A multicentric, randomized, comparative clinical trial to evaluate the efficacy and safety of S-etodolac in the treatment of osteoarthritis in Indian patients.

OBJECTIVE: To compare the efficacy and safety of S-etodolac with etodolac in the treatment of osteoarthritis in Indian patients. MATERIALS AND METHODS: This was a double-blind, multicentric, comparative clinical trial conducted in 108 Indian patients with osteoarthritis. All patients received either S-etodolac ER 300 mg or etodolac ER 600 mg tablets once daily. Assessment was done on the basis of WOMAC score and VAS pain score, patient's and physician's global assessment of the arthritic condition. All patients were evaluated after every 2 weeks for 4 weeks for efficacy and safety variables. RESULTS AND DISCUSSION: Total 49 patients in the test group and 52 patients in the reference group completed the study. There was significant improvement (p < 0.0001) in all WOMAC subscales (pain, stiffness and physical function), WOMAC total score and VAS pain score in both the groups. Patient's and physician's global assessment of the arthritic condition also improved significantly (p < 0.0001). All patients showed improvement in WOMAC and VAS pain score by (3) 20%. There was no significant difference between the groups for the efficacy parameters. The adverse events reported were few and no serious adverse events were reported. Total 5 patients in S-etodolac group and 2 patients in etodolac group dropped out of the study. Only 1 patient dropped out because of the side effects of burning sensation, palpitations and anxiety in the test group. CONCLUSION: The present study has established the efficacy, tolerability and safety of S-etodolac extended release tablets in the treatment of osteoarthritis in Indian patients.

Deep brain stimulation of the internal capsule enhances human cognitive control and prefrontal cortex function.

Deep brain stimulation (DBS) is a circuit-oriented treatment for mental disorders. Unfortunately, even well-conducted psychiatric DBS clinical trials have yielded inconsistent symptom relief, in part because DBS' mechanism(s) of action are unclear. One clue to those mechanisms may lie in the efficacy of ventral internal capsule/ventral striatum (VCVS) DBS in both major depression (MDD) and obsessive-compulsive disorder (OCD). MDD and OCD both involve deficits in cognitive control. Cognitive control depends on prefrontal cortex (PFC) regions that project into the VCVS. Here, we show that VCVS DBS' effect is explained in part by enhancement of PFC-driven cognitive control. DBS improves human subjects' performance on a cognitive control task and increases theta (5-8Hz) oscillations in both medial and lateral PFC. The theta increase predicts subjects' clinical outcomes. Our results suggest a possible mechanistic approach to DBS therapy, based on tuning stimulation to optimize these neurophysiologic phenomena.

Preclinical evaluation of radiation and systemic, RGD-targeted, adeno-associated virus phage-TNF gene therapy in a mouse model of spontaneously metastatic melanoma.

The incidence of melanoma in the United States continues to rise, with metastatic lesions notoriously recalcitrant to therapy. There are limited effective treatment options available and a great need for more effective therapies that can be rapidly integrated in the clinic. In this study, we demonstrate that the combination of RGD-targeted adeno-associated virus phage (RGD-AAVP-TNF) with hypofractionated radiation therapy results in synergistic inhibition of primary syngeneic B16 melanoma in a C57 mouse model. Furthermore, this combination appeared to modify the tumor microenvironment, resulting in decreased Tregs in the draining LN and increased tumor-associated macrophages within the primary tumor. Finally, there appeared to be a reduction in metastatic potential and a prolongation of overall survival in the combined treatment group. These results indicate the use of targeted TNF gene therapy vector with radiation treatment could be a valuable treatment option for patients with metastatic melanoma.

Semi-automatic cone beam CT segmentation of in vivo pre-clinical subcutaneous tumours provides an efficient non-invasive alternative for tumour volume measurements.

