Urinary bladder xanthomatous cystitis.

Xanthoma cystitis of urinary bladder is a rare entity and may present as an intravesical mass. A 38-year-old female presented with abdominal pain and imaging was done which was suggestive of a malignant mass with surrounding tissue infiltration. Partial cystectomy was performed, and histological examination of the mass showed xanthomatous cystitis.

SAR exploration at the C-3 position of tetrahydro-ß-carboline sstr3 antagonists.

MK-4256, a tetrahydro-ß-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-ß-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.

Are elite cricketers more prone to suicide? A psychological autopsy study of Test cricketer suicides.

OBJECTIVES: It has been hypothesised that the very nature of the game predisposes elite cricketers to higher rates of suicide. AIM: We aim to estimate the suicide rate of male Test cricketers and to determine the reasons for suicide. METHODS: The suicide rate in male Test cricketers was determined. A psychological autopsy was conducted using published biographical data. RESULTS: Twenty suicides amongst 2794 male Test cricketers from 1877 to 2014 yielded a suicide rate of 715.4 per 100,000 for that period. Health, financial and relationship issues were prominent; depression and alcohol misuse were common. CONCLUSIONS: Most suicides in Test cricketers occurred post-retirement in mid to late life with similar correlates to those found in the general male population. The idiosyncrasies of cricket are unlikely to contribute to suicide; however, the post-retirement welfare of Test cricketers should remain a focus of concern and the greater supports available to contemporary Test cricketers needs to extend beyond retirement.

Circadian regulation of intestinal lipid absorption by apolipoprotein AIV involves forkhead transcription factors A2 and O1 and microsomal triglyceride transfer protein.

We have shown previously that Clock, microsomal triglyceride transfer protein (MTP), and nocturnin are involved in the circadian regulation of intestinal lipid absorption. Here, we clarified the role of apolipoprotein AIV (apoAIV) in the diurnal regulation of plasma lipids and intestinal lipid absorption in mice. Plasma triglyceride in apoAIV(-/-) mice showed diurnal variations similar to apoAIV(+/+) mice; however, the increases in plasma triglyceride at night were significantly lower in these mice. ApoAIV(-/-) mice absorbed fewer lipids at night and showed blunted response to daytime feeding. To explain reasons for these lower responses, we measured MTP expression; intestinal MTP was low at night, and its induction after food entrainment was less in apoAIV(-/-) mice. Conversely, apoAIV overexpression increased MTP mRNA in hepatoma cells, indicating transcriptional regulation. Mechanistic studies revealed that sequences between -204/-775 bp in the MTP promoter respond to apoAIV and that apoAIV enhances expression of FoxA2 and FoxO1 transcription factors and their binding to the identified cis elements in the MTP promoter at night. Knockdown of FoxA2 and FoxO1 abolished apoAIV-mediated MTP induction. Similarly, knockdown of apoAIV in differentiated Caco-2 cells reduced MTP, FoxA2, and FoxO1 mRNA levels, cellular MTP activity, and media apoB. Moreover, FoxA2 and FoxO1 expression showed diurnal variations, and their expression was significantly lower in apoAIV(-/-) mice. These data indicate that apoAIV modulates diurnal changes in lipid absorption by regulating forkhead transcription factors and MTP and that inhibition of apoAIV expression might reduce plasma lipids.

Synthesis and evaluation of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-aminopropanamide as human cannabinoid-1 receptor (CB1R) inverse agonists.

Obesity is a chronic medical condition that is affecting large population throughout the world. CB1 as a target for treatment of obesity has been under intensive studies. Taranabant was discovered and then developed by Merck as the 1st generation CB1R inverse agonist. Reported here is part of our effort on the 2nd generation of CB1R inverse agonist from the acyclic amide scaffold. We replaced the oxygen linker in taranabant with nitrogen and prepared a series of amino heterocyclic analogs through a divergent synthesis. Although in general, the amine linker gave reduced binding affinity, potent and selective CB1R inverse agonist was identified from the amino heterocycle series. Molecular modeling was applied to study the binding of the amino heterocycle series at CB1 binding site. The in vitro metabolism of representative members was studied and only trace glucuronidation was found. Thus, it suggests that the right hand side of the molecule may not be the appropriate site for glucuronidation.

Seminal vesicle sparing laparoscopic radical prostatectomy using a low-energy source: Better continence and potency.

