD directly to families in their homes, regardless of their geographic proximity to a mental health facility. Videoteleconferencing (VTC) methods were used to deliver real-time cognitive-behavioral therapy centering on exposure and response prevention to affected families. Participants in the preliminary case series included 5 children between the ages of 4 and 8 (MAge = 6.5) who received the Internet-delivered treatment format. All youth completed a full treatment course, all showed OCD symptom improvements and global severity improvements from pre- to posttreatment, all showed at least partial diagnostic response, and 60% no longer met diagnostic criteria for OCD at posttreatment. No participants got worse, and all mothers characterized the quality of services received as “excellent.” The present work adds to a growing literature supporting the potential of VTC and related computer technology for meaningfully expanding the reach of supported treatments for OCD and lays the foundation for subsequent controlled evaluations to evaluate matters of efficacy and engagement relative to standard in-office evidence-based care. PMID:24295036

  3. Specific antibody reactivity against a 110-kilodalton Actinobacillus actinomycetemcomitans protein in subjects with periodontitis.

    PubMed Central

    Fleming, T F; Selmair, I; Schmidt, H; Karch, H

    1996-01-01

    The purpose of the present study was to determine the serum immunoglobulin A (IgA), IgM, and IgG reactivities against proteins of Actinobacillus actinomycetemcomitans in patients with periodontitis. Serum samples from 20 patients with early-onset periodontitis, 20 patients with adult periodontitis, and 20 age- and sex-matched healthy controls were assessed by immunoblot analysis. IgG antibody reactivity against a sarcosyl-insoluble 110-kDa protein of A. actinomycetemcomitans was detected in 65 and 45% of patients with early-onset periodontitis and adult peritonitis, respectively, and IgA antibodies against this protein were found in 70 and 55% of these patients, respectively. However, control subjects showed no IgG reactivity, and IgA antibodies against the sarcosyl-insoluble 110-kDa protein were detected in only 5% of the patients (P < 0.05). There was no IgM antibody reactivity against this protein in any of the diseased or healthy subjects. The sensitivity and specificity of serum IgA antibody reactivity against the 110-kDa protein in detecting subgingival A. actinomycetemcomitans infection, as determined by PCR, were 77 and 66%, respectively. The results of the study indicated that the sarcosyl-insoluble 110-kDa protein is a potential candidate for use in the serodiagnosis of periodontal disease. PMID:8914758

  4. Very early onset trichotillomania presenting with recurrent trichobezoar: conventional wisdom questioned.

    PubMed

    Menon, Vikas; Shaik, Subahani; Mohan, Pazhanivel

    2015-01-01

    Trichotillomania (TTM), a disorder characterized by compulsive hair pulling, is undergoing a conceptual and nosological re-evaluation. Little long-term information is available about this condition when it strikes in early childhood. Trichobezoar, an ingestional foreign body lodged in the gastrointestinal tract composed of swallowed hair, is usually associated with underlying psychiatric and emotional disturbances. In this report, we describe a young girl who had her symptom onset at the age of 3, but presented again after more than a decade with recurrent symptomatic large trichobezoars needing surgical removal both times. Her clinical course and presentation challenged contemporary understanding of TTM. PMID:25878449

  5. Very Early Onset Trichotillomania Presenting with Recurrent Trichobezoar: Conventional Wisdom Questioned

    PubMed Central

    Menon, Vikas; Shaik, Subahani; Mohan, Pazhanivel

    2015-01-01

    Trichotillomania (TTM), a disorder characterized by compulsive hair pulling, is undergoing a conceptual and nosological re-evaluation. Little long-term information is available about this condition when it strikes in early childhood. Trichobezoar, an ingestional foreign body lodged in the gastrointestinal tract composed of swallowed hair, is usually associated with underlying psychiatric and emotional disturbances. In this report, we describe a young girl who had her symptom onset at the age of 3, but presented again after more than a decade with recurrent symptomatic large trichobezoars needing surgical removal both times. Her clinical course and presentation challenged contemporary understanding of TTM. PMID:25878449

  6. Effects of smoking in patients with early-onset Parkinson's disease.

    PubMed

    Ishikawa, A; Miyatake, T

    1993-07-01

    Smoking a cigarette relieved symptoms in 6 patients with early-onset Parkinson's disease. In these patients smoking reduced tremor, rigidity, bradykinesia, and gait disturbance including frozen gait. These effects lasted for about 10-30 min, and relieved parkinsonian symptoms in the off-period. Nicotine chewing gum had a lesser effect. Nicotine is thought to activate the nigrostriatal dopaminergic pathway and increase the release of dopamine in the striatum, and this can explain the effects of smoking in these patients. PMID:8410063

  7. Asthma onset prior to multiple sclerosis and the contribution of sibling exposure in early life.

    PubMed

    Ponsonby, A-L; Dwyer, T; van der Mei, I; Kemp, A; Blizzard, L; Taylor, B; Kilpatrick, T; Simmons, R

    2006-12-01

    Higher sibling exposure is associated with a reduced risk of asthma and other T helper 2 (Th2)-type disorders, possibly through a beneficial effect of higher infection load. The effect on Th1 disorders such as multiple sclerosis (MS) is less clear. Here we examine the association between asthma and MS, taking into account early life sibling exposure. A population-based case-control study in Tasmania, Australia based on 136 cases of magnetic resonance imaging (MRI)-confirmed MS and 272 community controls, matched on sex and year of birth. Study measures include cumulative exposure to total, older or younger siblings by age 6 years, history of doctor-diagnosed asthma and serological IgG responses to herpes viruses. MS cases were more likely (P = 0.02) than controls to have asthma which began before age of onset of MS symptoms compared to the corresponding age for controls. The absence of younger sibling exposure by age 6 years potentiated (P = 0.04) the association between asthma and MS. Compared to those with younger sibling exposure and no asthma, the adjusted odds ratio for MS for those with asthma and no younger sibling exposure was 7.22 (95% CI: 2.52, 20.65). Early life sibling exposure was associated with altered IgG serological responses to Epstein-Barr virus (EBV) and herpes simplex virus 1 (HSV1) in adulthood. Reduced early life sibling exposure appeared to contribute to the excess of asthma among MS cases by the time of MS onset. MS development may reflect factors that relate to a general immuno-inflammatory up-regulation of immune activity as well as disease specific factors. The link between early life sibling exposure and the immune response to herpes group viral antigens is consistent with a protective role for early life infections. PMID:17100766

  8. Microbleeds in Late-Life Depression: Comparison of Early- and Late-Onset Depression

    PubMed Central

    Fang, Min; Xu, Yu; Hua, Ting; Liu, Xue-Yuan

    2014-01-01

    Late-life depression could be classified roughly as early-onset depression (EOD) and late-onset depression (LOD). LOD was proved to be associated with cerebral lesions including white matter hyperintensities (WMH) and silent brain infarctions (SBI), differently from EOD. However, it is unclear whether similar association is present between LOD and microbleeds which are also silent lesions. In this study, 195 patients of late-life depression were evaluated and divided into EOD, presenile-onset depression (POD), and LOD groups; 85 healthy elderly controls were enrolled as controls. Subjects were scanned by MRI including susceptibility weighted images to evaluate white matter hyperintensities (WMH), silent brain infarctions (SBI), and microbleeds. The severity of depression was evaluated with 15-item Geriatric Depression Scale. Psychosocial factors were investigated with Scale of Life Events and Lubben Social Network Scale. Logistic regression and linear regression were performed to identify the independent risk factors for depression. Results showed that LOD patients had higher prevalence of microbleeds than EOD, POD, and control patients. The prevalence of lobar microbleeds and microbleeds in the left hemisphere was the independent risk factor for the occurrence of LOD; a high number of microbleeds were associated with severe state of LOD, whereas life events and lack of social support were more important for EOD and POD. All these results indicated that Microbleeds especially lobar microbleeds and microbleeds in the left hemisphere were associated with LOD but not with EOD. PMID:24719883

  9. MAPPING THE PROGRESSION OF ATROPHY IN EARLY AND LATE ONSET ALZHEIMERS DISEASE

    PubMed Central

    Migliaccio, R; Agosta, F; Possin, KL; Canu, E; Filippi, M; Rabinovici, GD; Rosen, HJ; Miller, BL; Gorno-Tempini, ML

    2015-01-01

    The term early age-of-onset Alzheimers disease (EOAD) identifies patients who meet criteria for AD, but show onset of symptoms before the age of 65. We map progression of gray matter (GM) atrophy in EOAD patients compared to late onset AD (LOAD). T1-weighted MRI scans were obtained at diagnosis and one-year follow-up from 15 EOAD, 10 LOAD, and 38 age-matched controls. Voxel-based and tensor-based morphometry were used, respectively, to assess the baseline and progression of atrophy. At baseline, EOAD patients already showed a widespread atrophy in temporal, parietal, occipital and frontal cortices. After one year, EOAD had atrophy progression in medial temporal and medial parietal cortices. At baseline, LOAD patients showed atrophy in the medial temporal regions only, and, after one year, an extensive pattern of atrophy progression in the same neocortical cortices of EOAD. Although atrophy mainly involved different lateral neocortical or medial temporal hubs at baseline, it eventually progressed along the same brain default-network regions in both groups. The cortical region showing a significant progression in both groups was the medial precuneus/posterior cingulate. PMID:25737041

  10. Sulcal morphology as a new imaging marker for the diagnosis of early onset Alzheimer's disease.

    PubMed

    Hamelin, Lorraine; Bertoux, Maxime; Bottlaender, Michel; Corne, Helene; Lagarde, Julien; Hahn, Valrie; Mangin, Jean-Franois; Dubois, Bruno; Chupin, Marie; Cruz de Souza, Leonardo; Colliot, Olivier; Sarazin, Marie

    2015-11-01

    We investigated the utility of sulcal width measures in the diagnosis of Alzheimer's disease (AD). Sixty-six biologically confirmed AD patients (positive amyloid positron emission tomography [PET] and/or AD cerebrospinal fluid profile) were contrasted to 35 controls with negative amyloid PET. Patients were classified into prodromal or dementia stages as well as into late onset (LOAD, n= 31) or early onset (EOAD, n= 35) subgroups according to their age of onset. An automated method was used to calculate sulcal widths and hippocampal volumes (HV). In EOAD, the greatest ability to differentiate patients from age-matched controls, regardless of severity, was displayed by sulcal width of the temporoparietal cortex. In this region, diagnosis accuracy was better than the HV, especially at prodromal stage. In LOAD, HV provided the best discrimination power from age-matched controls. In conclusion, sulcal width measures are better markers than the HV for identifying prodromal AD in patients aged <65years. Incontrast, in older patients, the risk of over-diagnosis from using only sulcal enlargement is important. PMID:26256787

  11. Mapping the Progression of Atrophy in Early- and Late-Onset Alzheimer's Disease.

    PubMed

    Migliaccio, Raffaella; Agosta, Federica; Possin, Katherine L; Canu, Elisa; Filippi, Massimo; Rabinovici, Gil D; Rosen, Howard J; Miller, Bruce L; Gorno-Tempini, Maria Luisa

    2015-01-01

    The term early-onset Alzheimer's disease (EOAD) identifies patients who meet criteria for AD, but show onset of symptoms before the age of 65. We map progression of gray matter atrophy in EOAD patients compared to late-onset AD (LOAD). T1-weighted MRI scans were obtained at diagnosis and one-year follow-up from 15 EOAD, 10 LOAD, and 38 age-matched controls. Voxel-based and tensor-based morphometry were used, respectively, to assess the baseline and progression of atrophy. At baseline, EOAD patients already showed a widespread atrophy in temporal, parietal, occipital, and frontal cortices. After one year, EOAD had atrophy progression in medial temporal and medial parietal cortices. At baseline, LOAD patients showed atrophy in the medial temporal regions only, and, after one year, an extensive pattern of atrophy progression in the same neocortical cortices of EOAD. Although atrophy mainly involved different lateral neocortical or medial temporal hubs at baseline, it eventually progressed along the same brain default-network regions in both groups. The cortical region showing a significant progression in both groups was the medial precuneus/posterior cingulate. PMID:25737041

  12. Changes in subcortical structures in early- versus late-onset Alzheimer's disease.

    PubMed

    Cho, Hanna; Seo, Sang Won; Kim, Jeong-Hun; Kim, Changsoo; Ye, Byoung Seok; Kim, Geon Ha; Noh, Young; Kim, Hee Jin; Yoon, Cindy W; Seong, Joon-Kyung; Kim, Chang-Hun; Kang, Sue J; Chin, Juhee; Kim, Sung Tae; Lee, Kyung-Han; Na, Duk L

    2013-07-01

    Patients with early-onset Alzheimer's disease (EOAD) are reported to be different from those with late-onset Alzheimer's disease (LOAD) in terms of neuropsychological and neuroimaging findings. In this study, we aimed to compare the longitudinal volume changes of 6 subcortical structures (the amygdala, hippocampus, thalamus, putamen, globus pallidus, and caudate nucleus) between patients with EOAD and LOAD for 3 years. We prospectively recruited 36 patients with probable Alzheimer's disease (14 EOAD, 22 LOAD) and 14 normal control subjects. We analyzed the volume of subcortical structures using an automatic surface-based method. At baseline, there were no differences in the volumes of subcortical structures between patients with EOAD and LOAD. However, over 3 years of longitudinal follow-up, patients with EOAD showed more rapid volumetric decline in the caudate, putamen, and thalamus than patients with LOAD, which is consistent with neuropsychological results. Our findings suggested that the cognitive reserve theory might be applicable to explain different decline rates of the volumes of the basal ganglia and thalamus according to onset age. PMID:23394958

  13. Association of M235T variant of the angiotensinogen gene with familial hypertension of early onset.

    PubMed

    Schmidt, S; Sharma, A M; Zilch, O; Beige, J; Walla-Friedel, M; Ganten, D; Distler, A; Ritz, E

    1995-01-01

    A higher frequency of a variant of the angiotensinogen gene characterized by a transition in exon 2 causing a replacement of methionine by threonine (M235T) has recently been found in hypertensive individuals, but not all authors were able to confirm this observation. We examined (i) 219 patients with primary hypertension, (ii) 92 normotensive controls (spouses), and (iii) a sample of the general population (blood donors, n = 139). Analysis of genomic DNA was performed by PCR amplification and alleles were separated on agarose gels. In the general population and in normotensive spouses the respective frequencies of the T and M alleles were: general population: M = 0.6, T = 0.4; normotensive spouses: M = 0.59, T = 0.41. A significantly higher frequency of the 235T allele was found in hypertensive individuals with a family history of hypertension and an onset of hypertension before 50 years of age (spouses: 0.41 versus HT with age of onset < or = 50 years and family history of HT: 0.56; P = 0.01 by chi 2). In conclusion, the present study confirms the observation of a higher frequency of the 235T allele of the angiotensinogen gene in hypertension and identifies individuals with family history and early onset of hypertension as individuals at risk. PMID:7478115

  14. Sunbed use during adolescence and early adulthood is associated with increased risk of early-onset melanoma

    PubMed Central

    Cust, Anne E; Armstrong, Bruce K; Goumas, Chris; Jenkins, Mark A; Schmid, Helen; Hopper, John L; Kefford, Richard F; Giles, Graham G; Aitken, Joanne F; Mann, Graham J

    2010-01-01

    Sunbed use is associated with increased risk of melanoma. Younger people might be more susceptible to the carcinogenic effects of ultraviolet radiation. We investigated the association between sunbed use and risk of early-onset cutaneous malignant melanoma. From the Australian Melanoma Family Study, a multi-centre, population-based, case-control-family study, we analysed data for 604 cases diagnosed between ages 18 and 39 years and 479 controls. Data were collected by interview. Associations were estimated as odds ratios (ORs) using unconditional logistic regression, adjusting for age, sex, city, education, family history, skin colour, usual skin response to sunlight, and sun exposure. Compared with having never used a sunbed, the OR for melanoma associated with ever-use was 1.41 (95% confidence interval (CI) 1.01-1.96), and 2.01 (95% CI 1.22-3.31) for more than 10 lifetime sessions (Ptrend 0.01 with cumulative use). The association was stronger for earlier age at first use (Ptrend 0.02). The association was also stronger for melanoma diagnosed when aged 18-29 years (OR for more than 10 lifetime sessions = 6.57, 95% CI 1.41-30.49) than for melanoma diagnosed when 30-39 years (OR 1.60, 95% CI 0.92-2.77; Pinteraction 0.01). Among those who had ever used a sunbed and were diagnosed between 18-29 years of age, three quarters (76%) of melanomas were attributable to sunbed use. Sunbed use is associated with increased risk of early-onset melanoma, with risk increasing with greater use, an earlier age at first use and for earlier onset disease. PMID:20669232

  15. Reduced frontal white matter volume in children with early onset of adrenarche.

    PubMed

    Klauser, Paul; Whittle, Sarah; Simmons, Julian G; Byrne, Michelle L; Mundy, Lisa K; Patton, George C; Fornito, Alex; Allen, Nicholas B

    2015-02-01

    While there is growing evidence that puberty affects brain development, very little is known about the structural brain changes associated with dehydroepiandrosterone (DHEA), an adrenal hormone that exhibits dramatic increases during adrenarche, the earliest phase of puberty. Moreover, no research has investigated whether relatively early exposure to DHEA (i.e., early adrenarche) during this period is associated with differences in brain structure. We ran a whole-brain voxel-based morphometry analysis on T1-weighted magnetic resonance imaging brain scans to compare gray (GMV) and white matter volumes (WMV) between children experiencing relatively early (n=41) vs. relatively late (n=44) adrenarche. We also investigated the correlations between GMV or WMV and DHEA levels, and finally, tested for sex differences in group and correlation analyses. We observed reduced frontal WMV in a cluster located on the left corona radiata in children experiencing earlier adrenarche. In addition, WMV in this area was negatively correlated with DHEA levels. We did not observe any effect of gender in both the group and the correlation analyses. Early onset of adrenarche (as defined by relatively early exposure to DHEA) may be associated with differences in the development of frontal white matter tracts. PMID:25459897

  16. Kcne2 deletion causes early-onset nonalcoholic fatty liver disease via iron deficiency anemia

    PubMed Central

    Lee, Soo Min; Nguyen, Dara; Anand, Marie; Kant, Ritu; Köhncke, Clemens; Lisewski, Ulrike; Roepke, Torsten K.; Hu, Zhaoyang; Abbott, Geoffrey W.

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is an increasing health problem worldwide, with genetic, epigenetic, and environmental components. Here, we describe the first example of NAFLD caused by genetic disruption of a mammalian potassium channel subunit. Mice with germline deletion of the KCNE2 potassium channel β subunit exhibited NAFLD as early as postnatal day 7. Using mouse genetics, histology, liver damage assays and transcriptomics we discovered that iron deficiency arising from KCNE2-dependent achlorhydria is a major factor in early-onset NAFLD in Kcne2─/─ mice, while two other KCNE2-dependent defects did not initiate NAFLD. The findings uncover a novel genetic basis for NAFLD and an unexpected potential factor in human KCNE2-associated cardiovascular pathologies, including atherosclerosis. PMID:26984260

  17. Early onset ovarian hyperstimulation syndrome despite use of segmentation approach and ovarian hyperstimulation syndrome prophylaxis

    PubMed Central

    Mahajan, Nalini; Gupta, Shalu; Sharma, Shilpa; Rani, Kumkum; Naidu, Padmaja; Arora, Puneet R.

    2015-01-01

    We report a case of early onset severe ovarian hyperstimulation syndrome (OHSS) presenting with oliguria in an antagonist cycle triggered with GnRH agonist and a freeze-all approach. Prophylactic measures in the form of GnRH antagonist, cabergolin and plasma expanders were given after oocyte retrieval. Twenty-four hours after oocyte retrieval patient developed oliguria and moderate ascites. She was managed in ICU with albumin and diuretics. She responded to conservative management and did not require paracentesis. Severe OHSS can occur in PCOS patients even after using a segmented approach i.e. GnRH agonist trigger with a ‘freeze all’ policy. Patients at risk of OHSS should be closely monitored following ovum pickup even when an agonist trigger has been given, for early detection and management. PMID:26752860

  18. Neuropsychological functioning in early-onset first-episode psychosis: comparison of diagnostic subgroups.

    PubMed

    Zabala, Arantzazu; Rapado, Marta; Arango, Celso; Robles, Olalla; de la Serna, Elena; Gonzlez, Cristina; Rodrguez-Snchez, Jos Manuel; Andrs, Patricia; Mayoral, Mara; Bombn, Igor

    2010-04-01

    The aims of this study were to examine the nature and extent of cognitive impairment in first-episode early-onset psychosis (FE-EOP) soon after their stabilisation and to search for potential differences according to specific diagnostic sub-groups of patients. As part of a Spanish multicentre longitudinal study, 107 FE-EOP patients and 98 healthy controls were assessed on the following cognitive domains: attention, working memory, executive functioning, and verbal learning and memory. Three diagnostic categories were established in the patient sample: schizophrenia (n = 36), bipolar disorder (n = 19), and other psychosis (n = 52). Patients performed significantly worse than controls in all cognitive domains. The three diagnostic sub-groups did not differ in terms of impaired/preserved cognitive functions or degree of impairment. FE-EOP patients show significant cognitive impairment that, during this early phase, seems to be non-specific to differential diagnosis. PMID:19768481

  19. Early onset intellectual disability in chromosome 22q11.2 deletion syndrome.

    PubMed

    Cascella, Marco; Muzio, Maria Rosaria

    2015-01-01

    Chromosome 22q11.2 deletion syndrome, or DiGeorge syndrome, or velocardiofacial syndrome, is one of the most common multiple anomaly syndromes in humans. This syndrome is commonly caused by a microdelection from chromosome 22 at band q11.2. Although this genetic disorder may reflect several clinical abnormalities and different degrees of organ commitment, the clinical features that have driven the greatest amount of attention are behavioral and developmental features, because individuals with 22q11.2 deletion syndrome have a 30-fold risk of developing schizophrenia. There are differing opinions about the cognitive development, and commonly a cognitive decline rather than an early onset intellectual disability has been observed. We report a case of 22q11.2 deletion syndrome with both early assessment of mild intellectual disabilities and tetralogy of Fallot as the only physic manifestation. PMID:26358864

  20. Early onset ovarian hyperstimulation syndrome despite use of segmentation approach and ovarian hyperstimulation syndrome prophylaxis.

    PubMed

    Mahajan, Nalini; Gupta, Shalu; Sharma, Shilpa; Rani, Kumkum; Naidu, Padmaja; Arora, Puneet R

    2015-01-01

    We report a case of early onset severe ovarian hyperstimulation syndrome (OHSS) presenting with oliguria in an antagonist cycle triggered with GnRH agonist and a freeze-all approach. Prophylactic measures in the form of GnRH antagonist, cabergolin and plasma expanders were given after oocyte retrieval. Twenty-four hours after oocyte retrieval patient developed oliguria and moderate ascites. She was managed in ICU with albumin and diuretics. She responded to conservative management and did not require paracentesis. Severe OHSS can occur in PCOS patients even after using a segmented approach i.e. GnRH agonist trigger with a 'freeze all' policy. Patients at risk of OHSS should be closely monitored following ovum pickup even when an agonist trigger has been given, for early detection and management. PMID:26752860

  1. Kcne2 deletion causes early-onset nonalcoholic fatty liver disease via iron deficiency anemia.

    PubMed

    Lee, Soo Min; Nguyen, Dara; Anand, Marie; Kant, Ritu; Köhncke, Clemens; Lisewski, Ulrike; Roepke, Torsten K; Hu, Zhaoyang; Abbott, Geoffrey W

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is an increasing health problem worldwide, with genetic, epigenetic, and environmental components. Here, we describe the first example of NAFLD caused by genetic disruption of a mammalian potassium channel subunit. Mice with germline deletion of the KCNE2 potassium channel β subunit exhibited NAFLD as early as postnatal day 7. Using mouse genetics, histology, liver damage assays and transcriptomics we discovered that iron deficiency arising from KCNE2-dependent achlorhydria is a major factor in early-onset NAFLD in Kcne2(─/─) mice, while two other KCNE2-dependent defects did not initiate NAFLD. The findings uncover a novel genetic basis for NAFLD and an unexpected potential factor in human KCNE2-associated cardiovascular pathologies, including atherosclerosis. PMID:26984260

  2. Early microbial and metabolomic signatures predict later onset of necrotizing enterocolitis in preterm infants

    PubMed Central

    2013-01-01

    Background Necrotizing enterocolitis (NEC) is a devastating intestinal disease that afflicts 10% of extremely preterm infants. The contribution of early intestinal colonization to NEC onset is not understood, and predictive biomarkers to guide prevention are lacking. We analyzed banked stool and urine samples collected prior to disease onset from infants <29 weeks gestational age, including 11 infants who developed NEC and 21 matched controls who survived free of NEC. Stool bacterial communities were profiled by 16S rRNA gene sequencing. Urinary metabolomic profiles were assessed by NMR. Results During postnatal days 4 to 9, samples from infants who later developed NEC tended towards lower alpha diversity (Chao1 index, P = 0.086) and lacked Propionibacterium (P = 0.009) compared to controls. Furthermore, NEC was preceded by distinct forms of dysbiosis. During days 4 to 9, samples from four NEC cases were dominated by members of the Firmicutes (median relative abundance >99% versus <17% in the remaining NEC and controls, P < 0.001). During postnatal days 10 to 16, samples from the remaining NEC cases were dominated by Proteobacteria, specifically Enterobacteriaceae (median relative abundance >99% versus 38% in the other NEC cases and 84% in controls, P = 0.01). NEC preceded by Firmicutes dysbiosis occurred earlier (onset, days 7 to 21) than NEC preceded by Proteobacteria dysbiosis (onset, days 19 to 39). All NEC cases lacked Propionibacterium and were preceded by either Firmicutes (≥98% relative abundance, days 4 to 9) or Proteobacteria (≥90% relative abundance, days 10 to 16) dysbiosis, while only 25% of controls had this phenotype (predictive value 88%, P = 0.001). Analysis of days 4 to 9 urine samples found no metabolites associated with all NEC cases, but alanine was positively associated with NEC cases that were preceded by Firmicutes dysbiosis (P < 0.001) and histidine was inversely associated with NEC cases preceded by Proteobacteria dysbiosis (P = 0.013). A high urinary alanine:histidine ratio was associated with microbial characteristics (P < 0.001) and provided good prediction of overall NEC (predictive value 78%, P = 0.007). Conclusions Early dysbiosis is strongly involved in the pathobiology of NEC. These striking findings require validation in larger studies but indicate that early microbial and metabolomic signatures may provide highly predictive biomarkers of NEC. PMID:24450576

  3. Altered PDE10A expression detectable early before symptomatic onset in Huntington's disease.

    PubMed

    Niccolini, Flavia; Haider, Salman; Reis Marques, Tiago; Muhlert, Nils; Tziortzi, Andri C; Searle, Graham E; Natesan, Sridhar; Piccini, Paola; Kapur, Shitij; Rabiner, Eugenii A; Gunn, Roger N; Tabrizi, Sarah J; Politis, Marios

    2015-10-01

    There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers. PMID:26198591

  4. IRAK-M Is Involved in the Pathogenesis of Early-Onset Persistent Asthma

    PubMed Central

    Balaci, Lenuta; Spada, MariaCristina; Olla, Nazario; Sole, Gabriella; Loddo, Laura; Anedda, Francesca; Naitza, Silvia; Zuncheddu, MariaAntonietta; Maschio, Andrea; Altea, Daniele; Uda, Manuela; Pilia, Sabrina; Sanna, Serena; Masala, Marco; Crisponi, Laura; Fattori, Matilde; Devoto, Marcella; Doratiotto, Silvia; Rassu, Stefania; Mereu, Simonetta; Giua, Enrico; Cadeddu, NatalinaGraziella; Atzeni, Roberto; Pelosi, Umberto; Corrias, Adriano; Perra, Roberto; Torrazza, PierLuigi; Pirina, Pietro; Ginesu, Francesco; Marcias, Silvano; Schintu, MariaGrazia; Giacco, GennaroSergioDel; Manconi, PaoloEmilio; Malerba, Giovanni; Bisognin, Andrea; Trabetti, Elisabetta; Boner, Attilio; Pescollderungg, Lydia; Pignatti, PierFranco; Schlessinger, David; Cao, Antonio; Pilia, Giuseppe

    2007-01-01

    Asthma is a multifactorial disease influenced by genetic and environmental factors. In the past decade, several loci and >100 genes have been found to be associated with the disease in at least one population. Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes. We performed linkage and association analyses by transmission/disequilibrium test and case-control analysis in the candidate region 12q13-24, using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions should facilitate the study of multifactorial traits. We analyzed our cohort, using a cutoff age of 13 years at asthma onset, and detected significant linkage to a portion of 12q13-24. We identified IRAK-M as the gene contributing to the linkage and showed that it is associated with early-onset persistent asthma. We defined protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population. Sequence analysis in patients found mutations, including inactivating lesions, in the IRAK-M coding region. Immunohistochemistry of lung biopsies showed that IRAK-M is highly expressed in epithelial cells. We report that IRAK-M is involved in the pathogenesis of early-onset persistent asthma. IRAK-M, a negative regulator of the Toll-like receptor/IL-1R pathways, is a master regulator of NF-?B and inflammation. Our data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against asthma. PMID:17503328

  5. The gene of an early onset progressive cataract (cerulean cataract) maps to 17q24

    SciTech Connect

    Armitage, M.M.; Ferrell, R.E.; Kivlin, J.D.

    1994-09-01

    Cerulean cataract is an autosomal dominant, fully penetrant, early onset, progressive cataract characterized by blue or white opacifications in the nucleus and cortex of the lens. A five generation family with 44 available affected members in three generations allowed exclusion of linkage of the cerulean cataract phenotype to lens structural protein genes and to all of the chromosomal regions to which autosomal dominant cataract phenotypes have previously been mapped. Exclusion of the plausible candidate instigated a genome-wide search utilizing short tandem repeat polymorphims. The genome search localized the cerulean cataract disease gene to chromosomal region 17q24. The three markers closest to the disease gene are D17S802 [Z({theta})=9.20 at ({theta})=0.086], D17S836 [Z({theta})=4.22 at ({theta})=0.061], and AFMa238yb5 [Z({theta})=7.11 at ({theta})=0.032]. Multipoint analysis yielded a maximum lod score of Z({theta})=11.4 between D17S802 and D17S836 at recombination rates of 0.048 and 0.013 respectively. Three genes that map near the 17q24 chromosomal region and are known to contain highly polymorphic microsatellites were tested for linkage. The genes, DHP-sensitive calcium channel gamma subunit (CACNLG), human somatastatin receptor (SSTR2), and the skeletal muscle sodium channel alpha subunit (SCN4A), were all excluded [Z({theta})=-{infinity} at ({theta})=0] as the gene causing cerulean cataract. The galactokinase (GK1) gene has not been cloned, but its map location is 17q23-q25. Galactokinase deficiency is characterized by a recessive, progressive, early onset cataract. Because of the map location of galactokinase, the age-at-onset, and progressive nature of cataracts associated with galactokinase deficiency, galactokinase is being investigated as a candidate gene for the cerulean cataract phenotype.

  6. Cognitive Efficacy of Quetiapine and Olanzapine in Early-Onset First-Episode Psychosis

    PubMed Central

    Zabala, Arantzazu; Bombín, Igor; Parellada, Mara; Moreno, Dolores; Ruiz-Sancho, Ana; Arango, Celso

    2011-01-01

    The primary purpose of this study was to compare changes in cognition in early-onset psychosis after 6-months treatment with quetiapine or olanzapine. This is a randomized, single-blind, 6-month study in 50 adolescents with a diagnosis of early-onset psychosis. Patients were randomized to quetiapine (n = 24) or olanzapine (n = 26). A thorough neuropsychological battery was administered at baseline and after 6-month treatment. Out of the total sample included in the study, 32 patients completed at least 6-months treatment with the assigned medication (quetiapine, n = 16; olanzapine, n = 16). No changes were observed in cognitive performance after 6-month treatment with quetiapine or olanzapine. Although some trends toward cognitive improvement were observed for the olanzapine group after 6-month treatment, neither group showed statistically significant gains. Furthermore, there was no evidence of any differential efficacy of olanzapine or quetiapine on cognitive improvement in this sample of adolescents with psychosis. PMID:19706697

  7. Mutations in FBXL4, Encoding a Mitochondrial Protein, Cause Early-Onset Mitochondrial Encephalomyopathy

    PubMed Central

    Gai, Xiaowu; Ghezzi, Daniele; Johnson, MarkA.; Biagosch, CarolineA.; Shamseldin, HananE.; Haack, TobiasB.; Reyes, Aurelio; Tsukikawa, Mai; Sheldon, ClaireA.; Srinivasan, Satish; Gorza, Matteo; Kremer, LauraS.; Wieland, Thomas; Strom, TimM.; Polyak, Erzsebet; Place, Emily; Consugar, Mark; Ostrovsky, Julian; Vidoni, Sara; Robinson, AlanJ.; Wong, Lee-Jun; Sondheimer, Neal; Salih, MustafaA.; Al-Jishi, Emtethal; Raab, ChristopherP.; Bean, Charles; Furlan, Francesca; Parini, Rossella; Lamperti, Costanza; Mayr, JohannesA.; Konstantopoulou, Vassiliki; Huemer, Martina; Pierce, EricA.; Meitinger, Thomas; Freisinger, Peter; Sperl, Wolfgang; Prokisch, Holger; Alkuraya, FowzanS.; Falk, MarniJ.; Zeviani, Massimo

    2013-01-01

    Whole-exome sequencing and autozygosity mapping studies, independently performed in subjects with defective combined mitochondrial OXPHOS-enzyme deficiencies, identified a total of nine disease-segregating FBXL4 mutations in seven unrelated mitochondrial disease families, composed of six singletons and three siblings. All subjects manifested early-onset lactic acidemia, hypotonia, and developmental delay caused by severe encephalomyopathy consistently associated with progressive cerebral atrophy and variable involvement of the white matter, deep gray nuclei, and brainstem structures. A wide range of other multisystem features were variably seen, including dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosis, seizures, and episodic metabolic failure. Mitochondrial respiratory chain deficiency was present in muscle or fibroblasts of all tested individuals, together with markedly reduced oxygen consumption rate and hyperfragmentation of the mitochondrial network in cultured cells. In muscle and fibroblasts from several subjects, substantially decreased mtDNA content was observed. FBXL4 is a member of the F-box family of proteins, some of which are involved in phosphorylation-dependent ubiquitination and/or G protein receptor coupling. We also demonstrate that FBXL4 is targeted to mitochondria and localizes in the intermembrane space, where it participates in an approximately 400kDa protein complex. These data strongly support a role for FBXL4 in controlling bioenergetic homeostasis and mtDNA maintenance. FBXL4 mutations are a recurrent cause of mitochondrial encephalomyopathy onset in early infancy. PMID:23993194

  8. Deleterious Germline BLM Mutations and the Risk for Early-onset Colorectal Cancer

    PubMed Central

    de Voer, Richarda M.; Hahn, Marc-Manuel; Mensenkamp, Arjen R.; Hoischen, Alexander; Gilissen, Christian; Henkes, Arjen; Spruijt, Liesbeth; van Zelst-Stams, Wendy A.; Marleen Kets, C.; Verwiel, Eugene T.; Nagtegaal, Iris D.; Schackert, Hans K.; van Kessel, Ad Geurts; Hoogerbrugge, Nicoline; Ligtenberg, Marjolijn J.L.; Kuiper, Roland P.

    2015-01-01

    Bloom syndrome is an autosomal recessive disorder characterized by chromosomal instability and increased cancer risk, caused by biallelic mutations in the RECQL-helicase gene BLM. Previous studies have led to conflicting conclusions as to whether carriers of heterozygous BLM mutations have an increased risk to develop colorectal cancer (CRC). We recently identified two carriers of a pathogenic BLM mutation in a cohort of 55 early-onset CRC patients (?45 years of age), suggesting an overrepresentation compared to the normal population. Here, we performed targeted sequencing using molecular inversion probes to screen an additional cohort of 185 CRC patients (?50 years of age) and 532 population-matched controls for deleterious BLM mutations. In total, we identified three additional CRC patients (1.6%) and one control individual (0.2%) that carried a known pathogenic BLM mutation, suggesting that these mutations are enriched in early-onset CRC patients (P?=?0.05516). A comparison with local and publically available databases from individuals without suspicion for hereditary cancer confirmed this enrichment (P?=?0.003534). Analysis of family members of the five BLM mutation carriers with CRC suggests an incomplete penetrance for CRC development. Therefore, these data indicate that carriers of deleterious BLM mutations are at increased risk to develop CRC, albeit with a moderate-to-low penetrance. PMID:26358404

  9. Early-onset epileptic encephalopathies and the diagnostic approach to underlying causes

    PubMed Central

    Hwang, Su-Kyeong

    2015-01-01

    Early-onset epileptic encephalopathies are one of the most severe early onset epilepsies that can lead to progressive psychomotor impairment. These syndromes result from identifiable primary causes, such as structural, neurodegenerative, metabolic, or genetic defects, and an increasing number of novel genetic causes continue to be uncovered. A typical diagnostic approach includes documentation of anamnesis, determination of seizure semiology, electroencephalography, and neuroimaging. If primary biochemical investigations exclude precipitating conditions, a trial with the administration of a vitaminic compound (pyridoxine, pyridoxal-5-phosphate, or folinic acid) can then be initiated regardless of presumptive seizure causes. Patients with unclear etiologies should be considered for a further workup, which should include an evaluation for inherited metabolic defects and genetic analyses. Targeted next-generation sequencing panels showed a high diagnostic yield in patients with epileptic encephalopathy. Mutations associated with the emergence of epileptic encephalopathies can be identified in a targeted fashion by sequencing the most likely candidate genes. Next-generation sequencing technologies offer hope to a large number of patients with cryptogenic encephalopathies and will eventually lead to new therapeutic strategies and more favorable long-term outcomes. PMID:26692875

  10. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine

    PubMed Central

    Pierson, Tyler Mark; Yuan, Hongjie; Marsh, Eric D; Fuentes-Fajardo, Karin; Adams, David R; Markello, Thomas; Golas, Gretchen; Simeonov, Dimitre R; Holloman, Conisha; Tankovic, Anel; Karamchandani, Manish M; Schreiber, John M; Mullikin, James C; Tifft, Cynthia J; Toro, Camilo; Boerkoel, Cornelius F; Traynelis, Stephen F; Gahl, William A

    2014-01-01

    Objective Early-onset epileptic encephalopathies have been associated with de novo mutations of numerous ion channel genes. We employed techniques of modern translational medicine to identify a disease-causing mutation, analyze its altered behavior, and screen for therapeutic compounds to treat the proband. Methods Three modern translational medicine tools were utilized: (1) high-throughput sequencing technology to identify a novel de novo mutation; (2) in vitro expression and electrophysiology assays to confirm the variant protein's dysfunction; and (3) screening of existing drug libraries to identify potential therapeutic compounds. Results A de novo GRIN2A missense mutation (c.2434C>A; p.L812M) increased the charge transfer mediated by N-methyl-D-aspartate receptors (NMDAs) containing the mutant GluN2A-L812M subunit. In vitro analysis with NMDA receptor blockers indicated that GLuN2A-L812M-containing NMDARs retained their sensitivity to the use-dependent channel blocker memantine; while screening of a previously reported GRIN2A mutation (N615K) with these compounds produced contrasting results. Consistent with these data, adjunct memantine therapy reduced our proband's seizure burden. Interpretation This case exemplifies the potential for personalized genomics and therapeutics to be utilized for the early diagnosis and treatment of infantile-onset neurological disease. PMID:24839611

  11. Early-onset epileptic encephalopathies and the diagnostic approach to underlying causes.

    PubMed

    Hwang, Su-Kyeong; Kwon, Soonhak

    2015-11-01

    Early-onset epileptic encephalopathies are one of the most severe early onset epilepsies that can lead to progressive psychomotor impairment. These syndromes result from identifiable primary causes, such as structural, neurodegenerative, metabolic, or genetic defects, and an increasing number of novel genetic causes continue to be uncovered. A typical diagnostic approach includes documentation of anamnesis, determination of seizure semiology, electroencephalography, and neuroimaging. If primary biochemical investigations exclude precipitating conditions, a trial with the administration of a vitaminic compound (pyridoxine, pyridoxal-5-phosphate, or folinic acid) can then be initiated regardless of presumptive seizure causes. Patients with unclear etiologies should be considered for a further workup, which should include an evaluation for inherited metabolic defects and genetic analyses. Targeted next-generation sequencing panels showed a high diagnostic yield in patients with epileptic encephalopathy. Mutations associated with the emergence of epileptic encephalopathies can be identified in a targeted fashion by sequencing the most likely candidate genes. Next-generation sequencing technologies offer hope to a large number of patients with cryptogenic encephalopathies and will eventually lead to new therapeutic strategies and more favorable long-term outcomes. PMID:26692875

  12. Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism.

    PubMed

    Quadri, Marialuisa; Fang, Mingyan; Picillo, Marina; Olgiati, Simone; Breedveld, Guido J; Graafland, Josja; Wu, Bin; Xu, Fengping; Erro, Roberto; Amboni, Marianna; Pappat, Sabina; Quarantelli, Mario; Annesi, Grazia; Quattrone, Aldo; Chien, Hsin F; Barbosa, Egberto R; Oostra, Ben A; Barone, Paolo; Wang, Jun; Bonifati, Vincenzo

    2013-09-01

    Autosomal recessive, early-onset Parkinsonism is clinically and genetically heterogeneous. Here, we report the identification, by homozygosity mapping and exome sequencing, of a SYNJ1 homozygous mutation (p.Arg258Gln) segregating with disease in an Italian consanguineous family with Parkinsonism, dystonia, and cognitive deterioration. Response to levodopa was poor, and limited by side effects. Neuroimaging revealed brain atrophy, nigrostriatal dopaminergic defects, and cerebral hypometabolism. SYNJ1 encodes synaptojanin 1, a phosphoinositide phosphatase protein with essential roles in the postendocytic recycling of synaptic vesicles. The mutation is absent in variation databases and in ethnically matched controls, is damaging according to all prediction programs, and replaces an amino acid that is extremely conserved in the synaptojanin 1 homologues and in SAC1-like domains of other proteins. Sequencing the SYNJ1 ORF in unrelated patients revealed another heterozygous mutation (p.Ser1422Arg), predicted as damaging, in a patient who also carries a heterozygous PINK1 truncating mutation. The SYNJ1 gene is a compelling candidate for Parkinsonism; mutations in the functionally linked protein auxilin cause a similar early-onset phenotype, and other findings implicate endosomal dysfunctions in the pathogenesis. Our data delineate a novel form of human Mendelian Parkinsonism, and provide further evidence for abnormal synaptic vesicle recycling as a central theme in the pathogenesis. PMID:23804577

  13. Is the NACP/Synuclein gene involved in early-onset Alheimer`s disease?

    SciTech Connect

    Champion, D.; Clerget-Darpoux, F.; Frebourg, T.

    1994-09-01

    The major component of senile plaques (SP), the most specific histologic lesion of Alzheimer`s disease (AD) is the A4 peptide, derived from a large precursor protein (APP). Recently, a second major component of SP has been isolated. This 35 AA peptide was named non-A4 component amyloid (NAC) and its precursor - a 140 AA protein - was named NACP. Computer homology search has allowed us to establish that the NACP gene is homologous to the rat synuclein gene which is expressed in neurons. Since APP mutations have been shown to cause early-onset Alzheimer`s disease (EOAD) in several families, we investigated whether the NACP/synuclein gene was also involved in familial early-onset Alzheimer`s disease (FEOAD). RT-PCR and direct sequencing of the entire NACP open reading frame did not reveal any alteration of the NACP coding sequence in lymphocytes of 26 unrelated FEOAD patients. We showed that the NACP/synuclein gene was alternatively spliced and that the different transcripts potentially encoded for distinct proteins all containing the NAC peptide. Accumulation of NAC in SP might result from a dysregulation of NACP/synuclein expression.

