Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma

Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 triggers apoptosis in multiple myeloma (MM) cells, and importantly, that is distinct from bortezomib (Velcade) in its chemical structure, effects on proteasome activities, and mechanisms of action. Here, we demonstrate that combining NPI-0052 and bortezomb induces synergistic anti-MM activity both in vitro using MM cell lines or patient CD138(+) MM cells and in vivo in a human plasmacytoma xenograft mouse model. NPI-0052 plus bortezomib-induced synergistic apoptosis is associated with: (1) activation of caspase-8, caspase-9, caspase-3, and PARP; (2) induction of endoplasmic reticulum (ER) stress response and JNK; (3) inhibition of migration of MM cells and angiogenesis; (4) suppression of chymotrypsin-like (CT-L), caspase-like (C-L), and trypsin-like (T-L) proteolytic activities; and (5) blockade of NF-kappaB signaling. Studies in a xenograft model show that low dose combination of NPI-0052 and bortezomib is well tolerated and triggers synergistic inhibition of tumor growth and CT-L, C-L, and T-L proteasome activities in tumor cells. Immununostaining of MM tumors from NPI-0052 plus bortezomib-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Taken together, our study provides the preclinical rationale for clinical protocols evaluating bortezomib together with NPI-0052 to improve patient outcome in MM.     

Newly diagnosed arrhythmogenic right ventricular dysplasia in an octogenarian

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is thought to be a disease of the young, with the majority of newly diagnosed patients under 40 years of age. Establishing this diagnosis in elderly patients may be challenging, and a few reports exist of patients older than 70 years diagnosed with ARVD/C at autopsy. We report the case of an octogenarian with antemortem newly diagnosed ARVD/C. This case report represents the oldest patient to date to have a newly established diagnosis of ARVD/C and highlights the difficulty in making the diagnosis in the elderly.     

Tuberculous anal sepsis

INTRODUCTION: Tuberculosis is a neglected cause of anal sepsis, often is not recognized, and therefore is not treated properly. METHOD: All patients were reviewed who had tuberculous anal sepsis diagnosed by histology reports of fistulectomy specimens or abscess scrapings from January 1990 to April 1999. RESULTS: Twenty patients (median age, 53 years; 18 males) with anal tuberculous sepsis were identified. They presented with abscesses (n=2), abscesses and fistulas (n=6), or fistulas (n=12). All patients had a long history of anal complaints (3 months to 20 years), for which 15 patients were operated on previously. Nearly all fistulas (17/18) were complex, and secondary tracks or additional complicating features were common, even at first presentation. Eight patients had active concurrent pulmonary tuberculosis, and six showed evidence of previous pulmonary tuberculosis. Six patients had no signs of concurrent or previous tuberculosis elsewhere. Recurrence was observed only in cases where tuberculosis was initially not recognized, and antitubercular treatment therefore was not started. CONCLUSION: Contrary to views held previously, anal tubercular sepsis seems to have characteristic clinical features. It should be considered in cases of known pulmonary or extrapulmonary tuberculosis or if anal sepsis is persistent, recurrent, or complex in nature.     

Intravenous Paracetamol Infusion Versus Intramuscular Tramadol as an Intrapartum Labor Analgesic

Objectives

To compare intravenous paracetamol and intramuscular tramadol as labor analgesics.

Methods

This prospective-randomized study conducted in 200 primigravidae in active labor, distributed into two groups of 100 women each with one receiving intravenous 1,000 mg Paracetamol and other 100 mg intramuscular tramadol. Pain intensity is recorded by McGills scale before, one and 3 h after drug administration. Perinatal outcome is recorded.

Results

No difference in pain intensity is seen before drug administration. After 1 h of drug administration, in paracetamol group, 4 % women had horrible pain, and 29 % had distressing pain, while in tramadol group, 30 % women had horrible pain, and 60 % had distressing pain. After 3 h of drug administration, in paracetamol group, 26 % had distressing pain, while in tramadol group, 51 % women had horrible pain, and 35 % had distressing pain. Labor duration in paracetamol and tramadol group was 4.3 and 5.9 h, respectively. In paracetamol group, nausea is seen in 2.2 % and vomiting in 1.1 %, while in tramadol group, nausea is seen in 6.4 % and vomiting in 4.3 %.

Conclusions

Intravenous paracetamol is more effective labor analgesic with fewer maternal adverse effects and shortens labor as compared to intramuscular tramadol.

     

Type II diabetes mellitus and cardiovascular risk factors: Current therapeutic approaches

Worldwide, approximately 200 million people currently have type II diabetes mellitus (DM), a prevalence that has been predicted to increase to 366 million by 2030. Rates of cardiovascular disease (CVD) mortality and morbidity are particularly high in this population, representing a significant cost for health care systems. Type II DM patients generally carry a number of risk factors for CVD, including hyperglycemia, abnormal lipid profiles, alterations in inflammatory mediators and coagulation/thrombolytic parameters, as well as other 'nontraditional' risk factors, many of which may be closely associated with insulin resistance. Therefore, successful management of CVD associated with diabetes represents a major challenge to the clinicians. An effective way of tackling this problem is to detect the associated risk factors and to target treatment toward their improvement. Targeting hyperglycemia alone does not reduce the excess risk in diabetes, highlighting the need for aggressive treatment of other risk factors. Although the current use of statin therapy is effective at reducing low-density lipoprotein cholesterol, residual risk remains for other independent lipid and nonlipid factors. The peroxisome proliferator-activated receptor-gamma appears to be closely involved in regulating risk markers at multiple levels. A relatively new class of therapeutic agents that activate peroxisome proliferator-activated receptor-gamma, the thiazolidinedione insulin-sensitizing agents, is currently used to manage type II DM. These agents display a number of potential antiatherogenic properties, including effects on high-density lipoprotein cholesterol and triglycerides, as well as other beneficial nonlipid effects, such as regulating levels of mediators involved in inflammation and endothelial dysfunction. Research data suggest that simple strategies combining thiazolidinediones and statins could have complementary effects on CVD risk-factor profiles in diabetes, alongside the ability to control glycemia.     

