A novel HSF4 gene mutation (p.R405X) causing autosomal recessive congenital cataracts in a large consanguineous family from Pakistan

<p>Abstract</p> <p>Background</p> <p>Hereditary cataracts are most frequently inherited as autosomal dominant traits, but can also be inherited in an autosomal recessive or X-linked fashion. To date, 12 loci for autosomal recessive cataracts have been mapped including a locus on chromosome 16q22 containing the disease-causing gene <it>HSF4 </it>(Genbank accession number <ext-link ext-link-id="NM_001040667" ext-link-type="gen">NM_001040667</ext-link>). Here, we describe a family from Pakistan with the first nonsense mutation in <it>HSF4 </it>thus expanding the mutational spectrum of this heat shock transcription factor gene.</p> <p>Methods</p> <p>A large consanguineous Pakistani family with autosomal recessive cataracts was collected from Quetta. Genetic linkage analysis was performed for the common known autosomal recessive cataracts loci and linkage to a locus containing <it>HSF4 </it>(OMIM 602438) was found. All exons and adjacent splice sites of the heat shock transcription factor 4 gene (<it>HSF4</it>) were sequenced. A mutation-specific restriction enzyme digest (H<it>ph</it>I) was performed for all family members and unrelated controls.</p> <p>Results</p> <p>The disease phenotype perfectly co-segregated with markers flanking the known cataract gene HSF4, whereas other autosomal recessive loci were excluded. A maximum two-point LOD score with a Zmax = 5.6 at θ = 0 was obtained for D16S421. Direct sequencing of HSF4 revealed the nucleotide exchange c.1213C > T in this family predicting an arginine to stop codon exchange (p.R405X).</p> <p>Conclusion</p> <p>We identified the first nonsense mutation (p.R405X) in exon 11 of <it>HSF4 </it>in a large consanguineous Pakistani family with autosomal recessive cataract.</p

Familial Mediterranean Fever and Hyperimmunoglobulinemia D syndrome: two diseases with distinct clinical, serologic, and genetic features

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Cell death in hepatocellular carcinoma: Pathogenesis and therapeutic opportunities

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and the third leading cause of cancer death worldwide. Closely associated with liver inflammation and fibrosis, hepatocyte cell death is a common trigger for acute and chronic liver disease arising from different etiologies, including viral hepatitis, alcohol abuse, and fatty liver. In this review, we discuss the con-tribution of different types of cell death, including apoptosis, necroptosis, pyroptosis, or autophagy, to the progression of liver disease and the development of HCC. Interestingly, inflammasomes have recently emerged as pivotal innate sensors with a highly pathogenic role in various liver diseases. In this regard, an increased inflammatory response would act as a key element promoting a pro-oncogenic microenvironment that may result not only in tumor growth, but also in the formation of a premetastatic niche. Importantly, nonparenchymal hepatic cells, such as liver sinusoidal endothelial cells, hepatic stellate cells, and hepatic macrophages, play an important role in establishing the tumor microenvironment, stimulating tumorigenesis by paracrine communication through cytokines and/or angiocrine factors. Finally, we update the potential therapeutic options to inhibit tumorige-nesis, and we propose different mechanisms to consider in the tumor microenvironment field for HCC resolution. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Familial Mediterranean fever, Inflammation and Nephrotic Syndrome: Fibrillary Glomerulopathy and the M680I Missense Mutation

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by inflammatory serositis (fever, peritonitis, synovitis and pleuritis). The gene locus responsible for FMF was identified in 1992 and localized to the short arm of chromosome 16. In 1997, a specific FMF gene locus, MEFV, was discovered to encode for a protein, pyrin that mediates inflammation. To date, more than forty missense mutations are known to exist. The diversity of mutations identified has provided insight into the variability of clinical presentation and disease progression. CASE REPORT: We report an individual heterozygous for the M680I gene mutation with a clinical diagnosis of FMF using the Tel-Hashomer criteria. Subsequently, the patient developed nephrotic syndrome with biopsy-confirmed fibrillary glomerulonephritis (FGN). Further diagnostic studies were unremarkable with clinical workup negative for amyloidosis or other secondary causes of nephrotic syndrome. DISCUSSION: Individuals with FMF are at greater risk for developing nephrotic syndrome. The most serious etiology is amyloidosis (AA variant) with renal involvement, ultimately progressing to end-stage renal disease. Other known renal diseases in the FMF population include IgA nephropathy, IgM nephropathy, Henoch-Schönlein purpura as well as polyarteritis nodosa. CONCLUSION: To our knowledge, this is the first association between FMF and the M680I mutation later complicated by nephrotic syndrome and fibrillary glomerulonephritis

Health-related quality of life and late morbidity in concurrent chemoradiation and radiotherapy alone in patients with locally advanced cervical carcinoma

Objective: Concurrent chemoradiation has improved survival of patients with cervical carcinoma. However, follow-up of randomized studies is relatively short and data on long term toxicity are scarce, as is information on their health-related quality of life. This study assesses and compares incidences of late side-effects among patients treated with radiotherapy or chemoradiation using two toxicity scoring systems, and investigates impact on health-related quality of life. Methods: Between 1985 and 1993, 114 patients underwent radiotherapy (n=39) or chemoradiation (n=75) for stage IIA-IVB cervical carcinoma. Late side-effects were scored retrospectively by reviewing medical charts using standardised checklists, focusing on bladder- and intestinal side effects. Health-related quality of life was assessed once using the EORTC QLQ-C30. Results: No significant differences in late treatment-related side-effects between radiotherapy and chemoradiation groups were found. Grade >= 2 toxicity was found in 33% (bladder), and in 6% (bowel). Only 1.8% had both grade 3-4 toxicity. Bladder syndrome with high urinary frequency, urine incontinence and small bowel toxicity had a significant impact on health-related quality of life. Conclusion: Grade 2 are relatively frequent late side effects in curatively treated patients, but are not enhanced by the addition of chemotherapy. Their negative impact on health-related quality of life stresses the importance of new radiation techniques, aiming at reduction of these side effects

"LUDO" - Kids playing Distributed Denial of Service

Distributed denial of service attacks pose a serious threat to the availability of the network infrastructures and services. GE̿ANT, the pan-European network with terabit capacities witnesses close to hundreds of DDoS attacks on a daily basis. The reason is that DDoS attacks are getting larger, more sophisticated and frequent. At the same time, it has never been easier to execute DDoS attacks, e.g., Booter services offer paying customers without any technical knowledge the possibility to perform DDoS attacks as a service. Given the increasing size, frequency and complexity of DDoS attacks, there is a need to perform a collaborative mitigation. Therefore, we developed (i) a DDoSDB to share real attack data and allow collaborators to query, compare, and download attacks, (ii) the Security attack experimentation framework to test mitigation and response capabilities and (iii) a collaborative mitigation and response process among trusted partners to disseminate security event information. In addition to these developments, we present and would like to discuss our latest research results with experienced networking operators and bridging the gap between academic research and operational business

Spallation Neutron Production by 0.8, 1.2 and 1.6 GeV Protons on various Targets

Spallation neutron production in proton induced reactions on Al, Fe, Zr, W, Pb and Th targets at 1.2 GeV and on Fe and Pb at 0.8, and 1.6 GeV measured at the SATURNE accelerator in Saclay is reported. The experimental double-differential cross-sections are compared with calculations performed with different intra-nuclear cascade models implemented in high energy transport codes. The broad angular coverage also allowed the determination of average neutron multiplicities above 2 MeV. Deficiencies in some of the models commonly used for applications are pointed out.Comment: 20 pages, 32 figures, revised version, accepted fpr publication in Phys. Rev.