Atypical right diaphragmatic hernia (hernia of Morgagni), spigelian hernia and epigastric hernia in a patient with Williams syndrome: a case report

<p>Abstract</p> <p>Introduction</p> <p>Williams syndrome is rare genetic disorder resulting in neurodevelopmental problems. Hernias of the foramen of Morgagni are rare diaphragmatic hernias and they mostly present on the right side, in the anterior mediastinum. They are usually asymptomatic and are difficult to diagnose, especially in patients with learning disabilities.</p> <p>Case presentation</p> <p>This 49-year-old woman with Williams syndrome, cognitive impairment and aortic stenosis presented to physicians with right-sided chest pain. She had previously undergone repair of her right spigelian and epigastric hernia. Her abdominal examination was unremarkable. Chest X-ray suggested right-sided diaphragmatic hernia and pleural effusion for which she received treatment. The computed tomography scan showed a diaphragmatic hernia with some collapse/consolidation of the adjacent lung. Furthermore, the patient had aortic stenosis and was high risk for anaesthesia (ASA grade 3). She underwent successful laparoscopic repair of her congenital diaphragmatic hernia leading to a quick and uneventful postoperative recovery.</p> <p>Conclusion</p> <p>These multiple hernias suggest that patients with Williams syndrome may have some connective tissue disorder which makes them prone to develop hernias especially associated with those parts of the body which may have intracavity pressure variations like the abdomen. Diaphragmatic hernia may be the cause of chest pain in these patients. A computed tomography scan helps in early diagnosis, and laparoscopic repair helps in prevention of further complications, and leads to quick recovery especially in patients with learning disabilities. In the presence of significant comorbidities, a less invasive operative procedure with quick recovery becomes advisable.</p

Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome

Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome wide siRNA screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Caspase-3 regulates cell cycle in B cells: A consequence of substrate specificity

Caspases are important for apoptosis but are also involved in mammalian cell survival and cell division. Here we report that caspase-3 is a negative regulator of B cell cycling. Mice deficient in caspase-3 (Casp3-/- mice) have increased numbers of splenic B cells that show normal apoptosis but enhanced proliferation in vivo and hyperproliferation after mitogenic stimulation in vitro. Cdkn1a encodes p21 (also called Waf1 or Cip1), a cyclin-dependent kinase (CDK) inhibitor. Although expression of p21 was increased, CDK activities and proliferating cell nuclear antigen (PCNA) were increased in Casp3-/- B cells. Using Casp3-/-Cdkn1a-/- mice, we show that the hyperproliferation of Casp3-/- B cells is abolished when Cdkn1a is also deleted. Our genetic and biochemical data demonstrate that caspase-3 is essential in the regulation of B cell homeostasis.link_to_subscribed_fulltex

A genetic variant of p53 restricts the mucous secretory phenotype by regulating SPDEF and Bcl-2 expression

Despite implications for carcinogenesis and other chronic diseases, basic mechanisms of p53 and its variants in suppressing Bcl-2 levels, are poorly understood. Bcl-2 sustains mucous cell metaplasia, whereas p53−/− mice display chronically increased mucous cells. Here we show that p53 decreases bcl-2 mRNA half-life by interacting with the 5’ untranslated region (UTR). The p53-bcl-2 mRNA interaction is modified by the substitution of proline by arginine within the p53 proline-rich domain (PRD). Accordingly, more mucous cells are present in primary human airway cultures with p53Arg compared with p53Pro. Also, the p53Arg compared with p53Pro displays higher affinity to and activates the promoter region of SAM-pointed domain-containing Ets-like factor (SPDEF), a driver of mucous differentiation. On two genetic backgrounds, mice with targeted replacement of prolines in p53 PRD show enhanced expression of SPDEF and Bcl-2 and mucous cell metaplasia. Together, these studies define the PRD of p53 as a determinant for chronic mucus hypersecretion