  14. Submersion and early-onset acute respiratory distress syndrome: a case report.

    PubMed

    Diamond, Wayde; MacDonald, Russell D

    2011-01-01

    Drowning is a common cause of accidental death, particularly in younger people, and acute respiratory failure is common in these patients. This case report describes a healthy 18-year-old man who suffered a cardiorespiratory arrest due to submersion while swimming in a freshwater lake. First-responder cardiopulmonary resuscitation and defibrillation using an automated external defibrillator resulted in a return of spontaneous circulation. The patient was evacuated to a tertiary care center by a rotor-wing air medical crew. The crew experienced difficulties in oxygenating and ventilating the patient because of early-onset acute respiratory distress syndrome (ARDS). This case report describes the pathophysiology and prehospital management of a patient with suspected early-onset ARDS secondary to drowning. This case report is unique because it describes the oxygenation and ventilation difficulties encountered in managing this patient in the transport setting, and possible strategies to deal with these difficulties. Finally, this case report highlights the prehospital bypass decision-making process for patients requiring specialized medical care. PMID:21275574

  15. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure.

    PubMed

    Zivn, Martina; H?lkov, Helena; Matignon, Marie; Hodanov, Katerina; Vylet'al, Petr; Kalbcov, Marie; Baresov, Veronika; Sikora, Jakub; Blazkov, Hana; Zivn, Jan; Ivnek, Robert; Strneck, Viktor; Sovov, Jana; Claes, Kathleen; Lerut, Evelyne; Fryns, Jean-Pierre; Hart, P Suzanne; Hart, Thomas C; Adams, Jeremy N; Pawtowski, Audrey; Clemessy, Maud; Gasc, Jean-Marie; Gbler, Marie-Claire; Antignac, Corinne; Elleder, Milan; Kapp, Katja; Grimbert, Philippe; Bleyer, Anthony J; Kmoch, Stanislav

    2009-08-01

    Through linkage analysis and candidate gene sequencing, we identified three unrelated families with the autosomal-dominant inheritance of early onset anemia, hypouricosuric hyperuricemia, progressive kidney failure, and mutations resulting either in the deletion (p.Leu16del) or the amino acid exchange (p.Leu16Arg) of a single leucine residue in the signal sequence of renin. Both mutations decrease signal sequence hydrophobicity and are predicted by bioinformatic analyses to damage targeting and cotranslational translocation of preprorenin into the endoplasmic reticulum (ER). Transfection and in vitro studies confirmed that both mutations affect ER translocation and processing of nascent preprorenin, resulting either in reduced (p.Leu16del) or abolished (p.Leu16Arg) prorenin and renin biosynthesis and secretion. Expression of renin and other components of the renin-angiotensin system was decreased accordingly in kidney biopsy specimens from affected individuals. Cells stably expressing the p.Leu16del protein showed activated ER stress, unfolded protein response, and reduced growth rate. It is likely that expression of the mutant proteins has a dominant toxic effect gradually reducing the viability of renin-expressing cells. This alters the intrarenal renin-angiotensin system and the juxtaglomerular apparatus functionality and leads to nephron dropout and progressive kidney failure. Our findings provide insight into the functionality of renin-angiotensin system and stress the importance of renin analysis in families and individuals with early onset hyperuricemia, anemia, and progressive kidney failure. PMID:19664745

  16. Dominant Renin Gene Mutations Associated with Early-Onset Hyperuricemia, Anemia, and Chronic Kidney Failure

    PubMed Central

    ivn, Martina; H?lkov, Helena; Matignon, Marie; Hoda?ov, Kate?ina; Vylet'al, Petr; Kalb?ov, Marie; Bareov, Veronika; Sikora, Jakub; Blakov, Hana; ivn, Jan; Ivnek, Robert; Strneck, Viktor; Sovov, Jana; Claes, Kathleen; Lerut, Evelyne; Fryns, Jean-Pierre; Hart, P. Suzanne; Hart, Thomas C.; Adams, Jeremy N.; Pawtowski, Audrey; Clemessy, Maud; Gasc, Jean-Marie; Gbler, Marie-Claire; Antignac, Corinne; Elleder, Milan; Kapp, Katja; Grimbert, Philippe; Bleyer, Anthony J.; Kmoch, Stanislav

    2009-01-01

    Through linkage analysis and candidate gene sequencing, we identified three unrelated families with the autosomal-dominant inheritance of early onset anemia, hypouricosuric hyperuricemia, progressive kidney failure, and mutations resulting either in the deletion (p.Leu16del) or the amino acid exchange (p.Leu16Arg) of a single leucine residue in the signal sequence of renin. Both mutations decrease signal sequence hydrophobicity and are predicted by bioinformatic analyses to damage targeting and cotranslational translocation of preprorenin into the endoplasmic reticulum (ER). Transfection and invitro studies confirmed that both mutations affect ER translocation and processing of nascent preprorenin, resulting either in reduced (p.Leu16del) or abolished (p.Leu16Arg) prorenin and renin biosynthesis and secretion. Expression of renin and other components of the renin-angiotensin system was decreased accordingly in kidney biopsy specimens from affected individuals. Cells stably expressing the p.Leu16del protein showed activated ER stress, unfolded protein response, and reduced growth rate. It is likely that expression of the mutant proteins has a dominant toxic effect gradually reducing the viability of renin-expressing cells. This alters the intrarenal renin-angiotensin system and the juxtaglomerular apparatus functionality and leads to nephron dropout and progressive kidney failure. Our findings provide insight into the functionality of renin-angiotensin system and stress the importance of renin analysis in families and individuals with early onset hyperuricemia, anemia, and progressive kidney failure. PMID:19664745

  17. Validity of hematologic parameters in identification of early and late onset neonatal infection.

    PubMed

    Varsha; Rusia, Usha; Sikka, Meera; Faridi, M M A; Madan, Nishi

    2003-10-01

    This study was designed to evaluate the utility of hematological parameters and C-reactive protein (CRP) to formulate a sepsis screen to detect sepsis in early and late onset infection. Hundred and fifty neonates clinically suspected of bacterial infection, based on risk factors and/or clinical features were selected for the study. Blood was collected by venipuncture at the time of admission in all neonates. A total leukocyte count (TLC), differential leukocyte count (DLC), its derivatives [Total neutrophil count (TNC or T), ratio of immature to total neutrophil count (I/T), ratio of immature to mature neutrophil count (I/M)] and CRP were obtained. TLC = 10x10(9)/L, TNC = 8x10(9)/L, I/T = 0.16, I/M = 0.25 and CRP = 0.6 mg/dl were found to be good parameters in detection of sepsis. During the first three days of life leukopenia, neutropenia, elevated I/T ratio, elevated I/M ratio and CRP were good diagnostic aids while after 3 days of life CRP was the best single test. This emphasizes use of multiple indicators for detection of sepsis. Using these parameters a sepsis screen was formulated which detected >90% of proven early and late onset sepsis suggesting that other neonates with positive sepsis screen but blood culture negativity may have been truly infected. PMID:15025344

  18. Serial elongation-derotation-flexion casting for children with early-onset scoliosis.

    PubMed

    Canavese, Federico; Samba, Antoine; Dimeglio, Alain; Mansour, Mounira; Rousset, Marie

    2015-12-18

    Various early-onset spinal deformities, particularly infantile and juvenile scoliosis (JS), still pose challenges to pediatric orthopedic surgeons. The ideal treatment of these deformities has yet to emerge, as both clinicians and surgeons still face multiple challenges including preservation of thoracic motion, spine and cage, and protection of cardiac and lung growth and function. Elongation-derotation-flexion (EDF) casting is a technique that uses a custom-made thoracolumbar cast based on a three-dimensional correction concept. EDF can control progression of the deformity and - in some cases-coax the initially-curved spine to grow straighter by acting simultaneously in the frontal, sagittal and coronal planes. Here we provide a comprehensive review of how infantile and JS can affect normal spine and thorax and how serial EDF casting can be used to manage these spinal deformities. A fresh review of the literature helps fully understand the principles of the serial EDF casting technique and the effectiveness of conservative treatment in patients with early-onset spinal deformities, particularly infantile and juvenile scolisois. PMID:26716089

  19. Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.

    PubMed

    Gai, Xiaowu; Ghezzi, Daniele; Johnson, Mark A; Biagosch, Caroline A; Shamseldin, Hanan E; Haack, Tobias B; Reyes, Aurelio; Tsukikawa, Mai; Sheldon, Claire A; Srinivasan, Satish; Gorza, Matteo; Kremer, Laura S; Wieland, Thomas; Strom, Tim M; Polyak, Erzsebet; Place, Emily; Consugar, Mark; Ostrovsky, Julian; Vidoni, Sara; Robinson, Alan J; Wong, Lee-Jun; Sondheimer, Neal; Salih, Mustafa A; Al-Jishi, Emtethal; Raab, Christopher P; Bean, Charles; Furlan, Francesca; Parini, Rossella; Lamperti, Costanza; Mayr, Johannes A; Konstantopoulou, Vassiliki; Huemer, Martina; Pierce, Eric A; Meitinger, Thomas; Freisinger, Peter; Sperl, Wolfgang; Prokisch, Holger; Alkuraya, Fowzan S; Falk, Marni J; Zeviani, Massimo

    2013-09-01

    Whole-exome sequencing and autozygosity mapping studies, independently performed in subjects with defective combined mitochondrial OXPHOS-enzyme deficiencies, identified a total of nine disease-segregating FBXL4 mutations in seven unrelated mitochondrial disease families, composed of six singletons and three siblings. All subjects manifested early-onset lactic acidemia, hypotonia, and developmental delay caused by severe encephalomyopathy consistently associated with progressive cerebral atrophy and variable involvement of the white matter, deep gray nuclei, and brainstem structures. A wide range of other multisystem features were variably seen, including dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosis, seizures, and episodic metabolic failure. Mitochondrial respiratory chain deficiency was present in muscle or fibroblasts of all tested individuals, together with markedly reduced oxygen consumption rate and hyperfragmentation of the mitochondrial network in cultured cells. In muscle and fibroblasts from several subjects, substantially decreased mtDNA content was observed. FBXL4 is a member of the F-box family of proteins, some of which are involved in phosphorylation-dependent ubiquitination and/or G protein receptor coupling. We also demonstrate that FBXL4 is targeted to mitochondria and localizes in the intermembrane space, where it participates in an approximately 400 kDa protein complex. These data strongly support a role for FBXL4 in controlling bioenergetic homeostasis and mtDNA maintenance. FBXL4 mutations are a recurrent cause of mitochondrial encephalomyopathy onset in early infancy. PMID:23993194

  20. Deleterious Germline BLM Mutations and the Risk for Early-onset Colorectal Cancer.

    PubMed

    de Voer, Richarda M; Hahn, Marc-Manuel; Mensenkamp, Arjen R; Hoischen, Alexander; Gilissen, Christian; Henkes, Arjen; Spruijt, Liesbeth; van Zelst-Stams, Wendy A; Kets, C Marleen; Verwiel, Eugene T; Nagtegaal, Iris D; Schackert, Hans K; van Kessel, Ad Geurts; Hoogerbrugge, Nicoline; Ligtenberg, Marjolijn J L; Kuiper, Roland P

    2015-01-01

    Bloom syndrome is an autosomal recessive disorder characterized by chromosomal instability and increased cancer risk, caused by biallelic mutations in the RECQL-helicase gene BLM. Previous studies have led to conflicting conclusions as to whether carriers of heterozygous BLM mutations have an increased risk to develop colorectal cancer (CRC). We recently identified two carriers of a pathogenic BLM mutation in a cohort of 55 early-onset CRC patients (?45 years of age), suggesting an overrepresentation compared to the normal population. Here, we performed targeted sequencing using molecular inversion probes to screen an additional cohort of 185 CRC patients (?50 years of age) and 532 population-matched controls for deleterious BLM mutations. In total, we identified three additional CRC patients (1.6%) and one control individual (0.2%) that carried a known pathogenic BLM mutation, suggesting that these mutations are enriched in early-onset CRC patients (P?=?0.05516). A comparison with local and publically available databases from individuals without suspicion for hereditary cancer confirmed this enrichment (P?=?0.003534). Analysis of family members of the five BLM mutation carriers with CRC suggests an incomplete penetrance for CRC development. Therefore, these data indicate that carriers of deleterious BLM mutations are at increased risk to develop CRC, albeit with a moderate-to-low penetrance. PMID:26358404

  1. Serial elongation-derotation-flexion casting for children with early-onset scoliosis

    PubMed Central

    Canavese, Federico; Samba, Antoine; Dimeglio, Alain; Mansour, Mounira; Rousset, Marie

    2015-01-01

    Various early-onset spinal deformities, particularly infantile and juvenile scoliosis (JS), still pose challenges to pediatric orthopedic surgeons. The ideal treatment of these deformities has yet to emerge, as both clinicians and surgeons still face multiple challenges including preservation of thoracic motion, spine and cage, and protection of cardiac and lung growth and function. Elongation-derotation-flexion (EDF) casting is a technique that uses a custom-made thoracolumbar cast based on a three-dimensional correction concept. EDF can control progression of the deformity and - in some cases-coax the initially-curved spine to grow straighter by acting simultaneously in the frontal, sagittal and coronal planes. Here we provide a comprehensive review of how infantile and JS can affect normal spine and thorax and how serial EDF casting can be used to manage these spinal deformities. A fresh review of the literature helps fully understand the principles of the serial EDF casting technique and the effectiveness of conservative treatment in patients with early-onset spinal deformities, particularly infantile and juvenile scolisois. PMID:26716089

  2. Structured Regions of Alpha-synuclein Fibrils Include the Early Onset Parkinson's Disease Mutation Sites

    SciTech Connect

    Comellas Canal, Gemma; Lemkau, Luisel R.; Nieuwkoop, Andrew J.; Kloepper, Kathryn D.; Ladror, Daniel T.; Ebisu, Reika; Woods, Wendy S.; Lipton, Andrew S.; George, Julia M.; Rienstra, Chad M.

    2011-08-26

    Alpha-Synuclein (AS) fibrils constitute the major proteinaceous component of Lewy bodies (LBs), the pathological hallmark of Parkinson’s disease (PD) and other neurodegenerative diseases. Three single point mutations in the AS gene, as well as multiplication of the wild-type (WT) AS allele, have been previously identified in families with early-onset PD. Although AS fibrils have been the subject of intense study, critical details about their structure including the precise location of the B-strands and the extent of the core, the three-dimensional structure and the effects of the mutations—remain unknown. Here, we have used magic-angle spinning solid-state NMR spectroscopy to present a detailed characterization of the full-length WT AS fibrils. With improved sample preparations, isotopic labeling patterns and NMR experiments, we have confidently assigned more than 90% of the 13C and 15N backbone and sidechain chemical shifts of the detected residues from residue 39 to 97, and quantified the conformational dynamics throughout this region. Our results demonstrate that the core of AS fibrils extends with a repeated motif and that residues 30, 46 and 53-the early-onset PD mutant sites-are located in structured regions of AS fibrils.

  3. Placental fractalkine is up-regulated in severe early onset preeclampsia

    PubMed Central

    Siwetz, Monika; Dieber-Rotheneder, Martina; Cervar-Zivkovic, Mila; Kummer, Daniel; Kremshofer, Julia; Weiss, Gregor; Herse, Florian; Huppertz, Berthold; Gauster, Martin

    2015-01-01

    The pathogenesis of preeclampsia includes the release of placental factors into the maternal circulation inducing an inflammatory environment in the mother. One of the factors may be the pro-inflammatory chemokine fractalkine, which is expressed in the syncytiotrophoblast of human placenta, from where it is released into the maternal circulation by constitutive shedding. We examined whether placental fractalkine is up-regulated in severe early onset preeclampsia and whether the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin-6 are able to increase the expression of fractalkine. Gene expression analysis, ELISA, and immunohistochemistry consistently showed increased fractalkine expression in placentas from severe early onset preeclampsia, compared to gestational age-matched controls. Expression of the metalloproteinases ADAM10 and ADAM17, which convert transmembrane fractalkine into the soluble form, was significantly increased in these cases. Incubation of first trimester placental explants with TNF-α provoked a significant increase in fractalkine expression and release of the soluble form, whereas interleukin-6 had no effect. TNF-α-mediated up-regulation of placental fractalkine was reversed in the presence of the Aspirin-derivative salicylate, which impaired activation of NF-κB p65 in TNF-α-treated explants. Based on data from placental explants we suggest that increased maternal TNF-α may up-regulate the expression and release of placental fractalkine, which in turn may contribute to an exaggerated systemic inflammatory response in preeclampsia. PMID:25769431

  4. Plant macrofossil evidence for an early onset of the Holocene summer thermal maximum in northernmost Europe.

    PubMed

    Väliranta, M; Salonen, J S; Heikkilä, M; Amon, L; Helmens, K; Klimaschewski, A; Kuhry, P; Kultti, S; Poska, A; Shala, S; Veski, S; Birks, H H

    2015-01-01

    Holocene summer temperature reconstructions from northern Europe based on sedimentary pollen records suggest an onset of peak summer warmth around 9,000 years ago. However, pollen-based temperature reconstructions are largely driven by changes in the proportions of tree taxa, and thus the early-Holocene warming signal may be delayed due to the geographical disequilibrium between climate and tree populations. Here we show that quantitative summer-temperature estimates in northern Europe based on macrofossils of aquatic plants are in many cases ca. 2 °C warmer in the early Holocene (11,700-7,500 years ago) than reconstructions based on pollen data. When the lag in potential tree establishment becomes imperceptible in the mid-Holocene (7,500 years ago), the reconstructed temperatures converge at all study sites. We demonstrate that aquatic plant macrofossil records can provide additional and informative insights into early-Holocene temperature evolution in northernmost Europe and suggest further validation of early post-glacial climate development based on multi-proxy data syntheses. PMID:25858780

  5. Plant macrofossil evidence for an early onset of the Holocene summer thermal maximum in northernmost Europe

    PubMed Central

    Väliranta, M.; Salonen, J. S.; Heikkilä, M.; Amon, L.; Helmens, K.; Klimaschewski, A.; Kuhry, P.; Kultti, S.; Poska, A.; Shala, S.; Veski, S.; Birks, H. H.

    2015-01-01

    Holocene summer temperature reconstructions from northern Europe based on sedimentary pollen records suggest an onset of peak summer warmth around 9,000 years ago. However, pollen-based temperature reconstructions are largely driven by changes in the proportions of tree taxa, and thus the early-Holocene warming signal may be delayed due to the geographical disequilibrium between climate and tree populations. Here we show that quantitative summer-temperature estimates in northern Europe based on macrofossils of aquatic plants are in many cases ca. 2 °C warmer in the early Holocene (11,700–7,500 years ago) than reconstructions based on pollen data. When the lag in potential tree establishment becomes imperceptible in the mid-Holocene (7,500 years ago), the reconstructed temperatures converge at all study sites. We demonstrate that aquatic plant macrofossil records can provide additional and informative insights into early-Holocene temperature evolution in northernmost Europe and suggest further validation of early post-glacial climate development based on multi-proxy data syntheses. PMID:25858780

  6. Plant macrofossil evidence for an early onset of the Holocene summer thermal maximum in northernmost Europe

    NASA Astrophysics Data System (ADS)

    Vliranta, M.; Salonen, J. S.; Heikkil, M.; Amon, L.; Helmens, K.; Klimaschewski, A.; Kuhry, P.; Kultti, S.; Poska, A.; Shala, S.; Veski, S.; Birks, H. H.

    2015-04-01

    Holocene summer temperature reconstructions from northern Europe based on sedimentary pollen records suggest an onset of peak summer warmth around 9,000 years ago. However, pollen-based temperature reconstructions are largely driven by changes in the proportions of tree taxa, and thus the early-Holocene warming signal may be delayed due to the geographical disequilibrium between climate and tree populations. Here we show that quantitative summer-temperature estimates in northern Europe based on macrofossils of aquatic plants are in many cases ca. 2 C warmer in the early Holocene (11,700-7,500 years ago) than reconstructions based on pollen data. When the lag in potential tree establishment becomes imperceptible in the mid-Holocene (7,500 years ago), the reconstructed temperatures converge at all study sites. We demonstrate that aquatic plant macrofossil records can provide additional and informative insights into early-Holocene temperature evolution in northernmost Europe and suggest further validation of early post-glacial climate development based on multi-proxy data syntheses.

  7. Early-Onset Basal Cell Carcinoma and Indoor Tanning: A Population-Based Study

    PubMed Central

    Zens, M. Scot; Li, Zhigang; Stukel, Therese A.; Perry, Ann E.; Gilbert-Diamond, Diane; Sayarath, Vicki; Stephenson, Rita S.; Barton, Dorothea; Nelson, Heather H.; Spencer, Steven K.

    2014-01-01

    OBJECTIVE: Indoor tanning with UV radiation–emitting lamps is common among adolescents and young adults. Rising incidence rates of basal cell carcinoma (BCC) have been reported for the United States and elsewhere, particularly among those diagnosed at younger ages. Recent epidemiologic studies have raised concerns that indoor tanning may be contributing to early occurrence of BCC, and younger people may be especially vulnerable to cancer risk associated with this exposure. Therefore, we sought to address these issues in a population-based case–control study from New Hampshire. METHODS: Data on indoor tanning were obtained on 657 cases of BCC and 452 controls ≤50 years of age. RESULTS: Early-onset BCC was related to indoor tanning, with an adjusted odds ratio (OR) of 1.6 (95% confidence interval, 1.3–2.1). The strongest association was observed for first exposure as an adolescent or young adult, with a 10% increase in the OR with each age younger at first exposure (OR per year of age ≤23 = 1.1; 95% confidence interval, 1.0–1.2). Associations were present for each type of device examined (ie, sunlamps, tanning beds, and tanning booths). CONCLUSIONS: Our findings suggest early exposure to indoor tanning increases the risk of early development of BCC. They also underscore the importance of counseling adolescents and young adults about the risks of indoor tanning and for discouraging parents from consenting minors to this practice. PMID:24958589

  8. Periodontal Treatments and Procedures

    MedlinePLUS

    ... Augmentation Ridge Modification Periodontal Pocket Reduction Procedures Periodontal Plastic Surgery Procedures Love the Gums You're With ... Augmentation Ridge Modification Periodontal Pocket Reduction Procedures Periodontal Plastic Surgery Procedures Love the Gums You're With ...

  9. Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke.

    PubMed

    Xin, Baozhong; Jones, Stephen; Puffenberger, Erik G; Hinze, Claas; Bright, Alicia; Tan, Haiyan; Zhou, Aimin; Wu, Guiyun; Vargus-Adams, Jilda; Agamanolis, Dimitris; Wang, Heng

    2011-03-29

    We describe an autosomal recessive condition characterized with cerebral vasculopathy and early onset of stroke in 14 individuals in Old Order Amish. The phenotype of the condition was highly heterogeneous, ranging from severe developmental disability to normal schooling. Cerebral vasculopathy was a major hallmark of the condition with a common theme of multifocal stenoses and aneurysms in large arteries, accompanied by chronic ischemic changes, moyamoya morphology, and evidence of prior acute infarction and hemorrhage. Early signs of the disease included mild intrauterine growth restriction, infantile hypotonia, and irritability, followed by failure to thrive and short stature. Acrocyanosis, Raynaud's phenomenon, chilblain lesions, low-pitch hoarse voice, glaucoma, migraine headache, and arthritis were frequently observed. The early onset or recurrence of strokes secondary to cerebral vasculopathy seems to always be associated with poor outcomes. The elevated erythrocyte sedimentation rate (ESR), IgG, neopterin, and TNF-? found in these patients suggested an immune disorder. Through genomewide homozygosity mapping, we localized the disease gene to chromosome (Chr) 20q11.22-q12. Candidate gene sequencing identified a homozygous mutation, c.1411-2A > G, in the SAMHD1 gene, being associated with this condition. The mutation appeared at the splice-acceptor site of intron 12, resulted in the skipping of exon 13, and gave rise to an aberrant protein with in-frame deletion of 31 amino acids. Immunoblotting analysis showed lack of mutant SAMHD1 protein expression in affected cell lines. The function of SAMHD1 remains unclear, but the inflammatory vasculopathies of the brain found in the patients with SAMHD1 mutation indicate its important roles in immunoregulation and cerebral vascular hemeostasis. PMID:21402907

  10. DOCK2 and a Recessive Immunodeficiency with Early-Onset Invasive Infections

    PubMed Central

    Dobbs, Kerry; Domnguez Conde, Cecilia; Zhang, Shen-Ying; Parolini, Silvia; Audry, Magali; Chou, Janet; Haapaniemi, Emma; Keles, Sevgi; Bilic, Ivan; Okada, Satoshi; Massaad, Michel J.; Rounioja, Samuli; Alwahadneh, Adel M.; Serwas, Nina K.; Capuder, Kelly; Ciftci, Ergin; Felgentreff, Kerstin; Ohsumi, Toshiro K.; Pedergnana, Vincent; Boisson, Bertrand; Haskolo?lu, Sule; Ensari, Arzu; Schuster, Michael; Moretta, Alessandro; Itan, Yuval; Patrizi, Ornella; Rozenberg, Flore; Lebon, Pierre; Saarela, Janna; Knip, Mikael; Petrovski, Slav; Goldstein, David B.; Parrott, Roberta E.; Savas, Berna; Schambach, Axel; Tabellini, Giovanna; Bock, Christoph; Chatila, Talal; Comeau, Anne Marie; Geha, Raif S.; Abel, Laurent; Buckley, Rebecca H.; Ikincio?ullari, Aydan; Al-Herz, Waleed; Helminen, Merja; Do?u, Figen; Casanova, Jean-Laurent; Boztu?, Kaan; Notarangelo, Luigi D.

    2015-01-01

    Background Combined immunodeficiencies (CIDs) denote inborn errors of T-cell immunity with T cells present but quantitatively or functionally deficient. Impaired humoral immunity, either due to a primary B cell defect or secondary to the T-cell defect, is also frequent. Consequently, patients with CID display severe infections and/or autoimmunity. The specific molecular, cellular, and clinical features of many types of CID remain unknown. Methods We performed genetic and cellular immunological studies in five unrelated children who shared a history of early-onset invasive bacterial and viral infections, with lymphopenia and defective T-, B-, and NK-cell responses. Two patients died early in childhood, whereas the other three underwent allogeneic hematopoietic stem cell transplantation with normalization of T cell function and clinical improvement. Results We identified bi-allelic mutations in the Dedicator Of Cytokinesis 2 (DOCK2) gene in these five patients. RAC1 activation was impaired in T cells. Chemokine-induced migration and actin polymerization were defective in T, B, and NK cells. NK-cell degranulation was also affected. The production of interferon (IFN)-? and -? by peripheral blood mononuclear cells (PBMCs) was diminished following virus infection. Moreover, in DOCK2-deficient fibroblasts, virus replication was increased and there was enhanced virus-induced cell death, which could be normalized by treatment with IFN-?2? or upon expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a Mendelian disorder with pleiotropic defects of hematopoietic and non-hematopoietic immunity. Children with clinical features of CID, especially in the presence of early-onset, invasive infections may have this condition. PMID:26083206

  11. Early-Onset Stroke and Vasculopathy Associated with Mutations in ADA2

    PubMed Central

    Zhou, Q.; Yang, D.; Ombrello, A.K.; Zavialov, Andrey V.; Toro, C.; Zavialov, Anton V.; Stone, D.L.; Chae, J.J.; Rosenzweig, S.D.; Bishop, K.; Barron, K.S.; Kuehn, H.S.; Hoffmann, P.; Negro, A.; Tsai, W.L.; Cowen, E.W.; Pei, W.; Milner, J.D.; Silvin, C.; Heller, T.; Chin, D.T.; Patronas, N.J.; Barber, J.S.; Lee, C.-C.R.; Wood, G.M.; Ling, A.; Kelly, S.J.; Kleiner, D.E.; Mullikin, J.C.; Ganson, N.J.; Kong, H.H.; Hambleton, S.; Candotti, F.; Quezado, M.M.; Calvo, K.R.; Alao, H.; Barham, B.K.; Jones, A.; Meschia, J.F.; Worrall, B.B.; Kasner, S.E.; Rich, S.S.; Goldbach-Mansky, R.; Abinun, M.; Chalom, E.; Gotte, A.C.; Punaro, M.; Pascual, V.; Verbsky, J.W.; Torgerson, T.R.; Singer, N.G.; Gershon, T.R.; Ozen, S.; Karadag, O.; Fleisher, T.A.; Remmers, E.F.; Burgess, S.M.; Moir, S.L.; Gadina, M.; Sood, R.; Hershfield, M.S.; Boehm, M.; Kastner, D.L.; Aksentijevich, I.

    2014-01-01

    BACKGROUND We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood. METHODS We performed whole-exome sequencing in the initial three patients and their unaffected parents and candidate-gene sequencing in three patients with a similar phenotype, as well as two young siblings with polyarteritis nodosa and one patient with small-vessel vasculitis. Enzyme assays, immunoblotting, immunohistochemical testing, flow cytometry, and cytokine profiling were performed on samples from the patients. To study protein function, we used morpholino-mediated knockdowns in zebrafish and short hairpin RNA knockdowns in U937 cells cultured with human dermal endothelial cells. RESULTS All nine patients carried recessively inherited mutations in CECR1 (cat eye syndrome chromosome region, candidate 1), encoding adenosine deaminase 2 (ADA2), that were predicted to be deleterious; these mutations were rare or absent in healthy controls. Six patients were compound heterozygous for eight CECR1 mutations, whereas the three patients with polyarteritis nodosa or small-vessel vasculitis were homozygous for the p.Gly47Arg mutation. Patients had a marked reduction in the levels of ADA2 and ADA2-specific enzyme activity in the blood. Skin, liver, and brain biopsies revealed vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflammation. Knockdown of a zebrafish ADA2 homologue caused intracranial hemorrhages and neutropenia phenotypes that were prevented by coinjection with nonmutated (but not with mutated) human CECR1. Monocytes from patients induced damage in cocultured endothelial-cell layers. CONCLUSIONS Loss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis. (Funded by the National Institutes of Health Intramural Research Programs and others.) PMID:24552284

  12. Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections.

    PubMed

    Dobbs, Kerry; Domnguez Conde, Cecilia; Zhang, Shen-Ying; Parolini, Silvia; Audry, Magali; Chou, Janet; Haapaniemi, Emma; Keles, Sevgi; Bilic, Ivan; Okada, Satoshi; Massaad, Michel J; Rounioja, Samuli; Alwahadneh, Adel M; Serwas, Nina K; Capuder, Kelly; ifti, Ergin; Felgentreff, Kerstin; Ohsumi, Toshiro K; Pedergnana, Vincent; Boisson, Bertrand; Haskolo?lu, ?ule; Ensari, Arzu; Schuster, Michael; Moretta, Alessandro; Itan, Yuval; Patrizi, Ornella; Rozenberg, Flore; Lebon, Pierre; Saarela, Janna; Knip, Mikael; Petrovski, Slav; Goldstein, David B; Parrott, Roberta E; Savas, Berna; Schambach, Axel; Tabellini, Giovanna; Bock, Christoph; Chatila, Talal A; Comeau, Anne Marie; Geha, Raif S; Abel, Laurent; Buckley, Rebecca H; ?kincio?ullar?, Aydan; Al-Herz, Waleed; Helminen, Merja; Do?u, Figen; Casanova, Jean-Laurent; Boztu?, Kaan; Notarangelo, Luigi D

    2015-06-18

    Background Combined immunodeficiencies are marked by inborn errors of T-cell immunity in which the T cells that are present are quantitatively or functionally deficient. Impaired humoral immunity is also common. Patients have severe infections, autoimmunity, or both. The specific molecular, cellular, and clinical features of many types of combined immunodeficiencies remain unknown. Methods We performed genetic and cellular immunologic studies involving five unrelated children with early-onset invasive bacterial and viral infections, lymphopenia, and defective T-cell, B-cell, and natural killer (NK)-cell responses. Two patients died early in childhood; after allogeneic hematopoietic stem-cell transplantation, the other three had normalization of T-cell function and clinical improvement. Results We identified biallelic mutations in the dedicator of cytokinesis 2 gene (DOCK2) in these five patients. RAC1 activation was impaired in the T cells. Chemokine-induced migration and actin polymerization were defective in the T cells, B cells, and NK cells. NK-cell degranulation was also affected. Interferon-? and interferon-? production by peripheral-blood mononuclear cells was diminished after viral infection. Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and virus-induced cell death was enhanced; these conditions were normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a new mendelian disorder with pleiotropic defects of hematopoietic and nonhematopoietic immunity. Children with clinical features of combined immunodeficiencies, especially with early-onset, invasive infections, may have this condition. (Supported by the National Institutes of Health and others.). PMID:26083206

  13. Gray matter alterations in schizophrenia high-risk youth and early-onset schizophrenia: a review of structural MRI findings.

    PubMed

    Brent, Benjamin K; Thermenos, Heidi W; Keshavan, Matcheri S; Seidman, Larry J

    2013-10-01

    This article reviews the literature on structural magnetic resonance imaging findings in pediatric and young adult populations at clinical or genetic high-risk for schizophrenia and early-onset schizophrenia. The implications of this research are discussed for understanding the pathophysiology of schizophrenia and for early intervention strategies. The evidence linking brain structural changes in prepsychosis development and early-onset schizophrenia with disruptions of normal neurodevelopmental processes during childhood or adolescence is described. Future directions are outlined for research to address knowledge gaps regarding the neurobiological basis of brain structural abnormalities in schizophrenia and to improve the usefulness of these abnormalities for preventative interventions. PMID:24012081

  14. Lower Pre-Treatment T Cell Activation in Early- and Late-Onset Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

    PubMed Central

    Goovaerts, Odin; Jennes, Wim; Massinga-Loemb, Marguerite; Ondoa, Pascale; Ceulemans, Ann; Vereecken, Chris; Worodria, William; Mayanja-Kizza, Harriet; Colebunders, Robert; Kestens, Luc

    2015-01-01

    Background Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an inflammatory complication in HIV-TB co-infected patients receiving antiretroviral therapy (ART). The role of disturbed T cell reconstitution in TB-IRIS is not well understood. We investigated T cell activation and maturation profiles in patients who developed TB-IRIS at different intervals during ART. Methods Twenty-two HIV-TB patients who developed early-onset TB-IRIS and 10 who developed late-onset TB-IRIS were matched for age, sex and CD4 count to equal numbers of HIV-TB patients who did not develop TB-IRIS. Flow cytometry analysis was performed on fresh blood, drawn before and after ART initiation and during TB-IRIS events. T cell activation and maturation was measured on CD4+ and CD8+ T cells using CD45RO, CD38, HLA-DR, CCR7 and CD27 antibodies. Results CD8+ T cell activation before ART was decreased in both early-onset (77% vs. 82%, p = 0.014) and late-onset (71% vs. 83%, p = 0.012) TB-IRIS patients compared to non-IRIS controls. After ART initiation, the observed differences in T cell activation disappeared. During late-onset, but not early-onset TB-IRIS, we observed a skewing from memory to terminal effector CD4+ and CD8+ T cell populations (p?0.028). Conclusion Our data provide evidence of reduced CD8+ T cell activation before ART as a common predisposing factor of early- and late-onset TB-IRIS. The occurrence of TB-IRIS itself was not marked by an over-activated CD8+ T cell compartment. Late- but not early-onset TB-IRIS was characterized by a more terminally differentiated T cell phenotype. PMID:26208109

  15. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients

    PubMed Central

    Archer, H L; Evans, J; Edwards, S; Colley, J; Newbury?Ecob, R; O'Callaghan, F; Huyton, M; O'Regan, M; Tolmie, J; Sampson, J; Clarke, A; Osborne, J

    2006-01-01

    Objective To determine the frequency of mutations in CDKL5 in both male and female patients with infantile spasms or early onset epilepsy of unknown cause, and to consider whether the breadth of the reported phenotype would be extended by studying a different patient group. Methods Two groups of patients were investigated for CDKL5 mutations. Group 1 comprised 73 patients (57 female, 16 male) referred to Cardiff for CDKL5 analysis, of whom 49 (42 female, 7 male) had epileptic seizure onset in the first six months of life. Group 2 comprised 26 patients (11 female, 15 male) with infantile spasms previously recruited to a clinical trial, the UK Infantile Spasms Study. Where a likely pathogenic mutation was identified, further clinical data were reviewed. Results Seven likely pathogenic mutations were found among female patients from group 1 with epileptic seizure onset in the first six months of life, accounting for seven of the 42 in this group (17%). No mutations other than the already published mutation were found in female patients from group 2, or in any male patient from either study group. All patients with mutations had early signs of developmental delay and most had made little developmental progress. Further clinical information was available for six patients: autistic features and tactile hypersensitivity were common but only one had suggestive Rett?like features. All had a severe epileptic seizure disorder, all but one of whom had myoclonic jerks. The EEG showed focal or generalised changes and in those with infantile spasms, hypsarrhythmia. Slow frequencies were seen frequently with a frontal or fronto?temporal predominance and high amplitudes. Conclusions The spectrum of the epileptic seizure disorder, and associated EEG changes, in those with CDKL5 mutations is broader than previously reported. CDKL5 mutations are a significant cause of infantile spasms and early epileptic seizures in female patients, and of a later intractable seizure disorder, irrespective of whether they have suspected Rett syndrome. Analysis should be considered in these patients in the clinical setting. PMID:16611748

  16. Antiphosphorylcholine Antibody Levels Are Elevated in Humans with Periodontal Diseases

    PubMed Central

    Schenkein, Harvey A.; Gunsolley, John C.; Best, Al M.; Harrison, M. Travis; Hahn, Chin-Lo; Wu, Jiuhua; Tew, John G.

    1999-01-01

    Human immunoglobulin G2 (IgG2) serum concentrations and the IgG2 antibody response to Actinobacillus actinomycetemcomitans can be influenced by genes, by environmental factors such as smoking, and by periodontal disease status. Examination of the IgG2 response to phosphorylcholine (PC), a response thought to be mainly induced by the C polysaccharide of Streptococcus pneumoniae, suggested that periodontal disease status was also associated with this response. This prompted the hypothesis that PC is an important oral antigen associated with organisms in the periodontal flora and that anti-PC antibody is elevated as a consequence of periodontal disease. Subjects in various periodontal disease diagnostic categories in which attachment loss is exhibited were tested for anti-PC in serum. Those with adult periodontitis, localized juvenile periodontitis, generalized early-onset periodontitis, and gingival recession all had similar levels of anti-PC IgG2 serum antibody which were significantly greater than in the group of subjects with no attachment loss. Analysis of plaque samples from subgingival and supragingival sites in all diseases categories for reactivity with the anti-PC specific monoclonal antibody TEPC-15 revealed that a substantial proportion of the bacteria in dental plaque (30 to 40%) bear PC antigen; this antigen was not restricted to morphotypes resembling only cocci but was also present on rods and branched filamentous organisms. We found that S. mitis, S. oralis, and S. sanguis, as well as oral actinomycetes, including A. viscosus, A. odontolyticus, and A. israelii, incorporated substantial amounts of [3H]choline from culture media. Further analysis of antigens derived from these organisms by Western blot indicated that S. oralis, S. sanguis, A. viscosus, A. odontolyticus, and A. israelii contained TEPC-15-reactive antigens. The data show that many commonly occurring bacterial species found in dental plaque contain PC antigen and that immunization with plaque-derived PC antigens as a consequence of inflammation and periodontal attachment loss may influence systemic anti-PC antibody concentrations. PMID:10456935

  17. Apolipoprotein E genotype in sporadic early- and late-onset Alzheimer's disease.

    PubMed

    Masullo, C; Daniele, A; Seripa, D; Filippini, V; Gravina, C; Carbone, G; Gainotti, G; Fazio, V M

    1998-01-01

    The 84 isoform of apolipoprotein E (ApoE) has been proposed as a risk factor for Alzheimer's disease (AD), while the possible role of the epsilon2 allele in AD is controversial. We have studied the ApoE genotype in 38 patients with early-onset AD (EOAD) and in 43 patients with late-onset AD (LOAD). In the EOAD group we observed a significant increase of epsilon4 allele frequency as compared with normal controls, while there was a more than 3-fold decrease of epsilon2 allele frequency that did not reach statistical significance. In the LOAD group we found a highly significant increase of epsilon4 allele frequency as compared with normal controls, while there was a significant decrease of epsilon2 allele frequency. In both the EOAD and LOAD groups, no significant difference was observed between epsilon4 carriers and epsilon4 noncarriers as for age at disease onset, disease duration, and Mini-Mental State score at observation. However, in both EOAD and LOAD groups a statistical trend towards a longer disease duration was observed in epsilon4 carriers. In both the EOAD and LOAD groups, disease severity was compared in epsilon4 carriers versus epsilon4 noncarriers by means of analyses of covariance, with disease duration as covariate. No significant difference between epsilon4 carriers and epsilon4 noncarriers was observed in both EOAD and LOAD. The results of the present study confirm that epsilon4 allele seems to be associated with an increased risk for sporadic AD, while the significant decrease of epsilon2 allele frequency in the LOAD group supports the hypothesis of a possible protective role of epsilon2 allele in AD. PMID:9621997

  18. Early onset degenerative dementias: demographic characteristics and etiologic classification in a tertiary referral center.

    PubMed

    Maiovis, Pantelis; Ioannidis, Panagiotis; Konstantinopoulou, Elina; Karacostas, Dimitris

    2015-03-01

    Early onset dementia (EOD) is a major diagnostic challenge as it often presents with atypical features and may be attributed to treatable diseases. Primary degenerative dementias (Alzheimer's disease-AD, frontotemporal lobar degeneration-FTLD, Lewy body dementia-LBD), although traditionally considered to affect older people, are still a main cause of EOD. 491 demented patients were assessed from January 1, 2003 to December 31, 2010 in the Neurology Department of a tertiary referral center. Patients were classified as AD, behavioral variant frontotemporal dementia (bvFTD), non-fluent agrammatic variant primary progressive aphasia (naPPA), semantic variant PPA (svPPA), corticobasal degeneration (CBD), or progressive supranuclear palsy (PSP) who also met criteria for naPPA and LBD. Finally, their demographic characteristics were analysed, according to age at onset (EOD <65 years, late onset dementia-LOD ?65 years). From the 491 patients, 137 (27.9 %) were EOD. In the EOD group, 52 (38 %) were diagnosed with bvFTD, 34 (24.8 %) with AD, 27 (19.7 %) with naPPA, 10 (7.2 %) with svPPA, 12 (8.8 %) with CBD or PSP, and 2 (1.5 %) with LBD. Demographic characteristics did not differ significantly among diagnostic categories in the EOD group, while in the LOD group FTLD patients were younger and more frequently men compared to both AD and LBD patients. EOD patients had more years of education than LOD patients. Degenerative disorders as causes of EOD are not rare. High clinical alertness is warranted to achieve correct and timely diagnosis. PMID:24878660

  19. Onset of algal endosymbiont specificity varies among closely related species of Acropora corals during early ontogeny.

    PubMed

    Abrego, David; VAN Oppen, Madeleine J H; Willis, Bette L

    2009-08-01

    Juveniles of a number of corals with horizontal transmission of dinoflagellate endosymbionts naturally acquire and maintain Symbiodinium types that differ from those found in adult populations. However, the duration of this early period of symbiont flexibility and successional changes leading to dominance by the characteristic adult (homologous) type are unknown. To document natural succession of Symbiodinium types within juvenile corals, we monitored Symbiodinium communities in juveniles of Acropora tenuis and Acropora millepora for 3.5 years. Juveniles originating from one of three reef populations, characterized by differing adult coral-Symbiodinium associations, were raised in a common environment. In four out of five cases, juveniles became dominated initially by a nonhomologous adult type. Changes in Symbiodinium communities associated with A. tenuis juveniles led to the establishment of the adult homologous association at approximately 3.5 years of age. These changes were not linked to the onset of reproductive maturity, but may be linked to micro-environmental changes associated with vertical growth of juvenile corals. We hypothesize that fine-tuning of specificity mechanisms takes place during ontogeny in A. tenuis, leading to the eventual establishment of the adult homologous association. However, Symbiodinium communities in A. millepora juveniles did not change significantly over the 3.5 years, potentially reflecting (i) lack of specificity, (ii) more than a 3.5-year delay in the onset of specificity, or (iii) lack of availability of the adult Symbiodinium type. This study demonstrates that juvenile corals may survive for extended periods of time with nonhomologous Symbiodinium types and that closely related species of Acropora differ in the timing of the onset of specificity for algal symbionts. PMID:19627494

  20. A longitudinal assessment of changes in bacterial community composition associated with the development of periodontal disease in dogs.

