A case of pseudohypoaldosteronism type 1 with a mutation in the mineralocorticoid receptor gene

Pseudohypoaldosteronism type 1 (PHA1) is a rare form of mineralocorticoid resistance characterized in newborns by salt wasting with dehydration, hyperkalemia and failure to thrive. This disease is heterogeneous in etiology and includes autosomal dominant PHA1 owing to mutations of the NR3C2 gene encoding the mineralocorticoid receptor, autosomal recessive PHA1 due to mutations of the epithelial sodium channel (ENaC) gene, and secondary PHA1 associated with urinary tract diseases. Amongst these diseases, autosomal dominant PHA1 shows has manifestations restricted to renal tubules including a mild salt loss during infancy and that shows a gradual improvement with advancing age. Here, we report a neonatal case of PHA1 with a NR3C2 gene mutation (a heterozygous c.2146_2147insG in exon 5), in which the patient showed failure to thrive, hyponatremia, hyperkalemia, and elevated plasma renin and aldosterone levels. This is the first case of pseudohypoaldosteronism type 1 confirmed by genetic analysis in Korea

Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed

Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples

Pre-validation of the WHO organ dysfunction based criteria for identification of maternal near miss

<p>Abstract</p> <p>Background</p> <p>To evaluate the performance of the WHO criteria for defining maternal near miss and identifying deaths among cases of severe maternal morbidity (SMM) admitted for intensive care.</p> <p>Method</p> <p>Between October 2002 and September 2007, 673 women with SMM were admitted, and among them 18 died. Variables used for the definition of maternal near miss according to WHO criteria and for the SOFA score were retrospectively evaluated. The identification of at least one of the WHO criteria in women who did not die defined the case as a near miss. Organ failure was evaluated through the maximum SOFA score above 2 for each one of the six components of the score, being considered the gold standard for the diagnosis of maternal near miss. The aggregated score (Total Maximum SOFA score) was calculated using the worst result of the maximum SOFA score. Sensitivity, specificity, positive and negative predictive values of these WHO criteria for predicting maternal death and also for identifying cases of organ failure were estimated.</p> <p>Results</p> <p>The WHO criteria identified 194 cases of maternal near miss and all the 18 deaths. The most prevalent criteria among cases of maternal deaths were the use of vasoactive drug and the use of mechanical ventilation (≥1 h). For the prediction of maternal deaths, sensitivity was 100% and specificity 70.4%. These criteria identified 119 of the 120 cases of organ failure by the maximum SOFA score (Sensitivity 99.2%) among 194 case of maternal near miss (61.34%). There was disagreement in 76 cases, one organ failure without any WHO criteria and 75 cases with no failure but with WHO criteria. The Total Maximum SOFA score had a good performance (area under the curve of 0.897) for prediction of cases of maternal near miss according to the WHO criteria.</p> <p>Conclusions</p> <p>The WHO criteria for maternal near miss showed to be able to identify all cases of death and almost all cases of organ failure. Therefore they allow evaluation of the severity of the complication and consequently enable clinicians to build a plan of care or to provide an early transfer for appropriate reference centers.</p

Extensive Systemic Sarcoidosis with Testicular Involvement Mimicking Metastatic Testicular Cancer

Sarcoidosis is an idiopathic, multisystem disease that rarely involves the genitourinary tract. Here we present an unusual case of testicular sarcoidosis with extensive lymphadenopathy that mimicked a metastatic testicular tumor. A 27-year-old male presented with a palpable right testicular mass accompanied by multiple palpable inguinal lymph nodes. The scrotal ultrasound showed a hypoechoic lesion at the inferior portion of the right testis. Extensive enlarged lymph nodes were noted in multiple areas on the abdominal computed tomography. Preoperative testicular tumor markers were within the normal range. Exploration of the right testis with a frozen section analysis of the right testicular mass and of a palpable right inguinal lymph node showed granulomatous inflammation. The testis was salvaged and the final pathological diagnosis was sarcoidosis. Treatment with high-dose corticosteroids resulted in complete resolution of the intratesticular mass and a significant decrease in the extent of the lymphadenopathy

Management of abnormal uterine bleeding by northern, rural and isolated primary care physicians: PART I – How are we doing?

BACKGROUND: Canadian hysterectomy rates have declined in recent years. However, hysterectomy rates for discretionary indications, principally abnormal uterine bleeding (AUB), remain high in some regions. In northern Ontario, hysterectomy rates for women aged 34–45 are almost triple the rates in southern, urban areas. Primary care physicians (family doctors) usually manage AUB initially in these northern areas where a severe shortage of gynecologists exists. METHODS: We surveyed 194 family physicians in northern Ontario with a case scenario of a pre-menopausal woman with heavy vaginal bleeding to characterize management and to gain physicians' perspectives on the factors that affect it. RESULTS: To investigate her heavy vaginal bleeding, only 17% of physicians recommended a pelvic examination for the woman in our case scenario. Most physicians advocated a course of medical therapy before referral to a gynecologist, for whom the average waiting time was seven weeks. However, most physicians recommended referral after only one failed trial of medical treatment. Physicians felt that major deterrents to medical treatments were patient desires for immediate relief and/or permanent solutions, poor patient compliance and the high cost of medication. Only 25% of respondents indicated that they would perform an endometrial biopsy prior to referral. CONCLUSIONS: Family physicians would benefit from further education on appropriate investigations for AUB, primarily training in pelvic examination and endometrial biopsy techniques, as well as appropriate treatment algorithms. Further research into patient perspectives on treatment options is needed

