Severe epidermolysis bullosa/Kindler syndrome-like phenotype of an autoinflammatory syndrome in a child.

A 5-year-old boy presented with generalized cutaneous erosions, severe scarring, depigmentation and contractures affecting major joints. The lesions had initially affected his ears, nose, feet, and the genital and ocular mucosa, leading to significant depigmentation, scarring, contractures and mutilation. The whole of the trunk and limbs were involved at the time of presentation, with the exception of some islands of spared skin on the proximal thighs, legs, nipples and external genitalia. Electron microscopy revealed a split in the sublamina densa with the absence of anchoring fibrils, suggestive of dystrophic epidermolysis bullosa (EB). Immunofluorescence antigen mapping demonstrated a broad reticulate pattern of staining with collagen IV, VII, and laminin 332 in the floor of the blister, suggestive of Kindler syndrome. Next-generation sequencing revealed a de novo heterozygous missense mutation (a variant of unknown significance) in exon 22 of the phospholipase-C gamma 2 gene (PLCG2), which resulted in a substitution of serine by asparagine at codon 798 (p.Asp798Ser), a result that was validated using Sanger sequencing. The child was diagnosed with PLCG2-associated antibody deficiency and immune dysregulation (PLAID)/autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) syndrome. The cutaneous and corneal erosions, inflammation and scarring of this magnitude, and the eventual result of death have not been described previously for the PLAID/APLAID spectrum previously. In conclusion, this was an unusual acquired autoinflammatory severe EB-like disease that may be associated with de novo PLCG2 mutation.

Chylous ascites and podocytopathy as the presentation of childhood lupus-an unusual occurrence.

Systemic lupus erythematosus (SLE) is an autoimmune disorder that can affect virtually any organ. Chylous ascites as a presenting manifestation of SLE has been described in a handful of cases in adults. However, to the best of our knowledge this presentation has never been reported in the pediatric age group. Podocytopathy in SLE was initially considered to be a chance association. However, more recently it has been suggested that minimal change disease is not only a chance association; it is part of the lupus nephritis spectrum.

Optic nerve involvement in childhood onset systemic lupus erythematosus: Three cases and a review of the literature.

The ocular system can be affected in systemic lupus erythematosus (SLE) in one third of patients. However, optic nerve involvement is relatively uncommon, but is more so in pediatric SLE patients, where it can occur in 1% of cases. We report three children with SLE who presented with optic nerve involvement. Two children had optic neuritis, with optic neuritis being the first manifestation in one child. The third child had ischaemic optic neuropathy secondary to antiphospholipid syndrome. A careful work up for SLE should be performed in every child with optic nerve disease. Prompt diagnosis and early treatment results in a better prognosis.

Childhood lupus nephritis in a developing country-24 years' single-center experience from North India.

OBJECTIVE: Data on outcome of childhood lupus nephritis from developing countries are sparse. This study looks at outcome in children with lupus nephritis from a federal government-funded teaching hospital in North India. METHODS: This study included children less than 14 years of age with lupus nephritis who presented to a single center during a period of 24 years (1991 to 2013). Data on clinical characteristics and outcome were extracted from medical records. The primary outcome was actuarial survival (time-to-death) and secondary outcome was actuarial renal survival using Kaplan-Meier analysis. A worst-case scenario that assumed children who were lost to follow-up as having either died or gone into end-stage renal disease was also calculated. Log-rank test and Cox-regression were used to assess difference in survival by histological class and predictors of poor outcome, respectively. RESULTS: This study included 72 children, with a female:male ratio of 3:1, mean (±SD) age at onset of lupus 9.3 (±2.4) years and mean (±SD) time from onset-to-nephritis being 9.4 (±12.6) months. Renal biopsy was conducted in 53 children. The most common histological class was class IV (35 children). Mortality occurred in 22 children (30%), with half of these occurring at presentation. The two important causes of death were infection and end-stage renal disease. Actuarial survival was 81%, 67% and 59% at one, five and 10 years, respectively. In the worst-case scenario, actuarial survival was 72%, 53% and 38%, respectively. Renal survival was 96%, 89% and 78% (worst-case scenario 86%, 73% and 52%) at one, five and 10 years, respectively. There was no difference in survival by histological class. On univariate analysis, serum creatinine at presentation (hazard ratio = 2.2 (95% CI 1.3-3.9)) and serious infection (hazard ratio 7.9 (95% CI 2.6-23.5)) were statistically significant predictors of time-to-death. CONCLUSION: Outcome of children with lupus nephritis from India is worse than developed countries. Nearly one-third of the children died, half at presentation, with common causes being infection and end-stage renal disease.

Molecular analyses of novel ASAH1 mutations causing Farber lipogranulomatosis: analyses of exonic splicing enhancer inactivating mutation.