    PubMed

    Wallis, Corrin; Marshall, Mark; Colyer, Alison; O'Flynn, Ciaran; Deusch, Oliver; Harris, Stephen

    2015-12-31

    Periodontal disease is the most widespread oral disease in dogs. Whilst the involvement of bacteria in the aetiology of periodontitis is well established the role of individual species and their complex interactions with the host is not well understood. The objective of this research was therefore to perform a longitudinal study in dogs to identify the changes that occur in subgingival bacterial communities during the transition from mild gingivitis to the early stages of periodontitis (<25% attachment loss). Subgingival plaque samples were collected from individual teeth of 52 miniature schnauzer dogs every six weeks for up to 60 weeks. The microbial composition of plaque samples was determined using 454-pyrosequencing of the 16S rDNA. A group of aerobic Gram negative species, including Bergeyella zoohelcum COT-186, Moraxella sp. COT-017, Pasteurellaceae sp. COT-080, and Neisseria shayeganii COT-090 decreased in proportion as teeth progressed to mild periodontitis. In contrast, there was less evidence that increases in the proportion of individual species were associated with the onset of periodontitis, although a number of species (particularly members of the Firmicutes) became more abundant as gingivitis severity increased. There were small increases in Shannon diversity, suggesting that plaque community membership remains relatively stable but that bacterial proportions change during progression into periodontitis. This is the first study to demonstrate the temporal dynamics of the canine oral microbiota; it showed that periodontitis results from a microbial succession predominantly characterised by a reduction of previously abundant, health associated taxa. PMID:26507828

  1. Early-onset progressive osteoarthritis with hereditary progressive ophtalmopathy or Stickler syndrome.

    PubMed

    Couchouron, Tifenn; Masson, Charles

    2011-01-01

    Stickler syndrome is a group of rare genetic conditions (incidence, 1/7500 births) related to mutations in the collagen genes. Both the mutations and the clinical features vary widely across affected patients. The main manifestations are craniofacial birth defects, bone and joint symptoms, ocular abnormalities, and hearing loss. Stickler syndrome may be revealed at birth (25% of cases) by a combination of cleft palate, retrognathism, and micrognathism known as Pierre Robin sequence, which may cause neonatal respiratory problems. The ocular abnormalities include severe myopia, abnormalities of the vitreous, and a high risk of retinal detachment (60% of cases), which may cause blindness (4% of cases). Severe hearing loss with onset in early childhood may impair performance at school. Osteoarthritis (75% of patients) with onset before 30 years of age is a severe manifestation that causes chronic hip and low back pain and functional impairments. Joint replacement surgery is often required. The risk associated with multiple anesthesias is highest in patients with craniofacial defects. The bone status may deserve to be evaluated, as the combination of genetic abnormalities and physical impairments may promote bone loss. Clinicians should be cognizant of Stickler syndrome so that they can detect the disease in patients and their family members, prevent functional impairments, organize a multidisciplinary management strategy, and arrange for genetic counseling. PMID:20462780

  2. Effect of PSEN1 mutations on MAPT methylation in early-onset Alzheimer's disease.

    PubMed

    Coupland, Kirsten G; Kim, Woojin S; Halliday, Glenda M; Hallupp, Marianne; Dobson-Stone, Carol; Kwok, John B J

    2015-01-01

    The MAPT gene is a risk locus for multiple neurodegenerative diseases, including idiopathic Parkinson's and Alzheimer's disease. We examined whether altered DNA methylation of the MAPT promoter, with its potential to modulate gene expression, was a common phenomenon in Alzheimer's disease patients with differing aetiologies. We measured MAPT promoter methylation in a brain tissue cohort of early-onset Alzheimer's disease (EOAD) with defined causative mutations in the PSEN1 gene (Normal = 10, PSEN1 AD = 10), and idiopathic late-onset Alzheimer's disease (Normal = 12, LOAD = 12). We found a brain-region-specific decrease in MAPT promoter methylation in PSEN1 AD patients. Overexpression of PSEN1 reduced MAPT promoter activity in an in vitro luciferase study, and led to an increase in methylation of the endogenous MAPT promoter. Overexpression of PSEN1 with a deletion of exon 9 mutation (?ex9) led to a smaller reduction in MAPT promoter activity relative to wild-type PSEN1 in the luciferase assay, consistent with a decreased ability to modulate endogenous MAPT gene methylation. Our study indicates a novel effect of PSEN1 on MAPT methylation, and suggests a mutation-specific effect of the PSEN1 ?ex9 mutation. PMID:26159201

  3. Longitudinal changes of cortical thickness in early- versus late-onset Alzheimer's disease.

    PubMed

    Cho, Hanna; Jeon, Seun; Kang, Sue J; Lee, Jong-Min; Lee, Jae-Hong; Kim, Geon Ha; Shin, Ji Soo; Kim, Chi Hun; Noh, Young; Im, Kiho; Kim, Sung Tae; Chin, Juhee; Seo, Sang Won; Na, Duk L

    2013-07-01

    Early-onset Alzheimer's disease (EOAD) has been shown to progress more rapidly than late-onset Alzheimer's disease (LOAD). However, no studies have compared the topography of brain volume reduction over time. The purpose of this 3-year longitudinal study was to compare EOAD and LOAD in terms of their rates of decline in cognitive testing and topography of cortical thinning. We prospectively recruited 36 patients with AD (14 EOAD and 22 LOAD) and 14 normal controls. All subjects were assessed with neuropsychological tests and with magnetic resonance imaging at baseline, Year 1, and Year 3. The EOAD group showed more rapid decline than the LOAD group in attention, language, and frontal-executive tests. The EOAD group also showed more rapid cortical thinning in widespread association cortices. In contrast, the LOAD group presented more rapid cortical thinning than the EOAD group only in the left parahippocampal gyrus. Our study suggests that patients with EOAD show more rapid cortical atrophy than patients with LOAD, which accounts for faster cognitive decline on neuropsychological tests. PMID:23391426

  4. Medial temporal atrophy in early and late-onset Alzheimer's disease.

    PubMed

    Cavedo, Enrica; Pievani, Michela; Boccardi, Marina; Galluzzi, Samantha; Bocchetta, Martina; Bonetti, Matteo; Thompson, Paul M; Frisoni, Giovanni B

    2014-09-01

    Late-onset and early-onset Alzheimer's disease (LOAD, EOAD) affect different neural systems and may be separate nosographic entities. The most striking differences are in the medial temporal lobe, severely affected in LOAD and relatively spared in EOAD. We assessed amygdalar morphology and volume in 18 LOAD and 18 EOAD patients and 36 aged-matched controls and explored their relationship with the hippocampal volume. Three-dimensional amygdalar shape was reconstructed with the radial atrophy mapping technique, hippocampal volume was measured using a manual method. Atrophy was greater in LOAD than EOAD: 25% versus 17% in the amygdala and 20% versus 13% in the hippocampus. In the amygdala, LOAD showed significantly greater tissue loss than EOAD in the right dorsal central, lateral, and basolateral nuclei (20%-30% loss, p < 0.03), all known to be connected to limbic regions. In LOAD but not EOAD, greater hippocampal atrophy was associated with amygdalar atrophy in the left dorsal central and medial nuclei (r = 0.6, p < 0.05) also part of the limbic system. These findings support the notion that limbic involvement is a prominent feature of LOAD but not EOAD. PMID:24721821

  5. Functional connectivity changes differ in early and late-onset Alzheimer's disease.

    PubMed

    Gour, Natalina; Felician, Olivier; Didic, Mira; Koric, Lejla; Gueriot, Claude; Chanoine, Valrie; Confort-Gouny, Sylviane; Guye, Maxime; Ceccaldi, Mathieu; Ranjeva, Jean Philippe

    2014-07-01

    At a similar stage, patients with early onset Alzheimer's disease (EOAD) have greater neocortical but less medial temporal lobe dysfunction and atrophy than the late-onset form of the disease (LOAD). Whether the organization of neural networks also differs has never been investigated. This study aims at characterizing basal functional connectivity (FC) patterns of EOAD and LOAD in two groups of 14 patients matched for disease duration and severity, relative to age-matched controls. All subjects underwent an extensive neuropsychological assessment. Magnetic resonance imaging was used to quantify atrophy and resting-state FC focusing on : the default mode network (DMN), found impaired in earlier studies on AD, and the anterior temporal network (ATN) and dorso-lateral prefrontal network (DLPFN), respectively involved in declarative memory and executive functions. Patterns of atrophy and cognitive impairment in EOAD and LOAD were in accordance with previous reports. FC within the DMN was similarly decreased in both EOAD and LOAD relative to controls. However, a double-dissociated pattern of FC changes in ATN and DLPFN was found. EOAD exhibited decreased FC in the DLPFN and increased FC in the ATN relative to controls, while the reverse pattern was found in LOAD. In addition, ATN and DLPFN connectivity correlated respectively with memory and executive performances, suggesting that increased FC is here likely to reflect compensatory mechanisms. Thus, large-scale neural network changes in EOAD and LOAD endorse both common features and differences, probably related to a distinct distribution of pathological changes. PMID:24123475

  6. Mechanisms of Late-Onset Cognitive Decline after Early-Life Stress

    PubMed Central

    Brunson, Kristen L.; Kramr, Enik; Lin, Bin; Chen, Yuncai; Colgin, Laura Lee; Yanagihara, Theodore K.; Lynch, Gary; Baram, Tallie Z.

    2011-01-01

    Progressive cognitive deficits that emerge with aging are a result of complex interactions of genetic and environmental factors. Whereas much has been learned about the genetic underpinnings of these disorders, the nature of acquired contributing factors, and the mechanisms by which they promote progressive learning and memory dysfunction, remain largely unknown. Here, we demonstrate that a period of early-life psychological stress causes late-onset, selective deterioration of both complex behavior and synaptic plasticity: two forms of memory involving the hippocampus, were severely but selectively impaired in middle-aged, but not young adult, rats exposed to fragmented maternal care during the early postnatal period. At the cellular level, disturbances to hippocampal long-term potentiation paralleled the behavioral changes and were accompanied by dendritic atrophy and mossy fiber expansion. These findings constitute the first evidence that a short period of stress early in life can lead to delayed, progressive impairments of synaptic and behavioral measures of hippocampal function, with potential implications to the basis of age-related cognitive disorders in humans. PMID:16221841

  7. General Similarities but Consistent Differences Between Early- and Late-Onset Depression Among Korean Adults Aged 40 and Older.

    PubMed

    Park, Jee Eun; Sohn, Ji Hoon; Seong, Su Jeong; Suk, Hye Won; Cho, Maeng Je

    2015-08-01

    Differences in clinical characteristics, symptomatology, and psychiatric comorbidity between early-onset depression (EOD) and late-onset depression (LOD) were examined in a nationwide representative sample. The Korean Composite International Diagnostic Interview was used to investigate psychiatric diagnoses and age of onset. A total of 319 subjects aged 40 years and older with a current major depressive disorder (MDD) were included, and both a continuous and a dichotomous (40 years) age-of-onset indicator were used in the analyses. Despite general similarities between groups, EOD was related to chronic (recurrent and longer episode) and severe (higher lifetime suicidality) clinical features. Hypersomnia and suicidal plans/attempts were associated with EOD, whereas anhedonia was related to LOD. Lifetime generalized anxiety disorder was associated with EOD, whereas dysthymic disorder was related with higher age of MDD onset. This study provides additional evidence of consistent differences between EOD and LOD among middle-aged and older Asians. PMID:26186068

  8. Early-life vitamin D deficiency and childhood-onset coeliac disease.

    PubMed

    Tanpowpong, Pornthep; Camargo, Carlos A

    2014-04-01

    Many studies have investigated the aetiological roles of genetic and environmental factors in coeliac disease (CD) with the long-term goal of developing an effective primary prevention strategy. CD is a condition with dysregulated systemic and intestinal mucosal immune responses to dietary gluten proteins among genetically predisposed individuals. We recently described spring birth as a novel risk factor for CD in children. We believe that the association between season of birth and CD is due to seasonal differences in sunlight exposure and subsequent vitamin D status. Concomitant with global increases in CD prevalence, vitamin D deficiency also is increasingly recognized in children worldwide. Recent studies have shown that vitamin D deficiency can cause improper immune responses, abnormal intestinal mucosal integrity and impaired local defence to pathogenic microbial agents. In conjunction with other potential aetiological factors, we propose a hypothesis model of early-life vitamin D deficiency in the pathogenesis of childhood-onset CD. PMID:24581000

  9. WNT1 Mutations in Early-onset Osteoporosis and Osteogenesis Imperfecta

    PubMed Central

    Laine, Christine M.; Joeng, Kyu Sang; Campeau, Philippe M.; Kiviranta, Riku; Tarkkonen, Kati; Grover, Monica; Lu, James T.; Pekkinen, Minna; Wessman, Maija; Heino, Terhi J.; Nieminen-Pihala, Vappu; Aronen, Mira; Laine, Tero; Krger, Heikki; Cole, William G.; Lehesjoki, Anna-Elina; Nevarez, Lisette; Krakow, Deborah; Curry, Cynthia J.R.; Cohn, Daniel H.; Gibbs, Richard A.; Lee, Brendan H.; Mkitie, Outi

    2013-01-01

    SUMMARY This report identifies human skeletal diseases associated with mutations in WNT1. In ten family members with dominantly inherited early-onset osteoporosis, a heterozygous missense variation c.652T>G (p.Cys218Gly) in WNT1 segregated with the disease, and a homozygous nonsense mutation (c.884C>A, p.Ser295*) was identified in two siblings with recessive osteogenesis imperfecta. In vitro, aberrant forms of WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. Wnt1 was clearly expressed in bone marrow, especially in B cell lineage and hematopoietic progenitors; lineage tracing identified expression in a subset of osteocytes, suggesting altered cross-talk of WNT signaling between hematopoietic and osteoblastic lineage cells in these diseases. PMID:23656646

  10. Child, Parent, and Peer Predictors of Early-Onset Substance Use: A Multisite Longitudinal Study

    PubMed Central

    Kaplow, Julie B.; Curran, Patrick J.; Dodge, Kenneth A.

    2009-01-01

    The purpose of this study was to identify kindergarten-age predictors of early-onset substance use from demographic, environmental, parenting, child psychological, behavioral, and social functioning domains. Data from a longitudinal study of 295 children were gathered using multiple-assessment methods and multiple informants in kindergarten and 1st grade. Annual assessments at ages 10, 11, and 12 reflected that 21% of children reported having initiated substance use by age 12. Results from longitudinal logistic regression models indicated that risk factors at kindergarten include being male, having a parent who abused substances, lower levels of parental verbal reasoning, higher levels of overactivity, more thought problems, and more social problem solving skills deficits. Children with no risk factors had less than a 10% chance of initiating substance use by age 12, whereas children with 2 or more risk factors had greater than a 50% chance of initiating substance use. Implications for typology, etiology, and prevention are discussed. PMID:12041707

  11. Periaxin mutation causes early-onset but slow-progressive Charcot-Marie-Tooth disease.

    PubMed

    Kijima, Kazuki; Numakura, Chikahiko; Shirahata, Emi; Sawaishi, Yukio; Shimohata, Mitsuteru; Igarashi, Shuichi; Tanaka, Tomohiro; Hayasaka, Kiyoshi

    2004-01-01

    Periaxin (PRX) plays a significant role in the myelination of the peripheral nerve. To date, seven non-sense or frameshift PRX mutations have been reported in six pedigrees with Dejerine-Sottas neuropathy or severe Charcot-Marie-Tooth neuropathy (CMT). We detected a PRX mutation in three patients in the screening of 66 Japanese demyelinating CMT patients who were negative for the gene mutation causing dominant or X-linked demyelinating CMT. Three unrelated patients were homozygous for a novel R1070X mutation and presented early-onset but slowly progressive distal motor and sensory neuropathies. Mutations lacking the carboxyl-terminal acidic domain may show loss-of-function effects and cause severe demyelinating CMT. PMID:15197604

  12. Assessment of early onset of driver fatigue using multimodal fatigue measures in a static simulator.

    PubMed

    Jagannath, M; Balasubramanian, Venkatesh

    2014-07-01

    Driver fatigue is an important contributor to road accidents. This paper reports a study that evaluated driver fatigue using multimodal fatigue measures, i.e., surface electromyography (sEMG), electroencephalography (EEG), seat interface pressure, blood pressure, heart rate and oxygen saturation level. Twenty male participants volunteered in this study by performing 60 min of driving on a static simulator. Results from sEMG showed significant physical fatigue (? < 0.05) in back and shoulder muscle groups. EEG showed significant (? < 0.05) increase of alpha and theta activities and a significant decrease of beta activity during monotonous driving. Results also showed significant change in bilateral pressure distribution on thigh and buttocks region during the study. These findings demonstrate the use of multimodal measures to assess early onset of fatigue. This will help us understand the influence of physical and mental fatigue on driver during monotonous driving. PMID:24581559

  13. Severe agitation in severe early-onset Alzheimer’s disease resolves with ECT

    PubMed Central

    Aksay, Suna Su; Hausner, Lucrezia; Frölich, Lutz; Sartorius, Alexander

    2014-01-01

    Dementia-related behavioral disturbances are mostly treated with antipsychotics; however, the observed beneficial effects are modest and the risk of serious adverse effects high. We report the case of a 57-year-old woman with severe early-onset Alzheimer’s disease and severe agitation, whom we treated with electroconvulsive therapy (ECT). A significant clinical improvement was achieved over eight ECT sessions, which were tolerated well without cognitive worsening, and lasted approximately 3 months. Our case demonstrates the safe and effective use of ECT in pharmacotherapy-resistant severe agitation in Alzheimer’s disease. The risk–benefit profile of ECT for dementia-related agitation should be further investigated in clinical trials. PMID:25419138

  14. Early Onset Dapsone-induced Photosensitive Dermatitis: A Rare Side Effect of a Common Drug.

    PubMed

    Karjigi, S; Murthy, S C; Kallappa, H; Kusuma, M R; Reddy, Y N K

    2015-01-01

    Dapsone, a potent anti-inflammatory compound, is mainly used in the treatment of leprosy, dermatitis herpetiformis, erythema elevatum diutinum and other dermatoses. Cutaneous adverse reactions range from acneiform eruptions to toxic epidermal necrolysis. A 30-year-old, married women who was treated with paucibacillary multi drug therapy, developed itchy skin lesions over the both forearms, 'V ' area of the neck and upper back after one week of the drug administration which worsened on exposure to sunlights. A clinical diagnosis of dapsone-induced photosensitive dermatitis was confirmed by histopathology and recurrence of symptoms and signs after re-exposure to the drug. Photosensitivity due to dapsone is rare and very few reports are available in the literature. Our patient had an unusually early onset compared to the previously reported cases. PMID:26999988

  15. A Comparative Descriptive Study of Characteristics of Early- and Late-Onset Dementia Family Caregivers.

    PubMed

    Ducharme, Francine; Lachance, Lise; Kergoat, Marie-Jeanne; Coulombe, Rene; Antoine, Pascal; Pasquier, Florence

    2016-02-01

    Characteristics of early- and late-onset dementia family caregivers were described and compared. Based on a theoretical model of role transition, data were collected through structured interviews from 48 caregivers of adults with Alzheimer's disease or a related dementia older than the age of 70 and 48 caregivers of similarly diagnosed adults younger than the age of 60. A significantly higher proportion of caregivers of younger adults were spouses and gainfully employed compared with those of older adults; they had more years of schooling, took care of a person with more severe impairments, received more help, perceived themselves as better prepared to deal with future needs, and better informed about services. They did not differ from caregivers of older adults in terms of psychological distress, role confidence, self-efficacy, and social support. This study highlights differences and similarities to be considered in the development of services tailored to the specific needs of each group. PMID:25814627

  16. Alternative salt bridge formation in A?a hallmark of early-onset Alzheimer's disease?

    PubMed Central

    Schledorn, Maarten; Meier, Beat H.; Bckmann, Anja

    2015-01-01

    Recently the 3D structure of the Osaka mutant form (E22?) of Amyloid-?1-40 has been determined. We here compare the NMR chemical-shift with the published shifts of a brain-seeded form of wild-type A? and suggest that the determined mutant fold is accessible to the wild-type protein as well, with small conformational adaptations which accommodate the E22 residue missing in the Osaka mutant. In addition, we illustrate how other mutants could also conform to this model. The stabilization of the N-terminal part of the protein via an intermolecular salt bridge to Lys28 may represent a common structural motif for the mutants which are related to early-onset Alzheimer disease. This feature might connect to the observed increased toxicity of the mutant forms compared to wild-type A?1-40, where the salt bridge involving Lys28 is intramolecular. PMID:25988181

  17. Time perspective and early-onset substance use: a model based on stress-coping theory.

    PubMed

    Wills, T A; Sandy, J M; Yaeger, A M

    2001-06-01

    This research tested the relation of time perspective to early-onset substance use (tobacco, alcohol, and marijuana) with a sample of 454 elementary school students with a mean age of 11.8 years. An adaptation of the Zimbardo Time Perspective Inventory (P. G. Zimbardo & J. N. Boyd, 1999) was administered with measures derived from stress-coping theory. Independent effects showed future orientation inversely related to substance use and present orientation positively related to substance use. Structural modeling analysis indicated that the relation of time perspective measures to substance use was indirect, mediated through behavioral coping and anger coping. Proximal factors for substance use were negative affect, peer substance use, and resistance efficacy. Results are discussed with respect to epigenetic models and the role of executive functions in self-control ability. PMID:11419227

  18. Group B streptococcus and early-onset sepsis in the era of maternal prophylaxis.

    PubMed

    Koenig, Joyce M; Keenan, William J

    2009-06-01

    Despite an era of marked success with universal screening, Group B Streptococcus (GBS) continues to be an important cause of early-onset sepsis, and thus remains a significant public health issue. Improved eradication of GBS colonization and disease may involve universal screening in conjunction with rapid diagnostic technologies or other novel approaches. Given the complications and potential limitations associated with maternal intrapartum prophylaxis, however, vaccines may be the most effective means of preventing neonatal GBS disease. The global utility of conjugated GBS vaccines may be hampered by the variability of serotypes in diverse populations and geographic locations. Modern technologies, such as those involving proteomics and genomic sequencing, are likely to hasten the development of a universal vaccine against GBS. PMID:19501699

  19. Early-onset hearing loss reorganizes the visual and auditory network in children without cochlear implantation.

    PubMed

    Shi, Bin; Yang, Li-Zhuang; Liu, Ying; Zhao, Shu-Li; Wang, Ying; Gu, Feng; Yang, Zhiyu; Zhou, Yifeng; Zhang, Peng; Zhang, Xiaochu

    2016-02-10

    The present study investigates the effect of early-onset hearing loss on the reorganization of visual and auditory networks in children without cochlear implants. Eleven congenitally deaf children and 12 age-matched hearing children were included in the study. Bilateral transverse temporal cortices and bilateral lateral occipital cortices were defined as auditory and visual seeds, respectively (as verified using an independent component analysis). The four seed-based connectivity maps were computed for each participant. As a result, group analysis showed that the primary auditory cortex was less connected with the motor cortex, whereas the visual cortex showed strengthened connectivity with motor and speech cortices in congenitally deaf children compared with the controls. Moreover, we found that the differences in functional connectivity between deaf and control children were not because of morphometric changes. Our results provide neural evidence for the sensorimotor coupling model of speech development. PMID:26730516

  20. Effect of growing rod on sagittal and spinopelvic parameters in early-onset scoliosis patients.

    PubMed

    Sariyilmaz, Kerim; Akgul, Turgut; Ozkunt, Okan; Dikici, Fatih; Korkmaz, Murat; Sar, Cuneyt; Domanic, Unsal

    2016-05-01

    Growing rod is a commonly used surgery for early-onset scoliosis (EOS). However, the effect of growing-rod lengthening on the spinopelvic alignment is unclear. In this study, 21 EOS patients treated by growing rod were evaluated retrospectively and thoracic kyphosis (TK), lumbar lordosis (LL), pelvic incidence (PI) , sacral slope (SS), pelvic tilt (PT), and sagittal vertical axis (SVA) were measured. Preoperatively, the mean TK, LL, PI, PT, SS, and SVA were 27.4°, 35.2°, 43.8°, 7.5°, 33.8°, and 47.7 mm respectively. After the last lengthening, TK, LL, PI, PT, SS, and SVA were 28.3°, 28.06°, 41.4°, 7°, 5.2°, and 42.6 mm, respectively. The sagittal plane parameters in our EOS patients were not significantly altered during the lengthening period. PMID:27007546

  1. Early onset of fetal hydrops associated with the ?-thalassemia -?-(THAI) deletion.

    PubMed

    Yang, Yu; Li, Dong-Zhi

    2014-01-01

    ?-Thalassemia (?-thal) is common in southern China. Homozygosity for the -?-(SEA) (Southeast Asian) ?-globin gene deletion is the most common cause of the Hb Bart's (?4) disease. Occasionally, other ?(0)-thal deletions can also be found. In this study, we report a case with an atypical form of Hb Bart's disease. The fetus was a compound heterozygote for the -?-(SEA) and -?-(THAI) deletions and presented different clinical features from that of traditional Hb Bart's disease with the -?-(SEA) deletion in the homozygous state. The early onset of fetal hydrops is attributed to the decreased formation of embryonic Hb Portland (?2?2), which is proposed as a candidate for reactivation in cases of severe ?-thal. Our finding may have potentially important implications for clinical decisions in a program using ultrasonography to identify signs of homozygous ?(0)-thal. PMID:25370866

  2. Addressing the link between paraoxonase-1 gene variants and the incidence of early onset myocardial infarction

    PubMed Central

    Hashad, Ingy M.; Abou-Aisha, Khaled; Abdel-Maksoud, Sahar M.; Gad, Mohamed Z.

    2015-01-01

    Introduction The enzyme paraoxonase-1 (PON1) represents an endogenous defense mechanism against vascular oxidative stress, thereby contributing to the prevention of atherosclerosis. Several polymorphisms have been reported in the PON1 gene, including Q192R. PON1 phenotype is commonly expressed as the paraoxonase/arylesterase ratio (PON/ARE). The major aim of this study was to investigate the association between PON1 Q192R polymorphism, PON1 phenotypes and the incidence of early-onset acute myocardial infarction (AMI) in Egyptians. Material and methods The study subjects consisted of 102 AMI patients and 72 age-matched healthy controls. Genotyping and enzyme activities were determined using PCR-RFLP and kinetic spectrophotometric assays, respectively. Results The genotype distribution for the PON1 gene was significantly different between AMI patients (QQ = 38.24%, QR = 49.02%, RR = 12.75%) and controls (QQ = 66.67%, QR = 25%, RR = 8.33%). Allele frequencies were also significantly different between patients (Q = 62.75%, R = 37.25%) and controls (Q = 79.17%, R = 20.83%). The genotypes QR and RR showed higher risk for AMI compared to the homozygous QQ (odds ratio (OR) = 3.231, p < 0.001). The average PON/ARE ratio in MI patients (1.187 0.1) did not differ significantly from controls (1.118 0.26). However, it showed a significant difference among different genotypes in both AMI patients (QQ = 0.91 0.11, QR = 1.09 0.11 and RR = 2.65 0.4) (p = 0.0002) and controls (QQ = 0.68 0.1, QR = 1.07 0.11 and RR = 4.89 2.84) (p < 0.0001). Conclusions PON1 192R allele represents an independent risk factor for early-onset AMI in Egyptians, and PON1 Q192R polymorphism modulates the paraoxonase phenotype. PMID:26170843

  3. A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease.

    PubMed

    Kun-Rodrigues, Celia; Ganos, Christos; Guerreiro, Rita; Schneider, Susanne A; Schulte, Claudia; Lesage, Suzanne; Darwent, Lee; Holmans, Peter; Singleton, Andrew; Bhatia, Kailash; Bras, Jose

    2015-12-01

    Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that de novo mutations may account for a proportion of these early-onset, sporadic cases. We performed exome sequencing in full parent-child trios where the proband presents with typical PD to unequivocally identify de novo mutations. This approach allows us to test all genes in the genome in an unbiased manner. We have identified and confirmed 20 coding de novo mutations in 21 trios. We have used publicly available population genetic data to compare variant frequencies and our independent in-house dataset of exome sequencing in PD (with over 1200 cases) to identify additional variants in the same genes. Of the genes identified to carry de novo mutations, PTEN, VAPB and ASNA1 are supported by various sources of data to be involved in PD. We show that these genes are reported to be within a protein-protein interaction network with PD genes and that they contain additional rare, case-specific, mutations in our independent cohort of PD cases. Our results support the involvement of these three genes in PD and suggest that testing for de novo mutations in sporadic disease may aid in the identification of novel disease-causing genes. PMID:26362251

  4. Hyperghrelinemia in Prader-Willi syndrome begins in early infancy long before the onset of hyperphagia.

    PubMed

    Kweh, Frederick A; Miller, Jennifer L; Sulsona, Carlos R; Wasserfall, Clive; Atkinson, Mark; Shuster, Jonathan J; Goldstone, Anthony P; Driscoll, Daniel J

    2015-01-01

    Circulating total ghrelin levels are elevated in older children and adults with Prader-Willi syndrome (PWS). However, the presence or absence of hyperghrelinemia in young children with PWS remains controversial. We hypothesized that a more robust way to analyze appetite-regulating hormones in PWS would be by nutritional phases rather than age alone. Our objectives were to compare total serum ghrelin levels in children with PWS by nutritional phase as well as to compare total ghrelin levels in PWS (5 weeks to 21 years of age) to normal weight controls and individuals with early-onset morbid obesity (EMO) without PWS. Fasting serum total ghrelin levels were measured in 60 subjects with PWS, 39 subjects with EMO of unknown etiology, and in 95 normal non-obese sibling controls of PWS or EMO subjects (SibC) in this 12 year longitudinal study. Within PWS, total ghrelin levels were significantly (P < 0.001) higher in earlier nutritional phases: phase 1a (7,906  ±  5,887); 1b (5,057 ± 2,624); 2a (2,905 ± 1,521); 2b (2,615 ± 1,370) and 3 (2,423 ± 1,350). Young infants with PWS also had significantly (P = 0.009) higher total ghrelin levels than did the sibling controls. Nutritional phase is an important independent prognostic factor of total ghrelin levels in individuals with PWS. Circulating ghrelin levels are elevated in young children with PWS long before the onset of hyperphagia, especially during the early phase of poor appetite and feeding. Therefore, it seems unlikely that high ghrelin levels are directly responsible for the switch to the hyperphagic nutritional phases in PWS. PMID:25355237

  5. Genetic mutations in early-onset Parkinson's disease Mexican patients: molecular testing implications.

    PubMed

    Monroy-Jaramillo, Nancy; Guerrero-Camacho, Jorge Luis; Rodrguez-Violante, Mayela; Boll-Woehrlen, Marie-Catherine; Yescas-Gmez, Petra; Alonso-Vilatela, Mara Elisa; Lpez-Lpez, Marisol

    2014-04-01

    Mutations in PARK2, PINK1, and DJ-1 have been associated with autosomal recessive early-onset Parkinson's disease. Here, we report the prevalence of sequence and structural mutations in these three main recessive genes in Mexican Mestizo patients. The complete sequences of these three genes were analyzed by homo/heteroduplex DNA formation and direct sequencing; exon dosage was determined by multiplex ligation-dependent probe amplification and real-time PCR in 127 patients belonging to 122 families and 120 healthy Mexican Mestizo controls. All individuals had been previously screened for the three most common LRRK2 mutations. The presence of two mutations in compound heterozygous or homozygous genotypes was found in 16 unrelated patients, 10 had mutations in PARK2, six in PINK1, and none in DJ-1. Two PARK2-PINK1 and one PARK2-LRRK2 digenic cases were observed. Novel mutations were identified in PARK2 and PINK1 genes, including PINK1 duplication for the first time. Exon dosage deletions were the most frequent mutations in PARK2 (mainly in exons 9 and 12), followed by those in PINK1. The high prevalence of heterozygous mutations in PARK2 (12.3%) and the novel heterozygous and homozygous point mutations in PINK1 observed in familial and sporadic cases from various states of Mexico support the concept that single heterozygous mutations in recessive Parkinson's disease genes play a pathogenic role. These data have important implications for genetic counseling of Mexican Mestizo patients with early-onset Parkinson's disease. The presence of digenic inheritance underscores the importance of studying several genes in this disease. A step-ordered strategy for molecular diagnosis is proposed. PMID:24677602

  6. Managing the Risk for Early Onset Osteoporosis in Long-Duration Astronauts Due to Spaceflight

    NASA Technical Reports Server (NTRS)

    Sibonga, Jean D.

    2010-01-01

    Early Onset Osteoporosis is probably the most recognized but poorly understood long-term health risk due to spaceflight. Osteoporosis management is primarily prophylactic and clinical interventions rely upon the ability to predict fractures which is currently determined by surrogate measures of bone strength. The RMAT for Early Onset Osteoporosis identified some open issues related to the fact that long-duration astronauts compose a unique group of subjects for which clinical approaches for osteoporosis management do not apply. Long-duration astronauts are healthy, young (25 to 55 years of age), predominantly male, and physical fit relative to the typical osteoporosis patient. Moreover, during prolonged space missions (typically 6-month missions) the skeleton not only adapts to weightlessness, but is influenced by numerous risk factors induced by operational constraints, e.g., inability to maintain preflight weight-bearing and aerobic activities, sub-optimal dietary intake (e.g., high sodium content for food stability, lack of fresh fruit and vegetables), suppression of vitamin D metabolism by uv shielding, and remote medicine care. Moreover, adaptation results in novel changes to astronauts bones that cannot be detected by current medically-useful measures. Consequently, a panel of clinicians (recognized leaders and policy-makers in osteoporosis) was convened to review the dataset of bone measures and bone loss risk factors in long-duration astronauts. Driven by the queries in the RMAT, the panel was charged to determine 1) if an intervention is required to prevent this risk, 2) what type and at what time would intervention be optimal, 3) what is the clinical trigger that would require a medical response from flight surgeons and 4) how should research data be used in the clinical care of astronauts. Hence, the RMAT determined that a bone health policy need to be formulated specific for this unique cohort subjected to a novel skeletal condition

  7. Body energy reserves influence the onset of luteal activity after early weaning of beef cows.

    PubMed

    Bishop, D K; Wettemann, R P; Spicer, L J

    1994-10-01

    The influence of body energy reserves on the onset of luteal activity and concentrations of LH and IGF-I in serum was evaluated in postpartum anestrous beef cows after early weaning. Multiparous Hereford and Hereford x Angus cows (n = 24) were fed during gestation to establish body condition scores between 3 and 6 (BCS, 1 = emaciated; 9 = obese) at parturition. Concentrations of progesterone in plasma were determined weekly for 5 wk postpartum (PP). Anovulatory cows and their calves (n = 19) were confined in stalls on d 40 +/- 3 PP. Jugular cannulas were inserted on d 44 +/- 3 PP, and calves were weaned (d 0) the following day. Blood samples were collected from all cows for 4 h (every 10 min) before weaning and on d 1, 2, 4, 6, 8, and 10 after weaning and LH was quantified. Progesterone was quantified in daily blood samples until d 10, and in samples taken twice weekly until d 46. Within 25 d after weaning, 100% of the cows with BCS < or = 5 at weaning (n = 7) had initiated luteal activity, whereas only 43% (P < .01) of the cows with BCS < 5 (n = 12) had luteal activity. Mean serum IGF-I concentrations were correlated with BCS (r = .50; P < .05). Frequency of LH pulses was influenced (P < .01) by body condition at weaning but was not influenced by day after weaning. The number of LH pulses at weaning, serum IGF-I, and the interval to the onset of ovarian activity after early weaning of anestrous beef cows were influenced by BCS. PMID:7883630

  8. Hyperghrelinemia in Prader-Willi Syndrome Begins in Early Infancy Long Before the Onset of Hyperphagia

    PubMed Central

    Kweh, Frederick A.; Miller, Jennifer L.; Sulsona, Carlos R; Wasserfall, Clive; Atkinson, Mark; Shuster, Jonathan J.; Goldstone, Anthony P.; Driscoll, Daniel J.

    2015-01-01

    Circulating total ghrelin levels are elevated in older children and adults with Prader-Willi syndrome (PWS). However, the presence or absence of hyperghrelinemia in young children with PWS remains controversial. We hypothesized that a more robust way to analyze appetite-regulating hormones in PWS would be by nutritional phases rather than age alone. Our objectives were to compare total serum ghrelin levels in children with PWS by nutritional phase as well as to compare total ghrelin levels in PWS (5 weeks to 21 years of age) to normal weight controls and individuals with early-onset morbid obesity (EMO) without PWS. Fasting serum total ghrelin levels were measured in 60 subjects with PWS, 39 subjects with EMO of unknown etiology, and in 95 normal non-obese sibling controls of PWS or EMO subjects (SibC) in this 12 year longitudinal study. Within PWS, total ghrelin levels were significantly (P<0.001) higher in earlier nutritional phases: phase 1a (7,906 ± 5,887); 1b (5,057 ± 2,624); 2a (2,905 ± 1,521); 2b (2,615 ± 1,370) and 3 (2,423 ± 1,350). Young infants with PWS also had significantly (P=0.009) higher total ghrelin levels than did the sibling controls. Nutritional phase is an important independent prognostic factor of total ghrelin levels in individuals with PWS. Circulating ghrelin levels are elevated in young children with PWS long before the onset of hyperphagia, especially during the early phase of poor appetite and feeding. Therefore, it seems unlikely that high ghrelin levels are directly responsible for the switch to the hyperphagic nutritional phases in PWS. PMID:25355237

  9. Prolonged QT interval at onset of acute myocardial infarction in predicting early phase ventricular tachycardia

    SciTech Connect

    Taylor, G.J.; Crampton, R.S.; Gibson, R.S.; Stebbins, P.T.; Waldman, M.T.; Beller, G.A.

    1981-07-01

    The prospectively assessed time course of changes in ventricular repolarization during acute myocardial infarction (AMI) is reported in 32 patients admitted 2.0 +/- 1.8 (SD) hours after AMI onset. The initial corrected QT interval (QTc) upon hospitalization was longer in the 14 patients developing ventricular tachycardia (VT) within the first 48 hours as compared to QTc in the eight patients with frequent ventricular premature beats (VPBs) and to QTc in the 10 patients with infrequent VPBs. By the fifth day after AMI onset, the QTc shortened significantly only in the VT group, suggesting a greater initial abnormality of repolarization in these patients. All 32 patients had coronary angiography, radionuclide ventriculography, and myocardial perfusion scintigraphy before hospital discharge. Significant discriminating factors related to early phase VT in AMI included initially longer QT and QTc intervals, faster heart rate, higher peak serum levels of creatine kinase, acute anterior infarction, angiographically documented proximal stenosis of the left anterior descending coronary artery, and scintigraphic evidence of hypoperfusion of the interventricular septum. Prior infarction, angina pectoris, hypertension, multivessel coronary artery disease, and depressed left ventricular ejection fraction did not provide discrimination among the three different ventricular arrhythmia AMI groups. Researchers conclude that (1) the QT interval is frequently prolonged early in AMI, (2) the initial transiently prolonged ventricular repolarization facilitates and predicts complex ventricular tachyarrhythmias within the first 48 hours of AMI, (3) jeopardized blood supply to the interventricular septum frequently coexists, and (4) therapeutic enhancement of rapid recovery of the ventricular repolarization process merits investigation for prevention of VT in AMI.

  10. A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease

    PubMed Central

    Kun-Rodrigues, Celia; Ganos, Christos; Guerreiro, Rita; Schneider, Susanne A.; Schulte, Claudia; Lesage, Suzanne; Darwent, Lee; Holmans, Peter; Singleton, Andrew; Bhatia, Kailash; Bras, Jose

    2015-01-01

    Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that de novo mutations may account for a proportion of these early-onset, sporadic cases. We performed exome sequencing in full parent–child trios where the proband presents with typical PD to unequivocally identify de novo mutations. This approach allows us to test all genes in the genome in an unbiased manner. We have identified and confirmed 20 coding de novo mutations in 21 trios. We have used publicly available population genetic data to compare variant frequencies and our independent in-house dataset of exome sequencing in PD (with over 1200 cases) to identify additional variants in the same genes. Of the genes identified to carry de novo mutations, PTEN, VAPB and ASNA1 are supported by various sources of data to be involved in PD. We show that these genes are reported to be within a protein–protein interaction network with PD genes and that they contain additional rare, case-specific, mutations in our independent cohort of PD cases. Our results support the involvement of these three genes in PD and suggest that testing for de novo mutations in sporadic disease may aid in the identification of novel disease-causing genes. PMID:26362251

  11. Comparative Effectiveness of Second-Generation Antipsychotic Medications in Early-Onset Schizophrenia

    PubMed Central

    Olfson, Mark; Gerhard, Tobias; Huang, Cecilia; Lieberman, Jeffrey A.; Bobo, William V.; Crystal, Stephen

    2012-01-01

    Scant information exists to guide pharmacological treatment of early-onset schizophrenia. We examine variation across commonly prescribed second-generation antipsychotic medications in medication discontinuation and psychiatric hospital admission among children and adolescents clinically diagnosed with schizophrenia. A 45-state Medicaid claims file (20012005) was analyzed focusing on outpatients, aged 617 years, diagnosed with schizophrenia or a related disorder prior to starting a new episode of antipsychotic monotherapy with risperidone (n = 805), olanzapine (n = 382), quetiapine (n = 260), aripiprazole (n = 173), or ziprasidone (n = 125). Cox proportional hazard regressions estimated adjusted hazard ratios of 180-day antipsychotic medication discontinuation and 180-day psychiatric hospitalization for patients treated with each medication. During the first 180 days following antipsychotic initiation, most youth treated with quetiapine (70.7%), ziprasidone (73.3%), olanzapine (73.7%), risperidone (74.7%), and aripirazole (76.5%) discontinued their medication (?2 = 1.69, df = 4, P = .79). Compared with risperidone, the adjusted hazards of antipsychotic discontinuation did not significantly differ for any of the 4-comparator medications. The percentages of youth receiving inpatient psychiatric treatment while receiving their initial antipsychotic medication ranged from 7.19% (aripiprazole) to 9.89% (quetiapine) (?2 = 0.79, df = 4, P = .94). As compared with risperidone, the adjusted hazard ratio of psychiatric hospital admission was 0.96 (95% CI: 0.571.61) for olanzapine, 1.03 (95% CI: 0.591.81) for quetiapine, 0.85 (95% CI: 0.431.70) for aripiprazole, and 1.22 (95% CI: 0.602.51) for ziprasidone. The results suggest that rapid antipsychotic medication discontinuation and psychiatric hospital admission are common in the community treatment of early-onset schizophrenia. No significant differences were detected in risk of either adverse outcome across 5 commonly prescribed second-generation antipsychotic medications. PMID:21307041

  12. Neurocognitive Outcomes in the Treatment of Early-Onset Schizophrenia Spectrum Disorders Study

    PubMed Central

    Frazier, Jean A.; Giuliano, Anthony J.; Johnson, Jacqueline L.; Yakutis, Lauren; Youngstrom, Eric A.; Breiger, David; Sikich, Linmarie; Findling, Robert L.; McClellan, Jon; Hamer, Robert M.; Vitiello, Benedetto; Lieberman, Jeffrey A.; Hooper, Stephen R.

