A phase I/II randomized, double-blind, placebo-controlled, dose-ranging study evaluating the efficacy, safety and pharmacokinetics of ravuconazole in the treatment of onychomycosis

OBJECTIVE: To determine the effectiveness and safety of ravuconazole in the treatment of toenail onychomycosis. DESIGN: A phase I/II randomized, double-blind, double-dummy, placebo-controlled, dose-ranging study. Four 12-week dosing regimens were used: 200 mg/day; 100 mg/week; 400 mg/week and placebo. Subjects returned at weeks 2, 4, 6, 8, 10, 12, 14, 16, 24, 36 and 48 for assessment. Subjects were enrolled at 10 dermatology practices (seven in the United States, one in Canada, two in France). SUBJECTS: Adults with distal subungual onychomycosis of one great (hallux) toenail (minimum area of 25%), and at least 2 mm of proximal nail clear of disease were selected. Onychomycosis was confirmed by direct microscopy and/or fungal culture. Subjects with conditions known to produce abnormal-appearing nails were excluded. One hundred and fifty-one subjects were randomized in a 2:2:2:1 ratio to the treatments above. MAIN OUTCOME MEASURES: Primary efficacy was the effective cure rate at week 48 (mycological cure, and clinical cure or > 30% improvement). RESULTS: Effective cure was found in 56% of subjects using 200 mg/day. Effective cure was 10% in subjects receiving 100 mg/week, 8% of subjects using 400 mg/week, and 15% of subjects using placebo. Mycological cure was seen in 59% of subjects in the 200-mg/day group, which was significantly higher than the rates found in the other groups. Drug-related adverse events were infrequent in all treatment arms. Headache was the most frequently reported event. Abnormal laboratory tests were infrequent over the 12 weeks of dosing. Abnormal laboratory findings with increases beyond normal of Grade 2, 3 or 4 were found in 8/148 subjects (5.4%). Only the 200 mg daily regimen had a mean plasma steady state concentration of ravuconazole exceeding the MIC(90) adjusted for 98% protein binding (3000 ng/mL). CONCLUSIONS: For the treatment of onychomycosis, ravuconazole 200 mg/day for 12 weeks is the most effective of the regimens investigated. The safety of all regimens was acceptable. The concentrations of ravuconazole in the plasma compared to the adjusted MIC(90) may be useful in predicting the clinical and mycologic response of therapy.     

The outcome of bleeding duodenal ulcer in the era of H2 receptor antagonist therapy

We studied 2119 patients presenting with duodenal ulcer as sole lesion, in the period 1976-1993, the era of H2 receptor antagonist (H2RA) therapy, prior to the introduction of Helicobacter pylori eradication. We used clinical assessment and serial check endoscopy to investigate the incidence of bleeding at presentation (group I, n = 286, 13.5%), the long-term outcome in this group and in that presenting with pain alone (group II, n = 1833, 87%) with respect to ulcer recurrence and bleeding, and the effect of H2RA maintenance therapy. Most patients were treated with H2RA, principally cimetidine. In group I, seven patients died early on; 38 had urgent surgery, of whom six died post- operatively. The remainder were treated; five immediately re-bled, of whom three were operated on. On follow-up, 98/227 group I patients relapsed, 21 (21%) of whom rebled. Relapse in group II was 1017/1668, with only 42 (4%) bleeding (p < 0.001). In patients without maintenance treatment, relapse was markedly higher (50/78 group I, 529/742 group II), but group II still bled significantly less (20% group I vs. 3% group II). Relapse on maintenance was: 48/149 with five (10%) rebleeding in group I, and 488/926 with five (1%) bleeding in group II (p < 0.001). Despite the introduction of H2RA therapy, patients presenting with haemorrhage still have a risk of bleeding at ulcer relapse about 7-fold higher than that for those presenting with pain alone.      

INFLAMMATORY FIBROID POLYP OF PROXIMAL ILEUM CAUSING RECURRENT INTUSSUSCEPTION

SUMMARY A 64-year-old female presented with episodes of small bowel obstruction. Ultrasound and barium meal showed a polypoidal lesion in the proximal segment of small bowel. The patient underwent emergency surgery because of signs of impending acute intestinal obstruction. Pathology showed characteristic features of an inflammatory fibroid polyp (IFP) which is an important though rare benign cause of small bowel obstruction. We document clinical and pathological aspects of this case.     

cell surface glycoproteins of murine cytotoxic T lymphocytes. I. T 145, a new cell surface glycoprotein selectively expressed on Ly 1-2(+) cytotoxic T lymphocytes