Discovery of Sexual Dimorphisms in Metabolic and Genetic Biomarkers

Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8 x 10(-4); Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8 x 10(-10); Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation

Correlates of comorbid anxiety and externalizing disorders in childhood obsessive compulsive disorder

The present study examines the influence of diagnostic comorbidity on the demographic, psychiatric, and functional status of youth with a primary diagnosis of obsessive compulsive disorder (OCD). Two hundred and fifteen children (ages 5–17) referred to a university-based OCD specialty clinic were compared based on DSM-IV diagnostic profile: OCD without comorbid anxiety or externalizing disorder, OCD plus anxiety disorder, and OCD plus externalizing disorder. No age or gender differences were found across groups. Higher OCD severity was found for the OCD + ANX group, while the OCD + EXT group reported greater functional impairment than the other two groups. Lower family cohesion was reported by the OCD + EXT group compared to the OCD group and the OCD + ANX group reported higher family conflict compared to the OCD + EXT group. The OCD + ANX group had significantly lower rates of tic disorders while rates of depressive disorders did not differ among the three groups. The presence of comorbid anxiety and externalizing psychopathology are associated with greater symptom severity and functional and family impairment and underscores the importance of a better understanding of the relationship of OCD characteristics and associated disorders. Results and clinical implications are further discussed

Examining a staging model for anorexia nervosa: empirical exploration of a four stage model of severity.

Background: An illness staging model for anorexia nervosa (AN) has received increasing attention, but assessing the merits of this concept is dependent on empirically examining a model in clinical samples. Building on preliminary findings regarding the reliability and validity of the Clinician Administered Staging Instrument for Anorexia Nervosa (CASIAN), the current study explores operationalising CASIAN severity scores into stages and assesses their relationship with other clinical features. Method: In women with DSM-IV-R AN and sub-threshold AN (all met AN criteria using DSM 5), receiver operating curve (ROC) analysis (n = 67) assessed the relationship between the sensitivity and specificity of each stage of the CASIAN. Thereafter chi-square and post-hoc adjusted residual analysis provided a preliminary assessment of the validity of the stages comparing the relationship between stage and treatment intensity and AN sub-types, and explored movement between stages after six months (Time 3) in a larger cohort (n = 171). Results: The CASIAN significantly distinguished between milder stages of illness (Stage 1 and 2) versus more severe stages of illness (Stages 3 and 4), and approached statistical significance in distinguishing each of the four stages from one other. CASIAN Stages were significantly associated with treatment modality and primary diagnosis, and CASIAN Stage at Time 1 was significantly associated with Stage at 6 month follow-up. Conclusions: Provisional support is provided for a staging model in AN. Larger studies with longer follow-up of cases are now needed to replicate and extend these findings and evaluate the overall utility of staging as well as optimal staging models

Utilization of a mobile medical van for delivering pediatric care in the bateys of the Dominican Republic

Background Bateys are impoverished areas of housing for migrant Haitian sugar cane workers in the Dominican Republic (DR). In these regions, preventative health care is almost non-existent, public service accessibility is limited, and geographic isolation prevents utilization of care even by those families with resources. Consequently, the development of a viable mobile system is vital to the delivery of acute and preventative health care in this region. Aims This study evaluated an existing mobile medical system. The primary goal was to describe the population served, diseases treated, and resources utilized. A secondary goal was to determine qualitatively an optimal infrastructure for sustainable health care delivery within the bateys. Methods Information on basic demographic data, diagnosis, chronicity of disease, and medications dispensed was collected on all pediatric patients seen in conjunction with an existing mobile medical system over a 3-month period in the DR. Health statistics for the region were collected and interviews were conducted with health care workers (HCWs) and community members on existing and optimal health care infrastructure. Results Five hundred eighty-four pediatric patients were evaluated and treated. Median age was 5 years (range 2 weeks to 20 years), and 53.7% of patients seen were 5 years of age or younger. The mean number of complaints per patient was 2.8 (range 0 to 6). Thirty-six percent (373) of all diagnoses were for acute complaints, and 64% (657) were chronic medical problems. The most common pediatric illnesses diagnosed clinically were gastrointestinal parasitic infection (56.6%), skin/fungal infection (46.2%), upper respiratory tract infections (URIs) (22.8%), previously undiagnosed asthma and allergies (8.2%), and symptomatic anemia (7.2%). Thirty HCWs and community members were interviewed, and all cited the need for similar resources: a community clinic and hospital referral site, health promoters within each community, and the initiation of pediatric training for community HCWs. Conclusion A mobile medical system is a sustainable, efficient mechanism for delivering acute and preventive care in the Haitian bateys of the Dominican Republic. The majority of patients served were 8 years of age or younger with multiple presenting symptoms. A pediatric protocol for identifying the most appropriate drugs and supplies for mobile units in the DR can be created based upon diseases evaluated. Qualitative data from HCWs and community members identified the need for an integrative health care delivery infrastructure and community health promoters versed in pediatric care who can aid in education of batey members and monitor chronic and acute illnesses. We are planning follow-up visits to implement these programs