Body weight and abdominal fat gene expression profile in response to a novel hydroxycitric acid-based dietary supplement

Obesity is a global public health problem, with about 315 million people worldwide estimated to fall into the WHO-defined obesity categories. Traditional herbal medicines may have some potential in managing obesity. Botanical dietary supplements often contain complex mixtures of phytochemicals that have additive or synergistic interactions. The dried fruit rind of Garcinia cambogia, also known as Malabar tamarind, is a unique source of (-)-hydroxycitric acid (HCA), which exhibits a distinct sour taste and has been safely used for centuries in Southeastern Asia to make meals more filling. Recently it has been demonstrated that HCA-SX or Super Citrimax, a novel derivative of HCA, is safe when taken orally and that HCA-SX is bioavailable in the human plasma as studied by GC-MS. Although HCA-SX has been observed to be conditionally effective in weight management in experimental animals as well as in humans, its mechanism of action remains to be understood. We sought to determine the effects of low-dose oral HCA-SX on the body weight and abdominal fat gene expression profile of Sprague-Dawley rats. We observed that at doses relevant for human consumption dietary HCA-SX significantly contained body weight growth. This response was associated with lowered abdominal fat leptin expression while plasma leptin levels remained unaffected. Repeated high-density microarray analysis of 9960 genes and ESTs present in the fat tissue identified a small set (approximately 1% of all genes screened) of specific genes sensitive to dietary HCA-SX. Other genes, including vital genes transcribing for mitochondrial/nuclear proteins and which are necessary for fundamental support of the tissue, were not affected by HCA-SX. Under the current experimental conditions, HCA-SX proved to be effective in restricting body weight gain in adult rats. Functional characterization of HCA-SX-sensitive genes revealed that upregulation of genes encoding serotonin receptors represent a distinct effect of dietary HCA-SX supplementation.     

Ectopia lentis in Loeys‐Dietz syndrome type 4

Loeys‐Dietz syndrome is a heritable disorder of the connective tissue leading to multisystem involvement including craniofacial features, skeletal abnormalities, cutaneous findings and early‐onset and aggressive disease of the aorta and its branches. There are multiple types of Loeys‐Dietz syndrome related to pathogenic variants in TGFBR1, TGFBR2, SMAD3, TGFB2, and TGFB3. Individuals with Loeys‐Dietz syndrome may be misdiagnosed as having Marfan syndrome due to shared phenotypic features and aortic root dilation. However, ectopia lentis has been an important discriminating feature, being unique to Marfan syndrome and not reported to be associated with Loeys‐Dietz syndrome. We report the case of a 46‐year‐old woman with Loeys‐Dietz syndrome type 4 due to a pathogenic variant in TGFB2 who was diagnosed with ectopia lentis at age 44. The patient underwent whole exome sequencing and no other pathogenic variants were found to explain the ectopia lentis. Our findings indicate that ectopia lentis may be an uncommon finding in Loeys‐Dietz syndrome type 4 and emphasize the importance of genetic testing in familial thoracic aortic aneurysm disease.     

Clinico-Radio-Histopathological Correlation by C-Arm Image-Guided Biopsy in Spinal Tuberculosis

Background/Purpose of the StudyC-arm-guided biopsy is a safe and effective technique for evaluating TB spine and is useful in planning therapy. The purpose of this study was to find a correlation between clinically and radiologically suspected TB spine and C-arm image-guided biopsy-proven cases and to study the complications encountered.MethodsAfter evaluating the clinical, laboratory, X-ray and MRI findings, 92 patients with provisionally diagnosed tubercular spine were subjected to C-arm image-guided biopsy.ResultsAmong our 92 cases, histopathology was positive in 55 cases (59.78%). Out of these 55 histologically positive cases, CBNAAT was positive in 42 cases and negative in the rest 13 cases. Overall, among the 92 cases, CBNAAT was positive in 51(55.43%) of cases, and out of these, histopathology turned out to be positive in 42 of cases. Out of 41 cases with negative CBNAAT, histopathology was suggestive of tuberculosis in 13. The strength of agreement between CBNAAT and histopathology was statistically significant (p < 0.0001; kappa = 0.511). No complication such as bleeding, nerve/cord injury, infection, injury to aorta or pneumothorax was encountered during and after the C-arm biopsy in any case.ConclusionC-arm image-guided biopsy is reasonably accurate and should be used as a tool for diagnosis of TB spine. We recommend histopathological examination as a key component for the diagnosis of TB spine, as it is precise and consumes relatively shorter time. CBNAAT is more rapid but is not a substitute for histopathology for spine TB diagnosis.     

