Regulatory volume decrease by cultured non-pigmented ciliary epithelial cells.

Cells (ODM C1-2/SV40) derived from human non-pigmented ciliary epithelial cells were studied by electronic cell sizing. The time course of the cell volume (vc) was monitored after suspending cells in paired experimental and control, isosmotic and hyposmotic solutions of identical ionic composition. Following anisosmotic cell swelling, the cells displayed the regulatory volume decrease (RVD) previously described. The RVD primarily reflects loss of cell KCl since: (1) the K(+)-channel blockers quinidine and Ba2+ both inhibit the RVD; and (2) replacement of external Cl- with gluconate or addition of the Cl- channel blocker NPPB also inhibits the RVD. Bicarbonate has previously been reported to speed the RVD. This action likely reflects pH dependence of the channels since: (1) increasing the external pH speeds the RVD, whether or not HCO3- is present; and (2) DIDS (a blocker of Cl- channels and of Cl-/HCO3- exchange) is an effective inhibitor of the RVD, even after blocking Cl-/HCO3- exchange by removing external HCO3-. The RVD could also be inhibited by reducing the availability of Ca2+, either by omitting Ca2+ from the external medium or by blocking mobilization of intracellular Ca2+ with TMB-8. Furthermore, the RVD was slowed and incomplete in the presence of the calcium/calmodulin blocker trifluoperazine. We conclude that anisosmotic swelling triggers a series of events, mediated at least in part by calcium/calmodulin, leading to the extrusion of KCl through parallel K+ and Cl- channels.     

Regulatory review time and pharmaceutical research and development

In the United States, all newly developed drugs undergo a lengthy review process conducted by the US Food and Drug Administration (FDA). These regulatory delays have direct immediate costs for drug manufacturers and patients waiting for treatment. Under certain market conditions, regulatory delays may also affect future research and development (R&D) strategies of pharmaceutical companies. To estimate the magnitude of this effect, we match data on drugs in the development pipeline in 2006 to data that we collect on FDA review times for all drugs approved between 1999 and 2005. Employing a rich and novel set of controls that affect drug R&D decisions and, potentially, regulatory review lags, we find that on average, three additional months of delay result in one fewer drug in development in that drug category. Our results suggest that the length of the regulatory delay matters for pharmaceutical firms' R&D decisions and that the firms are likely unable to pass on these costs onto consumers.     

Giving rituximab in patients with occult or resolved hepatitis B virus infection: are the current guidelines good enough?

Introduction: Hepatitis B virus (HBV) reactivation after ‘resolved’ infection can occur in the setting of immunosuppression, including iatrogenically induced by anti-CD20 antibodies. The presence of antibodies against the HBV core antigen (anti-HBc) is a marker of risk for this phenomenon. The risk of this occurring in patients with circulating HBV surface antigen (HBsAg) is well characterized, but is less well characterized in patients who are HBsAg negative.

Areas covered: This article reviews the literature regarding HBV reactivation in the context of rituximab therapy. We have limited our review to HBsAg-negative patients, and clinical outcomes following HBV reactivation.

Expert opinion: We have recommended prophylactic anti-viral therapy for all HBsAg-negative/anti-HBc-positive patients undergoing rituximab therapy in combination with other immunosuppressive therapy.     

Evaluation of the thyroid disorders in children with familial Mediterranean fever

Clinical Rheumatology - Although it is well-known that autoimmune thyroid diseases are more common in most of the autoimmune connective tissue diseases, the relationship between autoinflammatory...     

Discrimination between non-functioning pituitary adenomas and hypophysitis using machine learning methods based on magnetic resonance imaging‑derived texture features

Purpose

Hypophysitis is a heterogeneous condition that includes inflammation of the pituitary gland and infundibulum, and it can cause symptoms related to mass effects and hormonal deficiencies. We aimed to evaluate the potential role of machine learning methods in differentiating hypophysitis from non-functioning pituitary adenomas.

