Unexpected discovery of 2 cases of hepatocyte nuclear factor 1α-mutated infracentimetric adenomatosis

We present 2 cases of hepatocyte nuclear factor 1α （HNF1α）-mutated adenomatosis, discovered for reasons unrelated to this disease, and identified using immunohistochemical methods. These new tools may further our understanding of the link between adenomas/adenomatosis subtypes and their complications, and their association with other abnormalities.     

Gα13 regulates methacholine-induced contraction of bronchial smooth muscle via phosphorylation of MLC20

Reversible airway constriction is induced by an increase in airway smooth muscle contractility in response to methacholine likely as a bronchospastic stimulus. Despite the finding of Gα₁₂ and Gα₁₃ up-regulation in airway hyperresponsive animals, their functional role of contraction in airway smooth muscle has not been directly explored. This study investigated the differential regulatory role of Gα₁₂/Gα₁₃ in methacholine-induced contraction of trachea and bronchus in Gα₁₂ or Gα₁₃ gene knockout mice after ovalbumin sensitization and challenges. Organ bath assays and videomicroscopy revealed that Gα₁₃ deficiency delayed methacholine-induced contractile response of bronchiolar smooth muscle, but not that of tracheal smooth muscle. In primary bronchial smooth muscle cells, knockdown of Gα₁₃ blocked methacholine-induced phosphorylation of 20 kDa regulatory light chain of myosin II (MLC₂₀), a prerequisite step for the contractile initiation of actin and myosin. Gα₁₃-dependent MLC₂₀ phosphorylation was confirmed in murine embryonic fibroblasts. After ovalbumin sensitization and challenges, wild type mice exhibited methacholine-induced bronchial contraction of lung tissue. Heterozygous absence of the Gα₁₃ gene abrogated methacholine-induced contractions, whereas homozygous absence of the Gα₁₂ gene failed to do so. Our findings indicate that Gα₁₃, but not Gα₁₂, specifically regulates cholinergic bronchial contraction in airway responsiveness via controlling phosphorylation of MLC₂₀ by methacholine.     

Toxic effects of low doses of Bisphenol-A on human placental cells

Humans are exposed daily to a great number of xenobiotics and their metabolites present as pollutants. Bisphenol-A (BPA) is extensively used in a broad range of products including baby bottles, food-storage containers, medical equipment, and consumer electronics. Thus, BPA is the most common monomer for polycarbonates intended for food contact. Levels of this industrial product are found in maternal blood, amniotic fluid, follicular fluid, placental tissue, umbilical cord blood, and maternal urine. In this study, we investigated toxic effects of BPA concentrations close to levels found in serum of pregnant women on human cytotrophoblasts (CTB). These cells were isolated from fresh placentas and exposed to BPA for 24 h. Our results showed that very low doses of BPA induce apoptosis (2 to 3 times) as assessed using M30 antibody immunofluorescent detection, and necrosis (1.3 to 1.7 times) as assessed through the cytosolic Adenylate Kinase (AK) activity after cell membrane damage. We also showed that BPA increased significantly the tumor-necrosis factor alpha (TNF-α) gene expression and protein excretion as measured by real-time RT-PCR and ELISA luminescent test, respectively. Moreover, we observed that induction of AK activation and TNF-α gene expression require lower levels of BPA than apoptosis or TNF-α protein excretion. Our findings suggest that exposure of placental cells to low doses of BPA may cause detrimental effects, leading in vivo to adverse pregnancy outcomes such as preeclampsia, intrauterine growth restriction, prematurity and pregnancy loss.     

The Cochlear Pericytes

Objectives : Cochlear pericytes are not well characterized. The aim of this study was to further advance the characterization of cochlear pericyte location and distribution, with particular focus on pericyte‐related proteins on the capillaries of the cochlear lateral wall that are functionally integral to structure, contraction, and gap junction transport. Materials and Methods : Cochlear pericytes were identified by the immunofluorescence labeling of pericyte marker proteins, including alpha–smooth muscle actin (α‐SMA), desmin, Thy‐1, tropomyosin, and NG2, and by morphological identification, using fluorescence, electron, and differential interference contrast microscopy. Results : Pericytes were predominately found in the capillary network of the cochlear lateral wall, with considerable morphological heterogeneity across different types of microvessels. For example, pericytes on the vessels of the spiral ligament (V/SL) strongly expressed a gap junction protein, connexin 40, and were positive for α‐SMA, tropomyosin, and desmin. In contrast, pericytes on the vessels of the stria vascularis (V/SV) were positive for desmin, and were negative for α‐SMA and tropomyosin. Conclusions : The capillary networks of the cochlear lateral wall comprise a rich population of pericytes. These pericytes are morphologically heterogeneous, with protein expression potentially indicative of function.     