OBJECTIVE: To evaluate the feasibility and accuracy of using cone beam CT (CBCT) scans obtained in radiation studies using the small-animal radiation research platform to perform semi-automatic tumour segmentation of pre-clinical tumour volumes. METHODS: Volume measurements were evaluated for different anatomical tumour sites, the flank, thigh and dorsum of the hind foot, for a variety of tumour cell lines. The estimated tumour volumes from CBCT and manual calliper measurements using different volume equations were compared with the "gold standard", measured by weighing the tumours following euthanasia and tumour resection. The correlation between tumour volumes estimated with the different methods, compared with the gold standard, was estimated by the Spearman's rank correlation coefficient, root-mean-square deviation and the coefficient of determination. RESULTS: The semi-automatic CBCT volume segmentation performed favourably compared with manual calliper measures for flank tumours ≤2 cm(3) and thigh tumours ≤1 cm(3). For tumours >2 cm(3) or foot tumours, the CBCT method was not able to accurately segment the tumour volumes and manual calliper measures were superior. CONCLUSION: We demonstrated that tumour volumes of flank and thigh tumours, obtained as a part of radiation studies using image-guided small-animal irradiators, can be estimated more efficiently and accurately using semi-automatic segmentation from CBCT scans. ADVANCES IN KNOWLEDGE: This is the first study evaluating tumour volume assessment of pre-clinical subcutaneous tumours in different anatomical sites using on-board CBCT imaging. We also compared the accuracy of the CBCT method to manual calliper measures, using various volume calculation equations.

False-negative BD MGIT™ TBc Identification Test results in routine tuberculosis diagnosis: a New Zealand perspective.

>We previously reported on a comparison of the AccuProbe(®) Gen-Probe(®) MTBC assay (AccuProbe) (BioMérieux, Marcy L'Etoile, France) with the Becton Dickinson (BD) MGIT™ TBc Identification (TBc) Test (BD, Franklin Lakes, NJ, USA) in our laboratory. In the period following the shift from the AccuProbe assay to the TBc test, we obtained six false-negative results. On sequencing the mpt64 gene, we found that these false-negative cases had mutations in the mpt64 gene due to deletion, insertion or substitution. Despite the occurrence of false-negative results, we found that the reduced cost and minimal technical expertise, combined with a new testing algorithm, still make this test the preferred option for rapidly identifying Mycobacterium tuberculosis complex in MGIT cultures in a low TB burden country such as New Zealand.

Estimation of insulin secretion using extracts of plasma from mice injected with anti-insulin serum: effects of arginine, glucose and anti-insulin serum.

Anti-insulin serum (AIS) injected intravenously into adult male mice was allowed to complex endogenous plasma insulin for a fixed time before blood samples were taken. In each plasma sample, insulin was separated from antibody using acid alcohol and the free insulin was estimated by radioimmunoassay. We consider AIS to be most useful for the estimations of in-vivo insulin secretion rates over the period 0.5-5 min after its injection. The lower limit is governed by the time required for mixing and complexing of endogenous insulin. The use of a short upper limit is because antibody complexed with antigen leaves plasma more rapidly than does free antibody, carrying antigen with it. Increases in insulin per ml plasma were appreciably greater in mice injected with glucose or L-arginine plus AIS than in mice injected with glucose or L-arginine only. Hence more realistic values for in-vivo insulin secretion rates may be obtained by the use of AIS to retain most insulin in plasma than by estimation of plasma insulin levels.

Morphological and cytoskeletal changes caused by non-membrane damaging cytotoxin of Vibrio cholerae on int 407 and HeLa cells.

Vibrio cholerae produces a non-membrane damaging cytotoxin (NMDCY), also known as cell rounding factor, which causes rapid rounding of cultured cells like HeLa, CHO and Vero and reportedly elicits enterotoxic activity in the rabbit ileal loop assay. Pursuing the concept that NMDCY might be an accessory factor contributing to the diarrhea caused by V. cholerae, we investigated the effect of NMDCY on Int 407 (intestinal cell line) and HeLa (non-intestinal cell line) cells using light, fluorescent and electron microscopy to gain insight into the cellular response evoked by NMDCY. Binding assays showed that NMDCY has affinity for both Int 407 and HeLa cells. Changes in the internal organelles and cytoskeletal structures of the cell lines were documented indicating changes in the secretory and metabolic function of the toxin-treated cells. Toxin-treated cells visualized under the electron microscope revealed retraction of cell body, formation of blebs on cell surface, changes in mitochondria having dilated and rarefied matrix and an extensively developed Golgi apparatus, endoplasmic reticulum and lysosomes compared to those in normal cells. Immunofluorescence study showed restructuring of microfilament network represented by actin, filamin and vinculin, as also of the microtubular component, tubulin and the intermediate filament, vimentin. Immunogold study further revealed that the toxin is internalized even within the nucleus. Moreover, a rise in the intracellular calcium level of the NMDCY-treated cells leads us to hypothesize that a cascade of events results in the final impairment of the cell machinery.