Methods

The radiomic parameters obtained from T1A-C images were used. Among the radiomic parameters, parameters capable of distinguishing between hypophysitis and non-functioning pituitary adenomas were selected. In order to avoid the effects of confounding factors and to improve the performance of the classifiers, parameters with high correlation with each other were eliminated. Machine learning algorithms were performed with the combination of gray-level run-length matrix-low gray level run emphasis, gray-level co-occurrence matrix-correlation, and gray-level co-occurrence entropy.

Results

A total of 34 patients were included, 17 of whom had hypophysitis and 17 had non-functioning pituitary adenomas. Among the 38 radiomics parameters obtained from post-contrast T1-weighted images, 10 tissue features that could differentiate the lesions were selected. Machine learning algorithms were performed using three selected parameters; gray level run length matrix-low gray level run emphasis, gray-level co-occurrence matrix-correlation, and gray level co-occurrence entropy. Error matrices were calculated by using the machine learning algorithm and it was seen that support vector machines showed the best performance in distinguishing the two lesion types.

Conclusions

Our analysis reported that support vector machines showed the best performance in distinguishing hypophysitis from non-functioning pituitary adenomas, emphasizing the importance of machine learning in differentiating the two lesions.

     

A case of primary Sjögren’s syndrome presenting primarily with central nervous system vasculitic involvement

Sjögren’s syndrome is primarily a chronic systemic autoimmune disease that affects exocrine organs. Neurologic symptoms frequently present as peripheral neuropathy due to small vessel vasculitis. Type and prevalence of central nervous system involvement are still controversial. In this report, we present a 35-year-old woman with primary Sjögren’s syndrome with central nervous system vasculitic involvement.     

Knockout of A3 adenosine receptors reduces mouse intraocular pressure

PURPOSE: To test the putative role of A(3) adenosine receptors (ARs) in modulating intraocular pressure (IOP). METHODS: IOP was monitored for up to 32 minutes in A3-knockout (A3AR-/-) and A3AR+/+ control mice by the servo-null approach. The IOP responses to adenosine, A3AR agonists and A3AR antagonists were studied singly or in combination in both strains. RESULTS: IOP was significantly lower in A3AR-/- mice (12.9 +/- 0.7 mm Hg) than in A3AR+/+ control animals (17.4 +/- 0.6 mm Hg). The nonselective AR agonist adenosine produced a much smaller increase in IOP (2.2 +/- 0.8 mm Hg) in the knockout than in A3AR+/+ control mice (14.9 +/- 2.4 mm Hg). The A3-selective agonist IB-MECA did not affect IOP in A3-knockout mice, but raised it in A3AR+/+ mice. The highly selective A3AR antagonist MRS 1191 did not affect IOP in A3AR-/- mice, but lowered it in A3AR+/+ control mice. Preadministering MRS 1191 did not affect the small adenosine-triggered increase in IOP in A3AR-/- mice, but markedly attenuated adenosine's effects on IOP in A3AR+/+ control mice. MRS 1523, an A3AR antagonist less selective than MRS 1191 in rats, decreased IOP in both A3AR-/- and A3AR+/+ animals. As in black Swiss outbred mice and other mammalian species, reducing aqueous humor inflow with acetazolamide lowered IOP and administering water intraperitoneally increased IOP in both A3AR-/- and A3AR+/+ mice. CONCLUSIONS: The reduced IOP and altered purinergic responses of IOP in A3AR knockout mice support the conclusion that A3ARs contribute to the regulation of IOP.     

Emergency endovascular management of pulmonary artery aneurysms in Behçet's disease: report of two cases and a review of the literature

his report describes two patients with a known history of Beh?et's disease in whom massive hemoptysis developed from rupture of pulmonary artery aneurysms. The high recurrence rate of complications related to pulmonary artery aneurysms and even the aneurysms themselves due to inadequacy of medical therapy and the disadvantages of surgical treatment make these aneurysms candidates for endovascular management. The pulmonary artery aneurysms reported here were successfully treated with endovascular embolization using n-butyl cyanoacrylate. Pulmonary artery aneurysm embolization in Beh?et's disease has been reviewed in the light of relevant literature.