Farber lipogranulomatosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the ASAH1 gene. In the largest ever study, we identified and characterized ASAH1 mutations from 11 independent Farber disease (FD) families. A total of 13 different mutations were identified including 1 splice, 1 polypyrimidine tract (PPT) deletion and 11 missense mutations. Eleven mutations were exclusive to the Indian population. The IVS6+4A>G splice and IVS5-16delTTTTC PPT deletion mutations resulted in skipping of exon 6 precluding thereby the region responsible for cleavage of enzyme precursor. A missense mutation (p.V198A) resulted in skipping of exon 8 due to inactivation of an exonic splicing enhancer (ESE) element. This is the first report of mutations affecting PPT and ESE in the ASAH1 gene resulting in FD.

Glucocorticoid regulation of brain-derived neurotrophic factor: relevance to hippocampal structural and functional plasticity.

Glucocorticoids serve as key stress response hormones that facilitate stress coping. However, sustained glucocorticoid exposure is associated with adverse consequences on the brain, in particular within the hippocampus. Chronic glucocorticoid exposure evokes neuronal cell damage and dendritic atrophy, reduces hippocampal neurogenesis and impairs synaptic plasticity. Glucocorticoids also alter expression and signaling of the neurotrophin, brain-derived neurotrophic factor (BDNF). Since BDNF is known to promote neuroplasticity, enhance cell survival, increase hippocampal neurogenesis and cellular excitability, it has been hypothesized that specific adverse effects of glucocorticoids may be mediated by attenuating BDNF expression and signaling. The purpose of this review is to summarize the current state of literature examining the influence of glucocorticoids on BDNF, and to address whether specific effects of glucocorticoids arise through perturbation of BDNF signaling. We integrate evidence of glucocorticoid regulation of BDNF at multiple levels, spanning from the well-documented glucocorticoid-induced changes in BDNF mRNA to studies examining alterations in BDNF receptor-mediated signaling. Further, we delineate potential lines of future investigation to address hitherto unexplored aspects of the influence of glucocorticoids on BDNF. Finally, we discuss the current understanding of the contribution of BDNF to the modulation of structural and functional plasticity by glucocorticoids, in particular in the context of the hippocampus. Understanding the mechanistic crosstalk between glucocorticoids and BDNF holds promise for the identification of potential therapeutic targets for disorders associated with the dysfunction of stress hormone pathways.

Fatal bronchiolitis obliterans complicating Stevens-Johnson syndrome following treatment with nimesulide: a case report.

Nimesulide is a frequently used non-steroidal anti-inflammatory drug with analgesic and antipyretic effects in children. In view of fatal adverse drug reactions, however, its safety has been questioned. A 5-year-old boy developed Stevens-Johnson syndrome following use of nimesulide which was later complicated by rapidly progressive fatal bronchiolitis obliterans.

Adrenalectomy to treat reactivated chronic hepatitis B infection in a patient with a steroid-secreting adrenal tumour.

We present a case of reactivation of chronic hepatitis B virus (HBV) infection by a steroid-producing adrenal tumour. The tumour caused a reactivation and subsequent flare of the patients' HBV. The adrenal tumour was treated with an adrenalectomy and as a consequence the patients' transaminitis and viral load fell rapidly without the need for any additional hepatitis B treatment. The role of hepatitis B and steroid priming is discussed and the possible immunological mechanisms that underpin this phenomenon.

Should ultrasound guided percutaneous renal biopsy in children be done in a day care setting?

Percutaneous renal biopsy (PRB) is an important diagnostic tool in pediatric nephrology units. But controversy exists whether the procedure can be done in the day care setting. This study was done to document complications of PRB done with automated gun under continuous ultrasonographic guidance and to find whether the procedure can be undertaken as a day care procedure. Retrospective analysis of 67 PRBs is presented. A total of 44% (n = 30) minor and 12% (n = 8) major complications such as gross hematuria, perinephric hematoma, and hemodynamic instability were observed through the study period. All major and 90% of minor complications were detected within four hours in the current study. The procedure may be undertaken in the day care setting with strict pre and postprocedure monitoring up to eight hours in children with normal blood pressures, renal functions, hemoglobin concentrations, and coagulation parameters.

A discussion of the British Society of Gastroenterology survey of emergency gastroenterology workload.

An electronic survey of 188 acute NHS hospitals was carried out to assess the provision of out-of-hours services for gastrointestinal emergencies in England. The response rate was 167/188 (89%) for the main questionnaire and 157/188 (84%) for a supplementary questionnaire. The survey revealed that the majority of gastroenterologists (135/157, 86%) participate in acute general medicine. A rota for out-of-hours endoscopy was in place in only 82/167 (49%) of hospitals. Trained nurse endoscopy assistance was available in 51/82 (62%) of those hospitals with a formal rota. Two thirds of gastroenterologists were telephoned up to five times each month for advice when not on call; 64% felt their emergency endoscopy service provision was unsatisfactory and 38% thought it was unsafe. This paper concludes that there is serious under provision of services for patients presenting with gastrointestinal emergencies in England.

A case of ACTH-independent bilateral macronodular adrenal hyperplasia and severe congestive heart failure.

