A novel likely pathogenic variant in a patient with Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by oculocutaneous albinism and variable pulmonary fibrosis, granulomatous colitis, or immunodeficiency. The diagnosis relies on clinical findings, platelet transmission electron microscopy studies showing absent dense granules, or the identification of a pathogenic genotype in one of 11 associated genes, including HPS1 We report a 2-wk-old male with significant iris transillumination defects, a pale fundus, and mild corectopia found by clinical exome sequencing to have a previously reported pathogenic variant, c.972dupC p.(Met325HisfsTer128), and a variant of uncertain significance, c.1846G>A p.(Glu616Lys), in HPS1 To determine whether his phenotype was consistent with HPS, follow-up studies of whole blood lumiaggregometry and platelet transmission electron microscopy were performed that revealed absent or markedly reduced platelet ATP secretion and virtually absent platelet dense granules, thus confirming the diagnosis. To the best of our knowledge, our case is the first in which the c.1846G>A p.(Glu616Lys) variant is identified in a patient with HPS. In addition, the case also highlights the importance of leveraging appropriate confirmatory clinical testing and reverse phenotyping, which allowed the care team to establish the clinical diagnosis of HPS and reclassify the previously reported variant of uncertain significance in HPS1 to likely pathogenic.

Deceptively benign low-grade fibromyxoid sarcoma: array-comparative genomic hybridization decodes the diagnosis.

Low-grade fibromyxoid sarcoma (previously known as Evans tumor) is a rare soft tissue neoplasm characterized by a deceptively bland appearance despite the potential for late metastasis or recurrence. We describe a 13-year-old patient with a popliteal fossa mass initially thought to be benign that, because of array-comparative genomic hybridization findings and subsequent immunohistochemistry, was diagnosed as low-grade fibromyxoid sarcoma. The array-comparative genomic hybridization demonstrated a loss of 11p11.2p15.5 and a gain of 16p11.2p13.3 with breakpoints involving the CREB3L1 (cAMP responsive element-binding protein 3-like 1) and FUS (fused in sarcoma) genes, respectively. Subsequent fluorescence in situ hybridization analysis of a dual-labeled break-apart FUS probe on interphase cells was positive. Our case highlights the importance of using genetic information obtained via array-comparative genomic hybridization to classify accurately pediatric soft tissue tumors.

Colonic in situ mantle cell lymphoma.

This report describes the first case, to our knowledge, of in situ mantle cell lymphoma (MCL) in the gastrointestinal tract identified retrospectively by immunostains and fluorescence in situ hybridization (FISH) analysis after progression to disseminated disease with pleomorphic morphology several years later. A 45-year-old man with blood per rectum underwent colonoscopy and had random biopsies interpreted as benign colonic mucosa. Two years later, he presented with ileocolic intussusception related to enlarged lymph nodes. Biopsies on the second presentation demonstrated widespread MCL. Reevaluation of the original colonic biopsies showed cyclin D1-positive cells within small lymphoid aggregates, confirmed by FISH for t(11;14). Postchemotherapy, lymphoid aggregates in colonic biopsies showed scattered cyclin D1- and FISH t(11;14)-positive cells, similar to the original in situ lymphoma. We discuss this case in the context of the current understanding of the evolution of MCL and the difficulties associated with detecting primary GI lymphoma.

COMT genotype influences the effect of alcohol on blood pressure: results from the COMBINE study.

BACKGROUND: Heavy drinking can cause chronic hypertension, possibly due to effects on the autonomic nervous system. Catechol- O-methyltransferase (COMT) inactivates catecholamines, and a G to A substitution in codon 108 in the soluble COMT mRNA (or codon 158 in the membrane-bound form) substitutes methionine for valine and alters enzyme activity. METHODS: We evaluated the association of COMT genotype at this locus with blood pressure (BP) in 839 alcohol-dependent individuals before and during participation in an alcoholism treatment trial. Hierarchical linear models were used to account for within-subject correlation on repeated BP measurements, and findings were adjusted for age, gender, ethnicity, alcohol use, body mass index, current smoking, hypertension history, and study site. RESULTS: Relative to those with the val-val genotype, those with the met-met genotype had higher adjusted systolic (+4.9 mm Hg, P < 0.01) and diastolic (+3.2 mm Hg, P < 0.01) BP at baseline. Those with the val-met genotype did not significantly differ from the val-val genotype. Changes in BP between baseline and 4 weeks of alcohol treatment also differed by genotype. Relative to the val-val genotype, the met-met genotype had a greater reduction in adjusted systolic pressure (-3.9 mm Hg, P < 0.01) and diastolic pressure (-2.8 mm Hg, P < 0.01). Corresponding relative reductions for the val-met genotype were -2.2 mm Hg systolic (P = 0.070) and -1.5 mm Hg diastolic (P < 0.05). CONCLUSION: Findings suggest that alcohol-induced BP elevation may be related to the effects of catecholamines and their genetically determined inactivation.

Vascular dysfunction in aging: potential effects of resveratrol, an anti-inflammatory phytoestrogen.

Epidemiological studies demonstrated that even in the absence of other risk factors (e.g. diabetes, hypertension, hyperhomocysteinemia, hypercholesterolemia), advanced age itself significantly increases cardiovascular morbidity by enhancing vascular oxidative stress and inflammation. Because the population in the Western world is rapidly aging, there is a substantial need for pharmacological interventions that delay the functional decline of the cardiovascular system. Resveratrol is an atoxic phytoestrogen found in more than 70 plants including grapevine and berries. Recent data suggest that nutritional intake of resveratrol and other polyphenol compounds may contribute to the "French paradox", the unexpectedly low cardiovascular morbidity in the Mediterranean population. There is increasing evidence that resveratrol exerts multifaceted anti-oxidant and/or anti-inflammatory effects in various disease models. Importantly, resveratrol was reported to slow aging and increase lifespan in simple organisms and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to activate NAD-dependent histone deacetylases (sirtuins), which may contribute to its anti-aging effects. This review focuses on the role of oxidative stress and inflammation in cardiovascular dysfunction in aging, and on emerging anti-aging therapeutic strategies offered by resveratrol and other polyphenol compounds.

Distribution of PACAP-38 in the central nervous system of various species determined by a novel radioimmunoassay.

Pituitary adenylate cyclase activating polypeptide (PACAP) occurs in two molecular forms: PACAP-38 and PACAP-27. Soon after the isolation and chemical characterization of PACAP, the first radioimmunoassay (RIA) methods have been developed, but it is a still rarely used laboratory technique in the field of PACAP research. The aim of the present study was to develop a novel, highly specific PACAP-38 assay to investigate the quantitative distribution of PACAP-38 in the central nervous system of various vertebrate species under the same technical and experimental conditions. Different areas of the brain and the spinal cord were removed from rats, chickens and fishes and the tissue samples were processed for PACAP-38 RIA. Our results indicate that the antiserum used in the RIA is C-terminal specific, without affinity for other members of the vasoactive intestinal polypeptide (VIP)/secretin/glucagon peptide family. The average ID50 value was 48.6+/-3.4 fmol/ml determined in 10 consecutive assays. Detection limit for PACAP-38 proved to be 2 fmol/ml. PACAP-38 immunoreactivity was present in the examined brain areas of each species studied, with highest concentration in the rat diencephalons. High levels of PACAP-38 were also detected in the rat telencephalon, followed by spinal cord and brainstem. The central nervous system of the fish also contained considerable concentrations of PACAP-38, whereas lowest concentrations were measured in the central nervous system of the chicken.