Characterization of non-membrane-damaging cytotoxin of non-toxigenic Vibrio cholerae O1 and its relevance to disease.

The non-membrane-damaging cytotoxin which causes dramatic cell rounding of cultured HeLa cells was purified to homogeneity from a clinical strain (WO5) of non-toxigenic Vibrio cholerae O1 Inaba belonging to the E1 Tor biotype. The purified protein has a denatured molecular weight of 35 kDa and a native molecular weight of approximately 37 kDa indicating the monomeric nature of the protein. The 15 N-terminal amino acid sequence of non-membrane-damaging cytotoxin showed complete homology to the hemagglutinin protease previously purified and characterized from V. cholerae O1. Purified non-membrane-damaging cytotoxin from V. cholerae O1 was immunologically and biochemically identical to that previously purified from V. cholerae O26. Non-membrane-damaging cytotoxin was found to be enterotoxic in rabbit ileal loop assay inducing accumulation of non-hemorrhagic fluid at 100 micrograms and elicited a concentration dependent increase in short circuit current and tissue conductance of rabbit ileal mucosa mounted on Ussing chambers. A significant serum immunoglobulin G response against non-membrane-damaging cytotoxin was elicited by patients infected with V. cholerae O139 but not with V. cholerae O1. These properties make non-membrane-damaging cytotoxin a potential virulence factor of V. cholerae which should be taken into consideration while making live, attenuated recombinant vaccine strains against cholera.

Phylogenetic lineages of tuberculosis isolates in New Zealand and their association with patient demographics.

SETTING: In New Zealand, the lineage genotypes of Mycobacterium tuberculosis clinical isolates and their role in the epidemiology of tuberculosis (TB) are currently unknown. OBJECTIVE: 1) To measure the relative frequency of each phylogenetic lineage of the M. tuberculosis complex in New Zealand, and 2) to examine its relationship with patient demographics and multidrug-resistant TB (MDR-TB). METHODS: All non-duplicate M. tuberculosis complex isolates recovered in 2010 and 2011 underwent large sequence polymorphism and/or single nucleotide polymorphism analyses. Mycobacterial interspersed repetitive units (MIRU) profiling was also performed for cluster identification. RESULTS: New Zealand isolates were dominated by lineage 4 (Euro-American: 37.8%, 95%CI 33.6-42.2), followed by lineage 1 (Indo-Oceanic: 22.6%, 95%CI 19.1-26.5), lineage 2 (East Asian: 19.5%, 95%CI 16.2-23.3) and lineage 3 (East-African Indian, which included Central Asian: 17.7%, 95%CI 14.5-21.3). Lineage 2 accounted for 58.1% of MDR-TB cases from 2002 to 2011. Among immigrants, the predominant lineages corresponded to high prevalence lineages in the country of origin. In New Zealand-born individuals, Maori and NZ Europeans share the same predominant lineage, lineage 4, with a higher proportion of non-unique MIRU types observed in Maori cases. Lineage 3 was more prevalent in Maori than in NZ Europeans. CONCLUSION: In New Zealand, M. tuberculosis complex phylogenetic lineage is associated with TB epidemiology in terms of ethnicity, country of origin and MDR-TB.

Leiomyosarcoma of the rectum following pelvic irradiation: a difficult histological diagnosis.

Rectal leiomyosarcomas are very rare mesenchymal tumours. This is a case report of a rectal leiomyosarcoma diagnosed initially as a leiomyoma in a patient who had undergone pelvic radiotherapy several years previously. In addition to its pathological rarity, this case is of particular interest because it reinforces the association between pelvic irradiation and rectal leiomyosarcomas and it highlights the importance of treating suspicious cases aggressively in spite of favourable preoperative radiological and histological assessment.

A case of triple volvulus.

Situs inversus is a rare congenital anomaly that has reportedly been associated with caecal volvulus. We describe a case of partial situs inversus complicated by intestinal obstruction secondary to three simultaneously occurring volvuli of the stomach, caecum and sigmoid colon. To our knowledge, this is the first documented case in the literature of multiple, simultaneously occurring volvuli.