Abdominal apoplexy: A rare case of spontaneous rupture of the superior mesenteric artery in a hypertensive patient

INTRODUCTIONSpontaneous rupture of an intra-abdominal visceral artery is an exceptionally rare and potentially fatal cause of abdominal apoplexy.PRESENTATION OF CASEWe present a case of a 54-year-old hypertensive male who developed hypovolemic shock in our Emergency Department after presenting with abrupt onset of abdominal pain and diarrhea. Intra-operative findings revealed rupture of the superior mesenteric artery with massive hemoperitoneum. The bleeding vessel was ligated and the patient made a full recovery after 3 weeks in the Intensive Care Unit.DISCUSSIONHigh index of suspicion is necessary for early preoperative diagnosis and must be considered in any patient with a history of hypertension presenting with abrupt abdominal pain, signs of peritoneal irritation and unexplained hypovolemic shock. Immediate resuscitation and prompt surgical control of bleeding is paramount in patient prognosis.CONCLUSIONThe seemingly unpredictable nature of abdominal apoplexy must be noted, a precipitating cause in most cases is untraceable and early diagnosis relies solely on awareness of the condition.     

Identification of a Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitor, BIP-135, that Prolongs the Median Survival Time of Δ7 SMA KO Mouse Model of Spinal Muscular Atrophy

The discovery of upregulated glycogen synthase kinase-3 (GSK-3) in various pathological conditions has led to the development of a host of chemically diverse small molecule GSK-3 inhibitors, such as BIP-135. GSK-3 inhibition emerged as an alternative therapeutic target for treating spinal muscular atrophy (SMA) when a number of GSK-3 inhibitors were shown to elevate survival motor neuron (SMN) levels in vitro and to rescue motor neurons when their intrinsic SMN level was diminished by SMN-specific short hairpin RNA (shRNA). Despite their cellular potency, the in vivo efficacy of GSK-3 inhibitors has yet to be evaluated in an animal model of SMA. Herein, we disclose that a potent and reasonably selective GSK-3 inhibitor, namely BIP-135, was tested in a transgenic Δ7 SMA KO mouse model of SMA, and found to prolong the median survival of these animals. In addition, this compound was shown to elevate the SMN protein level in SMA patient-derived fibroblast cells as determined by western blot, and was neuroprotective in a cell-based, SMA-related model of oxidative stress-induced neurodegeneration.     

Management of sepsis in the critically ill patient: key aspects

Severe sepsis is a major cause of morbidity and mortality in the critically ill patient. Management involves identification and treatment of the underlying causative infection, with antimicrobial agents and surgery where necessary, haemodynamic resuscitation with fluids and vasoactive agents, steroids (for septic shock) and immunomodulation with drotrecogin-α (activated), where not contraindicated. Every effort must be made to identify sepsis early so as to optimise the patient’s chances of a good outcome.     

The functional role of beta‐oscillations in the supplementary motor area during reaching and grasping after stroke: A question of structural damage to the corticospinal tract

Hand motor function is often severely affected in stroke patients. Non‐satisfying recovery limits reintegration into normal daily life. Understanding stroke‐related network changes and identifying common principles that might underlie recovered motor function is a prerequisite for the development of interventional therapies to support recovery. Here, we combine the evaluation of functional activity (multichannel electroencephalography) and structural integrity (diffusion tensor imaging) in order to explain the degree of residual motor function in chronic stroke patients. By recording neural activity during a reaching and grasping task that mimics activities of daily living, the study focuses on deficit‐related neural activation patterns. The study showed that the functional role of movement‐related beta desynchronization in the supplementary motor area (SMA) for residual hand motor function in stroke patients depends on the microstructural integrity of the corticospinal tract (CST). In particular, in patients with damaged CST, stronger task‐related activity in the SMA was associated with worse residual motor function. Neither CST damage nor functional brain activity alone sufficiently explained residual hand motor function. The findings suggest a central role of the SMA in the motor network during reaching and grasping in stroke patients, the degree of functional relevance of the SMA is depending on CST integrity.