    2012-01-01

    Objective To assess neurocognitive outcomes following antipsychotic intervention in youth enrolled in the National Institute of Mental Health (NIMH)-funded Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS). Method Neurocognitive functioning of youth (ages 819 years) with schizophrenia or schizoaffective disorder was evaluated in a four-site randomized, double-blind clinical trial comparing molindone, olanzapine or risperidone. The primary outcomes were overall group change from baseline in neurocognitive composite and six domain scores after 8 weeks and continued treatment up to 52 weeks. Age and sex were included as covariates in all analyses. Results Seventy-seven of 116 TEOSS participants (66%) had post-baseline neurocognitive data. No significant differences emerged in the neurocognitive outcomes of the three medication groups. Therefore, the three treatment groups were combined into one group to assess overall neurocognitive outcomes. Significant modest improvements were observed in the composite score and in three of six domain scores in the acute phase, and in four of six domain scores in the combined acute and maintenance phases. Partial correlation analyses revealed very few relationships among Positive and Negative Syndrome Scale (PANSS) baseline or change scores and neurocognition change scores. Conclusions Antipsychotic intervention in youth with early-onset schizophrenia spectrum disorders (EOSS) led to modest improvement in measures of neurocognitive function. The changes in cognition were largely unrelated to baseline symptoms or symptom change. Small treatment effect sizes, easily accounted for by practice effects, highlight the critical need for the development of more efficacious interventions for the enduring neurocognitive deficits seen in EOSS. PMID:22525956

  13. Prediction of individuals prone to suffer from early onset of hypertension.

    PubMed

    Sherpa, M T; Shrestha, R; Pramanik, T

    2012-06-01

    The present study was undertaken to predict the persons prone to suffer from early onset of hypertension. Healthy sedentary volunteers (age 18-25 years) having normal blood pressure were asked about their history of familial hypertension, smoking-habit, alcohol consumption, existing worries/anxieties; these being the predisposing factors of hypertension. The blood pressure of them was recorded (casual baseline blood pressure). Maximum voluntary contraction (MVC) was noted as maximum pressure (in Kg) sustained during 3 sec of handgrip using a handgrip dynamometer. Thereafter, the participant was asked to sustain isometric handgrip at one third of MVC for one minute with the same instrument (isometric handgrip-test). Then, blood pressure was measured and the subject was allowed to rest. Three minutes after the handgrip test, the blood pressure was noted again (recovery blood pressure). Handgrip-test produced a rise in systolic blood pressure in all male volunteers. Amongst them, with predisposing factors of hypertension, diastolic blood pressure remained significantly higher than casual baseline diastolic blood pressure even after 3 minutes of withdrawal of stressor. Whereas, in males with no predisposing factors of hypertension, the diastolic blood pressure approached almost the baseline casual blood pressure. In all female participants, no significant difference was noted between the casual baseline blood pressure and blood pressure after recovery. Results indicated that the young men who presented prolonged elevated diastolic blood pressure, in response to handgrip test would be at high risk of early onset of hypertension, as sympathetic over-activity prevails in them for longer time. PMID:23671955

  14. Early onset APOE E4-negative Alzheimer's disease patients show faster cognitive decline on non-memory domains.

    PubMed

    Smits, Lieke L; Pijnenburg, Yolande A L; van der Vlies, Annelies E; Koedam, Esther L G E; Bouwman, Femke H; Reuling, Ilona E W; Scheltens, Philip; van der Flier, Wiesje M

    2015-07-01

    Age at onset and APOE E4-genotype have been shown to influence clinical manifestation of Alzheimer's disease (AD). We investigated rate of decline in specific cognitive domains according to age at onset and APOE E4-genotype in patients with AD. 199 patients with probable AD underwent at least two annual neuropsychological assessments. Patients were classified according to age-at-onset (≤ 65 years vs >65 years) and APOE genotype (positive vs negative). The neuropsychological test battery compromised tests for memory, language, attention, executive and visuo-spatial functioning. For each domain compound z-scores were calculated, based on the baseline performance of patients. Average duration of follow-up was 1.5 ± 1 years. We used linear mixed models (LMM) to estimate effects of age, APOE and age⁎APOE on cognitive decline over time. At baseline, patients were 65 ± 8 years, 98(49%) were female and MMSE was 22 ± 4. LMM showed that early onset patients declined faster on executive functioning (β ± SE:-0.09 ± 0.06) than late onset patients, but age was not related to decline in the other cognitive domains. APOE E4 negative patients declined faster on language than APOE E4 positive patients (β ± SE:-0.1 ± 0.06). When we took age and APOE genotype into account simultaneously, we found that compared to late onset-E4 positive patients, early onset-E4 negative patients declined faster on language (β ± SE:-0.36 ± 0.1), attention (β ± SE:-0.42 ± 0.1), executive (β ± SE:-0.41 ± 0.1) and visuo-spatial functioning (β ± SE:-0.43 ± 0.1). Late onset-E4 negative and early onset-E4 positive patients showed intermediate rates of decline. We found no differences in decline on memory. We found that patients who develop AD despite absence of the two most important risk factors, show steepest cognitive decline on non-memory cognitive domains. PMID:25891378

  15. Early-Onset Severe Encephalopathy with Epilepsy: The BRAT1 Gene Should Be Added to the List of Causes.

    PubMed

    van de Pol, Laura A; Wolf, Nicole I; van Weissenbruch, Mirjam M; Stam, Cornelie J; Weiss, Janneke M; Waisfisz, Quinten; Kevelam, Sietske H; Bugiani, Mariana; van de Kamp, Jiddeke M; van der Knaap, Marjo S

    2015-12-01

    A variety of pathologies can underlie early-onset severe encephalopathy with epilepsy. To aid the diagnostic process in such patients we present an overview of causes, including the rapidly expanding list of genes involved. When no explanation is found, whole-exome sequencing (WES) can be used in an attempt to identify gene defects in patients suspected to suffer from a genetic form. We describe three siblings, born to consanguineous parents, with a lethal severe epileptic encephalopathy with early-infantile onset, including their magnetic resonance imaging, electroencephalography and, in one case, neuropathological findings. Using WES a homozygous frameshift mutation in the BRAT1 gene, c.638dup p.(Val214Glyfs*189), was identified. We present our cases in the context of all published cases with mutations in the BRAT1 gene and conclude that BRAT1 should be added to the growing list of genes related to early-onset severe encephalopathy with epilepsy. PMID:26535877

  16. Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient.

    PubMed

    Abidi, Affef; Mignon-Ravix, Cécile; Cacciagli, Pierre; Girard, Nadine; Milh, Mathieu; Villard, Laurent

    2016-04-01

    Variants in the WD repeat 45 (WDR45) gene in human Xp11.23 have recently been identified in patients suffering from neurodegeneration with brain iron accumulation, a genetically and phenotypically heterogeneous condition. WDR45 variants cause a childhood-onset encephalopathy accompanied by neurodegeneration in adulthood and iron accumulation in the basal ganglia. They have been almost exclusively found in females, and male lethality was suggested. Here we describe a male patient suffering from a severe and early neurological phenotype, initially presenting early-onset epileptic spasms in clusters associated with an abnormal interictal electroencephalography showing slow background activity, large amplitude asynchronous spikes and abnormal neurological development. This patient is a carrier of a 19.9-kb microdeletion in Xp11.23 containing three genes, including WDR45. These findings reveal that males with WDR45 deletions are viable, and can present with early-onset epileptic encephalopathy without brain iron accumulation. PMID:26173968

  17. Increased risk of cancer in patients with early-onset cataracts: A nationwide population-based study

    PubMed Central

    Chiang, Chun Chi; Lin, Cheng-Li; Peng, Chiao-Ling; Sung, Fung-Chang; Tsai, Yi-Yu

    2014-01-01

    Early-onset cataracts are associated with insufficient antioxidative activity, and, therefore, a potential risk of cancer. This study investigated the risk of cancer after being diagnosed with early-onset cataracts. Retrospective claims data from the Taiwan National Health Insurance Research Database were analyzed. Study subjects were comprised of patients with early-onset cataracts, aged 20–55 years (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] code 366.00, 366.01, 366.02, 366.03, 366.04, 366.09, 366.17 and 366.18) and newly diagnosed between 1997 and 2010 (n = 1281), and a comparison cohort without the disease (n = 5124). Both cohorts were followed up until 2010 to estimate the incidences of cancer. We used the Poisson regression model to compare incidence rate ratios and the 95% confidence interval (CI). Cox proportional hazards regression was used to assess the hazard ratio (HR) of cancer associated with early-onset cataracts. The overall incidence rate of all cancers was 2.19-fold higher in the early-onset cataract cohort than in the comparison cohort (8.06 vs 3.68 per 1000 person-years) with an adjusted HR of 2.13 (95% CI = 1.48, 3.07). The site-specific analysis also showed a strong relationship, with adjusted HR of 3.24 ((95% CI = 1.30, 8.10) for head and neck cancer, 3.29 (95% CI 1.16, 9.31) for hepatoma and 3.19 (95% CI 1.34, 7.58) for breast cancer. The present study suggests that patients with early-onset cataracts are at an increased risk of being diagnosed with cancer in subsequent years. PMID:24450445

  18. The Onset of Early Season Rainfall and its Mid-Summer Cessation in the Caribbean.

    NASA Astrophysics Data System (ADS)

    Allen, T. L.; Mapes, B. E.

    2014-12-01

    The annual rainfall cycle for the Caribbean basin reveals a distinct bimodal pattern with peaks during the late spring and late summer months. A relative minimum during the mid-summer, known as the mid-summer drought (MSD) separates the early rainfall season (ERS) from the late rainfall season. Accumulated rainfall totals during the ERS appear as a quasi-stationary rain-belt stretching across the Caribbean from the southwest to the northeast. We place late spring rains in the Caribbean in context of other subtropical convergence zones in order to address the onset and cessation of the ERS while also offering an explanation of a Caribbean rain-belt pattern. Upper tropospheric westerlies, mid-tropospheric positive temperature advection, and moist low level poleward flow are the three primary ingredients that conspire to produce the first peak of the annual bimodal rain signal and the related Caribbean early season rain-belt. The MSD ensues as the primary ingredients weaken across the Caribbean and enhanced rainfall shifts north along the North Atlantic Convergence Zone (NACZ). Seasonal rainfall totals from the ERS through the MSD periods reveal a continuous rain-belt that extends from the Caribbean to the NACZ termed the Caribbean Atlantic Rain-belt (CAR-belt). The Car-belt is present in the long term mean, but has signs of interannual variability.

  19. Early-Onset Aicardi-Goutires Syndrome: Magnetic Resonance Imaging (MRI) Pattern Recognition.

    PubMed

    Vanderver, Adeline; Prust, Morgan; Kadom, Nadja; Demarest, Scott; Crow, Yanick J; Helman, Guy; Orcesi, Simona; La Piana, Roberta; Uggetti, Carla; Wang, Jichuan; Gordisch-Dressman, Heather; van der Knaap, Marjo S; Livingston, John H

    2015-09-01

    Aicardi-Goutires syndrome is an inherited leukodystrophy with calcifying microangiopathy and abnormal central nervous system myelination. As fewer diagnostic computed tomographic (CT) scans are being performed due to increased availability of magnetic resonance imaging (MRI), there is a potential for missed diagnoses on the basis of calcifications. We review a series of patients with MRIs selected from IRB-approved leukodystrophy biorepositories to identify MRI patterns for recognition of early-onset Aicardi-Goutires syndrome and scored for a panel of radiologic predictors. Each individual predictor was tested against disease status using exact logistic regression. Features for pattern recognition of Aicardi-Goutires syndrome are temporal lobe swelling followed by atrophy with temporal horn dilatation, early global cerebral atrophy and visible calcifications, as evidenced by 94.44% of cases of Aicardi-Goutires syndrome correctly classified with a sensitivity of 90.9% and specificity of 96.9%. We identify a panel of MRI features predictive of Aicardi-Goutires syndrome in young patients that would differentiate it from other leukoencephalopathies. PMID:25535058

  20. New-Onset Diabetes After Transplantation: Results From a Double-Blind Early Corticosteroid Withdrawal Trial.

    PubMed

    Pirsch, J D; Henning, A K; First, M R; Fitzsimmons, W; Gaber, A O; Reisfield, R; Shihab, F; Woodle, E S

    2015-07-01

    New-onset diabetes after transplantation (NODAT) is an important complication following kidney transplantation. Data from the 5-year early steroid withdrawal double-blind randomized trial were analyzed to determine if steroid avoidance reduced the NODAT risk. Incidence, timing and risk factors for NODAT were evaluated using eight definitions. By American Diabetes Association definition, 36.3% of patients on chronic corticosteroids (CCS) and 35.9% on early corticosteroid withdrawal (CSWD) were diagnosed with NODAT by 5 years. The definition combining fasting blood glucose ?126 mg/dL on two occasions or treatment identified slightly more cases of NODAT: CCS (39.3%) and CSWD (39.4%). Through 5 years posttransplant, the proportion of NODAT patients requiring treatment were similar (CSWD 22.5% vs. CCS 21.5%); however, insulin therapy was lower with CSWD (3.7% vs. 11.6%; p = 0.049). By multivariate analysis, only age, but not corticosteroid use, was a significant risk factor for NODAT for more than one definition. Numerical, but not statistically significant trends toward lower NODAT rates with CSWD were observed through 5 years for insulin use, HbA1c ?6.0% and ?6.5% on two occasions. This prospective, randomized trial of CSWD indicates that CSWD has a limited impact in reducing NODAT when compared to low-dose prednisone (5 mg/day from month 6 to 5 years). PMID:25881802

  1. Periodontal breakdown in the Dmp1 null mouse model of hypophosphatemic rickets.

    PubMed

    Ye, L; Zhang, S; Ke, H; Bonewald, L F; Feng, J Q

    2008-07-01

    Dentin Matrix Protein 1 (DMP1) is highly expressed in alveolar bone and cementum, which are important components of the periodontium. Therefore, we hypothesized that Dmp1 is critical for the integrity of the periodontium, and that deletion may lead to increased susceptibility to disease. An early-onset periodontal defect was observed in the Dmp1 null mouse, a mouse model of hypophosphatemic rickets. The alveolar bone is porous, with increased proteoglycan expression. The cementum is also defective, as characterized by irregular, punctate fluorochrome labeling and elevated proteoglycan. The osteocyte and cementocyte lacuno-canalicular system of both alveolar bone and cementum is abnormal, with irregular lacunar walls and fewer canaliculi. As a consequence, there is significant interproximal alveolar bone loss, combined with detachment between the periodontal ligament (PDL) and cementum. We propose that defective alveolar bone and cementum may account for the periodontal breakdown and increased susceptibility to bacterial infection in Dmp1 null mice. PMID:18573980

  2. Reading Aloud in Persian: ERP Evidence for an Early Locus of the Masked Onset Priming Effect

    ERIC Educational Resources Information Center

    Timmer, Kalinka; Vahid-Gharavi, Narges; Schiller, Niels O.

    2012-01-01

    The current study investigates reading aloud words in Persian, a language that does not mark all its vowels in the script. Behaviorally, a "masked onset priming effect" (MOPE) was revealed for transparent words, with faster speech onset latencies in the phoneme-matching condition (i.e. phonological prime and target onset overlap; e.g. [image

  3. Reading Aloud in Persian: ERP Evidence for an Early Locus of the Masked Onset Priming Effect

    ERIC Educational Resources Information Center

    Timmer, Kalinka; Vahid-Gharavi, Narges; Schiller, Niels O.

    2012-01-01

    The current study investigates reading aloud words in Persian, a language that does not mark all its vowels in the script. Behaviorally, a "masked onset priming effect" (MOPE) was revealed for transparent words, with faster speech onset latencies in the phoneme-matching condition (i.e. phonological prime and target onset overlap; e.g. [image…

  4. Local-to-remote cortical connectivity in early- and adulthood-onset schizophrenia.

    PubMed

    Jiang, L; Xu, Y; Zhu, X-T; Yang, Z; Li, H-J; Zuo, X-N

    2015-01-01

    Schizophrenia is increasingly thought of as a brain network or connectome disorder and is associated with neurodevelopmental processes. Previous studies have suggested the important role of anatomical distance in developing a connectome with optimized performance regarding both the cost and efficiency of information processing. Distance-related disturbances during development have not been investigated in schizophrenia. To test the distance-related miswiring profiles of connectomes in schizophrenia, we acquired resting-state images from 20 adulthood-onset (AOS) and 26 early-onset schizophrenia (EOS) patients, as well as age-matched healthy controls. All patients were drug naive and had experienced their first psychotic episode. A novel threshold-free surface-based analytic framework was developed to examine local-to-remote functional connectivity profiles in both AOS and EOS patients. We observed consistent increases of local connectivity across both EOS and AOS patients in the right superior frontal gyrus, where the connectivity strength was correlated with a positive syndrome score in AOS patients. In contrast, EOS but not AOS patients exhibited reduced local connectivity within the right postcentral gyrus and the left middle occipital cortex. These regions' remote connectivity with their interhemispheric areas and brain network hubs was altered. Diagnosis-age interactions were detectable for both local and remote connectivity profiles. The functional covariance between local and remote homotopic connectivity was present in typically developing controls, but was absent in EOS patients. These findings suggest that a distance-dependent miswiring pattern may be one of the key neurodevelopmental features of the abnormal connectome organization in schizophrenia. PMID:25966366

  5. Local-to-remote cortical connectivity in early- and adulthood-onset schizophrenia

    PubMed Central

    Jiang, L; Xu, Y; Zhu, X-T; Yang, Z; Li, H-J; Zuo, X-N

    2015-01-01

    Schizophrenia is increasingly thought of as a brain network or connectome disorder and is associated with neurodevelopmental processes. Previous studies have suggested the important role of anatomical distance in developing a connectome with optimized performance regarding both the cost and efficiency of information processing. Distance-related disturbances during development have not been investigated in schizophrenia. To test the distance-related miswiring profiles of connectomes in schizophrenia, we acquired resting-state images from 20 adulthood-onset (AOS) and 26 early-onset schizophrenia (EOS) patients, as well as age-matched healthy controls. All patients were drug naive and had experienced their first psychotic episode. A novel threshold-free surface-based analytic framework was developed to examine local-to-remote functional connectivity profiles in both AOS and EOS patients. We observed consistent increases of local connectivity across both EOS and AOS patients in the right superior frontal gyrus, where the connectivity strength was correlated with a positive syndrome score in AOS patients. In contrast, EOS but not AOS patients exhibited reduced local connectivity within the right postcentral gyrus and the left middle occipital cortex. These regions' remote connectivity with their interhemispheric areas and brain network hubs was altered. Diagnosisage interactions were detectable for both local and remote connectivity profiles. The functional covariance between local and remote homotopic connectivity was present in typically developing controls, but was absent in EOS patients. These findings suggest that a distance-dependent miswiring pattern may be one of the key neurodevelopmental features of the abnormal connectome organization in schizophrenia. PMID:25966366

  6. Prevalence of Traumatic Brain Injury in Early Versus Late-Onset Alzheimers Disease

    PubMed Central

    Mendez, Mario F.; Paholpak, Pongsatorn; Lin, Andrew; Zhang, Jeannie Y.; Teng, Edmond

    2016-01-01

    Background Traumatic brain injury (TBI) is the most established environmental risk factor for Alzheimers disease (AD), but it is unclear if TBI is specifically associated with early-onset AD (EOAD). Objective To evaluate the relationship between TBI and EOAD (<65 years). Methods We identified 1,449 EOAD, 4,337 late-onset AD (LOAD), and corresponding EOAD-matched and LOAD-matched normal controls (NC) in the National Alzheimers Coordinating Center Uniform (NACC) database and compared the prevalence of any history of TBI as well as measures of cognition, function, behavior, and neuropathology. For validation, we determined TBI prevalence among 115 well-characterized clinic patients with EOAD. Results Part A: The prevalence of any TBI in the NACC-database EOAD participants (13.3%) was comparable to that observed in the clinic EOAD patients (13.9%) but significantly higher than in the NACC-database LOAD participants (7.7%; p < 0.0001) and trended to higher compared to EOAD-matched NC (11.1%; logistic regression p = 0.053). Part B: When we compared EOAD patients with documented non-acute and non-residually impairing TBI to EOAD without a documented history of prior TBI, those with TBI had significantly more disinhibition. Part C: Autopsies did not reveal differences in AD neuropathology based on a history of TBI. Conclusions These findings suggest, but do not establish, that TBI is a specific risk factor for EOAD and may lead to disinhibition, a feature that often results from the frontal effects of head injury. This study recommends further research on the effects of TBI in EOAD in larger numbers of participants. PMID:26401777

  7. Predictors of Parkin Mutations in Early Onset Parkinson disease: the CORE-PD Study

    PubMed Central

    Marder, K; Tang, M-X; Mejia-Santana, H; Rosado, L; Louis, ED; Comella, C; Colcher, A; Siderowf, A; Jennings, D; Nance, M; Bressman, S; Scott, WK; Tanner, C; Mickel, S; Andrews, H; Waters, C; Fahn, S; Ross, B; Cote, L; Frucht, S; Ford, B; Alcalay, RN; Rezak, M; Novak, K; Friedman, JH; Pfeiffer, R; Marsh, L; Hiner, B; Greg, Neils; Verbitsky, M; Kisselev, S; Caccoppolo, E; Ottman, R; Clark, LN

    2012-01-01

    Background Mutations in the parkin gene are the most common genetic cause of early-onset Parkinson’s disease (EOPD). Results from a multi-center study of cases with PD systematically sampled by age at onset (AAO) have not been reported. Objective To determine risk factors associated with carrying mutations in the parkin gene. Design Cross-sectional observational study Setting 13 movement disorders centers Participants 956 EOPD cases defined as AAO <51. Main Outcome Measures Presence of heterozygous, homozygous or compound heterozygous parkin mutations. Results 14.7% of cases reported a family history of PD in a first-degree relative using a previously validated interview. Sixty-four cases (6.7%) had parkin mutations (3.9% heterozygous, 0.6% homozygotes, 2.2% compound heterozgyotes). Copy Number Variation (CNV) was present in 52.3% (31.6% of heterozygotes, 83.3% of homozygotes, 81.0% of compound heterozygotes). Deletions in exons 3–4 and 255delA, were common in Hispanics, and specifically, in the Puerto Rican population. Earlier AAO, Hispanic ethnicity (OR compared to White non-Hispanic 2.7 95% CI 1.3–5.7, p<0.009) and family history of PD in a first-degree relative (OR 2.8 95%CI 1.5–5.3, p<0.002) were associated with carrying any mutation in the parkin gene (heterozygous, homozygous, compound heterozygous). Hispanic ethnicity was associated with carrying a heterozygous mutation (OR compared to non-Hispanic Caucasian 2.8 95%CI 1.1–7.2, p<0.03) after adjustment for covariates. Conclusion AAO, Hispanic ethnicity and family history of PD are associated with carrying any parkin mutation (heterozygous, homozygous, compound heterozygous) and heterozygous mutations alone. The increased odds of carrying a parkin mutation in Hispanics warrants further study. PMID:20558392

  8. Motor phenotype of LRRK2 G2019S carriers in Early Onset Parkinson Disease

    PubMed Central

    Alcalay, RN; Mejia-Santana, H; Tang, M-X; Rosado, L; Verbitsky, M; Kisselev, S; Ross, B; Louis, ED; Comella, C; Colcher, A; Jennings, D; Nance, M; Bressman, S; Scott, WK; Tanner, C; Mickel, S; Andrews, H; Waters, C; Fahn, S; Cote, L; Frucht, S; Ford, B; Rezak, M; Novak, K; Friedman, JH; Pfeiffer, R; Marsh, L; Hiner, B; Siderowf, A; Caccappolo, E; Ottman, R; Clark, LN; Marder, K

    2010-01-01

    Objective To determine the motor phenotype of LRRK2 G2019S mutation carriers Background LRRK2 mutation carriers were previously reported to manifest the tremor-dominant (TD) motor phenotype, which has been associated with slower motor progression and less cognitive impairment compared to the postural instability gait difficulty (PIGD) phenotype. Design Cross sectional observational study Setting 13 movement disorders centers Participants 925 Early Onset Parkinson Disease (EOPD) cases defined as age at onset (AAO) ?50. Main Outcome Measures LRRK2 mutation status and PD motor phenotype: TD or PIGD Methods Demographic information, family history of PD (FHPD), and the Unified Parkinson Disease Rating Scale (UPDRS) were collected on all participants. DNA samples were genotyped for LRRK2 mutations (G2019S, I2020T, R1441C and Y1699C). Logistic regression was used to examine associations of G2019S mutation status with motor phenotype adjusting for disease duration, Ashkenazi Jewish (AJ) ancestry, levodopa dose, and FHPD. Results 34 cases (3.7%) (14 previously reported) were G2019S carriers. No other mutations were found. Carriers were more likely to be AJ (55.9% vs. 11.9% p<0.001), but did not significantly differ in any other demographic or disease characteristics. Carriers had a lower tremor score (p=0.026) and were more likely to have a PIGD phenotype (92.3% vs. 58.9% p=0.003). The association of the G2019S mutation with PIGD phenotype remained after controlling for disease duration and AJ (OR= 17.7, p< 0.001). Conclusion EOPD G2019S LRRK2 carriers are more likely to manifest the PIGD phenotype, which may have implications for disease course. PMID:20008657

  9. LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population.

    PubMed

    Olhov, Monika; Hardy, Steven A; Hall, Julie; Yarham, John W; Haack, Tobias B; Wilson, William C; Alston, Charlotte L; He, Langping; Aznauryan, Erik; Brown, Ruth M; Brown, Garry K; Morris, Andrew A M; Mundy, Helen; Broomfield, Alex; Barbosa, Ines A; Simpson, Michael A; Deshpande, Charu; Moeslinger, Dorothea; Koch, Johannes; Stettner, Georg M; Bonnen, Penelope E; Prokisch, Holger; Lightowlers, Robert N; McFarland, Robert; Chrzanowska-Lightowlers, Zofia M A; Taylor, Robert W

    2015-12-01

    Mitochondrial Complex IV [cytochrome c oxidase (COX)] deficiency is one of the most common respiratory chain defects in humans. The clinical phenotypes associated with COX deficiency include liver disease, cardiomyopathy and Leigh syndrome, a neurodegenerative disorder characterized by bilateral high signal lesions in the brainstem and basal ganglia. COX deficiency can result from mutations affecting many different mitochondrial proteins. The French-Canadian variant of COX-deficient Leigh syndrome is unique to the Saguenay-Lac-Saint-Jean region of Qubec and is caused by a founder mutation in the LRPPRC gene. This encodes the leucine-rich pentatricopeptide repeat domain protein (LRPPRC), which is involved in post-transcriptional regulation of mitochondrial gene expression. Here, we present the clinical and molecular characterization of novel, recessive LRPPRC gene mutations, identified using whole exome and candidate gene sequencing. The 10 patients come from seven unrelated families of UK-Caucasian, UK-Pakistani, UK-Indian, Turkish and Iraqi origin. They resemble the French-Canadian Leigh syndrome patients in having intermittent severe lactic acidosis and early-onset neurodevelopmental problems with episodes of deterioration. In addition, many of our patients have had neonatal cardiomyopathy or congenital malformations, most commonly affecting the heart and the brain. All patients who were tested had isolated COX deficiency in skeletal muscle. Functional characterization of patients' fibroblasts and skeletal muscle homogenates showed decreased levels of mutant LRPPRC protein and impaired Complex IV enzyme activity, associated with abnormal COX assembly and reduced steady-state levels of numerous oxidative phosphorylation subunits. We also identified a Complex I assembly defect in skeletal muscle, indicating different roles for LRPPRC in post-transcriptional regulation of mitochondrial mRNAs between tissues. Patient fibroblasts showed decreased steady-state levels of mitochondrial mRNAs, although the length of poly(A) tails of mitochondrial transcripts were unaffected. Our study identifies LRPPRC as an important disease-causing gene in an early-onset, multisystem and neurological mitochondrial disease, which should be considered as a cause of COX deficiency even in patients originating outside of the French-Canadian population. PMID:26510951

  10. The contribution of founder mutations to early-onset breast cancer in French-Canadian women.

    PubMed

    Ghadirian, P; Robidoux, A; Zhang, P; Royer, R; Akbari, M; Zhang, S; Fafard, E; Costa, M; Martin, G; Potvin, C; Patocskai, E; Larouche, N; Younan, R; Nassif, E; Giroux, S; Narod, S A; Rousseau, F; Foulkes, W D

    2009-11-01

    In an ethnically-homogeneous population, it is valuable to identify founder mutations in cancer-predisposing genes. Founder mutations have been found in four breast-cancer-predisposing genes in French-Canadian breast cancer families. The frequencies of the mutant alleles have been measured neither in a large series of unselected breast cancer patients from Quebec, nor in healthy controls. These estimates are necessary to measure their contribution to the hereditary burden of breast cancer in Quebec and to help develop genetic screening policies which are appropriate for the province. We studied 564 French-Canadian women with early-onset invasive breast cancer who were treated at a single Montreal hospital. Patients had been diagnosed at age 50 or less, and were ascertained between 2004 and 2008. We screened all 564 patients for nine founder mutations: four in BRCA1, three in BRCA2 and one each in PALB2 and CHEK2. We also studied 6433 DNA samples from newborn infants from the Quebec City area to estimate the frequency of the nine variant alleles in the French-Canadian population. We identified a mutation in 36 of the 564 breast cancer cases (6.4%) and in 35 of 6443 controls (0.5%). In the breast cancer patients, the majority of mutations were in BRCA2 (54%). However, in the general population (newborn infants), the majority of mutations were in CHEK2 (54%). The odds ratio for breast cancer to age 50, given a BRCA1 mutation, was 10.1 (95% CI: 3.7-28) and given a BRCA2 mutation was 29.5 (95% CI: 12.9-67). The odds ratio for breast cancer to age 50, given a CHEK2 mutation, was 3.6 (95% CI: 1.4-9.1). One-half of the women with a mutation had a first- or second-degree relative diagnosed with breast or ovarian cancer. Thus, it can be concluded that a predisposing mutation in BRCA1, BRCA2, CHEK2 or PALB2 is present in approximately 6% of French-Canadian women with early-onset breast cancer. It is reasonable to offer screening for founder mutations to all French-Canadian women with breast cancer before age 50. The frequency of these mutations in the general population (0.5%) is too low to advocate population-based screening. PMID:19863560

  11. [Combined step-by-step rehabilitation of the patients presenting with early-onset rheumatoid arthritis].

    PubMed

    Orlova, E V; Karateev, D E; Kochetkov, A V; Denisov, L N; Surnov, A V

    2013-01-01

    The objective of the present study was to develop the program for combined step-by-step rehabilitation of the patients presenting with early-onset rheumatoid arthritis (RA); the secondary objective was to estimate the effectiveness of this program. A total of 34 patients were recruited for the participation in the study. They received medicamental therapy in combination with the rehabilitative treatment during 6 months. The hospital-based treatment included therapeutic exercises for large joints under the supervision of a specialist (45 min), occupational therapy (45 min), local aerial cryotherapy of wrist, knee, and ankle joints (10 sessions 15 min each at a temperature of -60 degrees C), ortheses, and the educational program (4 daily studies 90 min each). The outpatient and home-based treatment included therapeutic exercises for large joints (45 min), wrist exercises (45 min) three times every week, ortheses. 26 patients received only medicamental therapy (control group). The following characteristics were measured: the average power of extension of knee joints and of flexion of ankle joints (by means of En-TreeM analysis of movements), wrist grip strength, articular pain (100 mm VAS, DAS28, HAQ, RAPID3 indices). The rehabilitative program ensured excellent compliance with basal therapy, reduced requirements for symptomatic medicines, and improved adherence to the methods for the formation of the correct movement patterns, orthesis wearing, and regular therapeutic exercises. The rehabilitative treatment resulted in the relief of articular pain by 70.4% (p < 0.01), decrease of DAS28 by 31.9% (p < 0.05), HAQ by 75.8% (p < 0.01), and RAPID3 by 60.1% (p < 0.01). The grip strength of the more seriously injured wrist increased by 44.9% (p < 0.05) and that of the less damaged one by 31.3% (p < 0.05). The average extension power of the weaker knee joint increased by 88.7% (p < 0.01) and that of the stronger joint by 67.7% (p < 0.01). The average flexion power of the more seriously injured ankle joint increased by 81.6% (p < 0.01) and that of the less damaged one by 70.2% (p < 0.01). The two groups were significantly different in terms of the majority of characteristics evaluated. It is concluded that the combined rehabilitative treatment helps to control the activity of the disease, enhances the functional abilities, improves the locomotor activity and quality of life of the patients with early-onset rheumatoid arthritis. PMID:23520927

  12. LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population

    PubMed Central

    Oláhová, Monika; Hardy, Steven A.; Hall, Julie; Yarham, John W.; Haack, Tobias B.; Wilson, William C.; Alston, Charlotte L.; He, Langping; Aznauryan, Erik; Brown, Ruth M.; Brown, Garry K.; Morris, Andrew A. M.; Mundy, Helen; Broomfield, Alex; Barbosa, Ines A.; Simpson, Michael A.; Deshpande, Charu; Moeslinger, Dorothea; Koch, Johannes; Stettner, Georg M.; Bonnen, Penelope E.; Prokisch, Holger; Lightowlers, Robert N.; McFarland, Robert; Chrzanowska-Lightowlers, Zofia M. A.

    2015-01-01

    Mitochondrial Complex IV [cytochrome c oxidase (COX)] deficiency is one of the most common respiratory chain defects in humans. The clinical phenotypes associated with COX deficiency include liver disease, cardiomyopathy and Leigh syndrome, a neurodegenerative disorder characterized by bilateral high signal lesions in the brainstem and basal ganglia. COX deficiency can result from mutations affecting many different mitochondrial proteins. The French-Canadian variant of COX-deficient Leigh syndrome is unique to the Saguenay-Lac-Saint-Jean region of Québec and is caused by a founder mutation in the LRPPRC gene. This encodes the leucine-rich pentatricopeptide repeat domain protein (LRPPRC), which is involved in post-transcriptional regulation of mitochondrial gene expression. Here, we present the clinical and molecular characterization of novel, recessive LRPPRC gene mutations, identified using whole exome and candidate gene sequencing. The 10 patients come from seven unrelated families of UK-Caucasian, UK-Pakistani, UK-Indian, Turkish and Iraqi origin. They resemble the French-Canadian Leigh syndrome patients in having intermittent severe lactic acidosis and early-onset neurodevelopmental problems with episodes of deterioration. In addition, many of our patients have had neonatal cardiomyopathy or congenital malformations, most commonly affecting the heart and the brain. All patients who were tested had isolated COX deficiency in skeletal muscle. Functional characterization of patients’ fibroblasts and skeletal muscle homogenates showed decreased levels of mutant LRPPRC protein and impaired Complex IV enzyme activity, associated with abnormal COX assembly and reduced steady-state levels of numerous oxidative phosphorylation subunits. We also identified a Complex I assembly defect in skeletal muscle, indicating different roles for LRPPRC in post-transcriptional regulation of mitochondrial mRNAs between tissues. Patient fibroblasts showed decreased steady-state levels of mitochondrial mRNAs, although the length of poly(A) tails of mitochondrial transcripts were unaffected. Our study identifies LRPPRC as an important disease-causing gene in an early-onset, multisystem and neurological mitochondrial disease, which should be considered as a cause of COX deficiency even in patients originating outside of the French-Canadian population. PMID:26510951

  13. Role of periodontal pathogenic bacteria in RANKL-mediated bone destruction in periodontal disease

    PubMed Central

    Kajiya, Mikihito; Giro, Gabriela; Taubman, Martin A.; Han, Xiaozhe; Mayer, Marcia P.A.; Kawai, Toshihisa

    2010-01-01

    Accumulated lines of evidence suggest that hyperimmune responses to periodontal bacteria result in the destruction of periodontal connective tissue and alveolar bone. The etiological roles of periodontal bacteria in the onset and progression of periodontal disease (PD) are well documented. However, the mechanism underlying the engagement of periodontal bacteria in RANKL-mediated alveolar bone resorption remains unclear. Therefore, this review article addresses three critical subjects. First, we discuss earlier studies of immune intervention, ultimately leading to the identification of bacteria-reactive lymphocytes as the cellular source of osteoclast-induction factor lymphokine (now called RANKL) in the context of periodontal bone resorption. Next, we consider (1) the effects of periodontal bacteria on RANKL production from a variety of adaptive immune effector cells, as well as fibroblasts, in inflamed periodontal tissue and (2) the bifunctional roles (upregulation vs. downregulation) of LPS produced from periodontal bacteria in a RANKL-induced osteoclast-signal pathway. Future studies in these two areas could lead to new therapeutic approaches for the management of PD by down-modulating RANKL production and/or RANKL-mediated osteoclastogenesis in the context of host immune responses against periodontal pathogenic bacteria. PMID:21523224

  14. Epidural Brain Metastases in a Patient with Early Onset Pancreatic Cancer: A Case Report and Literature Review

    PubMed Central

    Mirrakhimov, Aibek E.; Khan, Farah N.

    2012-01-01

    We present a case of early onset pancreatic cancer related extra-axial brain metastases. A 46-year-old Caucasian non-Jewish nonobese male with a history of PC diagnosed 3 months ago with metastases to the liver, omentum, malignant ascites, and a history of a pulmonary embolism was admitted to the hospital because of a new onset headache, nausea, and vomiting which started 2 days prior to the encounter. Brain MRI was ordered, which showed acute bihemispheric subdural hematomas and left hemispheric extra-axial heterogeneously enhancing lesions consisting with metastatic disease. The patient was started on ondansentron, metoclopramide, and dexamethasone. The cranial irradiation was started, and the patient's headache and nausea significantly improved. There are only 9 published reports of extra-axial brain metastases related to the pancreatic cancer, whereas our paper is the first such case reported on a patient with epidural metastases and early onset pancreatic cancer. PMID:23119207

  15. Early-onset dropped head syndrome after radiotherapy for head and neck cancer: dose constraints for neck extensor muscles

    PubMed Central

    Inaba, Koji; Nakamura, Satoshi; Okamoto, Hiroyuki; Kashihara, Tairo; Kobayashi, Kazuma; Harada, Ken; Kitaguchi, Mayuka; Sekii, Shuhei; Takahashi, Kana; Murakami, Naoya; Ito, Yoshinori; Igaki, Hiroshi; Uno, Takashi; Itami, Jun

    2016-01-01

    Dropped head syndrome (DHS) is a famous but unusual late complication of multimodality treatment for head and neck carcinoma. We reported this early-onset complication and analyzed the dose to the neck extensor muscles. We examined the records of three patients with DHS after radiotherapy. The doses to the neck extensor muscles were compared between three patients with DHS and nine patients without DHS. The mean dose to the neck extensor muscles of the three patients with DHS were 58.5 Gy, 42.3 Gy and 60.9 Gy, while the dose was <50 Gy in all nine patients in the control group. The onset of this syndrome was 5 months, 6 months and 15 months. The early-onset DHS may have something to do with dose to the neck extensor muscles. The proposed dose to the neck extensor muscles might be <46 Gy (or at least <50 Gy). PMID:26684338

  16. A Long-Term Longitudinal Examination of the Effect of Early Onset of Alcohol and Drug Use on Later Alcohol Abuse

    PubMed Central

    Ohannessian, Christine McCauley; Finan, Laura J.; Schulz, Jessica; Hesselbrock, Victor

    2015-01-01

    Background Early onset of alcohol use has been linked to later alcohol problems in adulthood. Currently, it is not clear whether early onset of marijuana and tobacco use similarly predicts alcohol problems. Moreover, most studies examining the effect of early substance use onset on later problems only have followed youth into their early 20s. Therefore, the primary goal of this study was to examine whether early onset of alcohol, marijuana, and tobacco use predicts alcohol problems beyond the transition to adulthood. Methods The sample included 225 15-19 year old youth (60% girls; 62% Caucasian) who were surveyed in 1993-1998 (Time 1), 19982003 (Time 2), and 2003-2007 (Time 3). Participants reported their age of onset for regular drinking, tobacco use, and marijuana use. At each time of measurement, they also completed surveys relating to their alcohol use and abuse. Results Participants with an earlier age of onset of drinking regularly scored higher on the Michigan Alcoholism Screening Test (MAST) and drank more frequently to get high and drunk throughout their twenties. Tobacco use onset and marijuana use onset were not associated with later alcohol use or abuse. Conclusions Results from this study suggest that the relationship between the onset of substance use and later substance abuse may be substance specific. Of note, early onset of regular drinking was associated with alcohol problems during adulthood, underscoring the importance of delaying the onset of regular alcohol use among youth. PMID:25671782

  17. Combined Effect of TLR2 Gene Polymorphism and Early Life Stress on the Age at Onset of Bipolar Disorders

    PubMed Central

    Oliveira, José; Etain, Bruno; Lajnef, Mohamed; Hamdani, Nora; Bennabi, Meriem; Bengoufa, Djaouida; Sundaresh, Aparna; Chaabane, Arij Ben; Bellivier, Frank; Henry, Chantal; Kahn, Jean-Pierre; Charron, Dominique; Krishnamoorthy, Rajagopal; Leboyer, Marion; Tamouza, Ryad

    2015-01-01

    Gene-environment interactions may play an important role in modulating the impact of early-life stressful events on the clinical course of bipolar disorder (BD), particularly associated to early age at onset. Immune dysfunction is thought to be an important mechanism linking childhood trauma with early-onset BD, thus the genetic diversity of immune-related loci may account for an important part of the interindividual susceptibility to this severe subform. Here we investigated the potential interaction between genetic variants of Toll-like receptors 2 (TLR2) and 4 (TLR4), major innate immune response molecules to pathogens, and the childhood trauma questionnaire (CTQ) in age at onset of BD. We recruited 531 BD patients (type I and II or not otherwise specified), genotyped for the TLR2 rs4696480 and rs3804099 and TLR4 rs1927914 and rs11536891 single-nucleotide polymorphisms and recorded for history of childhood trauma using the CTQ. TLR2 and TLR4 risk genotype carrier state and history of childhood emotional, physical and sexual abuses were evaluated in relation to age at onset as defined by the age at first manic or depressive episode. We observed a combined effect of TLR2 rs3804099 TT genotype and reported sexual abuse on determining an earlier age at onset of BD by means of a Kaplan-Meier survival curve (p = 0.002; corrected p = 0.02). Regression analysis, however, was non-significant for the TLR2-CTQ sexual abuse interaction term. The negative effects of childhood sexual abuse on age at onset of BD may be amplified in TLR2 rs3804099 risk genotype carriers through immune-mediated pathways. Clinical characteristics of illness severity, immune phenotypes and history of early life infectious insults should be included in future studies involving large patient cohorts. PMID:25790282

  18. A Follow-up Study of Early Onset Psychosis: Comparison between Outcome Diagnoses of Schizophrenia, Mood Disorders, and Personality Disorders.