Long-Term Outcomes of Everolimus Therapy in De Novo Liver Transplantation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

BackgroundRisk of nephrotoxicity in liver transplant patients on calcineurin inhibitors (CnIs) is a concern. Several controlled trials reported benefit of everolimus (EVR) in minimizing this risk when combined with a reduced CnI dose.BackgroundTo systematically review the efficacy and safety of EVR, alone or with reduced CnI dose, as compared to CnI alone post-liver transplantation.MethodsWe searched MEDLINE, Scopus, and the Cochrane Library for randomized controlled trials comparing EVR- and CnI-based regimens post-liver transplantation. Assessment of studies and data extraction were undertaken independently.ResultsEight studies were selected, describing 769 patients. Cockcroft-Gault GFR was higher at one (P = .05), 3, and 5 years (P = .030) in patients on EVR compared to those receiving CnI therapy. The composite endpoint of efficacy failure was similar between the 2 arms after 1, 3, and 5 years of study. More patients discontinued EVR due to adverse effects in 1 year; however, no difference was noted after 3 or 5 years. A higher rates of proteinuria, peripheral edema, and incisional hernia occurred in patients on EVR.ConclusionsThe analysis confirms noninferiority of EVR and reduced CnI combination. Combination regimen resulted in better renal function compared to standard CnI therapy.     

Burosumab for the Treatment of Tumor-Induced Osteomalacia

Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..     

Comparison of renal function after open radical cystectomy,extracorporeal robot assisted radical cystectomy,and intracorporeal robot assisted radical cystectomy

PurposeRenal function outcomes following robot-assisted radical cystectomy (RARC) have not been well established. We sought to compare long-term renal function outcomes between open radical cystectomy, RARC with extracorporeal urinary diversion and intracorporeal urinary diversion at a high volume institution.Materials and MethodsWe retrospectively reviewed our institutional bladder cancer database for patients who underwent RC from 2010 to 2019 with pre-operative estimated glomerular filtration rate (eGFR) > 45 ml/min/1.73m². Changes in renal function were assessed through locally weighted scatter plot smoothing and comparison of median eGFR between surgical groups. Chronic Kidney Disease Stage 3B was defined as eGFR < 45 ml/min/1.73m². Renal function decline was defined as a ≥10 ml/min/1.73m² drop in eGFR. Kaplan Meier method with log-rank was used to compare CKD 3B-free survival and renal function decline. Cox Proportional Hazards model was used to identify predictors of CKD 3B.ResultsSix hundred and forty four patients were included with median follow-up of 32 months (IQR 12–56). Preoperative characteristics were similar among the groups with no differences in median pre-operative eGFR (ORC: 74.6, extracorporeal urinary diversion: 74.3, intracorporeal urinary diversion: 71.6 ml/min/1.73m², P = 0.15). Median postoperative eGFR on follow up was not different between groups (P = 0.56). 33% of patients developed CKD 3B. There were no differences in CKD 3B-free survival by surgical approach (P = 0.23) or urinary diversion (P = 0.09). 64% of patients experienced renal function decline with a median time of 2.4 years (P 0.23). Predictors of CKD were pathologic T3 disease or greater (HR: 1.77, P = 0.01), ureteroenteric anastomotic stricture (HR: 2.80, P < 0.001), preoperative CKD Stage 2 (HR: 1.81, P =0.02), and preoperative CKD Stage 3A (HR: 5.56, P < 0.001).ConclusionRenal function decline is common after RC. Tumor stage, pre-operative eGFR, and ureteral stricture development, not surgical approach, influence renal function decline.     

Association of antiviral prophylaxis and rituximab use with posttransplant lymphoproliferative disorders (PTLDs): A nationwide cohort study