OBJECTIVES: Ongoing with the newer developments in laparoscopic radical prostatectomy (LRP), we report our experience in a consecutive series of 42 patients with a mean 18-month follow-up. We also studied the use of a low-energy source, especially in the region of the prostatic apex and the neurovascular bundle and evaluated its outcome on continence and potency. MATERIALS AND METHODS: Between November 2003 and December 2008, 50 patients aged 50-80 yrs underwent LRP with vesicourethral anastomosis and of these, 42 patients who had a minimum follow-up of 3 months were selected for the study. Of these, the initial 16 patients were operated by the routine method and the 26 patients operated in the later part of our experience were operated upon using a minimal energy source. RESULTS: The mean follow-up was 18 months (range 3-60). Continence was evaluated at 1, 3, 6, and 12 months. Eleven of the 16 patients in Group I were continent as compared with 21 of 26 patients in Group II. The difference in continence rates was mainly due to less use of electrocautery and harmonic scalpel at the bladder neck. Of the eight patients who were potent pre-operatively in Group I, four remained potent 3 months after LRP. In Group II, 20 of the 26 patients were potent pre-operatively and 16 remained potent 3 months after LRP. CONCLUSIONS: Use of a low-energy source at the bladder neck and neurovascular bundle, sparing of seminal vesicle, and leaving behind a long, healthy stump of the urethra during apical dissection, is associated with better continence and potency without compromising oncological outcome.

Characterization of a novel and selective cannabinoid CB1 receptor inverse agonist, Imidazole 24b, in rodents.

We document in vitro and in vivo effects of a novel, selective cannabinoid CB(1) receptor inverse agonist, Imidazole 24b (5-(4-chlorophenyl)-N-cyclohexyl-4-(2,4-dichlorophenyl)-1-methyl-imidazole-2-carboxamide). The in vitro binding affinity of Imidazole 24b for recombinant human and rat CB(1) receptor is 4 and 10 nM, respectively. Imidazole 24b binds to human cannabinoid CB(2) receptor with an affinity of 297 nM; in vitro, it is a receptor inverse agonist at both cannabinoid CB(1) and CB(2) receptors as it causes a further increase of forskolin-induced cAMP increase. Oral administration of Imidazole 24b blocked CP-55940-induced hypothermia, demonstrating cannabinoid CB(1) receptor antagonist efficacy in vivo. Using ex vivo autoradiography, Imidazole 24b resulted in dose-dependent increases in brain cannabinoid CB(1) receptor occupancy (RO) at 2h post-dosing in rats, indicating that approximately 50% receptor occupancy is sufficient for attenuation of receptor agonist-induced hypothermia. Imidazole 24b administered to C57Bl/6 mice and to dietary-induced obese (DIO) Sprague-Dawley rats attenuated overnight food intake with a minimal effective dose of 10 mg/kg, p.o. Administration had no effect in cannabinoid CB(1) receptor-deficient mice. DIO rats were dosed orally with vehicle, Imidazole 24b (1, 3 or 10 mg/kg), or dexfenfluramine (3 mg/kg) for 2 weeks. At 3 mg/kg, Imidazole 24b reduced cumulative food intake, leading to a non-significant decrease in weight gain. Imidazole 24b at 10 mg/kg and dexfenfluramine treatment inhibited food intake and attenuated weight gain. These findings suggest that selective cannabinoid CB(1) receptor inverse agonists such as Imidazole 24b have potential for the treatment of obesity.

ACR Appropriateness Criteria® Radiologic Management of Central Venous Access.

Obtaining central venous access is one of the most commonly performed procedures in hospital settings. Multiple devices such as peripherally inserted central venous catheters, tunneled central venous catheters (eg, Hohn catheter, Hickman catheter, C. R. Bard, Inc, Salt Lake City UT), and implantable ports are available for this purpose. The device selected for central venous access depends on the clinical indication, duration of the treatment, and associated comorbidities. It is important for health care providers to familiarize themselves with the types of central venous catheters available, including information about their indications, contraindications, and potential complications, especially the management of catheters in the setting of catheter-related bloodstream infections. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- {[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity.

The discovery of novel acyclic amide cannabinoid-1 receptor inverse agonists is described. They are potent, selective, orally bioavailable, and active in rodent models of food intake and body weight reduction. A major focus of the optimization process was to increase in vivo efficacy and to reduce the potential for formation of reactive metabolites. These efforts led to the identification of compound 48 for development as a clinical candidate for the treatment of obesity.

Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes.

The imidazolyl-tetrahydro-ß-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-ß-carboline (17e, MK-1421).

Drug delivery to the central nervous system: a review.