T lymphocytes at various stages of maturation and differentiation have been isolated by cellular fractionation procedures and characterized by cell surface markers and functional assays, The cell surface glycoproteins of the various T-cell preparations have been selectively radiolabeled by the galactose oxidase-tritiated sodium borohydride technique and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography. Details are presented on the appearance of a new cell surface glycoprotein (T 145), present on immunocompetent T lymphocytes after activation by either major histocompatibility complex alloantigens or by concanavalin A. The intensity of T 145 expression on T lymphoblasts is shown to be directly correlated in time and extent to the levels of cytotoxicity generated in a variety of T-cell activations. Specific enrichment procedures of purified populations of mixed leukocyte culture blasts have shown Ly 1(+)2(-) blasts to be T 145(-) and Ly 1(-)2(+) blasts to be strongly T 145(+). Similar enrichment procedures on normal peripheral T cells have failed to reveal any significant expression of T 145 on a highly enriched population of Ly 1(-)2(+) T cells, Further studies on the stability of T 145 expression after induction have shown it to be a more permanent-type differentiation structure whose expression is clearly not linked to the blast stage of activation. T 145 would thus appear to represent a membrane glycoprotein whose exclusive expression on T lymphoblasts is further restricted to a defined group of cells endowed with cytolytic activity and bearing the Ly phenotype Ly 1(-)2(+).     

Antibodies against double-stranded DNA and development of polymyositis during treatment with interferon

Alpha interferons have become effective palliative treatments for patients with neuroendocrine tumours such as carcinoids and endocrine pancreatic tumours. However, several reports indicate an increased incidence of both autoantibodies and autoimmune diseases in patients treated with interferon-alpha (IFN-alpha). We studied the development of antibodies against double-stranded DNA (dsDNA) and clinical signs of autoimmune disease in 214 patients with malignant carcinoids or endocrine pancreatic tumours consecutively admitted for treatment with IFN-alpha. Seventeen patients (8%) developed antibodies against dsDNA, predominantly females (12 females and 5 males). One patient had clinical and laboratory signs of polymyositis. Among the other 16 patients, three developed hypothyroidism and in six patients the anti- dsDNA autoantibodies normalized despite continuing therapy. Although a significant number of patients developed autoantibodies against dsDNA, overt autoimmune disease related to these antibodies is a rare event and many patients spontaneously normalize these titres despite continuing IFN-alpha treatment.      

Effect of Co-Fermentation on Nutritional Composition,Anti-Nutritional Factors and Acceptability of Cookies from Fermented Sorghum (Sorghum bicolor) and Soybeans (Glycine max) Flour Blends

This study evaluated the effect of co-fermentation on nutritional composition, anti-nutritional factors, and acceptability of cookies from fermented sorghum (Sorghum bicolor) and soybean (Glycine max) flour blends. White sorghum and yellow soy-beans were soaked and fermented separately for 24 h, 48 h, and 72 h respectively at 27 ± 2°C with 0 h as control. Fermented sorghum and soy-beans were oven-dried at 60°C for 8 h, milled and sieved and then used for the production of cookies. Cookie samples produced from different flour blends were evaluated for nutritional (proximate and vitamins profile analyses), anti-nutritional (phytate, tannin and trypsin inhibitor activity) qualities, and sensory evaluation. Results showed that the moisture contents in percent of the cookies ranged from 9.65 ± 0.21–8.34 ± 0.16 for 0 h, 10.59 ± 0.22–10.21 ± 0.21 for 24 h, 10.46 ± 0.22–10.13 ± 0.21 for 48 h, and 10.28 ± 0.21–9.41 ± 0.19 for 72 h, respectively. The protein contents in % ranged from 10.98 ± 0.26–18.72 ± 0.32 for 0 h, 11.26 ± 0.26–20.42 ± 0.32 for 24 h, 12.01 ± 0.26–21.48 ± 0.32 for 48 h, and 12.41 ± 0.26–21.49 ± 0.32 for 72 h, respectively, while the fat contents in percent ranged from 9.73 ± 0.21–11.51 ± 0.24 for 0 h, 8.84 ± 0.16–11.42 ± 0.24 for 24 h, 8.69 ± 0.16–10.56 ± 0.22 for 48 h, and 8.31 ± 0.16–10.11 ± 0.22 for 72 h, respectively. In conclusion, fermentation of sorghum and soybeans through microbial activity led to the hydrolysis and the reduction of anti-nutritional factors, it also improves the nutritional composition of cookies from fermented sorghum and soybean flour blends, as there was an increase in protein and vitamin contents of cookies. Therefore, cookies from fermented sorghum and soybeans flour could be used as a remedy to solve the menace of protein-energy malnutrition in developing countries.     

Progressive cell‐mediated changes in articular cartilage and bone in mice are initiated by a single session of controlled cyclic compressive loading

We previously showed that repetitive cyclic loading of the mouse knee joint causes changes that recapitulate the features of osteoarthritis (OA) in humans. By applying a single loading session, we characterized the temporal progression of the structural and compositional changes in subchondral bone and articular cartilage. We applied loading during a single 5‐minute session to the left tibia of adult (26‐week‐old) C57Bl/6 male mice at a peak load of 9.0N for 1,200 cycles. Knee joints were collected at times 0, 1, and 2 weeks after loading. The changes in articular cartilage and subchondral bone were analyzed by histology, immunohistochemistry (caspase‐3 and cathepsin K), and microcomputed tomography. At time 0, no change was evident in chondrocyte viability or cartilage or subchondral bone integrity. However, cartilage pathology demonstrated by localized thinning and proteoglycan loss occurred at 1 and 2 weeks after the single session of loading. Transient cancellous bone loss was evident at 1 week, associated with increased osteoclast number. Bone loss was reversed to control levels at 2 weeks. We observed formation of fibrous and cartilaginous tissues at the joint margins at 1 and 2 weeks. Our findings demonstrate that a single session of noninvasive loading leads to the development of OA—like morphological and cellular alterations in articular cartilage and subchondral bone. The loss in subchondral trabecular bone mass and thickness returns to control levels at 2 weeks, whereas the cartilage thinning and proteoglycan loss persist. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1941–1949, 2016.     