    ERIC Educational Resources Information Center

    McClellan, Jon M.; And Others

    1993-01-01

    This study of 95 youths previously diagnosed with psychotic disorders found that at follow-up, 24 had a diagnosis of schizophrenia, 9 with psychotic mood disorders, 5 with personality disorders, and 1 with schizo-affective disorder. The study confirmed findings regarding early onset schizophrenia and psychotic mood disorders and emphasized the

  19. The Northern Ireland Early Onset Psychosis Study: Phenomenology and Co-Morbidity in the First 25 Cases

    ERIC Educational Resources Information Center

    Fulton, Karen; Short, Mary; Harvey-Smith, Diane; Rushe, Teresa M.; Mulholland, Ciaran

    2008-01-01

    Diagnosing psychotic disorders in young people is difficult. High rates of co-morbidity may be one reason for this difficulty, but it may also be the case that current diagnostic categories are not the most useful when approaching the care of young people with psychotic symptoms. The Northern Ireland Early Onset Psychosis Study is the first study

  20. Impaired Facial Expression Recognition in Children with Temporal Lobe Epilepsy: Impact of Early Seizure Onset on Fear Recognition

    ERIC Educational Resources Information Center

    Golouboff, Nathalie; Fiori, Nicole; Delalande, Olivier; Fohlen, Martine; Dellatolas, Georges; Jambaque, Isabelle

    2008-01-01

    The amygdala has been implicated in the recognition of facial emotions, especially fearful expressions, in adults with early-onset right temporal lobe epilepsy (TLE). The present study investigates the recognition of facial emotions in children and adolescents, 8-16 years old, with epilepsy. Twenty-nine subjects had TLE (13 right, 16 left) and

  1. Double-Blind Maintenance Safety and Effectiveness Findings from the Treatment of Early-Onset Schizophrenia Spectrum (TEOSS) Study

    ERIC Educational Resources Information Center

    Findling, Robert L.; Johnson, Jacqueline L.; McClellan, Jon; Frazier, Jean A.; Vitiello, Benedetto; Hamer, Robert M.; Lieberman, Jeffrey A.; Ritz, Louise; McNamara, Nora K.; Lingler, Jacqui; Hlastala, Stefanie; Pierson, Leslie; Puglia, Madeline; Maloney, Ann E.; Kaufman, Emily Michael; Noyes, Nancy; Sikich, Linmarie

    2010-01-01

    Objective: To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders. Method: Patients (8 to 19 years old) who had improved during an 8-week, randomized, double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication…

  2. Academic Skills in Children with Early-Onset Type 1 Diabetes: The Effects of Diabetes-Related Risk Factors

    ERIC Educational Resources Information Center

    Hannonen, Riitta; Komulainen, Jorma; Riikonen, Raili; Ahonen, Timo; Eklund, Kenneth; Tolvanen, Asko; Keskinen, Paivi; Nuuja, Anja

    2012-01-01

    Aim: The study aimed to assess the effects of diabetes-related risk factors, especially severe hypoglycaemia, on the academic skills of children with early-onset type 1 diabetes mellitus (T1DM). Method: The study comprised 63 children with T1DM (31 females, 32 males; mean age 9y 11mo, SD 4mo) and 92 comparison children without diabetes (40

  3. The Use of Voice Onset Time by Early Bilinguals to Distinguish Homorganic Stops in Canadian English and Canadian French

    ERIC Educational Resources Information Center

    Macleod, Andrea A. N.; Stoel-Gammon, Carol

    2009-01-01

    The goal of this study was to examine the extent to which bilingual speakers maintain language-specific phonological contrasts for homorganic stops when a cue is shared across both languages. To this end, voice onset time (VOT) was investigated in three groups of participants: early bilinguals speakers of Canadian French and Canadian English (n =…

  4. Verbal Behavior in Young Children with Autism Spectrum Disorders at the Onset of an Early Behavioral Intervention Program

    ERIC Educational Resources Information Center

    Rivard, Melina; Forget, Jacques

    2012-01-01

    The scope of this study was direct observation of verbal behaviors of 14 children with autism spectrum disorders at the onset of an early behavioral intervention (EBI) program delivered in a public services agency. Objectives were to (1) describe frequencies of vocal, verbal, and listener behaviors; (2) evaluate the relationship between the

  5. A Meta-Analysis of Neuropsychological Functioning in Patients with Early Onset Schizophrenia and Pediatric Bipolar Disorder

    ERIC Educational Resources Information Center

    Nieto, Rebeca Garcia; Castellanos, F. Xavier

    2011-01-01

    Despite the nosological distinction between bipolar disorder and schizophrenia, there is increasing evidence that these conditions share phenomenological characteristics. To examine the similarities in their patterns of cognitive impairment, we conducted a meta-analysis from 12 studies of Early Onset Schizophrenia (EOS) and 12 studies of Pediatric…

  6. A Meta-Analysis of Neuropsychological Functioning in Patients with Early Onset Schizophrenia and Pediatric Bipolar Disorder

    ERIC Educational Resources Information Center

    Nieto, Rebeca Garcia; Castellanos, F. Xavier

    2011-01-01

    Despite the nosological distinction between bipolar disorder and schizophrenia, there is increasing evidence that these conditions share phenomenological characteristics. To examine the similarities in their patterns of cognitive impairment, we conducted a meta-analysis from 12 studies of Early Onset Schizophrenia (EOS) and 12 studies of Pediatric

  7. Components of Negative Affect as Moderators of the Relationship between Early Drinking Onset and Binge-Drinking Behavior

    ERIC Educational Resources Information Center

    McNamara, Robert S.; Swaim, Randall C.; Rosen, Lee A.

    2010-01-01

    This study examines the moderating effects of negative affect on the relationship between early drinking onset and binge-drinking behavior. Six hundred and thirty-five eleventh- and twelfth-grade students completed the American Drug and Alcohol Survey and reported on a variety of measures, including items assessing anxiety, anger, depression, age

  8. Double-Blind Maintenance Safety and Effectiveness Findings from the Treatment of Early-Onset Schizophrenia Spectrum (TEOSS) Study

    ERIC Educational Resources Information Center

    Findling, Robert L.; Johnson, Jacqueline L.; McClellan, Jon; Frazier, Jean A.; Vitiello, Benedetto; Hamer, Robert M.; Lieberman, Jeffrey A.; Ritz, Louise; McNamara, Nora K.; Lingler, Jacqui; Hlastala, Stefanie; Pierson, Leslie; Puglia, Madeline; Maloney, Ann E.; Kaufman, Emily Michael; Noyes, Nancy; Sikich, Linmarie

    2010-01-01

    Objective: To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders. Method: Patients (8 to 19 years old) who had improved during an 8-week, randomized, double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication

  9. The effect of intrapartum antibiotics on early-onset neonatal sepsis in Dhaka, Bangladesh: a propensity score matched analysis

    PubMed Central

    2014-01-01

    Background We estimate the effect of antibiotics given in the intrapartum period on early-onset neonatal sepsis in Dhaka, Bangladesh using propensity score techniques. Methods We followed 600 mother-newborn pairs as part of a cohort study at a maternity center in Dhaka. Some pregnant women received one dose of intravenous antibiotics during labor based on clinician discretion. Newborns were followed over the first seven days of life for early-onset neonatal sepsis defined by a modified version of the World Health Organization Young Infants Integrated Management of Childhood Illnesses criteria. Using propensity scores we matched women who received antibiotics with similar women who did not. A final logistic regression model predicting sepsis was run in the matched sample controlling for additional potential confounders. Results Of the 600 mother-newborn pairs, 48 mothers (8.0%) received antibiotics during the intrapartum period. Seventy-seven newborns (12.8%) were classified with early-onset neonatal sepsis. Antibiotics appeared to be protective (odds ratio 0.381, 95% confidence interval 0.1151.258), however this was not statistically significant. The results were similar after adjusting for prematurity, wealth status, and maternal colonization status (odds ratio 0.361, 95% confidence interval 0.1061.225). Conclusions Antibiotics administered during the intrapartum period may reduce the risk of early-onset neonatal sepsis in high neonatal mortality settings like Dhaka. PMID:24742087

  10. Onset of clinical and MRI efficacy occurs early after fingolimod treatment initiation in relapsing multiple sclerosis.

    PubMed

    Kappos, Ludwig; Radue, Ernst-Wilhelm; Chin, Peter; Ritter, Shannon; Tomic, Davorka; Lublin, Fred

    2016-02-01

    To minimize the clinical burden associated with multiple sclerosis (MS), early control of focal and diffuse CNS disease activity is a treatment priority. A post hoc analysis was conducted to evaluate the onset of efficacy of fingolimod treatment in patients with relapsing MS. Data from patients who received fingolimod 0.5mg or placebo during either of two 24-month, double-blind, randomized, parallel-group clinical trials (FREEDOMS and FREEDOMS II) were pooled for analysis. Efficacy outcomes were: time to first confirmed relapse; annualized relapse rate (ARR); proportions of patients free from T1 gadolinium-enhancing lesions or new/newly enlarged T2 lesions; percentage brain volume loss (BVL); and change in Multiple Sclerosis Functional Composite (MSFC) z-score from baseline to 6months. An early benefit was seen with fingolimod (N=783) vs. placebo (N=773) for ARR at both 3 and 6months (3months, 0.32 vs. 0.52, p=0.0015; 6months, 0.21 vs. 0.45, p<0.0001). Time to first relapse was also delayed with fingolimod vs. placebo from day 48 onwards. At 6months, more patients in the fingolimod group than in the placebo group were free from new MRI activity (65.3 vs. 40.5%, p<0.0001) and had less BVL (37.1% reduction vs. placebo, p<0.001). MSFC z-score favored fingolimod over placebo at 6months, with improvements noted in 9-Hole Peg Test and Paced Auditory Serial Addition Test scores. Improvements in outcomes related to relapses, MRI, disability, cognition, and BVL occurred within 6months of treatment initiation with fingolimod. PMID:26645392

  11. A Novel Recessive NEFL Mutation Causes a Severe, Early-Onset Axonal Neuropathy

    PubMed Central

    Yum, Sabrina W.; Zhang, Junxian; Mo, Katie; Li, Jian; Scherer, Steven S.

    2015-01-01

    Objective To report the first cases of homozygous recessive mutations in NEFL, the gene that encodes the light subunit of neurofilaments (NFL). Methods Clinical and electrophysiologic data of all family members were evaluated, and a sural nerve biopsy from one affected child was examined by immunohistochemistry and electron microscopy. The ability of the mutant protein to form filaments was characterized in an established cell culture system. Results Four of five siblings developed a severe, progressive neuropathy beginning in early childhood. Serial nerve conduction studies showed progressively reduced amplitudes with age, and pronounced slowing at all ages. Visual evoked responses were slowed in three children, indicating that CNS axons were subclinically involved. All four affected children were homozygous for a nonsense mutation at glutamate 210 (E210X) in the NEFL gene; both parents were heterozygous carriers. A sural nerve biopsy from an affected patient at age 16 revealed markedly reduced numbers of myelinated axons; the remaining myelinated axons were small and lacked intermediate filaments. The E210X mutant protein did not form an intermediate filament network, and did not interfere with the filament formation by wild type human NFL in SW-13 vim- cells. Interpretation This is the first demonstration of a recessive NEFL mutation, which appears to cause a simple loss-of-function, resulting in a severe, early-onset axonal neuropathy with unique features. These results confirm that neurofilaments are the main determinant of axonal caliber and conduction velocity, and demonstrate for the first time that neurofilaments are required for the maintenance of myelinated PNS axons. PMID:20039262

  12. Classifying early-onset colorectal cancer according to tumor location: new potential subcategories to explore

    PubMed Central

    Perea, Jos; Cano, Juana M; Rueda, Daniel; Garca, Juan L; Inglada, Luca; Osorio, Irene; Arriba, Mara; Prez, Jessica; Gaspar, Miriam; Fernndez-Miguel, Tamara; Rodrguez, Yolanda; Bentez, Javier; Gonzlez-Sarmiento, Rogelio; Urioste, Miguel

    2015-01-01

    Early-onset Colorectal Cancer (ECRC) represents a significant and increasing proportion of Colorectal Cancer (CRC), but it is a heterogeneous entity that probably encompasses specific subclasses. On the premise that the carcinogenetic mechanism and progression of CRC may differ with location, we analyzed molecular and clinical characteristics of ECRC according to tumor location in order to identify more homogeneous subgroups of CRC. Right-sided ECRC is a subset in which most Lynch Syndrome cases are found, with earlier stages at diagnosis and better prognosis. At this location the CpG Island Methylator Phenotype (CIMP) is predominant and Chromosomal Instability (CI) is rare. Left-sided ECRC appears as a transitional or intermediate location, except for CI tumors, that seem to predominate at this location. Finally, rectal ECRC shows Microsatellite Stability, CIMP low-0 and low CI - with recurrent altered chromosomal regions in common with left-sided ECRC-, possibly in relation with Microsatellite And Chromosomal Stable tumors, but with an unexpected familial component and worse prognosis. All this suggest that the molecular basis of ECRC varies with tumor location, which could affect the clinical management of patients. PMID:26328262

  13. Early Onset Intrauterine Growth Restriction in a Mouse Model of Gestational Hypercholesterolemia and Atherosclerosis

    PubMed Central

    Busso, Dolores; Mascareño, Lilian; Salas, Francisca; Berkowitz, Loni; Santander, Nicolás; Quiroz, Alonso; Amigo, Ludwig; Valdés, Gloria; Rigotti, Attilio

    2014-01-01

    The susceptibility to develop atherosclerosis is increased by intrauterine growth restriction and prenatal exposure to maternal hypercholesterolemia. Here, we studied whether mouse gestational hypercholesterolemia and atherosclerosis affected fetal development and growth at different stages of gestation. Female LDLR KO mice fed a proatherogenic, high cholesterol (HC) diet for 3 weeks before conception and during pregnancy exhibited a significant increase in non-HDL cholesterol and developed atherosclerosis. At embryonic days 12.5 (E12.5), E15.5, and E18.5, maternal gestational hypercholesterolemia and atherosclerosis were associated to a 22–24% reduction in male and female fetal weight without alterations in fetal number/litter or morphology nor placental weight or structure. Feeding the HC diet exclusively at the periconceptional period did not alter fetal growth, suggesting that maternal hypercholesterolemia affected fetal weight only after implantation. Vitamin E supplementation (1,000 UI of α-tocopherol/kg) of HC-fed females did not change the mean weight of E18.5 fetuses but reduced the percentage of fetuses exhibiting body weights below the 10th percentile of weight (HC: 90% vs. HC/VitE: 68%). In conclusion, our results showed that maternal gestational hypercholesterolemia and atherosclerosis in mice were associated to early onset fetal growth restriction and that dietary vitamin E supplementation had a beneficial impact on this condition. PMID:25295255

  14. Altered expression of mRNA profiles in blood of early-onset schizophrenia

    PubMed Central

    Xu, Yong; Yao Shugart, Yin; Wang, Guoqiang; Cheng, Zaohuo; Jin, Chunhui; Zhang, Kai; Wang, Jun; Yu, Hao; Yue, Weihua; Zhang, Fuquan; Zhang, Dai

    2016-01-01

    To identify gene expression abnormalities in schizophrenia (SZ), we generated whole-genome gene expression profiles using microarrays on peripheral blood mononuclear cells (PBMCs) from 18 early-onset SZ cases and 12 controls. We detected 84 transcripts differentially expressed by diagnostic status, with 82 genes being upregulated and 2 downregulated. We identified two SZ associated gene coexpression modules (green and red), including 446 genes . The green module is positively correlated with SZ, encompassing predominantly up-regulated genes in SZ; while the red module was negatively correlated with disease status, involving mostly nominally down-regulated genes in SZ. The olfactory transduction pathway was the most enriched pathways for the genes within the two modules. The expression levels of several hub genes, including AKT1, BRCA1, CCDC134, UBD, and ZIC2 were validated using real-time quantitative PCR. Our findings indicate that mRNA coexpression abnormalities may serve as a promising mechanism underlying the development of SZ. PMID:26733343

  15. Impaired Verbal Learning Is Associated with Larger Caudate Volumes in Early Onset Schizophrenia Spectrum Disorders

    PubMed Central

    Juuhl-Langseth, Monica; Hartberg, Cecilie B.; Holmn, Aina; Thormodsen, Rune; Groote, Inge R.; Rimol, Lars M.; Emblem, Kyrre E.; Agartz, Ingrid; Rund, Bjrn R.

    2015-01-01

    Background Both brain structural abnormalities and neurocognitive impairments are core features of schizophrenia. We have previously reported enlargements in subcortical brain structure volumes and impairment of neurocognitive functioning as measured by the MATRICS Cognitive Consensus Battery (MCCB) in early onset schizophrenia spectrum disorders (EOS). To our knowledge, no previous study has investigated whether neurocognitive performance and volumetric abnormalities in subcortical brain structures are related in EOS. Methods Twenty-four patients with EOS and 33 healthy controls (HC) were included in the study. Relationships between the caudate nucleus, the lateral and fourth ventricles volumes and neurocognitive performance were investigated with multivariate linear regression analyses. Intracranial volume, age, antipsychotic medication and IQ were included as independent predictor-variables. Results The caudate volume was negatively correlated with verbal learning performance uniquely in the EOS group (r=-.454, p=.034). There were comparable positive correlations between the lateral ventricular volume and the processing speed, attention and reasoning and problem solving domains for both the EOS patients and the healthy controls. Antipsychotic medication was related to ventricular enlargements, but did not affect the brain structure-function relationship. Conclusion Enlargement of the caudate volume was related to poorer verbal learning performance in patients with EOS. Despite a 32% enlargement of the lateral ventricles in the EOS group, associations to processing speed, attention and reasoning and problem solving were similar for both the EOS and the HC groups. PMID:26230626

  16. Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer

    PubMed Central

    Tezcan, Gulcin; Tunca, Berrin; Ak, Secil; Cecener, Gulsah; Egeli, Unal

    2016-01-01

    Colorectal cancer (CRC) is the third most frequent cancer type and the incidence of this disease is increasing gradually per year in individuals younger than 50 years old. The current knowledge is that early-onset CRC (EOCRC) cases are heterogeneous population that includes both hereditary and sporadic forms of the CRC. Although EOCRC cases have some distinguishing clinical and pathological features than elder age CRC, the molecular mechanism underlying the EOCRC is poorly clarified. Given the significance of CRC in the world of medicine, the present review will focus on the recent knowledge in the molecular basis of genetic and epigenetic mechanism of the hereditary forms of EOCRC, which includes Lynch syndrome, Familial CRC type X, Familial adenomatous polyposis, MutYH-associated polyposis, Juvenile polyposis syndrome, Peutz-Jeghers Syndrome and sporadic forms of EOCRC. Recent findings about molecular genetics and epigenetic basis of EOCRC gave rise to new alternative therapy protocols. Although exact diagnosis of these cases still remains complicated, the present review paves way for better predictions and contributes to more accurate diagnostic and therapeutic strategies into clinical approach. PMID:26798439

  17. Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer.

    PubMed

    Tezcan, Gulcin; Tunca, Berrin; Ak, Secil; Cecener, Gulsah; Egeli, Unal

    2016-01-15

    Colorectal cancer (CRC) is the third most frequent cancer type and the incidence of this disease is increasing gradually per year in individuals younger than 50 years old. The current knowledge is that early-onset CRC (EOCRC) cases are heterogeneous population that includes both hereditary and sporadic forms of the CRC. Although EOCRC cases have some distinguishing clinical and pathological features than elder age CRC, the molecular mechanism underlying the EOCRC is poorly clarified. Given the significance of CRC in the world of medicine, the present review will focus on the recent knowledge in the molecular basis of genetic and epigenetic mechanism of the hereditary forms of EOCRC, which includes Lynch syndrome, Familial CRC type X, Familial adenomatous polyposis, MutYH-associated polyposis, Juvenile polyposis syndrome, Peutz-Jeghers Syndrome and sporadic forms of EOCRC. Recent findings about molecular genetics and epigenetic basis of EOCRC gave rise to new alternative therapy protocols. Although exact diagnosis of these cases still remains complicated, the present review paves way for better predictions and contributes to more accurate diagnostic and therapeutic strategies into clinical approach. PMID:26798439

  18. Reduced Cortisol in Boys with Early-Onset Conduct Disorder and Callous-Unemotional Traits

    PubMed Central

    von Polier, Georg G.; Herpertz-Dahlmann, Beate; Wiesler, Kristine; Rieke, Jana; Heinzel-Gutenbrunner, Monika; Bachmann, Christian J.; Vloet, Timo D.

    2013-01-01

    Background. A growing body of evidence suggests an association between altered hypothalamic-pituitary-adrenal axis reactivity and the development of persistent antisocial behavior in children. However the effects of altered cortisol levels remain poorly understood in the complex context of conduct disorder, callous-unemotional (CU) personality traits, and frequent comorbidities, such as attention deficit hyperactivity disorder (ADHD). The aim of the current study was to investigate associations among CU traits, antisocial behavior, and comorbid ADHD symptomatology with cortisol levels in male children and adolescents. Methods. The study included 37 boys with early-onset conduct disorder (EO-CD, mean age 11.9 years) and 38 healthy boys (mean age 12.5 years). Participants were subjected to multiple daytime salivary cortisol measurements and a psychometric characterization. Results. Subjects in the EO-CD group with elevated CU traits showed a diminished cortisol awakening response compared to healthy participants. In the EO-CD group, high CU traits and impulsivity were associated with decreased diurnal cortisol levels, while associations with antisocial behavior were not detected. The cortisol awakening response was significantly inversely associated with hyperactivity (P = 0.02) and marginally significant with CU traits (P = 0.07). Conclusions. These results indicate a specific association between CU traits and a diminished stress response, which is not explained by antisocial behavior in general. PMID:23841064

  19. Critical slowing down as early warning for the onset of collapse in mutualistic communities.

    PubMed

    Dakos, Vasilis; Bascompte, Jordi

    2014-12-01

    Tipping points are crossed when small changes in external conditions cause abrupt unexpected responses in the current state of a system. In the case of ecological communities under stress, the risk of approaching a tipping point is unknown, but its stakes are high. Here, we test recently developed critical slowing-down indicators as early-warning signals for detecting the proximity to a potential tipping point in structurally complex ecological communities. We use the structure of 79 empirical mutualistic networks to simulate a scenario of gradual environmental change that leads to an abrupt first extinction event followed by a sequence of species losses until the point of complete community collapse. We find that critical slowing-down indicators derived from time series of biomasses measured at the species and community level signal the proximity to the onset of community collapse. In particular, we identify specialist species as likely the best-indicator species for monitoring the proximity of a community to collapse. In addition, trends in slowing-down indicators are strongly correlated to the timing of species extinctions. This correlation offers a promising way for mapping species resilience and ranking species risk to extinction in a given community. Our findings pave the road for combining theory on tipping points with patterns of network structure that might prove useful for the management of a broad class of ecological networks under global environmental change. PMID:25422412

  20. Characterization of a novel genetically obese mouse model demonstrating early onset hyperphagia and hyperleptinemia.

    PubMed

    Nakahara, Keiko; Bannai, Makoto; Maruyama, Keisuke; Suzuki, Yoshihiro; Okame, Rieko; Murakami, Noboru

    2013-08-01

    Obesity is a critical risk factor for the development of metabolic syndrome, and many obese animal models are used to investigate the mechanisms responsible for the appearance of symptoms. To establish a new obese mouse model, we screened ?13,000 ICR mice and discovered a mouse demonstrating spontaneous obesity. We named this mouse "Daruma" after a traditional Japanese ornament. Following the fixation of the genotype, these animals exhibited obese phenotypes according to Mendel's law of inheritance. In the Daruma mouse, the leptin receptor gene sequence carried two base mutations that are good candidates for the variation(s) responsible for the obese phenotype. The Daruma mice developed characteristic visceral fat accumulation at 4 wk of age, and the white adipose and liver tissues exhibited increases in cell size and lipid droplets, respectively. No histological abnormalities were observed in other tissues of the Daruma mice, even after the mice reached 25 wk of age. Moreover, the onset of impaired leptin signaling was early and manifested as hyperleptinemia and hyperinsulinemia. Pair feeding completely inhibited obesity, although these mice rapidly developed hyperphagia and obesity followed by hyperleptinemia when pair feeding ceased and free-access feeding was permitted. Therefore, the Daruma mice exhibited unique characteristics and may be a good model for studying human metabolic syndrome. PMID:23736543

  1. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.

    PubMed

    Milner, Joshua D; Vogel, Tiphanie P; Forbes, Lisa; Ma, Chi A; Stray-Pedersen, Asbjrg; Niemela, Julie E; Lyons, Jonathan J; Engelhardt, Karin R; Zhang, Yu; Topcagic, Nermina; Roberson, Elisha D O; Matthews, Helen; Verbsky, James W; Dasu, Trivikram; Vargas-Hernandez, Alexander; Varghese, Nidhy; McClain, Kenneth L; Karam, Lina B; Nahmod, Karen; Makedonas, George; Mace, Emily M; Sorte, Hanne S; Perminow, Gri; Rao, V Koneti; O'Connell, Michael P; Price, Susan; Su, Helen C; Butrick, Morgan; McElwee, Joshua; Hughes, Jason D; Willet, Joseph; Swan, David; Xu, Yaobo; Santibanez-Koref, Mauro; Slowik, Voytek; Dinwiddie, Darrell L; Ciaccio, Christina E; Saunders, Carol J; Septer, Seth; Kingsmore, Stephen F; White, Andrew J; Cant, Andrew J; Hambleton, Sophie; Cooper, Megan A

    2015-01-22

    Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350. PMID:25359994

  2. Molecular alterations in gastric cancer with special reference to the early-onset subtype

    PubMed Central

    Skierucha, Małgorzata; Milne, Anya NA; Offerhaus, G Johan A; Polkowski, Wojciech P; Maciejewski, Ryszard; Sitarz, Robert

    2016-01-01

    Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g., Helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC. PMID:26937134

  3. NAPB - a novel SNARE-associated protein for early-onset epileptic encephalopathy.

    PubMed

    Conroy, J; Allen, N M; Gorman, K M; Shahwan, A; Ennis, S; Lynch, S A; King, M D

    2016-02-01

    Next-generation sequencing has accelerated the identification of disease genes in many rare genetic disorders including early-onset epileptic encephalopathies (EOEEs). While many of these disorders are caused by neuronal channelopathies, the role of synaptic and related neuronal proteins are increasingly being described. Here, we report a 6-year-old girl with unexplained EOEE characterized by multifocal seizures and profound global developmental delay. Recessive inheritance was considered due to parental consanguinity and Irish Traveller descent. Exome sequencing was performed. Variant prioritization identified a homozygous nonsense variant in the N-ethylmaleimide-sensitive factor attachment protein, beta (NAPB) gene resulting in a premature stop codon and 46% loss of the protein. NAPB plays a role in soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE)-complex dissociation and recycling (synaptic vesicle docking). Knockout mouse models of the murine ortholog Napb have been previously reported. These mice develop recurrent post-natal epileptic seizures in the absence of structural brain changes. The identification of a disease-causing variant in NAPB further recognizes the importance of the SNARE complex in the development of epilepsy and suggests that this gene should be considered in patients with unexplained EOEE. PMID:26235277

  4. Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features

    PubMed Central

    Lessel, Davor; Vaz, Bruno; Halder, Swagata; Lockhart, Paul J; Marinovic-Terzic, Ivana; Lopez-Mosqueda, Jaime; Philipp, Melanie; Sim, Joe C H; Smith, Katherine R; Oehler, Judith; Cabrera, Elisa; Freire, Raimundo; Pope, Kate; Nahid, Amsha; Norris, Fiona; Leventer, Richard J; Delatycki, Martin B; Barbi, Gotthold; von Ameln, Simon; Hgel, Josef; Degoricija, Marina; Fertig, Regina; Burkhalter, Martin D; Hofmann, Kay; Thiele, Holger; Altmller, Janine; Nrnberg, Gudrun; Nrnberg, Peter; Bahlo, Melanie; Martin, George M; Aalfs, Cora M; Oshima, Junko; Terzic, Janos; Amor, David J; Dikic, Ivan; Ramadan, Kristijan; Kubisch, Christian

    2015-01-01

    Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1)17 in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis17. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma. PMID:25261934

  5. Children's parasympathetic reactivity to specific emotions moderates response to intervention for early-onset aggression.

    PubMed

    Gatzke-Kopp, Lisa M; Greenberg, Mark; Bierman, Karen

    2015-01-01

    Following theories that individual differences in respiratory sinus arrhythmia (RSA) denote differential sensitivity to environmental influences, this study examines whether differences in RSA reactivity to specific emotional challenges predict differential response to intervention. We present data from a randomized clinical trial of a targeted intervention for early onset aggression. In collaboration with a high-risk urban school district, 207 kindergarten children (73% African American, 66% male), identified by their teachers as having high levels of aggressive and disruptive behavior, were recruited. All children received a universal social-emotional curriculum. One hundred children were randomly assigned to an additional intervention consisting of weekly peer-based social skills training. Complete RSA data were available for 139 of the children. Teacher-reported externalizing symptoms and emotion regulation in 1st grade (post intervention) were examined controlling for baseline levels. First-grade peer nominations of aggressive behavior, controlling for baseline nominations, were also examined as outcomes. No effect of resting RSA was found. However, greater reactivity to anger was associated with higher externalizing symptoms and lower emotion regulation skills in 1st grade relative to low reactive children. Lower reactivity to fear was associated with greater improvement over time, an effect that was enhanced in the targeted intervention condition. Results suggest that measures of affective reactivity may provide insight into children's capacity to benefit from different types of interventions. PMID:24308798

  6. Critical slowing down as early warning for the onset of collapse in mutualistic communities

    PubMed Central

    Dakos, Vasilis; Bascompte, Jordi

    2014-01-01

    Tipping points are crossed when small changes in external conditions cause abrupt unexpected responses in the current state of a system. In the case of ecological communities under stress, the risk of approaching a tipping point is unknown, but its stakes are high. Here, we test recently developed critical slowing-down indicators as early-warning signals for detecting the proximity to a potential tipping point in structurally complex ecological communities. We use the structure of 79 empirical mutualistic networks to simulate a scenario of gradual environmental change that leads to an abrupt first extinction event followed by a sequence of species losses until the point of complete community collapse. We find that critical slowing-down indicators derived from time series of biomasses measured at the species and community level signal the proximity to the onset of community collapse. In particular, we identify specialist species as likely the best-indicator species for monitoring the proximity of a community to collapse. In addition, trends in slowing-down indicators are strongly correlated to the timing of species extinctions. This correlation offers a promising way for mapping species resilience and ranking species risk to extinction in a given community. Our findings pave the road for combining theory on tipping points with patterns of network structure that might prove useful for the management of a broad class of ecological networks under global environmental change. PMID:25422412

  7. The early Miocene onset of a ventilated circulation regime in the Arctic Ocean.

    PubMed

    Jakobsson, Martin; Backman, Jan; Rudels, Bert; Nycander, Jonas; Frank, Martin; Mayer, Larry; Jokat, Wilfried; Sangiorgi, Francesca; O'Regan, Matthew; Brinkhuis, Henk; King, John; Moran, Kathryn

    2007-06-21

    Deep-water formation in the northern North Atlantic Ocean and the Arctic Ocean is a key driver of the global thermohaline circulation and hence also of global climate. Deciphering the history of the circulation regime in the Arctic Ocean has long been prevented by the lack of data from cores of Cenozoic sediments from the Arctic's deep-sea floor. Similarly, the timing of the opening of a connection between the northern North Atlantic and the Arctic Ocean, permitting deep-water exchange, has been poorly constrained. This situation changed when the first drill cores were recovered from the central Arctic Ocean. Here we use these cores to show that the transition from poorly oxygenated to fully oxygenated ('ventilated') conditions in the Arctic Ocean occurred during the later part of early Miocene times. We attribute this pronounced change in ventilation regime to the opening of the Fram Strait. A palaeo-geographic and palaeo-bathymetric reconstruction of the Arctic Ocean, together with a physical oceanographic analysis of the evolving strait and sill conditions in the Fram Strait, suggests that the Arctic Ocean went from an oxygen-poor 'lake stage', to a transitional 'estuarine sea' phase with variable ventilation, and finally to the fully ventilated 'ocean' phase 17.5 Myr ago. The timing of this palaeo-oceanographic change coincides with the onset of the middle Miocene climatic optimum, although it remains unclear if there is a causal relationship between these two events. PMID:17581581

  8. Therapeutic implications of novel mutations of the RFX6 gene associated with early-onset diabetes.

    PubMed

    Artuso, R; Provenzano, A; Mazzinghi, B; Giunti, L; Palazzo, V; Andreucci, E; Blasetti, A; Chiuri, R M; Gianiorio, F E; Mandich, P; Monami, M; Mannucci, E; Giglio, S

    2015-02-01

    Identification of the genetic defect underlying early-onset diabetes is important for determining the specific diabetes subtype, which would then permit appropriate treatment and accurate assessment of recurrence risk in offspring. Given the extensive genetic and clinical heterogeneity of the disease, high-throughput sequencing might provide additional diagnostic potential when Sanger sequencing is ineffective. Our aim was to develop a targeted next-generation assay able to detect mutations in several genes involved in glucose metabolism. All 13 known MODY genes, genes identified from a genome-wide linkage study or genome-wide association studies as increasing the risk of type 2 diabetes and genes causing diabetes in animal models, were included in the custom panel. We selected a total of 102 genes by performing a targeting re-sequencing in 30 patients negative for mutations in the GCK, HNF1α, HNF4α, HNF1β and IPF1 genes at the Sanger sequencing analysis. Previously unidentified variants in the RFX6 gene were found in three patients and in two of them we also detected rare variants in WFS1 and ABCC8 genes. All patients showed a good therapeutic response to dipeptidyl peptidase-4 (DPP4) inhibitors. Our study reveals that next-generation sequencing provides a highly sensitive method for identification of variants in new causative genes of diabetes. This approach may help in understanding the molecular etiology of diabetes and in providing more personalized treatment for each genetic subtype. PMID:25048417

  9. THE ROLE OF PROTEOMICS IN THE DIAGNOSIS OF CHORIOAMNIONITIS AND EARLY-ONSET NEONATAL SEPSIS

    PubMed Central

    Buhimschi, Catalin S.

    2010-01-01

    SYNOPSIS Intra-uterine infection is viewed as a unique pathological process which raises considerably the risk for early onset neonatal sepsis (EONS). By acting synergistically with prematurity, EONS increases the risk for adverse neonatal outcomes including intraventricular hemorrhage (IVH) and cerebral palsy which are often encountered as sequelae of sepsis. Although several distinct pathways for the pathogenesis of fetal damage have been proposed, the basic molecular mechanisms that modulate these events remain incompletely understood. Therefore, discovery of clinically and biologically relevant biomarkers able to reveal key pathogenic pathways and predict pregnancies at risk for antenatal fetal damage is a priority. Proteomics provides a unique opportunity to fill this gap. In the short run proteomic biomarkers may aid with medical decision-making including timing of delivery and steroid administration In the long run proteomic biomarkers may lead to development of targeted therapies against pathogenic variants of EONS. Herein, we aimed to illustrate the richness of the topic and set the stage for the argument that discovery of novel proteomic biomarkers is a critical step in improving outcomes and preventing long-term disability. PMID:20569812

  10. Transcriptional Onset of Lysozyme Genes during Early Development in Olive Flounder (Paralichthys olivaceus)

    PubMed Central

    Lee, Jang-Wook; Lee, Jeong-Ho; Noh, Jae Koo; Kim, Hyun Chul; Park, Choul-Ji; Park, Jong-Won; Kim, Kyung-Kil

    2014-01-01

    The immune system in teleost fish is not completely developed during embryonic and larval stages, therefore effective innate mechanisms is very important for survival in such an environment. However, the knowledge of the development of immune system assumed to be restricted. In many species, lysozymes have been considered as important genes of the first line immune defense. The early detection of lysozyme mRNA in previous reports, led to the investigation of its presence in oocytes. As a result, c-type lysozyme mRNA transcripts were detected in unfertilized oocytes indicating maternal transfer. Therefore, we investigated the expression patterns of lysozymes in flounder, including the matured oocyte. In our results, c-type lysozyme mRNA was first detected in unfertilized oocyte stage, observed the significantly decreased until hatching stage, and was significantly increased after hatching stage. On the other hand, g-type lysozyme mRNA transcripts were first detected at late neurula stage, and the mRNA level was significantly increased after 20 dph. It may be suggest that maternally supplied mRNAs are selectively degraded prior to the activation of embryonic transcription. This study will be help in understanding the maturation and onset of humoral immunity during development of olive flounder immune system. PMID:25949197

  11. On the early onset of the NLC season 2013 as observed at ALOMAR

    NASA Astrophysics Data System (ADS)

    Fiedler, Jens; Baumgarten, Gerd; Berger, Uwe; Gabriel, Axel; Latteck, Ralph; Lbken, Franz-Josef

    2015-05-01

    On 21 May the ALOMAR RMR-lidar in Northern Norway detected the first noctilucent clouds (NLC) in 2013. This unusual early NLC onset was accompanied by ?6 K lower temperatures and higher water vapor mixing ratios at NLC altitudes from the end of April until the beginning of June. The zonal mean temperature and dynamic conditions in the Arctic middle atmosphere deviated in spring 2013 significantly from the mean conditions of the last 20 years. Furthermore the planetary wave activity in the high latitude stratosphere was enhanced from 20 April to beginning of May. The colder and wetter upper mesosphere in May 2013 is attributed to this unusual late planetary wave activity in the stratosphere, introducing a strong upwelling in the mesosphere, lower temperatures and an upward transport of water vapor, which finally resulted in earlier existence conditions for mesospheric ice particles. We regard this as a first evidence for intra-hemispheric coupling in the northern hemisphere extending from the stratosphere into the mesopause region. Yet it is unclear whether this is an unusual extreme event or an indicator for a change in the circulation due to the observed long-term cooling of the middle atmosphere.

  12. Molecular alterations in gastric cancer with special reference to the early-onset subtype.

    PubMed

    Skierucha, Małgorzata; Milne, Anya Na; Offerhaus, G Johan A; Polkowski, Wojciech P; Maciejewski, Ryszard; Sitarz, Robert

    2016-02-28

    Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g., Helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC. PMID:26937134

  13. Facial, vocal and cross-modal emotion processing in early-onset schizophrenia spectrum disorders.

    PubMed

    Giannitelli, Marianna; Xavier, Jean; François, Anne; Bodeau, Nicolas; Laurent, Claudine; Cohen, David; Chaby, Laurence

    2015-10-01

    Recognition of emotional expressions plays an essential role in children's healthy development. Anomalies in these skills may result in empathy deficits, social interaction difficulties and premorbid emotional problems in children and adolescents with schizophrenia. Twenty-six subjects with early onset schizophrenia spectrum (EOSS) disorders and twenty-eight matched healthy controls (HC) were instructed to identify five basic emotions and a neutral expression. The assessment entailed presenting visual, auditory and congruent cross-modal stimuli. Using a generalized linear mixed model, we found no significant association for handedness, age or gender. However, significant associations emerged for emotion type, perception modality, and group. EOSS patients performed worse than HC in uni- and cross-modal emotional tasks with a specific negative emotion processing impairment pattern. There was no relationship between emotion identification scores and positive or negative symptoms, self-reported empathy traits or a positive history of developmental disorders. However, we found a significant association between emotional identification scores and nonverbal communication impairments. We conclude that cumulative dysfunctions in both nonverbal communication and emotion processing contribute to the social vulnerability and morbidity found in youths who display EOSS disorder. PMID:26297473

  14. Drosophila models of early onset cognitive disorders and their clinical applications.

    PubMed

    van der Voet, Monique; Nijhof, Bonnie; Oortveld, Merel A W; Schenck, Annette

    2014-10-01

    The number of genes known to cause human monogenic diseases is increasing rapidly. For the extremely large, genetically and phenotypically heterogeneous group of intellectual disability (ID) disorders, more than 600 causative genes have been identified to date. However, knowledge about the molecular mechanisms and networks disrupted by these genetic aberrations is lagging behind. The fruit fly Drosophila has emerged as a powerful model organism to close this knowledge gap. This review summarizes recent achievements that have been made in this model and envisions its future contribution to our understanding of ID genetics and neuropathology. The available resources and efficiency of Drosophila place it in a position to tackle the main challenges in the field: mapping functional modules of ID genes to provide conceptually novel insights into the genetic control of cognition, tailored functional studies to improve 'next-generation' diagnostics, and identification of reversible ID phenotypes and medication. Drosophila's behavioral repertoire and powerful genetics also open up perspectives for modeling genetically complex forms of ID and neuropsychiatric disorders, which overlap in their genetic etiologies. In conclusion, Drosophila provides many opportunities to advance future medical genomics of early onset cognitive disorders. PMID:24661984

  15. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations

    PubMed Central

    Vogel, Tiphanie P.; Forbes, Lisa; Ma, Chi A.; Stray-Pedersen, Asbjrg; Niemela, Julie E.; Lyons, Jonathan J.; Engelhardt, Karin R.; Zhang, Yu; Topcagic, Nermina; Roberson, Elisha D. O.; Matthews, Helen; Verbsky, James W.; Dasu, Trivikram; Vargas-Hernandez, Alexander; Varghese, Nidhy; McClain, Kenneth L.; Karam, Lina B.; Nahmod, Karen; Makedonas, George; Mace, Emily M.; Sorte, Hanne S.; Perminow, Gri; Rao, V. Koneti; OConnell, Michael P.; Price, Susan; Su, Helen C.; Butrick, Morgan; McElwee, Joshua; Hughes, Jason D.; Willet, Joseph; Swan, David; Xu, Yaobo; Santibanez-Koref, Mauro; Slowik, Voytek; Dinwiddie, Darrell L.; Ciaccio, Christina E.; Saunders, Carol J.; Septer, Seth; Kingsmore, Stephen F.; White, Andrew J.; Cant, Andrew J.; Hambleton, Sophie

    2015-01-01

    Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350. PMID:25359994

  16. Characterization of an Early-Onset, Autosomal Recessive, Progressive Retinal Degeneration in Bengal Cats

    PubMed Central

    Ofri, Ron; Reilly, Christopher M.; Maggs, David J.; Fitzgerald, Paul G.; Shilo-Benjamini, Yael; Good, Kathryn L.; Grahn, Robert A.; Splawski, Danielle D.; Lyons, Leslie A.

    2015-01-01

    Purpose A form of retinal degeneration suspected to be hereditary was discovered in a family of Bengal cats. A breeding colony was established to characterize disease progression clinically, electrophysiologically, and morphologically, and to investigate the mode of inheritance. Methods Affected and related cats were donated by owners for breeding trials and pedigree analysis. Kittens from test and complementation breedings underwent ophthalmic and neuro-ophthalmic examinations and ERG, and globes were evaluated using light microscopy. Results Pedigree analysis, along with test and complementation breedings, indicated autosomal recessive inheritance and suggested that this disease is nonallelic to a retinal degeneration found in Persian cats. Mutation analysis confirmed the disease is not caused by CEP290 or CRX variants found predominantly in Abyssinian and Siamese cats. Ophthalmoscopic signs of retinal degeneration were noted at 9 weeks of age and became more noticeable over the next 4 months. Visual deficits were behaviorally evident by 1 year of age. Electroretinogram demonstrated reduced rod and cone function at 7 and 9 weeks of age, respectively. Rod responses were mostly extinguished at 14 weeks of age; cone responses were minimal by 26 weeks. Histologic degeneration was first observed at 8 weeks, evidenced by reduced photoreceptor numbers, then rapid deterioration of the photoreceptor layer and, subsequently, severe outer retinal degeneration. Conclusions A recessively inherited primary photoreceptor degeneration was characterized in the Bengal cat. The disease is characterized by early onset, with histologic, ophthalmoscopic, and electrophysiological signs evident by 2 months of age, and rapid progression to blindness. PMID:26258614

  17. Cutaneous granulomas and epidermodysplasia verruciformis in early onset combined immunodeficiency syndrome.

    PubMed

    Wang, Yen T; Geng, Bob; Yoo, Ki-Young; Stiehm, Ewald R; Garcia-Lloret, Maria; Wong, Derek; Smart, Chandra; Worswick, Scott; Barnhill, Raymond L

    2014-02-01

    Cutaneous granulomas with prominent caseating necrosis are a rare manifestation of immunodeficiency. Extensive and recalcitrant cutaneous viral infections can also be seen. We present a case of an 18-year-old white man with an early onset poorly characterized combined immunodeficiency syndrome who, over the past 5 years, developed enlarging tender red-purple plaques on his extremities and pink near-confluent macules on his chest and back. Previous biopsies of the red-purple plaques showed features of granuloma annulare. Histopathological examination of old and new biopsies revealed both sarcoidal and palisading necrobiotic granulomas with perforating features and elastophagocytosis. Stains and tissue cultures were negative for bacterial and fungal organisms. In addition, biopsy of a macule on the back demonstrated verruca plana with characteristics of epidermodysplasia verruciformis. As an infant, the patient had failure to thrive and a combined immunodeficiency, but was lost to follow-up for 15 years. He currently continues to have severe hypogammaglobinemia and cellular immunodeficiency. Intravenous immunoglobulin and prednisone were initiated and his plaques improved rapidly. Topical imiquimod was ineffective for the verruca plana. The patient and his parents are currently undergoing whole exome sequencing including evaluation for epidermodysplasia verruciformis 1 and 2 gene mutations. This case highlights the importance of including genetic immunodeficiency disorders in the clinical and histopathological differential diagnosis for cutaneous sarcoidal or palisading necrobiotic granulomas and for extensive cutaneous viral infection. PMID:24247584

  18. Altered expression of mRNA profiles in blood of early-onset schizophrenia.

    PubMed

    Xu, Yong; Yao Shugart, Yin; Wang, Guoqiang; Cheng, Zaohuo; Jin, Chunhui; Zhang, Kai; Wang, Jun; Yu, Hao; Yue, Weihua; Zhang, Fuquan; Zhang, Dai

    2016-01-01

    To identify gene expression abnormalities in schizophrenia (SZ), we generated whole-genome gene expression profiles using microarrays on peripheral blood mononuclear cells (PBMCs) from 18 early-onset SZ cases and 12 controls. We detected 84 transcripts differentially expressed by diagnostic status, with 82 genes being upregulated and 2 downregulated. We identified two SZ associated gene coexpression modules (green and red), including 446 genes . The green module is positively correlated with SZ, encompassing predominantly up-regulated genes in SZ; while the red module was negatively correlated with disease status, involving mostly nominally down-regulated genes in SZ. The olfactory transduction pathway was the most enriched pathways for the genes within the two modules. The expression levels of several hub genes, including AKT1, BRCA1, CCDC134, UBD, and ZIC2 were validated using real-time quantitative PCR. Our findings indicate that mRNA coexpression abnormalities may serve as a promising mechanism underlying the development of SZ. PMID:26733343

  19. Common Variants in Promoter of ADTRP Associate with Early-Onset Coronary Artery Disease in a Southern Han Chinese Population

    PubMed Central

    Huang, Lei; Wu, Qiu-Ping; Tang, Shuang-Bo; Luo, Bin; Liu, Shui-Ping; Liu, Xiao-Shan; Li, Zhao-Hui; Quan, Li; Li, Yue; Shi, He; Lv, Guo-Li; Zhao, Jian; Cheng, Jian-Ding; Liu, Chao

    2015-01-01

    The first genome-wide association study for coronary artery disease (CAD) in the Han Chinese population, we reported recently, had identified rs6903956 in gene ADTRP on chromosome 6p24.1 as a novel susceptibility locus for CAD. The risk allele of rs6903956 was associated with decreased mRNA expression of ADTRP. To further study the correlation of ADTRP expression and CAD, in this study we evaluated the associations of eight common variants in the expression-regulating regions of ADTRP with CAD in the Southern Han Chinese population. Rs169790 in 3UTR, rs2076189 in 5UTR, four SNPs (rs2076188, rs7753407, rs11966356 and rs1018383) in promoter, and two SNPs (rs3734273, rs80355771) in the last intron of ADTRP were genotyped in 1716 CAD patients and 1572 controls. The correlations between these loci and total or early-onset CAD were investigated. None of these loci was discovered to associate with total CAD (P > 0.05). However, with early-onset CAD, significant both allelic and genotypic associations of rs7753407, rs11966356 and rs1018383 were identified, after adjustment for risk factors of age, gender, hypertension, diabetes, lipid profiles and smoking (adjusted P < 0.05). A haplotype AGCG (constructed by rs2076188, rs7753407, rs11966356 and rs1018383) was identified to protect subjects from early-onset CAD (OR = 0.332, 95% CI = 0.1050.879, adjusted P = 0.010). Real-time quantitative reverse transcription polymerase chain reaction assay showed that the risk alleles of the associated loci were significantly associated with decreased expression of ADTRP mRNA. Moreover, the average level of ADTRP mRNA expression in early-onset CAD cases was significantly lower than that in controls. Our results provide new evidence supporting the association of ADTRP with the pathogenesis of early-onset CAD. PMID:26375920

  20. Identification of the PS1 Thr147Ile Variant in a Family with Very Early Onset Dementia and Expressive Aphasia

    PubMed Central

    Denvir, James; Neitch, Shirley; Fan, Jun; Niles, Richard M.; Boskovic, Goran; Schreurs, Bernard G.; Primerano, Donald A.; Alkon, Daniel L.