The brain is a delicate organ, and evolution built very efficient ways to protect it. Unfortunately, the same mechanisms that protect it against intrusive chemicals can also frustrate therapeutic interventions. Many existing pharmaceuticals are rendered ineffective in the treatment of cerebral diseases due to our inability to effectively deliver and sustain them within the brain. General methods that can enhance drug delivery to the brain are, therefore, of great interest. Despite aggressive research, patients suffering from fatal and/or debilitating central nervous system (CNS) diseases, such as brain tumors, HIV encephalopathy, epilepsy, cerebrovascular diseases and neurodegenerative disorders, far outnumber those dying of all types of systemic cancer or heart disease. The clinical failure of much potentially effective therapeutics is often not due to a lack of drug potency but rather to shortcomings in the method by which the drug is delivered. Treating CNS diseases is particularly challenging because a variety of formidable obstacles often impede drug delivery to the brain and spinal cord. By localizing drugs at their desired site of action one can reduce toxicity and increase treatment efficiency. In response to the insufficiency in conventional delivery mechanisms, aggressive research efforts have recently focused on the development of new strategies to more effectively deliver drug molecules to the CNS. This review intends to detail the recent advances in the field of brain-targeting, rational drug design approach and drug delivery to CNS. To illustrate the complexity of the problems that have to be overcome for successful brain targeting, a brief intercellular characterization of the blood-brain barrier (BBB) is also included.

Liposomal amikacin dry powder inhaler: effect of fines on in vitro performance.

The aim of the present investigation was to prepare and evaluate the influence of adding fines on the in vitro performance of liposomal amikacin dry powder inhaler (AMK LDPI) formulations. Liposomes composed of hydrogenated soyaphosphatidylcholine, cholesterol and saturated soyaphosphatidylglycerol (AMK 1), or stearylamine (AMK 2) were prepared by a reverse phase evaporation technique, extruded to reduce size and separated from unentrapped drug. Purified liposomal dispersion was subjected to lyophilization using optimized cryoprotectant to achieve maximum percentage drug retention (PDR). Lactose carrier in varying mass ratios with or without addition of fines in different mixing sequences was used to formulate AMK LDPI formulations. AMK LDPI formulations were characterized for angle of repose, compressibility index, dispersibility index, scanning electron microscopy, and fine particle fraction (FPF). PDR was found to be 97.6% +/- 2.2% for AMK1 and 98.5% +/- 1.9% for AMK2 using sucrose as optimized cryoprotectant in lipid:sucrose ratio of 1:4. Lactose carrier containing 10% fines (wt/wt) was found to be the optimum blend at 1:5 mass ratio of liposome:lactose. The addition of fines and the order of mixing of fines were found to influence the FPF with significantly different device fractions. FPF of AMK LDPI formulations using Rotahaler as the delivery device at 30, 60, and 90 L/min were found to be 21.85% +/- 2.2% and 24.6% +/- 2.4%, 25.9% +/- 1.8% and 29.2% +/- 2.1%, and 29.5% +/- 2.6% and 34.2% +/- 2.0% for AMK1 and AMK2, respectively. From the studies performed in this investigation, it was observed that liposomal charge, addition of fines and order of mixing fines, has a significant effect (P < .05) on in vitro deposition of drug from LDPI formulation.

Ensuring precision in lower limb deformity correction through a combination of temporary external fixation followed by internal fixation: Results of a retrospective study.

BACKGROUND: It is important to plan preoperatively when contemplating internal fixation following deformity correction. Surgeons often find it difficult to retain the achieved correction till the end of internal fixation. To maintain precise correction we used hybrid technique which uses both external and internal fixation. The objective of the study was to evaluate the effectiveness of this hybrid technique in achieving and retaining desired correction. MATERIALS AND METHODS: In this retrospective study, we evaluated the magnitude of deformity with radiological parameters. We compared correction which was planned and correction which was achieved. The technique was used during surgery for corrective osteotomies. Before carrying out the osteotomy, rail fixator with two swivel clamps was applied. After osteotomy swivel clamps were loosened. Desired correction was achieved. While fixator held the fragments in corrected position, definitive internal fixation was carried out. External fixator was removed after completion of internal fixation. Position of mechanical axis ratio, mechanical lateral distal femoral angle and mechanical medial proximal tibial angle were measured before and 12 weeks after surgery. Student t-test was used to analyze the difference between correction which was planned and correction which was achieved. RESULTS: There was no statistical difference between the desired correction and the correction achieved. CONCLUSIONS: Temporary use of external fixator while correcting angular deformities of lower limb allows to achieve accurate correction.

Investigation of Cardiovascular Effects of Tetrahydro-ß-carboline sstr3 antagonists.

Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-à-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress.

The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes.

A structure-activity relationship study of the imidazolyl-ß-tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice.

Tuberculosis of spine with neurological deficit in advanced pregnancy: a report of three cases.