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation (SOT). Most PTLD cases are associated with Epstein–Barr virus (EBV) infection. The role of antiviral prophylaxis or rituximab therapy for prevention of PTLD in SOT recipients is controversial. In a nationwide cohort, we assessed the incidence, presentation, and outcome of histologically proven PTLD. We included 4765 patients with a follow-up duration of 23 807 person-years (py). Fifty-seven PTLD cases were identified; 39 (68%) were EBV positive (EBV+ PTLD). Incidence rates for EBV+ PTLD at 1, 2, and 3 years posttransplant were 3.51, 2.24, and 1.75/1000 py and 0.44, 0.25, and 0.29/1000 py for EBV− PTLD. We did not find an effect of antiviral prophylaxis on early and late EBV+ PTLD occurrence (early EBV+ PTLD: SHR 0.535 [95% CI 0.199–1.436], p = .264; late EBV+ PTLD: SHR 2.213, [95% CI 0.751–6.521], p = .150). However, none of the patients (0/191) who received a rituximab-containing induction treatment experienced PTLD, but 57 of 4574 patients without rituximab induction developed PTLD. In an adjusted restricted mean survival time model, PTLD-free survival was significantly longer (0.104 years [95% CI 0.077–0.131]) in patients receiving rituximab as induction treatment. This study provides novel data on the association of rituximab induction and reduced risk for PTLD.     

Two‐Stage Revision Hip Arthroplasty with or without the Use of an Interim Spacer for Managing Late Prosthetic Infection: A Systematic Review of the Literature

The aim of the present paper was to identify, appraise, and synthesize the available evidence on two‐stage revision hip arthroplasty with or without the use of an interim spacer for managing late prosthetic infection. The review methodology was designed by referencing the Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) checklist and flow diagram, and a Population, Intervention, Comparator, Outcomes and Study (PICOS) design framework was used to search for studies to incorporate within the review. Two independent investigators were involved in searching for relevant articles that fulfilled the inclusion criteria for the study. Critical appraisal of the selected articles was carried out using the relevant Critical Appraisal Skills Programme checklists. From an initial pool of 125 articles, four studies satisfied the inclusion criteria and quality assessment and were included for final review. Two patient groups were identified from within the selected studies: spacer and non‐spacer. Both groups were assessed in terms of functional outcome, infection cure rates, and technical difficulties encountered during treatment. Better functional outcome was reported in the spacer group, both in the interim period between the two stages and after completion of treatment. The use of spacers reduced operative difficulty during the second stage and accelerated patient discharge. Reinfection and infection persistence rates were higher in the non‐spacer group. Within the spacer group, articulated spacers performed better in all parameters. The results of this review reinforce the available evidence supporting the use of interim hip spacers in revision hip arthroplasty for managing prosthetic infection and also indicate that articulated hip spacers could be an attractive option going forward.     

Transfer of liposomal drug carriers from the blood to the peritoneal cavity of normal and ascitic tumor-bearing mice

Summary Previously we have demonstrated that the L1210 antitumor activity of liposomal doxorubicin increased significantly as the size of the liposomal carrier was reduced from 1.0 to 0.1 m. It is demonstrated herein that empty and drug-loaded small (0.1-m diameter) liposomes accumulate efficiently into the peritoneal cavity of normal and ascitic L1210 tumor-bearing animals following i.v. administration. In normal mice injected with 100 nm DSPC/chol liposomal doxorubicin (drug-to-lipid ratio of 0.2; wt/wt) approximately 2.8 g drug could be recovered from the peritoneal cavity following peritoneal lavage at 24 h. Although this represents only 0.7% of the injected doxorubicin dose, this level of drug is 2 orders of magnitude greater than that achieved following administration of an equivalent dose of free drug (20 mg/kg). The drug levels achieved within the peritoneal cavity are dependent on the physical characteristics (size, drug-to-lipid ratio and lipid composition) of the liposomes employed. Optimal delivery is obtained employing 100 nm DSPC/chol liposomal doxorubicin, a vesicle system that is known to retain entrapped drug following i.v. administration and exhibits extended circulation lifetimes. Analysis of drug and liposome distribution within the peritoneal cavity of normal mice indicates that as much as 50% of the measured doxorubicin and liposomal lipid is cell-associated. Flow cytometric analysis of the peritoneal cells demonstrated that cell-associated doxorubicin resides almost exclusively within resident peritoneal macrophages. The increased delivery of doxorubicin to the peritoneal cavity of normal mice following i.v. administration of small (0.1-m) liposomal doxorubicin is correlated with a pronounced (>90%) and prolonged (>14-day) suppression of resident peritoneal cells. Liposomal drug accumulation increased dramatically in animals with an established L1210 ascitic tumor. More than 5% of the injected dose was found in the peritoneal cavity of these animals 24 h after treatment with DSPC/chol liposomal doxorubicin as compared with a value of 0.03% of the injected dose achieved with free drug. It is proposed that accumulation of liposomes into the peritoneal cavity of normal and tumor-bearing mice may serve as a useful model for characterizing factors mediating the transfer of liposomes from the vascular compartment to extravascular sites.