    2015-01-01

    Background Early onset dementias have variable clinical presentations and are often difficult to diagnose. We established a family pedigree that demonstrated consistent recurrence of very early onset dementia in successive generations. Objective and Method In order to refine the diagnosis in this family, we sequenced the exomes of two affected family members and relied on discrete filtering to identify disease genes and the corresponding causal variants. Results Among the 720 nonsynonymous single nucleotide polymorphisms (SNPs) shared by two affected members, we found a C to T transition that gives rise to a Thr147Ile missense substitution in the presenilin 1 (PS1) protein. The presence of this same mutation in a French early-onset Alzheimer’s disease family, other affected members of the family, and the predicted high pathogenicity of the substitution strongly suggest that it is the causal variant. In addition to exceptionally young age of onset, we also observed significant limb spasticity and early loss of speech, concurrent with progression of dementia in affected family members. These findings extend the clinical presentation associated with the Thr147Ile variant. Lastly, one member with the Thr147Ile variant was treated with the PKC epsilon activator, bryostatin, in a compassionate use trial after successful FDA review. Initial improvements with this treatment were unexpectedly clear, including return of some speech, increased attentional focus, ability to swallow, and some apparent decrease in limb spasticity. Conclusions Our findings confirm the role of the PS1 Thr147Ile substitution in Alzheimer’s disease and expand the clinical phenotype to include expressive aphasia and very early onset of dementia. PMID:25812849

  1. Early drinking onset: a study of prevalence and determinants among 13-year-old adolescents in Norway.

    PubMed

    Adolfsen, Frode; Strm, Henriette Kyrrestad; Martinussen, Monica; Natvig, Henrik; Eisemann, Martin; Handegrd, Bjrn Helge; Koposov, Roman

    2014-10-01

    Early drinking onset is associated with different psychosocial adjustment problems among adolescents. The aim of this study was to assess determinants associated with early drinking and to identify factors predicting early drinking onset among adolescents. The study included 1,550 eighth-graders with a mean age of 13.5years from 41 schools. A total of 24% (boys 29%, girls 19%) had ever drunk alcohol, while 14% had drunk some alcohol in the last 30days. Further, early drinking was associated with gender, religion, school performance, smoking and bullying in the bivariate tests. Predictors of early drinking onset were identified by generalized linear mixed models with two multivariable models created. The first model included social and environmental variables. Entering intentions, expectancies, attitudes and norms into the multivariable analysis resulted in a significant improvement of the model fit constituting 86% in the second model. The percentage correctly classified those (56%) who had been drinking in the second model which was two times higher compared to the first model. Gender, religion and smoking emerged as significant predictors of drinking in both models. PMID:25070139

  2. Molecular Features and Methylation Status in Early Onset (≤40 Years) Colorectal Cancer: A Population Based, Case-Control Study

    PubMed Central

    Magnani, Giulia; Furlan, Daniela; Sahnane, Nora; Reggiani Bonetti, Luca; Domati, Federica; Pedroni, Monica

    2015-01-01

    Colorectal cancer is usually considered a disease of the elderly. However, a small fraction of patients develops colorectal cancer earlier. The aim of our study was to define the frequency of known hereditary colorectal syndromes and to characterise genetic and epigenetic features of early nonhereditary tumors. Thirty-three patients ≤40 years with diagnosis of colorectal cancer and 41 patients with disease at >60 years of age were investigated for MSI, Mismatch Repair proteins expression, KRAS and BRAF mutations, hypermethylation, and LINE-1 hypomethylation. Detection of germline mutations was performed in Mismatch Repair, APC and MUTYH genes. Early onset colorectal cancer showed a high incidence of hereditary forms (18%). KRAS mutations were detected in 36% of early nonhereditary tumors. Early onset colorectal cancer disclosed an average number of methylated genes significantly lower when compared to the controls (p = 0.02). Finally both of the two groups were highly methylated in ESR1, GATA5, and WT1 genes and were similar for LINE-1 hypomethylation. The genetic make-up of carcinomas differs from young to elderly patients. Early onset tumors showed more frequently a constitutional defective of Mismatch Repair System and a minor number of methylated genes. Hypermethylation of ESR1, GATA5, and WT1 genes suggests possible markers in the earlier diagnosis of colorectal tumorigenesis. PMID:26557847

  3. From apneic spells to the development of hypertensive hydrocephalus: a case report of homocystinuria with early onset.

    PubMed

    Cerbo, Rosa Maria; Cabano, Rita; Lombardi, Giuseppina; Bollani, Lina; Colombo, Roberto; Stronati, Mauro

    2010-03-01

    Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of homocysteine in the serum and an increased excretion of homocysteine in the urine. The infantile form is severe: the main clinical findings are neurologic signs, associated with hematological signs and bone alterations. Immediate restoration of plasma amino acids is the primary goal and early diagnosis is crucial not to delay the onset of possible treatment. We report a case of homocystinuria with early onset: an initial symptomatology was undervalued by the pediatrician with a delay in diagnosis. Despite the therapy, the patient developed tetraventricular hydrocephalus requiring ventricular drainage. In conclusion, we want to remember the necessity to perform a complete metabolic workup in a patient with clinical manifestations suggestive for homocystinuria, and the importance of early recognition of the signs and symptoms of hypertensive hydrocephalus, a possible complication of this condition. PMID:19509410

  4. Gray Matter Alterations in Schizophrenia High-Risk Youth and Early-Onset Schizophrenia: A Review of Structural MRI Findings

    PubMed Central

    Brent, Benjamin K.; Thermenos, Heidi W.; Keshavan, Matcheri S.; Seidman, Larry J.

    2013-01-01

    Synopsis The purpose of this article is to provide a review of the literature on structural MRI findings in pediatric and young adult populations at clinical or genetic high-risk for schizophrenia, as well as in early-onset schizophrenia. The authors discuss the implications of this research for understanding the pathophysiology of schizophrenia and for early intervention strategies for prevention of the illness. The evidence linking brain structural changes in pre-psychosis development and early-onset schizophrenia with disruptions of normal neurodevelopmental processes during childhood and/or adolescence are described. In addition, the authors outline future directions for research to address current knowledge gaps regarding the neurobiological basis of brain structural abnormalities in schizophrenia and to help improve the utility of these abnormalities for preventative interventions. PMID:24012081

  5. Nonsurgical periodontal therapy.

    PubMed

    Drisko, C H

    2001-01-01

    Regular home care by the patient in addition to professional removal of subgingival plaque is generally very effective in controlling most inflammatory periodontal diseases. When disease does recur, despite frequent recall, it can usually be attributed to lack of sufficient supragingival and subgingival plaque control or to other risk factors that influence host response, such as diabetes or smoking. Causative factors contributing to recurrent disease include deep inaccessible pockets, overhangs, poor crown margins and plaque-retentive calculus. In most cases, simply performing a thorough periodontal debridement under local anesthesia will stop disease progression and result in improvement in the clinical signs and symptoms of active disease. If however, clinical signs of disease activity persist following thorough mechanical therapy, such as increased pocket depths, loss of attachment and bleeding on probing, other pharmacotherapeutic therapies should be considered. Augmenting scaling and root planing or maintenance visits with adjunctive chemotherapeutic agents for controlling plaque and gingivitis could be as simple as placing the patient on an antimicrobial mouthrinse and/or toothpaste with agents such as fluorides, chlorhexidine or triclosan, to name a few. Since supragingival plaque reappears within hours or days after its removal, it is important that patients have access to effective alternative chemotherapeutic products that could help them achieve adequate supragingival plaque control. Recent studies, for example, have documented the positive effect of triclosan toothpaste on the long-term maintenance of both gingivitis and periodontitis patients. Daily irrigation with a powered irrigation device, with or without an antimicrobial agent, is also useful for decreasing the inflammation associated with gingivitis and periodontitis. Clinically significant changes in probing depths and attachment levels are not usually expected with irrigation alone. Recent reports, however, would indicate that, when daily irrigation with water was added to a regular oral hygiene home regimen, a significant reduction in probing depth, bleeding on probing and Gingival Index was observed. A significant reduction in cytokine levels (interleukin-1beta and prostaglandin E2, which are associated with destructive changes in inflamed tissues and bone resorption also occurs. If patient-applied antimicrobial therapy is insufficient in preventing, arresting, or reversing the disease progression, then professionally applied antimicrobial agents should be considered including sustained local drug delivery products. Other, more broadly based pharmacotherapeutic agents may be indicated for multiple failing sites. Such agents would include systemic antibiotics or host modulating drugs used in conjunction with periodontal debridement. More aggressive types of juvenile periodontitis or severe rapidly advancing adult periodontitis usually require a combination of surgical intervention in conjunction with systemic antibiotics and generally are not controlled with nonsurgical anti-infective therapy alone. It should be noted, however, that, to date, no home care products or devices currently available can completely control or eliminate the pathogenic plaques associated with periodontal diseases for extended periods of time. Daily home care and frequent recall are still paramount for long-term success. Nonsurgical therapy remains the cornerstone of periodontal treatment. Attention to detail, patient compliance and proper selection of adjunctive antimicrobial agents for sustained plaque control are important elements in achieving successful long-term results. Frequent re-evaluation and careful monitoring allows the practitioner the opportunity to intervene early in the disease state, to reverse or arrest the progression of periodontal disease with meticulous nonsurgical anti-infective therapy. PMID:11155183

  6. Huntington Disease: A Case Study of Early Onset Presenting as Depression

    ERIC Educational Resources Information Center

    Duesterhus, Pia; Schimmelmann, Benno Graf; Wittkugel, Oliver; Schulte-Markwort, Michael

    2004-01-01

    Huntington disease is a dominantly inherited, neurodegenerative disease characterized by choreiform movement disturbances and dementia, usually with adult onset. The rare juvenile-onset Huntington disease differs from the adult phenotype. A case presenting twice, at age 10 with all the signs of a major depression and age 14 with mutism and

  7. Huntington Disease: A Case Study of Early Onset Presenting as Depression

    ERIC Educational Resources Information Center

    Duesterhus, Pia; Schimmelmann, Benno Graf; Wittkugel, Oliver; Schulte-Markwort, Michael

    2004-01-01

    Huntington disease is a dominantly inherited, neurodegenerative disease characterized by choreiform movement disturbances and dementia, usually with adult onset. The rare juvenile-onset Huntington disease differs from the adult phenotype. A case presenting twice, at age 10 with all the signs of a major depression and age 14 with mutism and…

  8. Digging Deeper Using Neuroimaging Tools Reveals Important Clues to Early-Onset Schizophrenia

    ERIC Educational Resources Information Center

    Kumra, Sanjiv

    2008-01-01

    The article describes the use of structural neuroimaging to understand the psychopathology of childhood-onset schizophrenia. Results showed an increase in lateral volumes, reduced total and regional volumes of gray matter in the cortex and increased basal ganglia volumes as in adult-onset schizophrenia in comparison with healthy subjects.

  9. Octapeptide repeat insertions in the prion protein gene and early onset dementia

    PubMed Central

    Croes, E; Theuns, J; Houwing-Duisterma..., J; Dermaut, B; Sleegers, K; Roks, G; Van den Broeck, M; van Harten, B; van Swieten, J C; Cruts, M; Van Broeckhoven, C; van Duijn, C M

    2004-01-01

    Methods: Following identification of a two-octapeptide repeat insertion in PRNP, we conducted a meta-analysis to investigate the relation of number of PRNP octapeptide repeats with age at disease onset and duration of illness; identifying 55 patients with PRNP octapeptide repeat insertions. We used a linear mixed effects model to assess the relation of number of repeats with age at disease onset, and studied the effect of the number of inserted octapeptide repeats on disease duration with a Cox proportional hazards regression analysis. Results: We found an increasing number of repeats associated with younger age at onset (p<0.001). Duration of the disease decreased significantly with the length of the octapeptide repeat (p<0.001) when adjusting for age at onset. Conclusions: Our findings show significant inverse associations of the length of the PRNP octapeptide repeat with age at disease onset and disease duration in the spongiform encephalopathies. PMID:15258222

  10. Evaluation of lymphocyte populations and subpopulations extracted from inflamed periodontal tissues.

    PubMed

    Pietruska, Ma?gorzata D; Zimnoch, Lech; Waszkiel, Danuta; Stokowska, Wanda; Duraj, Ewa

    2002-01-01

    The aim of the present study was evaluation the distribution of B- and T-cells and T-cell subsets in periodontal tissues from patients with different periodontitis forms. Periodontal tissue samples were collected from group P patients during routine surgical procedures, while from group C during tooth extraction for orthodontic or prosthetic purposes. Directly after collection, tissue samples were placed in a criostat or fixed in 10% buffered formalin for 24 h at room temperature. Following fixation the material was embedded in paraffin and subjected to routine histological techniques. Examinations of B- and T-lymphocytes populations and T-lymphocytes subsets were made with the use of immunohistochemical method. In C group single T and B lymphocytes were found in histological examination in pocket epithelium zones. In early onset periodontitis (EOP) patients in inflammatory infiltration lymphocytes T were dominating while in adult periodontitis (AP) patients dominating were B lymphocytes. Mean CD4/CD8 ratio in control group was 1.7 and in EOP and AP patients 1.1 and 2.6 respectively. PMID:12533963

  11. Laser therapy for periodontitis

    NASA Astrophysics Data System (ADS)

    Efanov, O. I.

    2001-04-01

    An investigation was made of applying pulsed (lambda) equals 0.89 micrometers laser radiation in the treatment for early diagnosed periodontitis. The investigation was made on 65 patients (47 patients constituted the experimental group and 18 patients constituted a control group) affected by periodontitis. Clinical and functional tests revealed that laser therapy produced a string effect on the course of the illness. It reduced bleeding, inflammation, and pruritus. However, it did not produce an affect on electroexcitation. Biomicroscopic examinations and periodontium rheography revealed that the gingival blood flow became normal after the course of laser therapy. The capillary permeability and venous congestion decreased, which was confirmed by the increased time of vacuum tests, raised gingival temperature, reduced tissue clearance, and increased oxygen tension. Apart from that, laser therapy subsided fibrinolysis, proteolytic tissue activity, and decreased the exudative inflammation of periodontium.

  12. ATF6 Is Mutated in Early Onset Photoreceptor Degeneration With Macular Involvement

    PubMed Central

    Xu, Mingchu; Gelowani, Violet; Eblimit, Aiden; Wang, Feng; Young, Marielle P.; Sawyer, Briana L.; Zhao, Li; Jenkins, Glen; Creel, Donnell J.; Wang, Keqing; Ge, Zhongqi; Wang, Hui; Li, Yumei; Hartnett, M. Elizabeth; Chen, Rui

    2015-01-01

    Purpose. Photoreceptor degeneration (PRD) is a genetically heterogeneous retinal disorder. Although a number of genes involved in PRD have been identified, their genetic basis remains unknown in a significant number of patients. In this study, we aimed to identify novel disease-causing genes of PRD. Methods. Comprehensive ocular examinations were performed in a 2-year-old patient diagnosed with early onset PRD. Retinal capture sequencing was performed to screen causative mutations in known retinal disease-causing loci. Whole-exome sequencing (WES) and a series of variant-filtering strategies were applied for identifying novel disease-causing genes. Retina ATF6 expression was confirmed by immunohistochemistry. RT-PCR was performed to identify ATF6 mRNA in the patient. Results. The patient showed typical PRD features, with macular involvement and ellipsoid zone irregularities. Results of retinal capture sequencing were negative. WES data led to identification of biallelic loss-of-function mutations in the ATF6 gene. The first variant generates a premature stop codon (NCBI accession no. NM_007348: c.1126C>T, p.R376*) and the second variant affects a splicing donor site (NM_007348: c.1533+1G>C). Sanger sequencing confirmed the 2 alleles are from 1 parent each. Both of the variants are extremely rare in the population. The splicing variant causes either intron inclusion or exon skipping in the patient, thus severely disrupting ATF6 functional domains. ATF6 is expressed in three neuronal cell layers of mouse retina. Conclusions. Our results support ATF6 as a novel disease-causing gene for PRD and suggest that disrupted protein quality control mechanisms may be a novel pathological mechanism underlying human retinal degeneration. PMID:26070061

  13. Higher filtration fraction in formerly early-onset preeclamptic women without comorbidity.

    PubMed

    Toering, Tsjitske J; van der Graaf, Anne Marijn; Visser, Folkert W; Groen, Henk; Faas, Marijke M; Navis, Gerjan; Lely, A Titia

    2015-04-15

    Formerly preeclamptic women have an increased risk for developing end-stage renal disease, which has been attributed to altered renal hemodynamics and abnormalities in the renin-angiotensin-aldosterone system. Whether this is due to preeclampsia itself or to comorbid conditions is unknown. Renal hemodynamics and responsiveness to ANG II during low Na(+) intake (7 days, 50 mmol Na(+)/24 h) and high Na(+) (HS) intake (7 days, 200 mmol Na(+)/24 h) were studied in 18 healthy normotensive formerly early-onset preeclamptic women (fPE women) and 18 healthy control subjects (fHP women), all selected for absence of comorbidity. At the end of each diet, renal hemodynamics and blood pressure were measured before and during graded ANG II infusion. Both HS intake and former preeclampsia increased filtration fraction (FF) without an interaction between the two. FF was highest during HS intake in fPE women [0.31 0.12 vs. 0.29 0.11 in fHP women, generalized estimating equation analysis (body mass index corrected), P = 0.03]. The renal response to ANG II infusion was not different between groups. In conclusion, fPE women have a higher FF compared with fHP women. As this was observed in the absence of comorbidity, preeclampsia itself might exert long-term effects on renal hemodynamics. However, we cannot exclude the presence of prepregnancy alterations in renal function, which, in itself, lead to an increased risk for preeclampsia. In experimental studies, an elevated FF has been shown to play a pathogenic role in the development of hypertension and renal damage. Future studies, however, should evaluate whether the subtle differences in renal hemodynamics after preeclampsia contribute to the increased long-term renal risk after preeclampsia. PMID:25694481

  14. Policy implications of early onset breast cancer among Mexican-origin women

    PubMed Central

    Wilkinson, Anna V.; Etzel, Carol J.; Zhou, Renke; Jones, Lovell A.; Thompson, Patricia; Bondy, Melissa L.

    2010-01-01

    Overall, Latinas are more likely to be diagnosed with a more advanced stage of breast cancer, and are 20% more likely to die of breast cancer than non-Hispanic white women. It is estimated that from 2003–2006, $82.0 billion in direct medical care expenditures, in addition to 100,000 lives annually, could be saved by eliminating health disparities experienced by Latinos and increasing the use of up to five preventive services in the U.S. An additional 3,700 lives could be saved if 90% of women ≥40 years were recently screened for breast cancer. We examined risk for breast cancer in a case-control population-based sample of Mexican-origin women in Harris County, TX (n=714), where rates of breast cancer mortality for Latina women have doubled since 1990. Half of breast cancer cases (n=119) were diagnosed before the age of 50. In a multivariable model, women with a family history of breast cancer (OR=4.3), born in Mexico and having high levels of language acculturation (OR=2.5), and without health insurance (OR=1.6) were found to have the highest risk of breast cancer. Because Mexican-origin women were found to be of high-risk for early onset pre-menopausal breast cancer, we recommend policies targeting screening, education and treatment to prevent increased disparities in mortality. The inclusion of community members and policymakers as partners in these endeavors would further safeguard against an increase in cancer health disparities, and aid in formulating a policy agenda congruent with scientifically-based, community-driven policy efforts addressing breast cancer screening, education and treatment in this vulnerable population. PMID:21319396

  15. Complex sarcolemmal invaginations mimicking myotendinous junctions in a case of Laing early-onset distal myopathy.

    PubMed

    Reis, Gerald F; de la Motte, Grant; Gooding, Rebecca; Laing, Nigel G; Margeta, Marta

    2015-12-01

    Distal myopathies are a group of clinically and pathologically overlapping muscle diseases that are genetically complex and can represent a diagnostic challenge. Laing early-onset distal myopathy (MPD1) is a form of distal myopathy caused by mutations in the MYH7 gene, which encodes the beta myosin heavy chain protein expressed in type 1 skeletal muscle fibers and cardiac myocytes. Here, we present a case of genetically confirmed MPD1 with a typical clinical presentation but distinctive light microscopic and ultrastructural findings on muscle biopsy. A 39-year-old professional male cellist presented with a bilateral foot drop that developed by age 8; analysis of the family pedigree showed an autosomal dominant pattern of inheritance. The physical exam demonstrated bilateral weakness of ankle dorsiflexors, toe extensors and finger extensors; creatine kinase level was normal. Biopsy of the quadriceps femoris muscle showed predominance and hypotrophy of type 1 fibers, hybrid fibers with co-expression of slow and fast myosin proteins (both in highly atrophic and normal size range), moth-eaten fibers and mini-cores, lack of rimmed vacuoles and rare desmin-positive eosinophilic sarcoplasmic inclusions. In addition to these abnormalities often observed in MPD1, the biopsy demonstrated frequent clefted fibers with complex sarcolemmal invaginations; on ultrastructural examination, these structures closely mimicked myotendinous junctions but were present away from the tendon and were almost exclusively found in type 1 fibers. Sequencing analysis of the MYH7 gene in the index patient and other affected family members demonstrated a previously described heterozygous c.4522_4524delGAG (p.Glu1508del) mutation. This case widens the pathologic spectrum of MPD1 and highlights the pathologic and clinical variability that can accompany the same genetic mutation, suggesting a significant role for modifier genes in MPD1 pathogenesis. PMID:26094647

  16. Sibling sex ratio and birth order in early-onset gender dysphoric adolescents.

    PubMed

    Schagen, Sebastian E E; Delemarre-van de Waal, Henriette A; Blanchard, Ray; Cohen-Kettenis, Peggy T

    2012-06-01

    Several sibship-related variables have been studied extensively in sexual orientation research, especially in men. Sibling sex ratio refers to the ratio of brothers to sisters in the aggregate sibships of a group of probands. Birth order refers to the probands' position (e.g., first-born, middle-born, last-born) within their sibships. Fraternal birth order refers to their position among male siblings only. Such research was extended in this study to a large group of early-onset gender dysphoric adolescents. The probands comprised 94 male-to-female and 95 female-to-male gender dysphoric adolescents. The overwhelming majority of these were homosexual or probably prehomosexual. The control group consisted of 875 boys and 914 girls from the TRAILS study. The sibling sex ratio of the gender dysphoric boys was very high (241 brothers per 100 sisters) compared with the expected ratio (106:100). The excess of brothers was more extreme among the probands' older siblings (300:100) than among their younger siblings (195:100). Between-groups comparisons showed that the gender dysphoric boys had significantly more older brothers, and significantly fewer older sisters and younger sisters, than did the control boys. In contrast, the only notable finding for the female groups was that the gender dysphoric girls had significantly fewer total siblings than did the control girls. The results for the male probands were consistent with prior speculations that a high fraternal birth order (i.e., an excess of older brothers) is found in all homosexual male groups, but an elevated sibling sex ratio (usually caused by an additional, smaller excess of younger brothers) is characteristic of gender dysphoric homosexual males. The mechanisms underlying these phenomena remain unknown. PMID:21674256

  17. Stratification of Risk of Early-Onset Sepsis in Newborns ≥34 Weeks’ Gestation

    PubMed Central

    Puopolo, Karen M.; Wi, Soora; Turk, Benjamin J.; Kuzniewicz, Michael W.; Walsh, Eileen M.; Newman, Thomas B.; Zupancic, John; Lieberman, Ellice; Draper, David

    2014-01-01

    OBJECTIVE: To define a quantitative stratification algorithm for the risk of early-onset sepsis (EOS) in newborns ≥34 weeks’ gestation. METHODS: We conducted a retrospective nested case-control study that used split validation. Data collected on each infant included sepsis risk at birth based on objective maternal factors, demographics, specific clinical milestones, and vital signs during the first 24 hours after birth. Using a combination of recursive partitioning and logistic regression, we developed a risk classification scheme for EOS on the derivation dataset. This scheme was then applied to the validation dataset. RESULTS: Using a base population of 608 014 live births ≥34 weeks’ gestation at 14 hospitals between 1993 and 2007, we identified all 350 EOS cases <72 hours of age and frequency matched them by hospital and year of birth to 1063 controls. Using maternal and neonatal data, we defined a risk stratification scheme that divided the neonatal population into 3 groups: treat empirically (4.1% of all live births, 60.8% of all EOS cases, sepsis incidence of 8.4/1000 live births), observe and evaluate (11.1% of births, 23.4% of cases, 1.2/1000), and continued observation (84.8% of births, 15.7% of cases, incidence 0.11/1000). CONCLUSIONS: It is possible to combine objective maternal data with evolving objective neonatal clinical findings to define more efficient strategies for the evaluation and treatment of EOS in term and late preterm infants. Judicious application of our scheme could result in decreased antibiotic treatment in 80 000 to 240 000 US newborns each year. PMID:24366992

  18. Early-Onset Neonatal Sepsis: Still Room for Improvement in Procalcitonin Diagnostic Accuracy Studies

    PubMed Central

    Chiesa, Claudio; Pacifico, Lucia; Osborn, John F.; Bonci, Enea; Hofer, Nora; Resch, Bernhard

    2015-01-01

    Abstract To perform a systematic review assessing accuracy and completeness of diagnostic studies of procalcitonin (PCT) for early-onset neonatal sepsis (EONS) using the Standards for Reporting of Diagnostic Accuracy (STARD) initiative. EONS, diagnosed during the first 3 days of life, remains a common and serious problem. Increased PCT is a potentially useful diagnostic marker of EONS, but reports in the literature are contradictory. There are several possible explanations for the divergent results including the quality of studies reporting the clinical usefulness of PCT in ruling in or ruling out EONS. We systematically reviewed PubMed, Scopus, and the Cochrane Library databases up to October 1, 2014. Studies were eligible for inclusion in our review if they provided measures of PCT accuracy for diagnosing EONS. A data extraction form based on the STARD checklist and adapted for neonates with EONS was used to appraise the quality of the reporting of included studies. We found 18 articles (19982014) fulfilling our eligibility criteria which were included in the final analysis. Overall, the results of our analysis showed that the quality of studies reporting diagnostic accuracy of PCT for EONS was suboptimal leaving ample room for improvement. Information on key elements of design, analysis, and interpretation of test accuracy were frequently missing. Authors should be aware of the STARD criteria before starting a study in this field. We welcome stricter adherence to this guideline. Well-reported studies with appropriate designs will provide more reliable information to guide decisions on the use and interpretations of PCT test results in the management of neonates with EONS. PMID:26222858

  19. A Mouse Model of Early-Onset Renal Failure Due to a Xanthine Dehydrogenase Nonsense Mutation

    PubMed Central

    Gorvin, Caroline M.; Head, Rosie; Loh, Nellie Y.; Devuyst, Olivier; Thomas, Gethin; Brown, Steve D. M.; Brown, Matthew; Croucher, Peter; Cox, Roger; Thakker, Rajesh V.

    2012-01-01

    Chronic kidney disease (CKD) is characterized by renal fibrosis that can lead to end-stage renal failure, and studies have supported a strong genetic influence on the risk of developing CKD. However, investigations of the underlying molecular mechanisms are hampered by the lack of suitable hereditary models in animals. We therefore sought to establish hereditary mouse models for CKD and renal fibrosis by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea, and identified a mouse with autosomal recessive renal failure, designated RENF. Three-week old RENF mice were smaller than their littermates, whereas at birth they had been of similar size. RENF mice, at 4-weeks of age, had elevated concentrations of plasma urea and creatinine, indicating renal failure, which was associated with small and irregularly shaped kidneys. Genetic studies using DNA from 10 affected mice and 91 single nucleotide polymorphisms mapped the Renf locus to a 5.8Mbp region on chromosome 17E1.3. DNA sequencing of the xanthine dehydrogenase (Xdh) gene revealed a nonsense mutation at codon 26 that co-segregated with affected RENF mice. The Xdh mutation resulted in loss of hepatic XDH and renal Cyclooxygenase-2 (COX-2) expression. XDH mutations in man cause xanthinuria with undetectable plasma uric acid levels and three RENF mice had plasma uric acid levels below the limit of detection. Histological analysis of RENF kidney sections revealed abnormal arrangement of glomeruli, intratubular casts, cellular infiltration in the interstitial space, and interstitial fibrosis. TUNEL analysis of RENF kidney sections showed extensive apoptosis predominantly affecting the tubules. Thus, we have established a mouse model for autosomal recessive early-onset renal failure due to a nonsense mutation in Xdh that is a model for xanthinuria in man. This mouse model could help to increase our understanding of the molecular mechanisms associated with renal fibrosis and the specific roles of XDH and uric acid. PMID:23024809

  20. Frequency, magnitude and character of hyperthermal events at the onset of the Early Eocene Climatic Optimum

    NASA Astrophysics Data System (ADS)

    Lauretano, V.; Littler, K.; Polling, M.; Zachos, J. C.; Lourens, L. J.

    2015-10-01

    Recent studies have shown that the Early Eocene Climatic Optimum (EECO) was preceded by a series of short-lived global warming events, known as hyperthermals. Here we present high-resolution benthic stable carbon and oxygen isotope records from ODP Sites 1262 and 1263 (Walvis Ridge, SE Atlantic) between ~ 54 and ~ 52 million years ago, tightly constraining the character, timing, and magnitude of six prominent hyperthermal events. These events, which include Eocene Thermal Maximum (ETM) 2 and 3, are studied in relation to orbital forcing and long-term trends. Our findings reveal an almost linear relationship between δ13C and δ18O for all these hyperthermals, indicating that the eccentricity-paced covariance between deep-sea temperature changes and extreme perturbations in the exogenic carbon pool persisted during these events towards the onset of the EECO, in accordance with previous observations for the Paleocene Eocene Thermal Maximum (PETM) and ETM2. The covariance of δ13C and δ18O during H2 and I2, which are the second pulses of the "paired" hyperthermal events ETM2-H2 and I1-I2, deviates with respect to the other events. We hypothesize that this could relate to a relatively higher contribution of an isotopically heavier source of carbon, such as peat or permafrost, and/or to climate feedbacks/local changes in circulation. Finally, the δ18O records of the two sites show a systematic offset with on average 0.2 ‰ heavier values for the shallower Site 1263, which we link to a slightly heavier isotopic composition of the intermediate water mass reaching the northeastern flank of the Walvis Ridge compared to that of the deeper northwestern water mass at Site 1262.

  1. Estimating the Probability of Neonatal Early-Onset Infection on the Basis of Maternal Risk Factors

    PubMed Central

    Draper, David; Wi, Soora; Newman, Thomas B.; Zupancic, John; Lieberman, Ellice; Smith, Myesha; Escobar, Gabriel J.

    2011-01-01

    OBJECTIVE: To develop a quantitative model to estimate the probability of neonatal early-onset bacterial infection on the basis of maternal intrapartum risk factors. METHODS: This was a nested case-control study of infants born at ?34 weeks' gestation at 14 California and Massachusetts hospitals from 1993 to 2007. Case-subjects had culture-confirmed bacterial infection at <72 hours; controls were randomly selected, frequency-matched 3:1 according to year and birth hospital. We performed multivariate analyses and split validation to define a predictive model based only on information available in the immediate perinatal period. RESULTS: We identified 350 case-subjects from a cohort of 608 014 live births. Highest intrapartum maternal temperature revealed a linear relationship with risk of infection below 100.5F, above which the risk rose rapidly. Duration of rupture of membranes revealed a steadily increasing relationship with infection risk. Increased risk was associated with both late-preterm and postterm delivery. Risk associated with maternal group B Streptococcus colonization is diminished in the era of group B Streptococcus prophylaxis. Any form of intrapartum antibiotic given >4 hours before delivery was associated with decreased risk. Our model showed good discrimination and calibration (c statistic = 0.800 and Hosmer-Lemeshow P = .142 in the entire data set). CONCLUSIONS: A predictive model based on information available in the immediate perinatal period performs better than algorithms based on risk-factor threshold values. This model establishes a prior probability for newborn sepsis, which could be combined with neonatal physical examination and laboratory values to establish a posterior probability to guide treatment decisions. PMID:22025590

  2. Disrupted rich club network in behavioral variant frontotemporal dementia and early-onset Alzheimer's disease.

    PubMed

    Daianu, Madelaine; Mezher, Adam; Mendez, Mario F; Jahanshad, Neda; Jimenez, Elvira E; Thompson, Paul M

    2016-03-01

    In network analysis, the so-called "rich club" describes the core areas of the brain that are more densely interconnected among themselves than expected by chance, and has been identified as a fundamental aspect of the human brain connectome. This is the first in-depth diffusion imaging study to investigate the rich club along with other organizational changes in the brain's anatomical network in behavioral frontotemporal dementia (bvFTD), and a matched cohort with early-onset Alzheimer's disease (EOAD). Our study sheds light on how bvFTD and EOAD affect connectivity of white matter fiber pathways in the brain, revealing differences and commonalities in the connectome among the dementias. To analyze the breakdown in connectivity, we studied three groups: 20 bvFTD, 23 EOAD, and 37 healthy elderly controls. All participants were scanned with diffusion-weighted magnetic resonance imaging (MRI), and based on whole-brain probabilistic tractography and cortical parcellations, we analyzed the rich club of the brain's connectivity network. This revealed distinct patterns of disruption in both forms of dementia. In the connectome, we detected less disruption overall in EOAD than in bvFTD [false discovery rate (FDR) critical Pperm  = 5.7 × 10(-3) , 10,000 permutations], with more involvement of richly interconnected areas of the brain (chi-squared P = 1.4 × 10(-4) )-predominantly posterior cognitive alterations. In bvFTD, we found a greater spread of disruption including the rich club (FDR critical Pperm  = 6 × 10(-4) ), but especially more peripheral alterations (chi-squared P = 6.5 × 10(-3) ), particularly in medial frontal areas of the brain, in line with the known behavioral socioemotional deficits seen in these patients. Hum Brain Mapp 37:868-883, 2016. © 2015 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc. PMID:26678225

  3. Cognitive performance of GBA mutation carriers with early-onset PD

    PubMed Central

    Caccappolo, E.; Mejia-Santana, H.; Tang, M.-X.; Rosado, L.; Orbe Reilly, M.; Ruiz, D.; Ross, B.; Verbitsky, M.; Kisselev, S.; Louis, E.; Comella, C.; Colcher, A.; Jennings, D.; Nance, M.; Bressman, S.; Scott, W.K.; Tanner, C.; Mickel, S.; Andrews, H.; Waters, C.; Fahn, S.; Cote, L.; Frucht, S.; Ford, B.; Rezak, M.; Novak, K.; Friedman, J.H.; Pfeiffer, R.; Marsh, L.; Hiner, B.; Siderowf, A.; Payami, H.; Molho, E.; Factor, S.; Ottman, R.; Clark, L.N.; Marder, K.

    2012-01-01

    Objective: To assess the cognitive phenotype of glucocerebrosidase (GBA) mutation carriers with early-onset Parkinson disease (PD). Methods: We administered a neuropsychological battery and the University of Pennsylvania Smell Identification Test (UPSIT) to participants in the CORE-PD study who were tested for mutations in PARKIN, LRRK2, and GBA. Participants included 33 GBA mutation carriers and 60 noncarriers of any genetic mutation. Primary analyses were performed on 26 GBA heterozygous mutation carriers without additional mutations and 39 age- and PD duration–matched noncarriers. Five cognitive domains, psychomotor speed, attention, memory, visuospatial function, and executive function, were created from transformed z scores of individual neuropsychological tests. Clinical diagnoses (normal, mild cognitive impairment [MCI], dementia) were assigned blind to genotype based on neuropsychological performance and functional impairment as assessed by the Clinical Dementia Rating (CDR) score. The association between GBA mutation status and neuropsychological performance, CDR, and clinical diagnoses was assessed. Results: Demographics, UPSIT, and Unified Parkinson's Disease Rating Scale–III performance did not differ between GBA carriers and noncarriers. GBA mutation carriers performed more poorly than noncarriers on the Mini-Mental State Examination (p = 0.035), and on the memory (p = 0.017) and visuospatial (p = 0.028) domains. The most prominent differences were observed in nonverbal memory performance (p < 0.001). Carriers were more likely to receive scores of 0.5 or higher on the CDR (p < 0.001), and a clinical diagnosis of either MCI or dementia (p = 0.004). Conclusion: GBA mutation status may be an independent risk factor for cognitive impairment in patients with PD. PMID:22442429

  4. Cooperative Genome-Wide Analysis Shows Increased Homozygosity in Early Onset Parkinson's Disease

    PubMed Central

    Nalls, Michael A.; Martinez, Maria; Schulte, Claudia; Holmans, Peter; Gasser, Thomas; Hardy, John; Singleton, Andrew B.; Wood, Nicholas W.; Brice, Alexis; Heutink, Peter; Williams, Nigel; Morris, Huw R.

    2012-01-01

    Parkinson's disease (PD) occurs in both familial and sporadic forms, and both monogenic and complex genetic factors have been identified. Early onset PD (EOPD) is particularly associated with autosomal recessive (AR) mutations, and three genes, PARK2, PARK7 and PINK1, have been found to carry mutations leading to AR disease. Since mutations in these genes account for less than 10% of EOPD patients, we hypothesized that further recessive genetic factors are involved in this disorder, which may appear in extended runs of homozygosity. We carried out genome wide SNP genotyping to look for extended runs of homozygosity (ROHs) in 1,445 EOPD cases and 6,987 controls. Logistic regression analyses showed an increased level of genomic homozygosity in EOPD cases compared to controls. These differences are larger for ROH of 9 Mb and above, where there is a more than three-fold increase in the proportion of cases carrying a ROH. These differences are not explained by occult recessive mutations at existing loci. Controlling for genome wide homozygosity in logistic regression analyses increased the differences between cases and controls, indicating that in EOPD cases ROHs do not simply relate to genome wide measures of inbreeding. Homozygosity at a locus on chromosome19p13.3 was identified as being more common in EOPD cases as compared to controls. Sequencing analysis of genes and predicted transcripts within this locus failed to identify a novel mutation causing EOPD in our cohort. There is an increased rate of genome wide homozygosity in EOPD, as measured by an increase in ROHs. These ROHs are a signature of inbreeding and do not necessarily harbour disease-causing genetic variants. Although there might be other regions of interest apart from chromosome 19p13.3, we lack the power to detect them with this analysis. PMID:22427796

  5. Early Oligocene Onset of Deep-Water Production in the North Atlantic

    NASA Astrophysics Data System (ADS)

    Thomas, D. J.; Via, R. K.

    2005-12-01

    The present mode of meridional overturning circulation is characterized by deep-water formation in both the North Atlantic and the Southern Ocean. However, a growing body of evidence indicates that the Southern Ocean was the dominant region of deep-water formation during the extreme warmth of the early Cenozoic. Establishment of a bipolar mode of deep-water circulation occurred during the tectonic evolution of the Atlantic basins and overall cooling of the Cenozoic. However, neither the timing nor the cause of this transition is known. Formation of the Panama Isthmus is assumed to represent the final step in this transition, yet it is unclear when deep waters first began forming in the North Atlantic prior to the development of true NADW. To reconstruct the evolution of Atlantic deep-sea circulation from the early Cenozoic mode to the bipolar mode, we generated neodymium isotope records from fossil fish teeth and bones. These records come from a depth transect of three Walvis Ridge sites cored during Ocean Drilling Program Leg 208. The depth transect, spanning more than 2200m water depth, enables us to resolve the vertical water mass structure through time to reconstruct changes in the relative deep-water contributions from the Southern Ocean and North Atlantic. Nd isotope data from the three sites indicates that a single water mass encompassed the entire depth range from ~55 to at least 17 million years ago. Published data from ODP Site 689 (2080m present water depth; ~1500m paleodepth in the Paleogene) in the Weddell Sea indicate similar values and the same trend with the Walvis Ridge data from ~46 to 33 Ma, suggesting a single Southern Ocean intermediate/deep-water mass until ~33 Ma. Approximately 33 Ma, Weddell Sea ?Nd(t) values diverge from Walvis Ridge values, and remain consistently more radiogenic for the duration of the Site 689 record. Walvis Ridge ?Nd(t) values become increasingly unradiogenic to the top of the investigated section. The most plausible explanation for decrease in Walvis Ridge ?Nd(t) values as well as the divergence in Nd isotopic composition from Weddell Sea values is the onset of and gradual increase in a North Atlantic deep-water contribution to the waters in the southeastern Atlantic. Thus, we suggest that significant deep-water production began in the Atlantic 33Ma.