Cortisol secretion in ACTH independent bilateral macronodular adrenal hyperplasia (AIMAH) can be regulated by aberrant adrenal receptors. We describe a patient with Cushing's syndrome (CS) due to AIMAH and concomitant Class IV congestive heart failure (CHF). Clinical testing for the presence of aberrant receptors revealed a pronounced serum cortisol (257%) and aldosterone response (212%) to the administration of ACTH and a partial serum cortisol (35%) and aldosterone (106%) response to upright posture. This suggested the possible presence of aberrant hormone receptors for ACTH [melanocortin 2 receptor (MC2-R)], vasopressin, catecholamines or angiotensin II (AT-II) on the patient's adrenal glands. Adrenal tissue from the patient demonstrated an eight-fold increased expression of MC2-R compared to normal adrenal tissue. This increased expression was consistent with the increase in cortisol and aldosterone seen in response to exogenous ACTH. We propose that the severe CHF resulted in activation of the renin-angiotensin system, with an increased production of AT-II. The elevated circulating levels of AT-II may have led to increased expression of MC2-R on the patient's adrenal glands and increased responsiveness to ACTH. This unusual case of CS may elucidate a heretofore unknown mechanism for the development of AIMAH.

Non-cytolytic inhibition of hepatitis B virus replication in human hepatocytes.

BACKGROUND/AIMS: Interferon-gamma (IFN-gamma) has been shown to abolish hepatitis B virus (HBV) gene expression and replication in HBV transgenic mice without destroying infected hepatocytes. We investigated the characteristics of IFN-gamma induced non-cytolytic inhibition of viral replication in human HBV infection. METHODS: We used an in vitro model where lymphocytes from 15 HBsAg positive patients were co-cultured with transfected hepatocytes supporting HBV replication. The effector and target cells were separated by a membrane, which allowed transfer of soluble factors only, to determine whether IFN-gamma produced from antigen-specific CD4+ T cells or mitogen stimulated lymphocytes inhibits HBV replication. RESULTS: IFN-gamma produced following lymphocyte stimulation reduced cytoplasmic HBV DNA in the target cells. The degree of HBV DNA reduction correlated with the level of IFN-gamma in the supernatants. Further investigations using naturally infected human hepatocytes confirmed that recombinant IFN-gamma reduces HBV DNA and HBV RNA in these cells as well, in parallel with the induction of cellular interferon-responsive genes. This antiviral effect was without significant cytotoxicity and was more pronounced in hepatocytes from patients with low HBV replication. CONCLUSIONS: These results provide direct evidence that IFN-gamma can inhibit both HBV transcription and replication in human hepatocytes without cell lysis.

Transplant glomerulopathy as a cause of late graft loss.

Several pathophysiological processes contribute to chronic kidney transplant rejection. Among the most distinctive is transplant glomerulopathy, characterized by widening of the subendothelial space with accumulation of flocculent material and duplication of the basement membrane. The current study assessed the course of graft loss in patients with and without this form of injury. Twenty-five patients with prominent transplant glomerulopathy were identified from biopsies performed at a single center during 4 years. These patients were compared with control patients with a similar degree of renal dysfunction in whom biopsies showed chronic rejection without transplant glomerulopathy. Patients with transplant glomerulopathy showed an increased rate of graft loss after biopsy. Biopsies were performed longer after transplantation in these patients, however, than in control patients with an equal degree of graft dysfunction. Graft survival from the time of transplantation was therefore not different between the two groups. Morphological studies showed that transplant glomerulopathy was not associated with increased severity of chronic vascular injury characterized by arterial and arteriolar intimal thickening or hyalinosis. These findings show that transplant glomerulopathy may develop late after transplantation and separately from chronic vascular rejection. The appearance of transplant glomerulopathy on a biopsy specimen is followed by accelerated graft loss.

Nursing home resident use of care directives.

BACKGROUND: The Patient Self-Determination Act of 1991 requires that nursing homes reimbursed by Medicare or Medicaid inform all residents upon admission of their rights to enact care directives in the event of terminal illness. This study investigated the relationship between care directive use and resident functional status. METHODS: We analyzed a version of the Minimum Data Set (MDS+) from a single state. We selected residents who were admitted to a nursing home in the first half of 1993 and followed them in the nursing home through the end of 1994. We created logistic models to examine independent correlates associated with having an advance directive or a do-not-resuscitate (DNR) order on admission. We then created similar logistic models to examine independent correlates associated with writing an advance directive or DNR order subsequent to admission. RESULTS: Of the 2,780 residents, 11% (292) had advance directives and 17% (466) had DNR orders upon admission. Of those without care directives upon admission, 6% (143) subsequently had an advance directive and 15% (339) subsequently had a DNR order. Cross-sectionally, older individuals and whites were more likely to have a care directive. Having poor cognitive and physical function was associated with having a DNR order upon admission. Longitudinally, longer stayers and whites were more likely to have an advance directive. Residents who lost physical function were more likely to have an advance directive and those who lost cognitive function were more likely to have a DNR order. CONCLUSIONS: Care directive use is influenced by a number of sociodemographic and functional characteristics.