BACKGROUND CONTEXT: Early decompression in spinal tuberculosis (TB) with complete paraplegia has a better prognosis in relation to the neurological recovery and deformity progression. Advanced pregnancy can complicate this picture in view of the various fetomaternal factors. The prevalent literature is inconclusive regarding the time and extent of surgical intervention. Delay in the surgical intervention may adversely affect the prognosis. PURPOSE: To emphasize the importance of early decompression in spinal TB complicated by neurological deficit in advanced pregnancy. STUDY DESIGN: A case report of three patients to analyze the surgical management of neurological deficit because of spinal TB in pregnancy. OUTCOME MEASURES: Neurological recovery, progression of deformity, healing of the TB lesion, and outcome of the pregnancy. METHODS: Three patients presented with spinal TB with neurological deficit complicating third trimester of pregnancy. The first patient was initially managed conservatively but was operated after a spontaneous abortion. The remaining two patients were managed by urgent Caesarean section followed by spinal decompression and fusion. RESULTS: The first patient who underwent delayed decompression showed good healing of the TB lesion but continued to have spastic paraparesis with kyphosis. This was later managed by repeat decompression and instrumented fusion, without neurological recovery. The other two patients treated by early decompression and fusion showed complete healing with neurological recovery. CONCLUSIONS: Early decompression and instrumented fusion in spinal TB, complicated by neurological deficit in advanced pregnancy, can give good results with respect to neurological recovery, healing of the lesion, and arrest of deformity progression. Neonatal prognosis depends on the fetal maturity. Antitubercular therapy is an essential component of the management; it poses little hazard of inducing congenital anomalies, but possibility of maternal drug toxicity should be considered.

Role of day care vesicovaginal fistula fulguration in small vesicovaginal fistula.

OBJECTIVES: Vesicovaginal fistula (VVF) is a common condition that physically and mentally debilitates the patient. In the developing countries such as India, it results mainly due to neglected obstetric care. Options for surgical repair of VVF consist of transvaginal, transvesical, laparoscopic repair. Endoscopic management of VVF on day care basis by fulgurating the fistulous tract is a minimally invasive method for small fistula involving the lower genitourinary tract. We evaluated the efficacy of fulguration for the conservative treatment of urinary fistula of different etiologies by using endoscopic approach. MATERIALS AND METHODS: From September 2008 to July 2009, five patients with VVF of <0.7 cm underwent VVF fulguration under cystoscopic guidance on day care basis. Perurethral catheter was kept for 3 weeks postoperatively and was removed when cystogram showed healing of the fistula. All the patients were on anticholinergic medications postoperatively. RESULTS: Of the five patients who underwent endoscopic fulguration, four patients had positive outcome and one patient showed persistent VVF on follow-up cystogram. This patient underwent repair of the fistula by vaginal route. CONCLUSIONS: Endoscopic transvesical vesicovaginal fistula fulguration appears to be a safe and effective procedure for small VVF on day care basis, with decreasing morbidity, improving cosmesis, and decreased hospital stay.

Laparoscopic transabdominal transvesical vesicovaginal fistula repair.

BACKGROUND AND PURPOSE: Transabdominal transvesical repair has been the standard management for difficult vesicovaginal fistulae as a result of obstetric and gynecologic surgery. We describe a laparoscopic transvesical technique that minimizes operative morbidity. PATIENTS AND METHODS: This retrospective study included 25 women who underwent laparoscopic surgery for vesicovaginal fistula from June 2003 to November 2008. All patients were underwent laparoscopic surgery by the transabdominal transvesical route. Patients were investigated by intravenous urography, micturating cystography, cystoscopy, and retrograde pyelography. RESULTS: Of the 25 patients who underwent laparoscopic surgery, 3 patients' operations had to be converted to open surgery because of dense adhesions. Of the 22 cases completed laparoscopically, leakage per vagina occurred in 3 patients. One patient underwent fulguration of residual fistula and was cured, one underwent vaginal repair, and other patient was lost to follow-up. CONCLUSIONS: Laparoscopic transvesical vesicovaginal fistula repair appears to be a safe and effective procedure that adheres to the principles of a transabdominal transvesical fistula repair while decreasing morbidity and improving cosmesis.

Nonfamilial hyperphosphatemic tumoral calcinosis with ulnar neuropathy.

We present a case of multiple large juxta-articular painless masses involving both the elbows and right hip in a 27-year old south Asian male who presented with ulnar neuropathy and constitutional symptoms. Radiology, blood investigations and biopsy confirmed it to be hyperphosphatemic tumoral calcinosis. Patient was also diagnosed with an extremely rare association, testicular microlithiasis. Complete surgical excision with low phosphate diet resulted in complete neurological recovery and no recurrence at 30 months. Tumoral calcinosis should be considered in the differential diagnosis of a case with multiple, symptomatic juxta-articular masses.