  6. Temporal-lobe morphology differs between healthy adolescents and those with early-onset of depression

    PubMed Central

    Ramezani, Mahdi; Johnsrude, Ingrid; Rasoulian, Abtin; Bosma, Rachael; Tong, Ryan; Hollenstein, Tom; Harkness, Kate; Abolmaesumi, Purang

    2014-01-01

    Major depressive disorder (MDD) has previously been linked to structural changes in several brain regions, particularly in the medial temporal lobes (Bellani, Baiano, Brambilla, 2010; Bellani, Baiano, Brambilla, 2011). This has been determined using voxel-based morphometry, segmentation algorithms, and analysis of shape deformations (Bell-McGinty et al., 2002; Bergouignan et al., 2009; Posener et al., 2003; Vasic et al., 2008; Zhao et al., 2008): these are methods in which information related to the shape and the pose (the size, and anatomical position and orientation) of structures is lost. Here, we incorporate information about shape and pose to measure structural deformation in adolescents and young adults with and without depression (as measured using the Beck Depression Inventory and Diagnostic and Statistical Manual of Mental Disorders criteria). As a hypothesis-generating study, a significance level of p<0.05, uncorrected for multiple comparisons, was used, so that subtle morphological differences in brain structures between adolescent depressed individuals and control participants could be identified. We focus on changes in cortical and subcortical temporal structures, and use a multi-object statistical pose and shape model to analyze imaging data from 16 females (aged 1621) and 3 males (aged 18) with early-onset MDD, and 25 female and 1 male normal control participants, drawn from the same age range. The hippocampus, parahippocampal gyrus, putamen, and superior, inferior and middle temporal gyri in both hemispheres of the brain were automatically segmented using the LONI Probabilistic Brain Atlas (Shattuck et al., 2008) in MNI space. Points on the surface of each structure in the atlas were extracted and warped to each participant's structural MRI. These surface points were analyzed to extract the pose and shape features. Pose differences were detected between the two groups, particularly in the left and right putamina, right hippocampus, and left and right inferior temporal gyri. Shape differences were detected between the two groups, particularly in the left hippocampus and in the left and right parahippocampal gyri. Furthermore, pose measures were significantly correlated with BDI score across the whole (clinical and control) sample. Since the clinical participants were experiencing their very first episodes of MDD, morphological alteration in the medial temporal lobe appears to be an early sign of MDD, and is unlikely to result from treatment with antidepressants. Pose and shape measures of morphology, which are not usually analyzed in neuromorphometric studies, appear to be sensitive to depressive symptomatology. PMID:25379426

  7. A new clinical feature associated with familial early-onset of dystonic-guttural tics: An unusual diagnosis of PANDAS

    PubMed Central

    Vitaliti, Giovanna; Trifiletti, Rosario R.; Falsaperla, Raffaele; Parano, Enrico; Spalice, Alberto; Pavone, Piero

    2014-01-01

    Until today there is a large debate about the existence of PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) or PANS (pediatric acute onset neuropsychiatric syndrome). These children usually have dramatic, “overnight” onset of symptoms, including motor or vocal tics, obsessions, and/or compulsions. In addition to these symptoms, children may also have comorbid features of associated disorders. Herein, we report a family with an early onset of tics, with exclusively dystonic and guttural tics. All patients had a particularly strong excitement trigger. Two of the patients were shown to have signs suggestive of PANDAS and all family members were Group A beta-hemolytic Streptococcus (GABHS) carriers. The PANDAS spectrum is probably a group of disorders. We have described a PANDAS variant, in which the family seems to share common autoimmune pattern and may be viewed in the large spectrum of PANDAS. PMID:24891915

  8. High-resolution taxonomic profiling of the subgingival microbiome for biomarker discovery and periodontitis diagnosis.

    PubMed

    Szafranski, Szymon P; Wos-Oxley, Melissa L; Vilchez-Vargas, Ramiro; Jáuregui, Ruy; Plumeier, Iris; Klawonn, Frank; Tomasch, Jürgen; Meisinger, Christa; Kühnisch, Jan; Sztajer, Helena; Pieper, Dietmar H; Wagner-Döbler, Irene

    2015-02-01

    The oral microbiome plays a key role for caries, periodontitis, and systemic diseases. A method for rapid, high-resolution, robust taxonomic profiling of subgingival bacterial communities for early detection of periodontitis biomarkers would therefore be a useful tool for individualized medicine. Here, we used Illumina sequencing of the V1-V2 and V5-V6 hypervariable regions of the 16S rRNA gene. A sample stratification pipeline was developed in a pilot study of 19 individuals, 9 of whom had been diagnosed with chronic periodontitis. Five hundred twenty-three operational taxonomic units (OTUs) were obtained from the V1-V2 region and 432 from the V5-V6 region. Key periodontal pathogens like Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia could be identified at the species level with both primer sets. Principal coordinate analysis identified two outliers that were consistently independent of the hypervariable region and method of DNA extraction used. The linear discriminant analysis (LDA) effect size algorithm (LEfSe) identified 80 OTU-level biomarkers of periodontitis and 17 of health. Health- and periodontitis-related clusters of OTUs were identified using a connectivity analysis, and the results confirmed previous studies with several thousands of samples. A machine learning algorithm was developed which was trained on all but one sample and then predicted the diagnosis of the left-out sample (jackknife method). Using a combination of the 10 best biomarkers, 15 of 17 samples were correctly diagnosed. Training the algorithm on time-resolved community profiles might provide a highly sensitive tool to detect the onset of periodontitis. PMID:25452281

  9. Serum immunoglobulin G subclass concentrations in periodontally healthy and diseased individuals.

    PubMed Central

    Lu, H; Wang, M; Gunsolley, J C; Schenkein, H A; Tew, J G

    1994-01-01

    Patients with localized juvenile periodontitis (LJP) often have high titers of antibody reactive with the serotype-specific immunodominant carbohydrate antigen of Actinobacillus actinomycetemcomitans serotype b. The vast majority of this A. actinomycetemcomitans serotype b-specific antibody is immunoglobulin G2 (IgG2). The present study was undertaken to determine whether the overall total levels of IgG2 in the sera of LJP patients are elevated. LJP patients and nonperiodontitis (NP) controls matched for age, race (black and white), and gender were studied. Additional controls included patients with adult periodontitis (AP) and patients similar in age to LJP patients but with the more-severe, generalized form of early-onset periodontitis (SP). Sera from over 700 periodontally characterized subjects were examined by using radial immunodiffusion to quantitate IgG2 as well as IgG1, -3, and -4, which were included for comparison. Serum IgG2 levels increased with age, and this was most dramatic around puberty. Black subjects in all periodontal groups had nearly 1 mg more IgG2 per ml than their white counterparts. Serum IgG2 levels were elevated (about 30 to 40%) in LJP patients of both races compared with their age- and race-matched NP controls (P < 0.01). In contrast, SP patients and AP patients had IgG2 levels comparable to their age- and race-matched NP controls. No other IgG subclass concentration correlated with periodontal diagnosis except for IgG3, which was elevated in white LJP patients. We reason that the high levels of serum IgG2 in LJP may be helpful in localizing periodontal destruction. PMID:8168929

  10. High-Resolution Taxonomic Profiling of the Subgingival Microbiome for Biomarker Discovery and Periodontitis Diagnosis

    PubMed Central

    Szafranski, Szymon P.; Wos-Oxley, Melissa L.; Vilchez-Vargas, Ramiro; Jáuregui, Ruy; Plumeier, Iris; Klawonn, Frank; Tomasch, Jürgen; Meisinger, Christa; Kühnisch, Jan; Sztajer, Helena; Pieper, Dietmar H.

    2014-01-01

    The oral microbiome plays a key role for caries, periodontitis, and systemic diseases. A method for rapid, high-resolution, robust taxonomic profiling of subgingival bacterial communities for early detection of periodontitis biomarkers would therefore be a useful tool for individualized medicine. Here, we used Illumina sequencing of the V1-V2 and V5-V6 hypervariable regions of the 16S rRNA gene. A sample stratification pipeline was developed in a pilot study of 19 individuals, 9 of whom had been diagnosed with chronic periodontitis. Five hundred twenty-three operational taxonomic units (OTUs) were obtained from the V1-V2 region and 432 from the V5-V6 region. Key periodontal pathogens like Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia could be identified at the species level with both primer sets. Principal coordinate analysis identified two outliers that were consistently independent of the hypervariable region and method of DNA extraction used. The linear discriminant analysis (LDA) effect size algorithm (LEfSe) identified 80 OTU-level biomarkers of periodontitis and 17 of health. Health- and periodontitis-related clusters of OTUs were identified using a connectivity analysis, and the results confirmed previous studies with several thousands of samples. A machine learning algorithm was developed which was trained on all but one sample and then predicted the diagnosis of the left-out sample (jackknife method). Using a combination of the 10 best biomarkers, 15 of 17 samples were correctly diagnosed. Training the algorithm on time-resolved community profiles might provide a highly sensitive tool to detect the onset of periodontitis. PMID:25452281

  11. Predictors of schizophrenia spectrum disorders in early-onset first episodes of psychosis: a support vector machine model.

    PubMed

    Pina-Camacho, Laura; Garcia-Prieto, Juan; Parellada, Mara; Castro-Fornieles, Josefina; Gonzalez-Pinto, Ana M; Bombin, Igor; Graell, Montserrat; Paya, Beatriz; Rapado-Castro, Marta; Janssen, Joost; Baeza, Inmaculada; Del Pozo, Francisco; Desco, Manuel; Arango, Celso

    2015-04-01

    Identifying early-onset schizophrenia spectrum disorders (SSD) at a very early stage remains challenging. To assess the diagnostic predictive value of multiple types of data at the emergence of early-onset first-episode psychosis (FEP), various support vector machine (SVM) classifiers were developed. The data were from a 2-year, prospective, longitudinal study of 81 patients (age 9-17 years) with early-onset FEP and a stable diagnosis during follow-up and 42 age- and sex-matched healthy controls (HC). The input was different combinations of baseline clinical, neuropsychological, magnetic resonance imaging brain volumetric and biochemical data, and the output was the diagnosis at follow-up (SSD vs. non-SSD, SSD vs. HC, and non-SSD vs. HC). Enhanced recursive feature elimination was performed for the SSD vs. non-SSD classifier to select and rank the input variables with the highest predictive value for a diagnostic outcome of SSD. After validation with a test set and considering all baseline variables together, the SSD vs. non-SSD, SSD vs. HC and non-SSD vs. HC classifiers achieved an accuracy of 0.81, 0.99 and 0.99, respectively. Regarding the SSD vs. non-SSD classifier, a combination of baseline clinical variables (severity of negative, disorganized symptoms and hallucinations or poor insight) and neuropsychological variables (impaired attention, motor coordination, and global cognition) showed the highest predictive value for a diagnostic outcome of SSD. Neuroimaging and biochemical variables at baseline did not add to the predictive value. Thus, comprehensive clinical/cognitive assessment remains the most reliable approach for differential diagnosis during early-onset FEP. SVMs may constitute promising multivariate tools in the search for predictors of diagnostic outcome in FEP. PMID:25109600

  12. Fibrinogen Degradation Products and Periodontitis: Deciphering the Connection

    PubMed Central

    2015-01-01

    Introduction Fibrinogen degradation products (e.g. D-dimer) arise from digested fibrin clots and fibrinogen. Elevated concentrations accompany activation of coagulation and fibrinolysis and indicate chronic inflammatory diseases. D-Dimer tests are a quick, noninvasive method to rule out abnormal clotting. Periodontitis strongly affects the haemostatic system and evokes a procoagulant state. Correlation of chronic periodontitis with early indicators of disease (biomarkers) might be useful. Aim The aim of the study was to examine whether the plasma D-dimer concentration reflects the progression of chronic periodontitis and the beneficial effect of periodontal therapy. Materials and Methods Forty randomly selected subjects were divided into four groups, Group I: 10 healthy subjects, Group II: 10 with mild periodontitis, Group III: 10 with moderate periodontitis, Group IV: 10 with severe periodontitis. After thorough dental and periodontal examination, 3 mL of venous blood was collected for measurement of fibrinogen degradation products. Results The patients with moderate and chronic periodontitis exhibited high concentrations of D-dimer (mean value 434.98–535.52 mcg/mL), whereas subjects with mild or no periodontitis exhibited values of 329.78–211.29 mcg/mL. Concentrations of D-dimer were significantly reduced after therapy of all classes of periodontitis. Conclusion Periodontal treatment can reduce amount of D-dimer in the plasma. A higher than normal concentration is observed in chronic periodontitis. PMID:26816985

  13. Hippocampal volume and subcortical white matter lesions in late life depression: comparison of early and late onset depression

    PubMed Central

    Janssen, Joost; Pol, Hilleke E Hulshoff; de Leeuw, Frank‐Erik; Schnack, Hugo G; Lampe, Indrag K; Kok, Rob M; Kahn, Rene S; Heeren, Thea J

    2007-01-01

    Background Reduced hippocampal volume and increased prevalence of subcortical white matter lesions are associated with both recurrent early onset depression (EOD) and late onset depression (LOD). It is not clear whether these two factors differentially affect the age of onset of first depression. Therefore, we wished to investigate the relationship between age of first depression onset and hippocampal volume, with adjustment for subcortical white matter lesions. Methods MRI brain scans were used to compare hippocampal volumes and white matter lesions between age matched female patients (>60 years) with recurrent EOD and LOD and healthy controls. Results When comparing the three groups and adjusting for age, the Mini‐Mental State Examination score, total brain volume and total hippocampal volume were significantly smaller in patients with EOD compared with controls (5.6 vs 6.1 ml; p = 0.04). The prevalence of larger subcortical white matter lesions was higher in patients with LOD compared with patients with EOD (47% vs 8%; p = 0.002). Patients with LOD did not differ in hippocampal volume from patients with EOD or from controls. Conclusions In late life depression, age of first depression onset may distinguish between different independent neuropathological mechanisms. A small hippocampus volume may be a neuranatomical marker of EOD depression and larger subcortical white matter lesions could be an intermediate between cerebrovascular disease and LOD. PMID:17210630

  14. DNA methylation profiling of human placentas reveals promoter hypomethylation of multiple genes in early-onset preeclampsia

    PubMed Central

    Yuen, Ryan KC; Peaherrera, Maria S; von Dadelszen, Peter; McFadden, Deborah E; Robinson, Wendy P

    2010-01-01

    Preeclampsia and intrauterine growth restriction (IUGR) are two of the most common adverse pregnancy outcomes, but their underlying causes are mostly unknown. Although multiple studies have investigated gene expression changes in these disorders, few studies have examined epigenetic changes. Analysis of the DNA methylation pattern associated with such pregnancies provides an alternative approach to identifying cellular changes involved in these disorders. We analyzed methylation of 1505 CpG sites associated with 807 genes in 26 placentas from early-onset preeclampsia (EOPET), late-onset preeclampsia, IUGR and control subjects using an Illumina GoldenGate Methylation panel. Thirty-four loci were hypomethylated (false discovery rate <10% and methylation difference >10%) in the early-onset preeclamptic placentas while no and only five differentially methylated loci were found in late-onset preeclamptic and IUGR placentas, respectively. Hypomethylation of 4 loci in EOPET was further confirmed by bisulfite pyrosequencing of 26 independent placental samples. The promoter of TIMP3 was confirmed to be significantly hypomethylated in EOPET placentas (P=0.00001). Our results suggest that gene-specific hypomethylation may be a common phenomenon in EOPET placentas, and that TIMP3 could serve as a potential prenatal diagnostic marker for EOPET. PMID:20442742

  15. Investigation of automatically detected high frequency oscillations (HFOs) as an early predictor of seizure onset zone.

    PubMed

    Su Liu; Ince, Nuri F; Abosch, Aviva; Henry, Thomas R; Zhiyi Sha

    2015-08-01

    High frequency oscillations (HFOs) during inter-ictal state have been considered as a potential biomarker of epileptogenic regions in brain. The purpose of the current study is to improve and automatize the detection of HFOs basing on HFO distinguishing features followed by unsupervised clustering method, and to predict seizure onset zone (SOZ) using the clustered HFOs. The algorithm successfully separated HFOs of different sub-categories from noise, artifacts, and inter-ictal spikes. We tested this technique on two subjects, and assessed the performance of SOZ prediction by computing the overlapping rate of HFO generative channels and seizure onset channels. In both subjects, we were able to localize the seizure onset area 3 to 4 days before the actual onset of the seizure, with high specificity over 95%. The algorithm showed significant improvement comparing to another existing technique. PMID:26737806

  16. An Inherited Small Microdeletion at 15q13.3 in a Patient with Early- Onset Obsessive-Compulsive Disorder

    PubMed Central

    Cappi, Carolina; Hounie, Ana Gabriela; Mariani, Daniel B.; Diniz, Juliana Belo; Silva, Aderbal R. T.; Reis, Viviane N. S.; Busso, Ariane F.; Silva, Amanda Gonalves; Fidalgo, Felipe; Rogatto, Silvia Regina; Miguel, Euripedes C.; Krepischi, Ana C.; Brentani, Helena

    2014-01-01

    Copy number variations (CNVs) have been previously associated with several different neurodevelopmental psychiatric disorders, such as autism, schizophrenia, and attention deficit hyperactivity disorder (ADHD). The present study consisted of a pilot genome-wide screen for CNVs in a cohort of 16 patients with early-onset obsessive-compulsive disorder (OCD) and 12 mentally healthy individuals, using array-based comparative genomic hybridization (aCGH) on 44K arrays. A small rare paternal inherited microdeletion (?64 kb) was identified in chromosome 15q13.3 of one male patient with very early onset OCD. The father did not have OCD. The deletion encompassed part of the FMN1 gene, which is involved with the glutamatergic system. This finding supports the hypothesis of a complex network of several genes expressed in the brain contributing for the genetic risk of OCD, and also supports the glutamatergic involvement in OCD, which has been previously reported in the literature. PMID:25303678

  17. Academic Skills in Children with Early-Onset Type 1 Diabetes: The Effects of Diabetes-Related Risk Factors

    ERIC Educational Resources Information Center

    Hannonen, Riitta; Komulainen, Jorma; Riikonen, Raili; Ahonen, Timo; Eklund, Kenneth; Tolvanen, Asko; Keskinen, Paivi; Nuuja, Anja

    2012-01-01

    Aim: The study aimed to assess the effects of diabetes-related risk factors, especially severe hypoglycaemia, on the academic skills of children with early-onset type 1 diabetes mellitus (T1DM). Method: The study comprised 63 children with T1DM (31 females, 32 males; mean age 9y 11mo, SD 4mo) and 92 comparison children without diabetes (40…

  18. Retinol Binding Protein 4 – A Novel Association with Early-Onset Preeclampsia

    PubMed Central

    Vaisbuch, Edi; Romero, Roberto; Mazaki-Tovi, Shali; Erez, Offer; Kim, Sun Kwon; Chaiworapongsa, Tinnakorn; Gotsch, Francesca; Than, Nandor Gabor; Dong, Zhong; Pacora, Percy; Lamont, Ronald; Yeo, Lami; Hassan, Sonia S.; Kusanovic, Juan Pedro

    2010-01-01

    Objective Dysregulation of maternal circulating adipokines has been implicated in several “great obstetrical syndromes” including preeclampsia (PE), small-for-gestational age (SGA) neonate and fetal death (FD). It has been suggested that adipokines provide a molecular link between metabolic derangements and inflammatory response in complicated pregnancies. Retinol binding protein 4 (RBP4), a novel adipokine, plays a role in obesity-related disorders, as well as in the regulation of the immune response. The aim of this study was to determine whether there are changes in maternal plasma concentrations of RBP4 in patients with PE and in those with an SGA neonate or FD. Study design This cross-sectional study included patients in the following groups: 1) normal pregnancy (n=134); 2) PE (n=104); 3) SGA neonate (n=28); and 4) FD (n=37). Maternal plasma RBP4 concentrations were determined by ELISA. Non-parametric statistics were used for analysis. Results 1) The median maternal plasma RBP4 concentration was higher among patients with PE than in those with a normal pregnancy (p=0.03); 2) The median maternal plasma RBP4 concentrations of patients with preterm PE (<37 weeks) was higher than that of those with term PE (p=0.017) and than that of those with a normal pregnancy (p=0.002); 3) The median maternal plasma RBP4 concentration did not differ significantly between patients with a normal pregnancy and those with an SGA neonate or with an FD; 4) Among normal pregnant women, the maternal plasma RBP4 concentrations did not correlate with pre-pregnancy body mass index, gestational age at blood sampling and neonatal birthweight. Conclusions 1) Preeclampsia, but not pregnancy with an SGA neonate or an FD, is associated with a higher median maternal plasma concentration of RBP4 than normal pregnancy; 2) Preterm PE, and specifically early-onset PE, is associated with higher median RBP4 concentrations in maternal plasma compared to term PE. These findings suggest a role for RBP4 in the pathogenesis of preterm PE, but not in SGA and FD. PMID:19708829

  19. A risk factor for early-onset infection in premature newborns: invasion of chorioamniotic tissues by leukocytes.

    PubMed

    Korbage de Araujo, M C; Schultz, R; do Rosrio Dias de Oliveira, L; Ramos, J L; Vaz, F A

    1999-09-01

    The authors report a prospective study of correlation between histopathological alterations of the placenta, risk factors and early-onset bacterial infections in 224 premature newborns. They used a mathematical model for evaluation and prediction of neonatal bacterial infection according to the localization in chorioamniotic tissues (chorioamniotic plate, amniotic membranes and umbilical cord) invaded by leukocytes. Septicemia, pneumonia or omphalitis were documented in 45 (20%) infected premature newborns and inflammatory lesions in the placenta were observed in all of them. In order of statistical significance, the most important variables for early-onset bacterial neonatal infection were invasion of the chorioamniotic plate, amniotic membranes and umbilical cord tissues by PMNL (P < 0.0000), premature rupture of membranes (P < 0.0000), birthweight lower than 1500 g (P < 0.0000), gestational age under 34 weeks (P < 0.0001), foul smell (P < 0.0038), no antibiotics before delivery (P < 0.0066) and intrapartum fever (P < 0.0087). By logistic stepwise multiple regression analysis, invasion of fetal chorioamniotic plate and of amniotic membranes by leukocytes were the only statistically significant variables. The probability of neonatal infection in premature newborns, when polymorphonuclear neutrophils were present in chorioamniotic plate and in amniotic membranes, was 62.5%, while the probability was 0.5% when these tissues were normal. These data suggest that histological chorioamnionitis has to be considered as an important risk factor for early-onset infection in premature newborns. PMID:10530902

  20. Early-onset encephalopathy with epilepsy associated with a novel splice site mutation in SMC1A.

    PubMed

    Lebrun, Nicolas; Lebon, Sébastien; Jeannet, Pierre-Yves; Jacquemont, Sébastien; Billuart, Pierre; Bienvenu, Thierry

    2015-12-01

    We report on the clinical and molecular characterization of a female patient with early-onset epileptic encephalopathy, who was found to carry a de novo novel splice site mutation in SMC1A. This girl shared some morphologic and anthropometric traits described in patients with clinical diagnosis of Cornelia de Lange syndrome and with SMC1A mutation but also has severe encephalopathy with early-onset epilepsy. In addition, she had midline hand stereotypies and scoliosis leading to the misdiagnosis of a Rett overlap syndrome. Molecular studies found a novel de novo splice site mutation (c.1911 + 1G > T) in SMC1A. This novel splice mutation was associated with an aberrantly processed mRNA that included intron 11 of the gene. Moreover, quantitative approach by RT-PCR showed a severe reduction of the SMC1A transcript suggesting that this aberrant transcript may be unstable and degraded. Taken together, our data suggest that the phenotype may be due to a loss-of-function of SMC1A in this patient. Our findings suggest that loss-of-function mutations of SMC1A may be associated with early-onset encephalopathy with epilepsy. © 2015 Wiley Periodicals, Inc. PMID:26358754

  1. Genetic Analysis of PARK2 and PINK1 Genes in Brazilian Patients with Early-Onset Parkinson's Disease

    PubMed Central

    Moura, Karla Cristina Vasconcelos; Campos Junior, Mário; de Rosso, Ana Lúcia Zuma; Nicaretta, Denise Hack; Pereira, João Santos; Silva, Delson José; dos Santos, Flávia Lima; Rodrigues, Fabíola da Costa; Santos-Rebouças, Cíntia Barros; Pimentel, Márcia Mattos Gonçalves

    2013-01-01

    Parkinson's disease is the second most frequent neurodegenerative disorder in the world, affecting 1-2% of individuals over the age of 65. The etiology of Parkinson's disease is complex, with the involvement of gene-environment interactions. Although it is considered a disease of late manifestation, early-onset forms of parkinsonism contribute to 5–10% of all cases. In the present study, we screened mutations in coding regions of PARK2 and PINK1 genes in 136 unrelated Brazilian patients with early-onset Parkinson's disease through automatic sequencing. We identified six missense variants in PARK2 gene: one known pathogenic mutation, two variants of uncertain role, and three nonpathogenic changes. No pathogenic mutation was identified in PINK1 gene, only benign polymorphisms. All putative pathogenic variants found in this study were in heterozygous state. Our data show that PARK2 point mutations are more common in Brazilian early-onset Parkinson's disease patients (2.9%) than PINK1 missense variants (0%), corroborating other studies worldwide. PMID:24167364

  2. Very low birth weight neonates who survive early-onset sepsis do not have an increased risk of developing late-onset sepsis

    PubMed Central

    Lin, Cheryl B.; Hornik, Christoph P.; Clark, Reese; Cotten, C. Michael; Benjamin, Daniel K.; Cohen-Wolkoweiz, Michael; Smith, P. Brian; Wynn, James L.

    2012-01-01

    SUMMARY Background Very low birth weight neonates (≤1500 g, VLBWs) have a high rate of infection and distinct baseline immune function compared with more mature populations. In critically ill children and adults, sepsis increases subsequent infection risk. It is unknown whether sepsis modifies the risk of subsequent infection in VLBWs. Methods We conducted a retrospective cohort study of VLBWs ≤32 weeks gestation at birth cared for in 312 neonatal intensive care units in the United States from 1997–2011 (n=103,376). Early-onset sepsis (EOS, culture-positive only) and late-onset sepsis (LOS, culture-positive or clinical) cases were identified. Cox proportional hazards models were used to control for clinical variables between neonates with and without EOS to determine if EOS modified risk of LOS, necrotizing enterocolitis (NEC), or death. Results LOS occurred in 12,112/102,317 (11.8%) neonates without EOS and in 133/1059 (12.6%) of those with EOS. After adjustment for clinical variables, the risk of LOS was not different between neonates with or without a history of EOS (hazard ratio [HR]=0.92; 95% confidence interval [CI] 0.74, 1.16). EOS increased the risk of 120-day mortality (HR=1.78; 95% CI 1.49, 2.13). Conclusions In contrast to findings in children and adults, EOS was not associated with an increased risk of LOS in this cohort. Age-specific investigations are needed to determine if post-sepsis immunologic alterations are present. PMID:22840605

  3. Characterization of a Novel Periodontal Ligament-specific Periostin Isoform

    PubMed Central

    Yamada, S.; Tauchi, T.; Awata, T.; Maeda, K.; Kajikawa, T.; Yanagita, M.; Murakami, S.

    2014-01-01

    Periostin is a mesenchymal cell marker predominantly expressed in collagen-rich fibrous connective tissues, including heart valves, tendons, perichondrium, periosteum, and periodontal ligament (PDL). Knockdown of periostin expression in mice results in early-onset periodontitis and failure of cardiac healing after acute myocardial infarction, suggesting that periostin is essential for connective tissue homeostasis and regeneration. However, its role(s) in periodontal tissues has not yet been fully defined. In this study, we describe a novel human isoform of periostin (PDL-POSTN). Isoform-specific analysis by reverse-transcription polymerase chain-reaction (RT-PCR) revealed that PDL-POSTN was predominantly expressed in the PDL, with much lower expression in other tissues and organs. A PDL cell line transfected with PDL-POSTN showed enhanced alkaline phosphatase (ALPase) activity and calcified nodule formation, compared with cells transfected with the full-length periostin isoform. A neutralizing antibody against integrin-?v inhibited both ALPase activity and calcified nodule formation in cells transfected with PDL-POSTN. Furthermore, co-immunoprecipitation assays revealed that PDL-POSTN bound to integrin ?v?3 more strongly than the common isoform of periostin, resulting in strong activation of the integrin ?v?3-focal adhesion kinase (FAK) signaling pathway. These results suggest that PDL-POSTN positively regulates cytodifferentiation and mineralization in PDL cells through integrin ?v?3. PMID:25012810

  4. Neuroanatomical correlates of emotional blunting in behavioral variant frontotemporal dementia and early-onset Alzheimers disease

    PubMed Central

    Lee, Grace J.; Lu, Po H.; Mather, Michelle J.; Shapira, Jill; Jimenez, Elvira; Leow, Alex D.; Thompson, Paul M.; Mendez, Mario F.

    2014-01-01

    Background Emotional blunting is a characteristic feature of behavioral variant frontotemporal dementia (bvFTD) and can help discriminate between patients with bvFTD and other forms of younger-onset dementia. Objective We compared the presence of emotional blunting symptoms in patients with bvFTD and early-onset Alzheimers disease (AD), and investigated the neuroanatomical associations between emotional blunting and regional brain volume. Methods Twenty-five individuals with bvFTD (n=11) and early-onset AD (n=14) underwent magnetic resonance imaging (MRI) and were rated on symptoms of emotional blunting using the Scale for Emotional Blunting (SEB). The two groups were compared on SEB ratings and MRI-derived brain volume using tensor-based morphometry (TBM). Voxel-wise linear regression was performed to determine neuroanatomical correlates of SEB scores. Results The bvFTD group had significantly higher SEB scores compared to the AD group. On MRI, bvFTD patients had smaller bilateral frontal lobe volume compared to AD patients, while AD patients had smaller bilateral temporal and left parietal volume than bvFTD patients. In bvFTD, SEB ratings were strongly correlated with right anterior temporal volume, while the association between SEB and the right orbitofrontal cortex was non-significant. Conclusions Symptoms of emotional blunting were more prevalent in bvFTD than early-onset AD patients. These symptoms were particularly associated with right-sided atrophy, with significant involvement of the right anterior temporal region. Based on these findings, the SEB may be a useful diagnostic instrument for identifying a key clinical feature of bvFTD and appears to measure symptoms that are localized to the right anterior temporal lobe. PMID:24685626

  5. Early-Onset Psychoses: Comparison of Clinical Features and Adult Outcome in 3 Diagnostic Groups

    ERIC Educational Resources Information Center

    Ledda, Maria Giuseppina; Fratta, Anna Lisa; Pintor, Manuela; Zuddas, Alessandro; Cianchetti, Carlo

    2009-01-01

    A comparison of clinical features and adult outcome in adolescents with three types of psychotic disorders: schizophrenic (SPh), schizoaffective (SA) and bipolar with psychotic features (BPP). Subjects (n = 41) were finally diagnosed (DSM-IV criteria) with SPh (n = 17), SA (n = 11) or BPP (n = 13). Clinical evaluation took place at onset and at a

  6. Phenotypic profile of early-onset familial Alzheimer's disease caused by presenilin-1 E280A mutation.

    PubMed

    Sepulveda-Falla, Diego; Glatzel, Markus; Lopera, Francisco

    2012-01-01

    Presenilin 1 (PS1) mutations are the most common cause of early-onset familial Alzheimer's disease (EOFAD). They show a common phenotypic profile characterized by early age of onset, severe dementia and distinct neurodegeneration. The largest population of EOFAD carries the E280A mutation in PS1 and resides in Antioquia, Colombia, currently comprising around 5,000 individuals. Carriers start showing memory impairment in the third decade of life, followed by progressive impairment of language and other cognitive processes. They reach mild cognitive impairment around 45 and dementia around 50 years of age. There is some phenotypic variability among the carriers of this single PS1 mutation. Some patients present with epilepsy, verbal impairment, and cerebellar ataxia. Neuropathologically, PS1 E280A cases show pronounced brain atrophy, severe amyloid-? pathology, distinct hyperphosphorylated tau-related pathology, and cerebellar damage. The earliest event identified by functional magnetic imaging resonance is hyperactivation within the right anterior hippocampus around 33 years of age. This well-studied population with a clear pre-clinical profile and wide phenotypic variability in age of onset and clinical presentation is ideally suited for clinical trials and to study molecular mechanisms of Alzheimer's disease. PMID:22766738

  7. Loss of functional connectivity is greater outside the default mode network in nonfamilial early-onset Alzheimer's disease variants.

    PubMed

    Lehmann, Manja; Madison, Cindee; Ghosh, Pia M; Miller, Zachary A; Greicius, Michael D; Kramer, Joel H; Coppola, Giovanni; Miller, Bruce L; Jagust, William J; Gorno-Tempini, Maria L; Seeley, William W; Rabinovici, Gil D

    2015-10-01

    The common and specific involvement of brain networks in clinical variants of Alzheimer's disease (AD) is not well understood. We performed task-free ("resting-state") functional imaging in 60 nonfamilial AD patients, including 20 early-onset AD (age at onset <65 years, amnestic/dysexecutive deficits), 24 logopenic aphasia (language deficits), and 16 posterior cortical atrophy patients (visual deficits), as well as 60 healthy controls. Seed-based connectivity analyses were conducted to assess differences between groups in 3 default mode network (DMN) components (anterior, posterior, and ventral) and 4 additional non-DMN networks: left and right executive-control, language, and higher visual networks. Significant decreases in connectivity were found across AD variants compared with controls in the non-DMN networks. Within the DMN components, patients showed higher connectivity in the anterior DMN, in particular in logopenic aphasia. No significant differences were found for the posterior and ventral DMN. Our findings suggest that loss of functional connectivity is greatest in networks outside the DMN in early-onset and nonamnestic AD variants and may thus be a better biomarker in these patients. PMID:26242705

  8. High-frequency 3D echodentographic imaging modality for early assessment of periodontal diseases: in vitro study

    NASA Astrophysics Data System (ADS)

    Mahmoud, Ahmed M.; Ngan, Peter; Crout, Richard; Mukdadi, Osama M.

    2009-02-01

    The use of ultrasound in dentistry is still an open growing area of research. Currently, there is a lack of imaging modalities to accurately predict minute structures and defects in the jawbone. In particular, the inability of 2D radiographic images to detect bony periodontal defects resulted from infection of the periodontium. This study investigates the feasibility of high frequency ultrasound to reconstruct high resolution 3D surface images of human jawbone. Methods: A dentate and non-dentate mandibles were used in this study. The system employs high frequency single-element ultrasound focused transducers (15-30 MHz) for scanning. Continuous acquisition using a 1 GHz data acquisition card is synchronized with a high precision two-dimensional stage positioning system of +/-1 μm resolution for acquiring accurate and quantitative measurements of the mandible in vitro. Radio frequency (RF) signals are acquired laterally 44-45.5 μm apart for each frame. Different frames are reconstructed 500 μm apart for the 3D reconstruction. Signal processing algorithms are applied on the received ultrasound signals for filtering, focusing, and envelope detection before frame reconstruction. Furthermore, an edge detection technique is adopted to detect the bone surface in each frame. Finally, all edges are combined together in order to render a 3D surface image of the jawbone. Major anatomical landmarks on the resultant images were confirmed with the anatomical structures on the mandibles to show the efficacy of the system. Comparison were also made with conventional 2D radiographs to show the superiority of the ultrasound imaging system in diagnosing small defects in the lateral, axial and elevation planes of space. Results: The landmarks on all ultrasound images matched with those on the mandible, indicating the efficacy of the system in detecting small structures in human jaw bones. Comparison with conventional 2D radiographic images of the same mandible showed superiority of the 3D ultrasound images in detecting defects in the elevation plane of space. These results suggest that the high frequency ultrasound system shows great potential in providing a non-invasive method to characterize the jawbone and detect periodontal diseases at earlier stages.

  9. Newly Identified Pathogens Associated with Periodontitis

    PubMed Central

    Prez-Chaparro, P.J.; Gonalves, C.; Figueiredo, L.C.; Faveri, M.; Lobo, E.; Tamashiro, N.; Duarte, P.; Feres, M.

    2014-01-01

    There is substantial evidence supporting the role of certain oral bacteria species in the onset and progression of periodontitis. Nevertheless, results of independent-culture diagnostic methods introduced about a decade ago have pointed to the existence of new periodontal pathogens. However, the data of these studies have not been evaluated together, which may generate some misunderstanding on the actual role of these microorganisms in the etiology of periodontitis. The aim of this systematic review was to determine the current weight of evidence for newly identified periodontal pathogens based on the results of association studies. This review was conducted and reported in accordance with the PRISMA statement. The MEDLINE, EMBASE, and Cochrane databases were searched up to September 2013 for studies (1) comparing microbial data of subgingival plaque samples collected from subjects with periodontitis and periodontal health and (2) evaluating at least 1 microorganism other than the already-known periodontal pathogens. From 1,450 papers identified, 41 studies were eligible. The data were extracted and registered in predefined piloted forms. The results suggested that there is moderate evidence in the literature to support the association of 17 species or phylotypes from the phyla Bacteroidetes, Candidatus Saccharibacteria, Firmicutes, Proteobacteria, Spirochaetes, and Synergistetes. The phylum Candidatus Saccharibacteria and the Archaea domain also seem to have an association with disease. These data point out the importance of previously unidentified species in the etiology of periodontitis and might guide future investigations on the actual role of these suspected new pathogens in the onset and progression of this infection. PMID:25074492

  10. Are early onset aging conditions correlated to daily activity functions in youth and adults with Down syndrome?

    PubMed

    Lin, Jin-Ding; Lin, Lan-Ping; Hsu, Shang-Wei; Chen, Wen-Xiu; Lin, Fu-Gong; Wu, Jia-Ling; Chu, Cordia

    2014-11-13

    This study aims to answer the research question of "Are early onset aging conditions correlated to daily activity functions in youth and adults with Down syndrome (DS)?" A cross-sectional survey was employed to recruit 216 individuals with DS over 15 years of age in the analyses. A structured questionnaire included demographic data, brief self-reported aging conditions, Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID) and activity of daily living (ADL) scales were completed by the primary caregivers who were well-suited for providing information on the functioning conditions of the DS individuals. Results showed that the most five frequent aging conditions (sometimes, usually and always) included frailty (20.2%), vision problem (15.8%), loss of language ability (15.3%), sleep problem (14.9%) and memory impairment (14.5%). Other onset aging conditions included more chronic diseases (13.9%), hearing loss (13%), chewing ability and tooth loss (12.5%), incontinence (11.1%), depressive syndrome (7.7%), falls and gait disorder (7.2%), loss of taste and smell (7.2%). The data also showed scores of DSQIID, onset aging conditions and ADL has significant relationships each other in Pearson's correlation tests. Finally, multiple linear regression analyses indicated onset aging conditions (?=-0.735, p<0.001) can significantly predicted the variation in ADL scores after adjusting other factors (R(2)=0.381). This study suggests that the authority should initiate early intervention programs aim to improve healthy aging and ADL functions for people with DS. PMID:25462513

  11. Immediate periodontal bone plate changes induced by rapid maxillary expansion in the early mixed dentition: CT findings

    PubMed Central

    Garib, Daniela Gamba; Menezes, Maria Helena Ocké; da Silva Filho, Omar Gabriel; dos Santos, Patricia Bittencourt Dutra

    2014-01-01

    Objective This study aimed at evaluating buccal and lingual bone plate changes caused by rapid maxillary expansion (RME) in the mixed dentition by means of computed tomography (CT). Methods The sample comprised spiral CT exams taken from 22 mixed dentition patients from 6 to 9 years of age (mean age of 8.1 years) presenting constricted maxillary arch treated with Haas-type expanders. Patients were submitted to spiral CT scan before expansion and after the screw activation period with a 30-day interval between T1 and T2. Multiplanar reconstruction was used to measure buccal and lingual bone plate thickness and buccal bone crest level of maxillary posterior deciduous and permanent teeth. Changes induced by expansion were evaluated using paired t test (p < 0.05). Results Thickness of buccal and lingual bone plates of posterior teeth remained unchanged during the expansion period, except for deciduous second molars which showed a slight reduction in bone thickness at the distal region of its buccal aspect. Buccal bone dehiscences were not observed in the supporting teeth after expansion. Conclusion RME performed in mixed dentition did not produce immediate undesirable effects on periodontal bone tissues. PMID:25162564

  12. Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo.

    PubMed

    Laberge, Greggory; Mailloux, Christina M; Gowan, Katherine; Holland, Paulene; Bennett, Dorothy C; Fain, Pamela R; Spritz, Richard A

    2005-08-01

    Generalized vitiligo is an autoimmune disorder in which acquired white patches of skin and overlying hair result from autoimmune loss of melanocytes from involved areas. Although usually sporadic, family clustering of vitiligo may occur, in a non-Mendelian pattern typical of multifactorial, polygenic inheritance. Sporadic vitiligo is associated with autoimmune thyroid disease, pernicious anemia, Addison's disease, and lupus; these same disorders occur at increased frequency in patients' first-degree relatives. Here, we studied 133 'multiplex' generalized vitiligo families, with multiple affected family members. The age of onset of vitiligo is earlier in these 'multiplex' families than in patients with sporadic vitiligo. Affected members of the multiplex vitiligo families have elevated frequencies of autoimmune thyroid disease, rheumatoid arthritis, psoriasis, adult-onset insulin-dependent diabetes mellitus, pernicious anemia, and Addison's disease. Probands' unaffected siblings have elevated frequencies of most of these same autoimmune diseases, particularly if the proband had non-vitiligo autoimmune disease. Familial generalized vitiligo is thus characterized by earlier disease onset and a broader repertoire of associated autoimmune diseases than sporadic vitiligo. This mostly likely reflects a greater inherited genetic component of autoimmune susceptibility in these families. These findings have important implications for autoimmune disease surveillance in families in which multiple members are affected with vitiligo. PMID:16029422

  13. Outcome of Early Juvenile Onset Metachromatic Leukodystrophy After Unrelated Cord Blood Transplantation: A Case Series and Review of the Literature.