Health-related quality of life predicts future health care utilization and mortality in veterans with self-reported physician-diagnosed arthritis: the veterans arthritis quality of life study

OBJECTIVE: To investigate whether health-related quality of life (HRQOL) measures predict health care utilization and mortality in a cohort of veterans with self-reported physician-diagnosed arthritis. METHODS: A cohort of veterans from the Upper Midwest Veterans Integrated Service Network (VISN) was mailed a self-administered questionnaire that was composed of the SF-36V (modified from SF-36 for use in veterans) and questions regarding demographics, current smoking status, limitation of activities of daily living (ADLs), and preexisting physician-diagnosed medical conditions, including arthritis. Within subjects reporting physician-diagnosed arthritis, we analyzed the associations between the SF-36V component summary scales (physical and mental component summary, PCS and MCS, respectively) and the occurrence of any hospitalization, number of hospitalizations, number of outpatient visits, and mortality, for the year after survey administration, using multivariable regression analyses. RESULTS: Of 34,440 survey responders who answered a question regarding arthritis, 18,464 (58%) subjects reported physician-diagnosed arthritis. Arthritic patients in the lowest tertile of PCS scores had significantly higher odds of any hospitalization (Odds ratio (OR) 1.49, 95% confidence interval (CI) [1.25-1.76]) and mortality (OR 1.69, 95% CI [1.18-2.42]), and a significantly higher number of hospitalizations/year (Rate ratio (RR) 1.09, 95% CI [1.05-1.13]) and outpatient visits/year (RR 1.07, 95% CI [1.03-1.11]). Arthritic patients in the lowest tertile of MCS scores had significantly higher odds of any hospitalization (OR 1.20, 95% CI [1.02-1.41]), mortality (OR 2.14, 95% CI [1.56-2.94]), and a significantly higher number of hospitalizations/year (RR 1.05, 95% CI [1.02-1.09]) and outpatient visits/year (RR 1.07, 95% CI [1.03-1.11]). CONCLUSIONS: HRQOL, as assessed by the SF-36V, predicts future inpatient and outpatient health care utilization and mortality in veterans with self-report of physician-diagnosed arthritis.     

Breeding ecology of visceral leishmaniasis vector sandfly in Bihar state of India

Soil samples weighing 255.3 kg, collected from 50 villages of 5 visceral leishmaniasis (VL) endemic districts of Bihar state were examined for sandfly breeding, using the soil incubation method. Breeding of sandflies was detected in 46% of the villages and 7.3% of the soil samples examined. Intra-domestic soil was found to be infested with 2 species of sandflies, Phlebotomus argentipes Annandale and Brunetti and Phlebotomus papatasi (Scopoli). In comparison with human houses, P. argentipes was found to show greater propensity to breed in cattle sheds; breeding prevalences in villages and soil samples, for the species, were significantly higher in cattle sheds than in human houses. The preference for breeding sites by the sandflies appeared to be associated with the pH of the soil. P. argentipes thus preferred to breed in the alkaline soil of cattle shed, and P. papatasi in the soil with neutral pH, of human houses. The emergence of adult P. argentipes from soil samples was mainly observed from April to October.     

Spatial mapping of proteoglycan content in articular cartilage using near-infrared (NIR) spectroscopy

Diagnosis of articular cartilage pathology in the early disease stages using current clinical diagnostic imaging modalities is challenging, particularly because there is often no visible change in the tissue surface and matrix content, such as proteoglycans (PG). In this study, we propose the use of near infrared (NIR) spectroscopy to spatially map PG content in articular cartilage. The relationship between NIR spectra and reference data (PG content) obtained from histology of normal and artificially induced PG-depleted cartilage samples was investigated using principal component (PC) and partial least squares (PLS) regression analyses. Significant correlation was obtained between both data (R² = 91.40%, p<0.0001). The resulting correlation was used to predict PG content from spectra acquired from whole joint sample, this was then employed to spatially map this component of cartilage across the intact sample. We conclude that NIR spectroscopy is a feasible tool for evaluating cartilage contents and mapping their distribution across mammalian joint.OCIS codes: (170.6510) Spectroscopy, tissue diagnostics; (170.6935) Tissue characterization; (170.3880) Medical and biological imaging     

Comparison of objective lenses for multiphoton microscopy in turbid samples

Optimization of illumination and detection optics is pivotal for multiphoton imaging in highly scattering tissue and the objective lens is the central component in both of these pathways. To better understand how basic lens parameters (NA, magnification, field number) affect fluorescence collection and image quality, a two-detector setup was used with a specialized sample cell to separate measurement of total excitation from epifluorescence collection. Our data corroborate earlier findings that low-mag lenses can be superior at collecting scattered photons, and we compare a set of commonly used multiphoton objective lenses in terms of their ability to collect scattered fluorescence, providing guidance for the design of multiphoton imaging systems. For example, our measurements of epi-fluorescence beam divergence in the presence of scattering reveal minimal beam broadening, indicating that often-advocated over-sized collection optics are not as advantageous as previously thought. These experiments also provide a framework for choosing objective lenses for multiphoton imaging by relating the results of our measurements to various design parameters of the objectives lenses used.OCIS codes: (110.0113) Imaging through turbid media, (180.2520) Fluorescence microscopy, (180.4315) Nonlinear microscopy, (180.6900) Three-dimensional microscopy