Role of mechanistic target of rapamycin (mTOR) in renal function and ischaemia–reperfusion induced kidney injury

Despite the presence of many studies on the role of mechanistic target of rapamycin (mTOR) in cardiorenal tissues, the definitive role of mTOR in the pathogenesis of renal injury subsequent to ischaemia–reperfusion (IR) remains unclear. The aims of the current study were to characterize the role of mTOR in normal kidney function and to investigate the role of mTOR activation in IR‐induced kidney injury. In euvolemic anaesthetized rats, treatment with the mTOR inhibitor rapamycin increased blood pressure (121 ± 2 to 144 ± 3 mmHg; P<.05), decreased glomerular filtration rate (GFR; 1.6 ± 0.3 to 0.5 ± 0.2 mL/min; P<.05) and increased urinary sodium excretion (UNaV; 14 ± 1 to 109 ± 25 mmol/L per hour; P<.05). In rats subjected to IR, autophagy induction, p‐mTOR expression and serum creatinine increased (1.9 ± 0.2 to 3 ± 0.3 mg/dL; P<.05); treatment with rapamycin blunted p‐mTOR expression but further increased autophagy induction and serum creatinine (3 ± 0.3 to 5 ± 0.6 mg/dL; P<.05). In contrast, clenbuterol, an mTOR activator, blunted the effect of rapamycin on serum creatinine (4 ± 0.6 vs 2.3 ± 0.3 mg/dL; P<.05), autophagy induction and p‐mTOR expression. IR also increased 24 hour protein excretion (9 ± 3 to 17 ± 2 mg/day; P<.05) and kidney injury molecule‐1 (KIM‐1) expression, and rapamycin treatment further increased KIM‐1 expression. Clenbuterol exacerbated protein excretion (13 ± 2 to 26 ± 4 mg/day; P<.05) and antagonized the effect of rapamycin on KIM‐1 expression. Histopathological data demonstrated kidney injury in IR rats that was worsened by rapamycin treatment but attenuated by clenbuterol treatment. Thus, mTOR signalling is crucial for normal kidney function and protecting the kidney against IR injury through autophagy suppression.     

peroxisome proliferator-activated receptor alpha activation-mediated regulation of endothelin-1 production via nitric oxide and protein kinase C signaling pathways in piglet cerebral microvascular endothelial cell culture

Elevated endothelin (ET)-1 has been implicated in cerebrovascular complications following brain trauma characterized by dysregulation of endothelial nitric oxide synthase (eNOS), protein kinase C (PKC), and cerebral function. Recently, vascular expression of PPARalpha has been observed and suggested to improve vascular dysfunction. We speculate that activation of PPARalpha in cerebral microvessels can improve cerebral dysfunction following trauma, and we tested the hypothesis that activation of cerebral endothelial peroxisome proliferator-activated receptor (PPAR)alpha will attenuate ET-1 production via a mechanism involving nitric oxide (NO) and PKC. Phorbol 12-myristate 13-acetate (PMA) (1 microM), bradykinin (BK, 1 microM), angiotensin II (AII, 1 microM), or hemoglobin (Hem, 10 microM) increased ET-1 levels by 24-, 11.4-, 3.6-, or 1.3-fold increasing ET-1 levels from 0.36 +/- 0.08 to 8.6 +/- 0.8, 4.1 +/- 0.7, 1.30 +/- 0.1, or 0.47 +/- 0.03 fmol/microg protein (p < 0.05), respectively. Clofibrate (10 microM) reduced basal ET-1 from 0.36 +/- 0.08 (control) to 0.03 +/- 0.01 and blunted vasoactive agent-induced increase to 0.12 +/- 0.07 (PMA), 0.6 +/- 0.04 (BK), 0.25 +/- 0.03 (AII), or 0.12 +/- 0.03 (Hem) fM/microg protein (p < 0.05). L-arginine methyl ester (100 microM) inhibited clofibrate-induced reduction in basal ET-1 production. Clofibrate increased PPARalpha expression, accompanied by increased NO production and eNOS expression. PKC inhibition by calphostin C (10 microM) blocked these effects, whereas activation by PMA reduced basal PPARalpha expression. Thus, PPARalpha activation attenuated ET-1 production by agents that mediate brain injury through mechanisms that probably result from PPARalpha-induced increase in eNOS expression/NO production and complex PKC signaling pathways. Therefore, PPARalpha activators can be appropriate therapeutic agents to alleviate cerebrovascular dysfunction following cerebral vasospasm.