    PubMed

    Chen, Xuqin; Gill, Deepak; Shaw, Peter; Ouvrier, Robert; Troedson, Christopher

    2016-03-01

    The purpose of this study was to determine whether transplantation of umbilical cord blood from unrelated donors before the development of symptoms could halt the progression of early juvenile onset cases of MLD in whom the disease was diagnosed based on the family history. Three asymptomatic children (aged 2 years 4 months, 2 years 8 months and 5 years 5 months, two of whom were sisters) underwent unrelated umbilical cord blood transplantation (UCBT) and two untreated symptomatic siblings were included in the study. In 14-year and 6-year follow-ups after transplantation, clinical examination, ARSA enzyme levels, neurophysiological, neuroimaging, and psychological status were assessed. All three transplanted patients remain well, and the parameters evaluated remain stable. Of the treated patients, the two sisters had ongoing evidence of demyelinating sensorimotor neuropathy on nerve conduction tests, and with a early sensorimotor neuropathy in the older sister , and the other patient has mild intellectual impairment. One of the two un-transplanted controls, 15 years after MLD diagnosis, has relentlessly progressed to full dependency with epilepsy, severe mental retardation, dystonic movements, dysphagia and recurrent respiratory problems. Six years after diagnosis, the other control has a slowly progressive course with spastic dystonic quadriplegia, epilepsy, dysphagia, continual drooling and incontinence. Our data show that, in comparison with their untreated siblings, UCBT significantly slowed the progression of the disease in the treated patients. We conclude that UCBT benefits children with pre-symptomatic early juvenile onset MLD by favourably altering the natural history of the disease. PMID:26187619

  14. Familial periodontal disease in the cayo santiago rhesus macaques.

    PubMed

    Gonzalez, Octavio A; Orraca, Luis; Kensler, Terry B; Gonzalez-Martinez, Janis; Maldonado, Elizabeth; Ebersole, Jeffrey L

    2016-01-01

    Substantial ongoing research continues to explore the contribution of genetics and environment to the onset, extent and severity of periodontal disease(s). Existing evidence supports that periodontal disease appears to have an increased prevalence in family units with a member having aggressive periodontitis. We have been using the nonhuman primate as a model of periodontal disease for over 25 years with these species demonstrating naturally occurring periodontal disease that increases with age. This report details our findings from evaluation of periodontal disease in skulls from 97 animals (5-31 years of age) derived from the skeletons of the rhesus monkeys (Macaca mulatta) on Cayo Santiago. Periodontal disease was evaluated by determining the distance from the base of the alveolar bone defect to the cemento-enamel junction on 1st/2nd premolars and 1st/2nd molars from all four quadrants. The results demonstrated an increasing extent and severity of periodontitis with aging across the population of animals beyond only compensatory eruption. Importantly, irrespective of age, extensive heterogeneity in disease expression was observed among the animals. Linking these variations to multi-generational matriarchal family units supported familial susceptibility of periodontitis. As the current generations of animals that are descendants from these matrilines are alive, studies can be conducted to explore an array of underlying factors that could account for susceptibility or resistance to periodontal disease. Am. J. Primatol. 78:143-151, 2016. 2016 Wiley Periodicals, Inc. PMID:25708960

  15. Early-Onset Convulsive Seizures Induced by Brain Hypoxia-Ischemia in Aging Mice: Effects of Anticonvulsive Treatments

    PubMed Central

    Peng, Jessie; Patel, Nisarg; Huang, Yayi; Gao, Xiaoxing; Aljarallah, Salman; Eubanks, James H.; McDonald, Robert; Zhang, Liang

    2015-01-01

    Aging is associated with an increased risk of seizures/epilepsy. Stroke (ischemic or hemorrhagic) and cardiac arrest related brain injury are two major causative factors for seizure development in this patient population. With either etiology, seizures are a poor prognostic factor. In spite of this, the underlying pathophysiology of seizure development is not well understood. In addition, a standardized treatment regimen with anticonvulsants and outcome assessments following treatment has yet to be established for these post-ischemic seizures. Previous studies have modeled post-ischemic seizures in adult rodents, but similar studies in aging/aged animals, a group that mirrors a higher risk elderly population, remain sparse. Our study therefore aimed to investigate early-onset seizures in aging animals using a hypoxia-ischemia (HI) model. Male C57 black mice 18-20-month-old underwent a unilateral occlusion of the common carotid artery followed by a systemic hypoxic episode (8% O2 for 30 min). Early-onset seizures were detected using combined behavioral and electroencephalographic (EEG) monitoring. Brain injury was assessed histologically at different times post HI. Convulsive seizures were observed in 65% of aging mice post-HI but not in control aging mice following either sham surgery or hypoxia alone. These seizures typically occurred within hours of HI and behaviorally consisted of jumping, fast running, barrel-rolling, and/or falling (loss of the righting reflex) with limb spasms. No evident discharges during any convulsive seizures were seen on cortical-hippocampal EEG recordings. Seizure development was closely associated with acute mortality and severe brain injury on brain histological analysis. Intra-peritoneal injections of lorazepam and fosphenytoin suppressed seizures and improved survival but only when applied prior to seizure onset and not after. These findings together suggest that seizures are a major contributing factor to acute mortality in aging mice following severe brain ischemia and that early anticonvulsive treatment may prevent seizure genesis and improve overall outcomes. PMID:26630670

  16. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis

    PubMed Central

    Martin, Hilary C.; Kim, Grace E.; Pagnamenta, Alistair T.; Murakami, Yoshiko; Carvill, Gemma L.; Meyer, Esther; Copley, Richard R.; Rimmer, Andrew; Barcia, Giulia; Fleming, Matthew R.; Kronengold, Jack; Brown, Maile R.; Hudspith, Karl A.; Broxholme, John; Kanapin, Alexander; Cazier, Jean-Baptiste; Kinoshita, Taroh; Nabbout, Rima; Bentley, David; McVean, Gil; Heavin, Sinad; Zaiwalla, Zenobia; McShane, Tony; Mefford, Heather C.; Shears, Deborah; Stewart, Helen; Kurian, Manju A.; Scheffer, Ingrid E.; Blair, Edward; Donnelly, Peter; Kaczmarek, Leonard K.; Taylor, Jenny C.

    2014-01-01

    In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders. PMID:24463883

  17. Tea, coffee, and caffeine and early-onset basal cell carcinoma in a case-control study.

    PubMed

    Ferrucci, Leah M; Cartmel, Brenda; Molinaro, Annette M; Leffell, David J; Bale, Allen E; Mayne, Susan T

    2014-07-01

    Tea and coffee are hypothesized to play a protective role in skin carcinogenesis through bioactive components, such as caffeine, yet the epidemiologic evidence is mixed. Existing data support an inverse association with basal cell carcinoma (BCC), more so than for melanoma or squamous cell carcinoma. To understand whether tea, coffee, and caffeine are related to early-onset BCC, we evaluated data from 767 non-Hispanic Whites under age 40 in a case-control study in Connecticut. BCC cases (n=377) were identified through Yale's Dermatopathology database. Controls (n=390) were randomly sampled from individuals in the same database with benign skin diagnoses and frequency matched to cases on age, sex, and biopsy site. Participants completed an in-person interview including assessment of caffeinated coffee and hot tea. We calculated multivariate odds ratios (ORs) and 95% confidence intervals (CIs) with unconditional logistic regression for regular consumption and frequency and duration measures. Combined regular consumption of caffeinated coffee plus hot tea was inversely associated with early-onset BCC (OR=0.60, 95% CI=0.38-0.96). Those in the highest category of caffeine from these sources had a 43% reduced risk of BCC compared with nonconsumers (OR=0.57, 95% CI=0.34-0.95, P-trend=0.037). Our findings suggest a modest protective effect for caffeinated coffee plus tea in relation to early-onset BCC that may, in part, be due to caffeine. This study adds to the growing body of literature suggesting potential health benefits from these beverages. PMID:24841641

  18. Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs.

    PubMed

    Westra, Inge M; Oosterhuis, Dorenda; Groothuis, Geny M M; Olinga, Peter

    2014-01-15

    Induction of fibrosis during prolonged culture of precision-cut liver slices (PCLS) was reported. In this study, the use of rat PCLS was investigated to further characterize the mechanism of early onset of fibrosis in this model and the effects of antifibrotic compounds. Rat PCLS were incubated for 48h, viability was assessed by ATP and gene expression of PDGF-B and TGF-?1 and the fibrosis markers Hsp47, ?Sma and Pcol1A1 and collagen1 protein expressions were determined. The effects of the antifibrotic drugs imatinib, sorafenib and sunitinib, PDGF-pathway inhibitors, and perindopril, valproic acid, rosmarinic acid, tetrandrine and pirfenidone, TGF?-pathway inhibitors, were determined. After 48h of incubation, viability of the PCLS was maintained and gene expression of PDGF-B was increased while TGF-?1 was not changed. Hsp47, ?Sma and Pcol1A1 gene expressions were significantly elevated in PCLS after 48h, which was further increased by PDGF-BB and TGF-?1. The increased gene expression of fibrosis markers was inhibited by all three PDGF-inhibitors, while TGF?-inhibitors showed marginal effects. The protein expression of collagen 1 was inhibited by imatinib, perindopril, tetrandrine and pirfenidone. In conclusion, the increased gene expression of PDGF-B and the down-regulation of fibrosis markers by PDGF-pathway inhibitors, together with the absence of elevated TGF-?1 gene expression and the limited effect of the TGF?-pathway inhibitors, indicated the predominance of the PDGF pathway in the early onset of fibrosis in PCLS. PCLS appear a useful model for research of the early onset of fibrosis and for testing of antifibrotic drugs acting on the PDGF pathway. PMID:24321339

  19. Tea, coffee, and caffeine and early-onset basal cell carcinoma in a case-control study

    PubMed Central

    Ferrucci, Leah M.; Cartmel, Brenda; Molinaro, Annette M.; Leffell, David J.; Bale, Allen E.; Mayne, Susan T.

    2014-01-01

    Objectives Tea and coffee are hypothesized to play a protective role in skin carcinogenesis via bioactive components, such as caffeine, yet the epidemiologic evidence is mixed. Existing data supports an inverse association with basal cell carcinoma (BCC) more so than for melanoma or squamous cell carcinoma. To understand if tea, coffee, and caffeine are related to early-onset BCC, we evaluated data from 767 non-Hispanic Whites under age 40 in a case-control study in Connecticut. Methods BCC cases (n=377) were identified through Yale's Dermatopathology database. Controls (n=390) were randomly sampled from individuals in the same database with benign skin diagnoses and frequency matched to cases on age, gender, and biopsy site. Subjects completed an in-person interview including assessment of caffeinated coffee and hot tea. We calculated multivariate odds ratios (OR) and 95% confidence intervals (CIs) with unconditional logistic regression for regular consumption and frequency and duration measures. Results Combined regular consumption of caffeinated coffee plus hot tea was inversely associated with early-onset BCC (OR=0.60, 95% CI=0.38–0.96). Those in the highest category of caffeine from these sources had a 43% reduced risk of BCC compared to non-consumers (OR=0.57, 95% CI=0.34–0.95, p-trend=0.037). Conclusions Our findings suggest a modest protective effect for caffeinated coffee plus tea in relation to early-onset BCC that may, in part, be due to caffeine. This study adds to the growing body of literature suggesting potential health benefits from these beverages. PMID:24841641

  20. Early-Onset Atopic Dermatitis in Children: Which Are the Phenotypes at Risk of Asthma? Results from the ORCA Cohort

    PubMed Central

    Amat, Flore; Saint-Pierre, Philippe; Bourrat, Emmanuelle; Nemni, Ariane; Couderc, Rmy; Boutmy-Deslandes, Emmanuelle; Sahraoui, Fatiha; Pans, Isabelle; Bagot, Martine; Fouer, Sbastien; Just, Jocelyne

    2015-01-01

    Background Atopic dermatitis (AD) is known to predate asthma and other atopic disorders described under the term atopic march. However, this classic sequence is not always present and only a few studies have addressed children at risk of developing asthma. The objective of this study is to define early-onset AD phenotypes leading to asthma. Methods We performed a cluster analysis with 9 variables of 214 infants with early-onset AD prospectively enrolled in the ORCA cohort and followed each year on the occurrence of asthma until the age of 6. Results We identified 3 clusters - cluster 1 (n = 94) with low to no sensitization to food (27.7%) or aeroallergens (10.6%) and moderate AD severity (SCORAD 25.29 +/- 14.6) called AD with low sensitization; - cluster 2 (n = 84) characterized by a higher AD severity (SCORAD 32.66+/-16.6) and frequent sensitization to food (98.9%) or aeroallergens (26.2%), most likely multiple (96.4% for food allergens), called AD with multiple sensitizations - cluster 3 (n = 36) with parental history, moderate AD severity (SCORAD 24.46+/-15.7), moderate rate of sensitization to food allergens (38.9%) (exclusively single) with no sensitization to aeroallergens, called AD with familial history of asthma. Percentages of children suffering from asthma at the age of 6 were higher in clusters 2 and 3 (36.1% and 33.3% respectively versus 14.9% in cluster 1, p<0.01). Conclusion Two phenotypes in infants with early-onset AD convey a higher risk of developing asthma during childhood: multiple sensitization and familial history of asthma. PMID:26107938

  1. Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs

    SciTech Connect

    Westra, Inge M.; Oosterhuis, Dorenda; Groothuis, Geny M.M.; Olinga, Peter

    2014-01-15

    Induction of fibrosis during prolonged culture of precision-cut liver slices (PCLS) was reported. In this study, the use of rat PCLS was investigated to further characterize the mechanism of early onset of fibrosis in this model and the effects of antifibrotic compounds. Rat PCLS were incubated for 48 h, viability was assessed by ATP and gene expression of PDGF-B and TGF-β1 and the fibrosis markers Hsp47, αSma and Pcol1A1 and collagen1 protein expressions were determined. The effects of the antifibrotic drugs imatinib, sorafenib and sunitinib, PDGF-pathway inhibitors, and perindopril, valproic acid, rosmarinic acid, tetrandrine and pirfenidone, TGFβ-pathway inhibitors, were determined. After 48 h of incubation, viability of the PCLS was maintained and gene expression of PDGF-B was increased while TGF-β1 was not changed. Hsp47, αSma and Pcol1A1 gene expressions were significantly elevated in PCLS after 48 h, which was further increased by PDGF-BB and TGF-β1. The increased gene expression of fibrosis markers was inhibited by all three PDGF-inhibitors, while TGFβ-inhibitors showed marginal effects. The protein expression of collagen 1 was inhibited by imatinib, perindopril, tetrandrine and pirfenidone. In conclusion, the increased gene expression of PDGF-B and the down-regulation of fibrosis markers by PDGF-pathway inhibitors, together with the absence of elevated TGF-β1 gene expression and the limited effect of the TGFβ-pathway inhibitors, indicated the predominance of the PDGF pathway in the early onset of fibrosis in PCLS. PCLS appear a useful model for research of the early onset of fibrosis and for testing of antifibrotic drugs acting on the PDGF pathway. - Highlights: • During culture, fibrosis markers increased in precision-cut liver slices (PCLS). • Gene expression of PDGF-β was increased, while TGFβ was not changed in rat PCLS. • PDGF-pathway inhibitors down-regulated this increase of fibrosis markers. • TGFβ-pathway inhibitors had only minor effects on fibrosis markers. • Rat PCLS can be used to study the early onset of fibrosis.

  2. Rare Variants in PLD3 Do Not Affect Risk for Early-Onset Alzheimer Disease in a European Consortium Cohort.

    PubMed

    Cacace, Rita; Van den Bossche, Tobi; Engelborghs, Sebastiaan; Geerts, Nathalie; Laureys, Annelies; Dillen, Lubina; Graff, Caroline; Thonberg, Håkan; Chiang, Huei-Hsin; Pastor, Pau; Ortega-Cubero, Sara; Pastor, Maria A; Diehl-Schmid, Janine; Alexopoulos, Panagiotis; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Nacmias, Benedetta; Sorbi, Sandro; Sanchez-Valle, Raquel; Lladó, Albert; Gelpi, Ellen; Almeida, Maria Rosário; Santana, Isabel; Tsolaki, Magda; Koutroumani, Maria; Clarimon, Jordi; Lleó, Alberto; Fortea, Juan; de Mendonça, Alexandre; Martins, Madalena; Borroni, Barbara; Padovani, Alessandro; Matej, Radoslav; Rohan, Zdenek; Vandenbulcke, Mathieu; Vandenberghe, Rik; De Deyn, Peter P; Cras, Patrick; van der Zee, Julie; Sleegers, Kristel; Van Broeckhoven, Christine

    2015-12-01

    Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late-onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole-genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early-onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency <1%, 20 missense and two splicing mutations. Burden analysis did not provide significant evidence for an enrichment of rare PLD3 variants in EOAD patients in any of the patient/control cohorts. Also, meta-analysis of the PLD3 data, including a published dataset of a German EOAD cohort, was not significant (P = 0.43; OR = 1.53, 95% CI 0.60-3.31). Consequently, our data do not support a role for PLD3 rare variants in the genetic etiology of EOAD in European EOAD patients. Our data corroborate the negative replication data obtained in LOAD studies and therefore a genetic role of PLD3 in AD remains to be demonstrated. PMID:26411346

  3. Differences and Similarities in the Transcriptional Profile of Peripheral Whole Blood in Early and Late-Onset Preeclampsia: Insights into the Molecular Basis of the Phenotype of Preeclampsia

    PubMed Central

    Chaiworapongsa, Tinnakorn; Romero, Roberto; Whitten, Amy; Tarca, Adi L; Bhatti, Gaurav; Draghici, Sorin; Chaemsaithong, Piya; Miranda, Jezid; Kim, Chong Jai; Hassan, Sonia S

    2014-01-01

    Objective Preeclampsia (PE) has been sub-divided into early- and late-onset phenotypes. The pathogenesis of these two phenotypes has not been elucidated. To gain insight into the mechanisms of disease, the transcriptional profiles of whole blood from women with early- and late-onset PE were examined. Methods A cross-sectional study was conducted to include women with: 1) early-onset PE (diagnosed prior to 34 weeks, n=25); 2) late-onset PE (after 34 weeks, n=47); and 3) uncomplicated pregnancy (n=61). Microarray analysis of mRNA expression in peripheral whole blood was undertaken using Affymetrix microarrays. Differential gene expression was evaluated using a moderated t-test (false discovery rate <0.1 and fold change >1.5), adjusting for maternal WBC count and gestational age. Validation by real-time qRT-PCR was performed in a larger sample size [early PE (n=31), late PE (n=72) and controls (n=99)] in all differentially expressed genes. Gene Ontology analysis and pathway analysis were performed. Results 1) 43 and 28 genes were differentially expressed in early- and late-onset PE compared to the control group respectively; 2) qRT-PCR confirmed the microarray results for early and late-onset PE in 77% (33/43) and 71% (20/28) of genes, respectively; 3) 20 genes that are involved in coagulation (SERPINI2), immune regulation (VSIG4, CD24), developmental process (H19) and inflammation (S100A10) were differentially expressed in early-onset PE alone. In contrast, only seven genes that encoded proteins involved in innate immunity (LTF, ELANE) and cell-to-cell recognition in the nervous system (CNTNAP3) were differentially expressed in late-onset PE alone. Thirteen genes that encode proteins involved in host defense (DEFA4, BPI, CTSG, LCN2), tight junctions in blood-brain barrier (EMP1) and liver regeneration (ECT2) were differentially expressed in both early- and late-onset PE. Conclusion Early- and late-onset PE are characterized by a common signature in the transcriptional profile of whole blood. A small set of genes were differentially regulated in early- and late-onset PE. Future studies of the biological function, expression timetable and protein expression of these genes may provide insight into the pathophysiology of PE. PMID:23793063

  4. Early DWI Reversal Following Endovascular Reperfusion Is Typically Transient in Patients Imaged 3-6 Hours After Onset

    PubMed Central

    Inoue, Manabu; Mlynash, Michael; Christensen, Soren; Wheeler, Hayley M.; Straka, Matus; Tipirneni, Aaryani; Kemp, Stephanie M.; Zaharchuk, Greg; Olivot, Jean-Marc; Bammer, Roland; Lansberg, Maarten G.; Albers, Gregory W.

    2014-01-01

    Background and Purpose The aim of this study was to assess the frequency and extent of early diffusion-weighted imaging (DWI) lesion reversal following endovascular therapy and to determine if early reversal is sustained or transient. Methods MRI with DWI perfusion imaging was performed before (DWI 1) and within 12 hours after (DWI 2) endovascular treatment; follow up MRI was obtained on Day 5. Both DWIs were co-registered to follow up MRI. Early DWI reversal was defined as the volume of the DWI 1 lesion that was not superimposed on the DWI 2 lesion. Permanent reversal was the volume of the DWI 1 lesion not superimposed on the Day 5 infarct. Associations between early DWI reversal and clinical outcomes in patients with and without reperfusion were assessed. Results 110 patients had technically adequate DWI prior to endovascular therapy [performed median (IQR) 4.5 (2.8 6.2) hours after onset]; 60 were eligible for this study. Thirty-two percent had early DWI reversal >10 ml; 17% had sustained reversal. The median volume of tissue salvage at 5 days was 3 ml (IQR 1.77.0). Only 2 patients (3%) had a final infarct volume that was smaller than their baseline DWI lesion. Early DWI reversal was not an independent predictor of clinical outcome and was not associated with early reperfusion. Conclusions Early DWI reversal occurred in about one third of patients following endovascular therapy in patients; however, reversal was often transient and was not associated with a significant volume of tissue salvage or favorable clinical outcome. PMID:24558095

  5. A founder mutation in ADAMTSL4 causes early-onset bilateral ectopia lentis among Jews of Bukharian origin.

    PubMed

    Reinstein, Eyal; Smirin-Yosef, Pola; Lagovsky, Irina; Davidov, Bella; Peretz Amit, Gabriela; Neumann, Doron; Orr-Urtreger, Avi; Ben-Shachar, Shay; Basel-Vanagaite, Lina

    2016-01-01

    The term isolated ectopia lentis (EL; subluxation or dislocation of the human crystalline lens) is applied to patients with EL, without skeletal features and in the absence of aortic root dilatation. To date, the only gene shown to cause autosomal-recessive isolated EL is ADAMTSL4. Here we report a novel founder mutation in ADAMTSL4 gene in children of Bukharian Jewish origin presenting with early-onset bilateral EL. A carrier frequency of 1:48 was determined among unrelated healthy Bukharian Jews. Given the complications associated with disease and the allele frequency, a population screening for individuals of this ancestry is warranted in order to allow prenatal, pre-implantation or early postnatal diagnosis. PMID:26653794

  6. The onset of inter-human contacts: longitudinal ultrasound observations in early twin pregnancies.

    PubMed

    Arabin, B; Bos, R; Rijlaarsdam, R; Mohnhaupt, A; van Eyck, J

    1996-09-01

    Twin pregnancies provide us with the opportunity to observe first reactions towards touch in utero, and this study illustrates the onset and development of these contacts. Forty women with twin pregnancies volunteered to take part in this study, 25 of whom (five monochorionic, 20 dichorionic pairs) fulfilled the inclusion criteria. Between 8 and 12 weeks' gestation, ultrasound examinations were performed transvaginally, and from 13 weeks onwards transabdominally, at weekly intervals. Ultrasound findings were recorded on videotapes and were analyzed retrospectively. The first contacts producing reactions in the co-twin were defined as primary contacts, which could be slow or fast arm/leg/head/body contacts. Primary contacts followed an action-reaction model, and usually lasted < 3 s. These contacts were initially slow and then became fast. The first reactions of the co-twin towards touch were observed at 65 postmenstrual days. Contacts of longer duration between both bodies including extremities, or contacts initiated by sucking movements towards the co-twin were defined as complex contacts and were observed from 85 and 92 post-menstrual days, respectively. Nearly all contacts occurred significantly earlier in monochorionic compared to dichorionic twins. Female/female pairs seemed to develop complex body contacts earlier than male/male pairs, but for the onset of other contacts we have not yet found significant differences between gender combinations. PMID:8915085

  7. Diaphragm muscle weakness in mice is early-onset post-myocardial infarction and associated with elevated protein oxidation

    PubMed Central

    Mangner, Norman; Werner, Sarah; Glaser, Stefanie; Kullnick, Yvonne; Schrepper, Andrea; Doenst, Torsten; Oberbach, Andreas; Linke, Axel; Steil, Leif; Schuler, Gerhard; Adams, Volker

    2014-01-01

    Heart failure induced by myocardial infarction (MI) causes diaphragm muscle weakness, with elevated oxidants implicated. We aimed to determine whether diaphragm muscle weakness is 1) early-onset post-MI (i.e., within the early left ventricular remodeling phase of 72 h); and 2) associated with elevated protein oxidation. Ligation of the left coronary artery to induce MI (n = 10) or sham operation (n = 10) was performed on C57BL6 mice. In vitro contractile function of diaphragm muscle fiber bundles was assessed 72 h later. Diaphragm mRNA and protein expression, enzyme activity, and individual carbonylated proteins (by two-dimensional differential in-gel electrophoresis and mass spectrometry) were subsequently assessed. Infarct size averaged 57 1%. Maximal diaphragm function was reduced (P < 0.01) by 20% post-MI, with the force-frequency relationship depressed (P < 0.01) between 80 and 300 Hz. The mRNA expression of inflammation, atrophy, and regulatory Ca2+ proteins remained unchanged post-MI, as did the protein expression of key contractile proteins. However, enzyme activity of the oxidative sources NADPH oxidase and xanthine oxidase was increased (P < 0.01) by 45 and 33%, respectively. Compared with sham, a 57 and 45% increase (P < 0.05) was observed in the carbonylation of sarcomeric actin and creatine kinase post-MI, respectively. In conclusion, diaphragm muscle weakness was rapidly induced in mice during the early left ventricular remodeling phase of 72 h post-MI, which was associated with increased oxidation of contractile and energetic proteins. Collectively, these findings suggest diaphragm muscle weakness may be early onset in heart failure, which is likely mediated in part by posttranslational oxidative modifications at the myofibrillar level. PMID:25359720

  8. Is Early Onset Androgenic Alopecia a Marker of Metabolic Syndrome and Carotid Artery Atherosclerosis in Young Indian Male Patients?

    PubMed Central

    Banger, Harmeet Singh; Malhotra, Suresh Kumar; Singh, Sohan; Mahajan, Mridula

    2015-01-01

    Background: Androgenic alopecia (AGA) is a common cosmetically and psychosocially distressing condition. High androgen level contributes to the development of atherosclerosis, thrombosis leading to hypertension and hypercholesterolemia. Objectives: To study the clinico-epidemiological profile of AGA and the presence of metabolic syndrome (MetS) and carotid artery atherosclerosis in male patients with early onset AGA as compared to controls. Materials and Methods: In this case-control study, 100 male patients of age 18-35 years with AGA and an equal number of age-matched healthy controls attending skin and STD OPD were included. Assessment of the degree of hair loss, evaluation of MetS and carotid artery color Doppler for the atherosclerotic plaque was done in all patients. Results: Statistically significant number of patients with early onset AGA 22/100 (22%) (P < 0.05) fulfilled the criteria for MetS compared to 8/100 (8%) in the control group. There were statistically significant differences in mean values of waist circumference, serum triglycerides, serum cholesterol, systolic blood pressure, diastolic blood pressure, fasting glucose concentration, and very low-density lipoprotein (LDL). However, no significant differences were observed in the mean values of high-density lipoprotein cholesterol and LDL cholesterol. The atherosclerotic plaque was found in two patients of the study group, and no plaque was found in control patients. Conclusion: We suggest that all men with AGA should be thoroughly investigated, and lifestyle changes should be started in the early period of life so as to reduce the risk of various problems associated with MetS. AGA can be considered as an early marker for MetS. PMID:26903742

  9. Differentiated clinical presentation of early and late-onset Alzheimer's disease: is 65 years of age providing a reliable threshold?

    PubMed

    Palas, Antonio; Gutirrez-Iglesias, Beln; Alegret, Montse; Pujadas, Francesc; Olabarrieta, Mikel; Libana, Diana; Quintana, Manolo; lvarez-Sabn, Jos; Boada, Merc

    2015-05-01

    Early-onset and late-onset Alzheimer's disease (EOAD and LOAD) are two forms of the disease with the same characteristic neuropathological hallmarks. However, higher burdens of neuritic plaques and neurofibrillary tangles in frontal and parietal lobes have been found in EOAD than in LOAD patients. Thus, the EOAD subjects may have a differentiated clinical presentation compared to the LOAD ones. Some authors have found less hippocampal memory presentations and more focal cortical abnormalities (such as visuoconstructive or executive dysfunction) in EOAD than LOAD patients. The aim of the present study was to determine which initial clinical profiles differ between EOAD and LOAD; and to analyze whether another age cut-off could discriminate better between EOAD and LOAD clinical presentations than the conventional limit of 65. All patients fulfilling NINCDS-ADRDA criteria for probable Alzheimer's disease who referred to our Hospital between October 2007 and December 2012 were included in the study. The conventional age limit of 65 was established to distinguish between EOAD and LOAD. Baseline neuropsychological scores, adjusted for age and education, were compared between both groups. A total of 181 patients (38 EOAD, 143 LOAD) entered in the analysis. Sex distribution and time of evolution of symptoms did not differ between groups. The EOAD patients performed worse than LOAD in attentional, imitation praxis and verbal learning tests. In addition, the age cut-off of 70 was found to differentiate between early- and late-onset groups better than the standard cut-off of 65 years old. Our results support a differentiated neuropsychological impairment pattern in EOAD compared to LOAD. PMID:25791224

  10. Increased oxidized low-density lipoprotein causes blood-brain barrier disruption in early-onset preeclampsia through LOX-1

    PubMed Central

    Schreurs, Malou P. H.; Hubel, Carl A.; Bernstein, Ira M.; Jeyabalan, Arun; Cipolla, Marilyn J.

    2013-01-01

    Early-onset preeclampsia (EPE) is a severe form of preeclampsia that involves life-threatening neurological complications. However, the underlying mechanism by which EPE affects the maternal brain is not known. We hypothesized that plasma from women with EPE increases blood-brain barrier (BBB) permeability vs. plasma from women with late-onset preeclampsia (LPE) or normal pregnancy (NP) and investigated its underlying mechanism by perfusing cerebral veins from nonpregnant rats (n=6–7/group) with human plasma from women with EPE, LPE, or NP and measuring permeability. We show that plasma from women with EPE significantly increased BBB permeability vs. plasma from women with LPE or NP (P<0.001). BBB disruption in response to EPE plasma was due to a 260% increase of circulating oxidized LDL (oxLDL) binding to its receptor, LOX-1, and subsequent generation of peroxynitrite (P<0.001). A rat model with pathologically high lipid levels in pregnancy showed symptoms of preeclampsia, including elevated blood pressure, growth-restricted fetuses, and LOX-1-dependent BBB disruption, similar to EPE (P<0.05). Thus, we have identified LOX-1 activation by oxLDL and subsequent peroxynitrite generation as a novel mechanism by which disruption of the BBB occurs in EPE. As increased BBB permeability is a primary means by which seizure and other neurological symptoms ensue, our findings highlight oxLDL, LOX-1, and peroxynitrite as important therapeutic targets in EPE.—Schreurs, M. P. H., Hubel, C. A., Bernstein, I. M., Jeyabalan, A., and Cipolla, M. J. Increased oxidized low-density lipoprotein causes blood-brain barrier disruption in early-onset preeclampsia through LOX-1. PMID:23230281

  11. Identification of PSEN2 mutation p.N141I in Argentine pedigrees with early-onset familial Alzheimer's disease.

    PubMed

    Muchnik, Carolina; Olivar, Natividad; Dalmasso, Mara Carolina; Azurmendi, Pablo Javier; Liberczuk, Cynthia; Morelli, Laura; Brusco, Luis Ignacio

    2015-10-01

    Presenilin 2 gene (PSEN2) mutations account for <5% of all early-onset familial Alzheimer's disease (EOFAD) cases and only 13 have strong evidence for pathogenicity. We aimed to investigate the presence of PSEN2 mutation p.N141I and characterize the clinical phenotypes in 2 Argentine pedigrees (AR2 and AR3) with clinical symptoms of EOFAD. Detailed clinical assessments and genetic screening for PSEN2 and APOE genes were carried out in 19 individuals of AR2 and AR3 families. The p.N141I mutation was identified in all affected subjects and was associated with prominent early onset, rapidly progressive dementia, neurologic, and behavioral symptoms. AR2 and AR3 families share the same Volga German ancestry as all the families reported presenting this mutation. To our knowledge, this is the first report of PSEN2 mutation p.N141I in Argentina and even more, in South America. Our contribution increases the total number of described families carrying this mutation and help to improve the characterization of clinical phenotype in EOFAD associated to PSEN2 mutations. PMID:26166204

  12. ATM germline mutations in Spanish early-onset breast cancer patients negative for BRCA1/BRCA2 mutations.

    PubMed

    Brunet, J; Gutirrez-Enrquez, S; Torres, A; Brez, V; Sanjos, S; Galceran, J; Izquierdo, A; Menndez, J A; Gum, J; Borrs, J

    2008-05-01

    Heterozygous carriers of ATM (ataxia telangiectasia mutated gene) mutations have increased risk of breast cancer (BC). We have estimated the prevalence of mutations in the ATM gene among Spanish patients with early-onset BC. Forty-three patients diagnosed with BC before the age of 46 years, and negative for BRCA1 and BRCA2 mutations, were analysed for the presence of ATM mutations. A total of 34 ATM sequence variants were detected: 1 deleterious mutation, 10 unclassified variants and 23 polymorphisms. One patient (2.3%) carried the ATM deleterious mutation (3802delG that causes ataxia telangiectasia in the homozygous state) and 13 patients carried the 10 ATM unclassified variants. The truncating mutation 3802delG and eight of the rare variants were not detected in a control group of 150 individuals. Different bioinformatic sequence analysis tools were used to evaluate the effects of the unclassified ATM changes on RNA splicing and function protein. This in silico analysis predicted that the missense variants 7653 T>C and 8156 G>A could alter the splicing by disrupting an exonic splicing enhancer motif and the 3763 T>G, 6314 G>C, and 8156 G>A variants would affect the ATM protein function. These are the initial results concerning the prevalence of germline mutations in the ATM gene among BC cases in a Spanish population, and they suggest that ATM mutations can confer increased susceptibility to early-onset BC. PMID:18384426

  13. Early representation of shape by onset synchronization of border-ownership-selective cells in the V1-V2 network.

    PubMed

    Hatori, Yasuhiro; Sakai, Ko

    2014-04-01

    Construction of surface is a crucial step toward the representation of shape through the integration of local information. Physiological studies have reported that the primary visual cortex (V1) codes the medial axis (MA) that is a skeletal structure equidistant from nearby contours, suggesting the early representation of surface in V1. Although the neural basis of surface construction has not been clarified, the onset synchronization of border ownership (BO)-selective cells is a plausible candidate for the generation of surface. We investigated computationally the representation of surface in a biophysically detailed model of primate V1-V2 networks. The simulation results showed that the simultaneous arrival of signals from BO-selective cells evoked strong responses of V1 cells located around the MA. The simulation results lead to a prediction that the perception of the direction of figure (DOF) depends on the degree of synchronous presentation of contour. We conducted a psychophysical experiment and showed that the perception of the DOF is biased toward a highly synchronized contour. These results suggest a crucial role of the onset synchronization of BO-selective cells for the construction of early representation of shape. PMID:24695133

  14. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.

    PubMed

    Zhou, Qing; Wang, Hongying; Schwartz, Daniella M; Stoffels, Monique; Park, Yong Hwan; Zhang, Yuan; Yang, Dan; Demirkaya, Erkan; Takeuchi, Masaki; Tsai, Wanxia Li; Lyons, Jonathan J; Yu, Xiaomin; Ouyang, Claudia; Chen, Celeste; Chin, David T; Zaal, Kristien; Chandrasekharappa, Settara C; P Hanson, Eric; Yu, Zhen; Mullikin, James C; Hasni, Sarfaraz A; Wertz, Ingrid E; Ombrello, Amanda K; Stone, Deborah L; Hoffmann, Patrycja; Jones, Anne; Barham, Beverly K; Leavis, Helen L; van Royen-Kerkof, Annet; Sibley, Cailin; Batu, Ezgi D; Gl, Ahmet; Siegel, Richard M; Boehm, Manfred; Milner, Joshua D; Ozen, Seza; Gadina, Massimo; Chae, JaeJin; Laxer, Ronald M; Kastner, Daniel L; Aksentijevich, Ivona

    2016-01-01

    Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity. Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in TNFAIP3, which encodes the NF-?B regulatory protein A20, in six unrelated families with early-onset systemic inflammation. The disorder resembles Behet's disease, which is typically considered a polygenic disorder with onset in early adulthood. A20 is a potent inhibitor of the NF-?B signaling pathway. Mutant, truncated A20 proteins are likely to act through haploinsufficiency because they do not exert a dominant-negative effect in overexpression experiments. Patient-derived cells show increased degradation of I?B? and nuclear translocation of the NF-?B p65 subunit together with increased expression of NF-?B-mediated proinflammatory cytokines. A20 restricts NF-?B signals via its deubiquitinase activity. In cells expressing mutant A20 protein, there is defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1 after stimulation with tumor necrosis factor (TNF). NF-?B-dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease. PMID:26642243

  15. Coercive Family Process and Early-Onset Conduct Problems From Age 2 to School Entry

    PubMed Central

    Smith, Justin D.; Dishion, Thomas J.; Shaw, Daniel S.; Wilson, Melvin N.; Winter, Charlotte C.; Patterson, Gerald R.

    2013-01-01

    The emergence and persistence of conduct problems during early childhood is a robust predictor of behavior problems in school and future maladaptation. In this study we examined the reciprocal influences between observed coercive interactions between children and caregivers, oppositional and aggressive behavior, and growth in parent report of early childhood (ages 2–5) and school-age conduct problems (age 7.5 and 8.5). Participants were drawn from the Early Steps multisite randomized prevention trial that includes an ethnically diverse sample of male and female children and their families (N = 731). A parallel process growth model combining latent trajectory and cross-lagged approaches revealed the amplifying effect of observed coercive caregiver–child interactions on children's noncompliance, whereas child oppositional and aggressive behaviors did not consistently predict increased coercion. The slope and initial levels of child oppositional and aggressive behaviors and the stability of caregiver–child coercion were predictive of teacher-reported oppositional behavior at school age. Families assigned to the Family Check-Up condition had significantly steeper declines in child oppositional and aggressive behavior and moderate reductions in oppositional behavior in school and in coercion at age 3. Results were not moderated by child gender, race/ethnicity, or assignment to the intervention condition. The implications of these findings are discussed with respect to understanding the early development of conduct problems and to designing optimal strategies for reducing problem behavior in early childhood with families most in need. PMID:24690305

  16. Early infantile sensory-motor neuropathy with late onset respiratory distress.

    PubMed

    Blaschek, Astrid; Gläser, Dieter; Kuhn, Marius; Schroeder, Andreas Sebastian; Wimmer, Cornelius; Heimkes, Bernd; Schön, Carola; Müller-Felber, Wolfgang

    2014-03-01

    Children with spinal muscular atrophy with respiratory distress (SMARD1) usually present within their first year of life, with respiratory failure due to diaphragmatic paralysis and progressive distal limb weakness. We present a child with a confirmed compound heterozygous IGHMBP2 mutation c.[676G>T];[2083A>T] in whom severe sensory-motor neuropathy preceded diaphragmatic paralysis by almost 3years. Autonomic system involvement with neurogenic bladder and urine retention were found at 3years. In summary, our patient highlights the broad spectrum of phenotypes observed in SMARD1. Currently, no prediction of phenotype according to genotype is possible, suggesting that yet unknown factors cause the observed phenotypic variation. Even in the absence of obvious diaphragmatic weakness, SMARD1 should be considered in severe infantile onset neuropathies. High throughput techniques, such as next generation sequencing, will possibly offer a useful approach in the heterogeneous group of inherited neuropathies. PMID:24342282

  17. Medical decision support using machine learning for early detection of late-onset neonatal sepsis

    PubMed Central

    Mani, Subramani; Ozdas, Asli; Aliferis, Constantin; Varol, Huseyin Atakan; Chen, Qingxia; Carnevale, Randy; Chen, Yukun; Romano-Keeler, Joann; Nian, Hui; Weitkamp, Jrn-Hendrik

    2014-01-01

    Objective The objective was to develop non-invasive predictive models for late-onset neonatal sepsis from off-the-shelf medical data and electronic medical records (EMR). Design The data used in this study are from 299 infants admitted to the neonatal intensive care unit in the Monroe Carell Jr. Childrens Hospital at Vanderbilt and evaluated for late-onset sepsis. Gold standard diagnostic labels (sepsis negative, culture positive sepsis, culture negative/clinical sepsis) were assigned based on all the laboratory, clinical and microbiology data available in EMR. Only data that were available up to 12?h after phlebotomy for blood culture testing were used to build predictive models using machine learning (ML) algorithms. Measurement We compared sensitivity, specificity, positive predictive value and negative predictive value of sepsis treatment of physicians with the predictions of models generated by ML algorithms. Results The treatment sensitivity of all the nine ML algorithms and specificity of eight out of the nine ML algorithms tested exceeded that of the physician when culture-negative sepsis was included. When culture-negative sepsis was excluded both sensitivity and specificity exceeded that of the physician for all the ML algorithms. The top three predictive variables were the hematocrit or packed cell volume, chorioamnionitis and respiratory rate. Conclusions Predictive models developed from off-the-shelf and EMR data using ML algorithms exceeded the treatment sensitivity and treatment specificity of clinicians. A prospective study is warranted to assess the clinical utility of the ML algorithms in improving the accuracy of antibiotic use in the management of neonatal sepsis. PMID:24043317

  18. Voluntary wheel running delays disease onset and reduces pain hypersensitivity in early experimental autoimmune encephalomyelitis (EAE).

    PubMed

    Benson, Curtis; Paylor, John W; Tenorio, Gustavo; Winship, Ian; Baker, Glen; Kerr, Bradley J

    2015-09-01

    Multiple sclerosis (MS) is classically defined by motor deficits, but it is also associated with the secondary symptoms of pain, depression, and anxiety. Up to this point modifying these secondary symptoms has been difficult. There is evidence that both MS and the animal model experimental autoimmune encephalomyelitis (EAE), commonly used to study the pathophysiology of the disease, can be modulated by exercise. To examine whether limited voluntary wheel running could modulate EAE disease progression and the co-morbid symptoms of pain, mice with EAE were allowed access to running wheels for 1h every day. Allowing only 1h every day of voluntary running led to a significant delay in the onset of clinical signs of the disease. The development of mechanical allodynia was assessed using Von Frey hairs and indicated that wheel running had a modest positive effect on the pain hypersensitivity associated with EAE. These behavioral changes were associated with reduced numbers of cFOS and phosphorylated NR1 positive cells in the dorsal horn of the spinal cord compared to no-run EAE controls. In addition, within the dorsal horn, voluntary wheel running reduced the number of infiltrating CD3(+) T-cells and reduced the overall levels of Iba1 immunoreactivity. Using high performance liquid chromatography (HPLC), we observed that wheel-running lead to significant changes in the spinal cord levels of the antioxidant glutathione. Oxidative stress has separately been shown to contribute to EAE disease progression and neuropathic pain. Together these results indicate that in mice with EAE, voluntary motor activity can delay the onset of clinical signs and reduce pain symptoms associated with the disease. PMID:26033473

  19. Early-onset psychoses: comparison of clinical features and adult outcome in 3 diagnostic groups.

    PubMed

    Ledda, Maria Giuseppina; Fratta, Anna Lisa; Pintor, Manuela; Zuddas, Alessandro; Cianchetti, Carlo

    2009-09-01

    A comparison of clinical features and adult outcome in adolescents with three types of psychotic disorders: schizophrenic (SPh), schizoaffective (SA) and bipolar with psychotic features (BPP). Subjects (n = 41) were finally diagnosed (DSM-IV criteria) with SPh (n = 17), SA (n = 11) or BPP (n = 13). Clinical evaluation took place at onset and at a 3-year follow-up in all 41, and at least after 5 years in 36 patients. Symptoms were rated on the basis of the Positive and Negative Syndrome Scale (PANSS), integrating items from the Brief Psychiatric Rating Scale (BPRS) and the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL). The Children Global Assessment Scale (C-GAS) and the Global Assessment Scale (GAF) were used to evaluate global functioning. Significant differences in clinical features were found in the three diagnostic groups as regards several parameters, some present on one and not on other rating scales, underscoring the insufficiency of a single scale for accurate analysis of the features of a psychotic disorder. At onset, a comparison using the simple presence/absence of symptoms showed scant differences among groups, while differences emerged if symptom severity was included in the comparison. Functioning at 3- and 5-year follow-ups showed a significantly better outcome in the BPP group and more substantial deterioration, with similar evolution, in the SPh and SA groups. The integration of several rating scales differentiated between diagnostic groups more effectively. The similar adult functioning outcome in the SPh and SA groups showed how difficult it is to clearly separate these two disorders. PMID:19280338

  20. Early pubertal onset and its relationship with sexual risk taking, substance use and anti-social behaviour: a preliminary cross-sectional study

    PubMed Central

    2009-01-01

    Background In many countries age at pubertal onset has declined substantially. Relatively little attention has been paid to how this decline may affect adolescent behaviours such as substance use, violence and unprotected sex and consequently impact on public health. Methods In the UK, two opportunistic samples (aged 16-45 years), paper-based (n = 976) and online (n = 1117), examined factors associated with earlier pubertal onset and whether earlier age of onset predicted sexual risk-taking, substance use and anti-social behaviours during early adolescence. Results Overall, 45.6% of females reported menarche ? 12 years and 53.3% of males were categorised as having pubertal onset ? 11 years. For both sexes earlier pubertal onset was associated with poorer parental socio-economic status. Other pre-pubertal predictors of early onset were being overweight, more childhood illnesses (females) and younger age at time of survey (males). For both sexes earlier puberty predicted having drunk alcohol, been drunk, smoked and used drugs <14 years as well as having a sexual debut and unprotected sex <16 years. Males with earlier pubertal onset were more likely to report fighting and aggressive responses to emotional upset during early adolescence while females were more likely to report being bullied and having taken more time off school. Conclusion Results provide sufficient evidence for changes in age of pubertal onset to be further explored as a potential influence on trends in adolescent risk behaviours. Further insight into the relationship between early puberty and both obesity and socio-economic status may help inform early interventions to tackle the development of risk behaviours and health inequalities during early adolescence. PMID:19958543

  1. Early onset of neurological symptoms in fragile X premutation carriers exposed to neurotoxins

    PubMed Central

    Paul, Ripon; Pessah, Isaac N.; Gane, Louise; Ono, Michele; Hagerman, Paul J.; Brunberg, James A.; Tassone, Flora; Bourgeois, James A.; Adams, Patrick E.; Nguyen, Danh V.; Hagerman, Randi

    2014-01-01

    We present four cases of fragile X premutation carriers with early neurological symptoms, including symptoms consistent with multiple sclerosis (MS) and fragile X-associated tremor/ataxia syndrome (FXTAS). Each