Efficacy and tolerability of fixed-dose combination of dexketoprofen and dicyclomine injection in acute renal colic.

Objective. To evaluate the efficacy and tolerability of a fixed-dose combination of dexketoprofen and dicyclomine (DXD) injection in patients with acute renal colic. Patients and Methods. Two hundred and seventeen patients were randomized to receive either DXD (n = 109) or fixed-dose combination of diclofenac and dicyclomine injection (DLD; n = 108), intramuscularly. Pain intensity (PI) was self-evaluated by patients on visual analogue scale (VAS) at baseline and at 1, 2, 4, 6, and 8 hours. Efficacy parameters were proportion of responders, difference in PI (PID) at 8 hours, and sum of analogue of pain intensity differences (SAPID). Tolerability was assessed by patients and physicians. Results. DXD showed superior efficacy in terms of proportion of responders (98.17% versus 81.48; P < 0.0001), PID at 8 hours (P = 0.002), and SAPID(0-8 hours) (P = 0.004). The clinical global impression for change in pain was significantly better for DXD than DLD. The incidence of adverse events was comparable in both groups. However, global assessment of tolerability was rated significantly better for DXD. Conclusion. DXD showed superior efficacy and tolerability than DLD in patients clinically diagnosed to be suffering from acute renal colic.

Girdlestones excision arthroplasty: current update.

Girdlestones procedure has become a salvage operation reserved for patients with significant co-morbidities. Recent literature addresses this infrequently used intervention inadequately. This observational study aims to update current literature and review the modern role of this intervention in orthopaedic practice. Twenty-four records were obtained from which patient demographics, indications and co-morbidities were investigated. Seventeen patients completed an abridged Harris Hip Scoring questionnaire and commented on satisfaction. The average age was 78 years and patients had multiple co-morbidities. Dementia was the most frequent condition but several patients suffered from cardiovascular and respiratory disease. The most common operative indication was persistent prosthetic infection with Staphylococcus aureus, the most common pathogen. Overall mortality was 41% but all surviving patients had complete resolution of infection and 65% had adequate pain control. No patients mobilised without aids although 29% of patients were able to manage stairs and 29% were able to mobilise outdoors. Only 29% were unsatisfied with the outcome. This study demonstrates that Girdlestones candidates are an ageing high-risk group and shows that the Girdlestones procedure can, in select cases, provide good functional outcomes. However such intervention comes at the expense of high mortality and should therefore only be used as a last resort.

A comparison of PAH, PCB, and pesticide concentrations in air at two rural sites on Lake Superior.

Atmospheric concentrations of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and pesticides were compared at Brule River and Eagle Harbor, two rural sites on Lake Superior that are part of the Integrated Atmospheric Deposition Network (IADN). Brule River lies 40 km southwest of Duluth, MN, a small industrial city, and Eagle Harbor is in Michigan's upper peninsula, 400 km east of Brule River. Pesticide and PCB concentrations were similar at both sites. Day-by-day regression analyses of the data showed that PAH concentrations, an indication of urban contamination, were significantly higher at Brule Riverthan at Eagle Harbor. Concentration ranges for all compounds at both sites were well within global background levels, despite the differences observed between the two sites. Clearly, pollution from Duluth is influencing PAH concentrations at Brule River more than at Eagle Harbor.

On the rapidity with which LRH induces release of LH and FSH from perifused anterior pituitary tissues of the rat.

In a series of perifusion (superfusion) experiments, data were obtained which indicated that LRH and K+, when effective, induced increase in LH and/or FSH release within about one minute after arriving in the vicinity of the test rat pituitary tissues. Hormone release stimulating effects of LRH or high K+ continued for some time after washout of test agent. To secure these data perifusion flow was set at 2.5 or more ml/min., each test solution was pulsed for two minutes only, effluent samples were collected at 15 second intervals shortly before, during and after each pulse, and both mixing and dead space time were minimized by introducing each new test solution directly in front of the tissue chamber, via a 4-way or 5-way pulse control stopcock through which two streams of perifusion fluid (Control and Test) passed continually. LH and FSH in effluent samples were estimated by radioimmunoassay.