May-Hegglin Anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome Are not Distinct Entities but Represent a Variable Expression of a Single Illness

May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Döhle-like bodies. Mutations in the MYH9 gene encoding for the nonmuscle myosin heavy chain IIA (NMMHC-IIA) have been identified in all these syndromes. To understand the role of the MYH9 mutations, we report the molecular defects in 12 new cases, which together with our previous works represent a cohort of 19 families. Since no genotype-phenotype correlation was established, we performed an accurate clinical and biochemical re-evaluation of patients. In addition to macrothrombocytopenia, an abnormal distribution of NMMHC-IIA within leukocytes was observed in all individuals, including those without Döhle-like bodies. Selective, high-tone hearing deficiency and cataract was diagnosed in 83% and 23%, respectively, of patients initially referred as having May-Hegglin anomaly or Sebastian syndrome. Kidney abnormalities, such as hematuria and proteinuria, affected not only patients referred as Fechtner syndrome and Epstein syndrome but also those referred as May-Hegglin anomaly and Sebastian syndrome. These findings allowed us to conclude that May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but rather a single disorder with a continuous clinical spectrum varying from mild macrothrombocytopenia with leukocyte inclusions to a severe form complicated by hearing loss, cataracts, and renal failure. For this new nosologic entity, we propose the term "MHY9-related disease," which better interprets the recent knowledge in this field and identifies all patients at risk of developing renal, hearing, or visual defects

The nucleotide sequence of the Escherichia coli K12 nusB (groNB) gene.

The nusB (groNB) gene product of Escherichia coli plays a pivotal role in allowing bacteriophage lambda N protein to function as an antiterminator of mRNA transcription and in modulating host gene expression. In addition it is essential for bacterial viability since mutations in it result in a cold-sensitivity phenotype for growth. We have previously cloned the nusB gene and shown it to code for a 14,500-Mr protein. Here we present the primary DNA sequence of the nusB gene. From the sequence we deduce that it codes for a slightly basic protein (21 basic as opposed to 20 acidic amino acids) composed of 139 amino acids with a cumulative 15,689-Mr. The predicted N-terminal amino acid sequence as well as the overall amino acid composition agrees well with that of the purified protein

Null mutation in P4h-tm leads to decreased fear and anxiety and increased social behavior in mice

Abstract HIF prolyl 4-hydroxylases (HIF-P4Hs, also known as PHDs and EGLNs) are crucial enzymes that modulate the hypoxia inducible factor (HIF) response and help to maintain cellular oxygen homeostasis. This function is especially well-known for cytoplasmic or nuclear enzymes HIF-P4H-1–3 (PHDs 1–3, EGLNs 2, 1 and 3, respectively), but the physiological role is still obscure for a fourth suggested HIF-P4H, P4H-TM that is a transmembrane protein and resides in the endoplasmic reticulum. Recently however, both experimental and clinical evidence of the P4H-TM involvement in CNS physiology has emerged. In this study, we first investigated the expression pattern of P4H-TM in the mouse brain and found a remarkably selective abundance in brains areas that are involved in social behaviors and anxiety including amygdala, lateral septum and bed nucleus of stria terminalis. Next, we performed behavioral assays in P4h-tm−/− mice to investigate a possible phenotype associated to these brain areas. In locomotor activity tests, we found that P4h-tm−/− mice were significantly more active than their wild-type (WT) littermate mice, and habituation to test environment did not abolish this effect. Instead, spatial learning and memory seemed normal in P4h-tm−/− mice as assessed by Morris swim task. In several tests assessing anxiety and fear responses, P4h-tm−/− mice showed distinct courageousness, and they presented increased interaction towards fellow mice in social behavior tests. Most strikingly, P4h-tm−/− mice practically lacked behavioral despair response, a surrogate marker of depression, in forced swim and tail suspension tests. Instead, mutant mice of all other Hif-p4h isoforms lacked such a behavioral phenotype. In summary, this study presents a remarkable anatomy-physiology association between the brain expression of P4H-TM and the behavioral phenotype in P4h-tm−/− mice. Future studies will reveal whether P4H-TM may serve as a novel target for anti-depressant and anti-anxiety pharmacotherapy

High NRBP1 expression in prostate cancer is linked with poor clinical outcomes and increased cancer cell growth

We recently established the rationale that NRBP1 (nuclear receptor binding protein 1) has a potential growth-promoting role in cell biology. NRBP1 interacts directly with TSC-22, a potential tumor suppressor gene that is differently expressed in prostate cancer. Consequently, we analyzed the role of NRBP1 expression in prostate cancer cell lines and its expression on prostate cancer tissue microarrays (TMA)

Metabolic profiles help discriminate mild cognitive impairment from dementia stage in Alzheimer’s disease

Abstract Accurate differentiation between neurodegenerative diseases is developing quickly and has reached an effective level in disease recognition. However, there has been less focus on effectively distinguishing the prodromal state from later dementia stages due to a lack of suitable biomarkers. We utilized the Disease State Index (DSI) machine learning classifier to see how well quantified metabolomics data compares to clinically used cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD). The metabolic profiles were quantified for 498 serum and CSF samples using proton nuclear magnetic resonance spectroscopy. The patient cohorts in this study were dementia (with a clinical AD diagnosis) (N = 359), mild cognitive impairment (MCI) (N = 96), and control patients with subjective memory complaints (N = 43). DSI classification was conducted for MCI (N = 51) and dementia (N = 214) patients with low CSF amyloid-β levels indicating AD pathology and controls without such amyloid pathology (N = 36). We saw that the conventional CSF markers of AD were better at classifying controls from both dementia and MCI patients. However, quantified metabolic subclasses were more effective in classifying MCI from dementia. Our results show the consistent effectiveness of traditional CSF biomarkers in AD diagnostics. However, these markers are relatively ineffective in differentiating between MCI and the dementia stage, where the quantified metabolomics data provided significant benefit