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.

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.

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.

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.

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.

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.

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 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.

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.

Concentrations and spatial variations of polybrominated diphenyl ethers and other organohalogen compounds in Great Lakes air.

Air samples were analyzed from urban, rural, and remote sites near the Great Lakes to investigate the occurrence, concentrations, and spatial and temporal differences of polybrominated diphenyl ethers (PBDE) in air. The concentrations of PBDEs were compared to those of other organohalogen compounds such as PCBs and organochlorine pesticides. The samples were collected in 1997-1999 as part of the Integrated Atmospheric Deposition Network (IADN). To minimize the variability of the data, we selected only samples taken when the atmospheric temperature was 20 +/- 3 degrees C. PBDEs were found in all samples, indicating that these compounds are widely distributed and that they can be transported through the atmosphere to remote areas. The total concentrations of PBDEs were similar to some of the organochlorine pesticides such as sigmaDDT and ranged from 5 pg/m3 near Lake Superior to about 52 pg/m3 in Chicago. In fact, the spatial trend was well correlated to those of PCBs. Our results indicate a relatively constant level from mid-1997 to mid-1999. At 20 +/- 3 degrees C, about 80% of the tetrabromo homologues are in the gas phase and about 70% of the hexabromo homologues are associated with the particle phase. Thus, particle-to-gas partitioning in the atmosphere is an important process for these compounds.

Expanding multiple antibiotic resistance among clinical strains of Vibrio cholerae isolated from 1992-7 in Calcutta, India.

Antimicrobial susceptibilities of Vibrio cholerae strains isolated from cholera patients admitted to the Infectious Diseases Hospital, Calcutta, India for 6 years were analysed to determine the changing trends; 840 V. cholerae strains isolated in 1992-1997 were included in this study. Among V. cholerae serogoup O1 and O139, ampicillin resistance increased from 1992 (35 and 70%, respectively) to 1997 (both serogroups 100%). Resistance to furazolidone and streptomycin was constantly high among V. cholerae O1 strains with gradual increase in resistance to other drugs such as ciprofloxacin, co-trimoxazole, neomycin and nalidixic acid. V. cholerae O139 strains exhibited susceptibilities to furazolidone and streptomycin comparable with those of O1 strains. However, after initial increase in resistance to chloramphenicol and co-trimoxazole, all the V. cholerae O139 strains became susceptible to these two drugs from 1995 onwards. Both V. cholerae O1 and O139 remained largely susceptible to gentamicin and tetracycline. V. cholerae non-O1, non-O139 strains, in contrast, exhibited high levels of resistance to virtually every class of antimicrobial agents tested in this study especially from 1995. Kruskal-Wallis one-way analysis showed that V. cholerae O1 Ogawa serogroup exhibited significant yearly increase in resistance to nine antibiotics followed by non-O1 non-O139 and O139 strains to six antibiotics and two antibiotics respectively. Interesting observation encountered in this study was the dissipation of some of the resistant patterns commonly found among V. cholerae non-O1 non-O139 or O1 serogroups to the O139 serogroup and vice versa during the succeeding years.

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.

Molecular analysis of non-O1, non-O139 Vibrio cholerae associated with an unusual upsurge in the incidence of cholera-like disease in Calcutta, India.

There was an inexplicable upsurge in the incidence of non-O1, non-O139 Vibrio cholerae among hospitalized patients admitted to the Infectious Diseases Hospital, Calcutta, India, between February and March 1996. Of the 18 strains of V. cholerae isolated during this period, 15 belonged to the non-O1, non-O139 serogroups (4 belonged to O144, 3 belonged to O11, 1 each belonged to O6, O8, O12, O19, O39, and O58, and 2 strains could not be typed), 2 belonged to the O139 serogroup, and 1 belonged to the O1 serogroup. Cell-free culture supernatants of 13 representative non-O1, non-O139 V. cholerae strains evoked a distinct cytotoxic effect on CHO and HeLa cells, and the strains examined produced the nonmembrane-damaging cytotoxin. By several PCR assays, it was determined that none of the non-O1, non-O139 strains were positive for the ctxA, zot, ace, and tcpA genes and for the genes representing the heat-labile toxin, heat-stable toxin, and verotoxin of Escherichia coli and the various variants of these genes. Studies on the clonality of non-O1, non-O139 V. cholerae strains by restriction fragment length polymorphism (RFLP) analysis of rRNA genes and of other genes (hlyA, hlyU, hlx, toxR, and attRS1) and by pulsed-field gel electrophoresis (PFGE) collectively indicate that the upsurge which occurred in February and March 1996 was caused by strains belonging to different clones. Overall, there was an excellent correlation between the results of ribotyping, RFLP analysis of various genes, and PFGE, with strains belonging to a particular serogroup showing nearly identical restriction patterns and PFGE profiles. It is clear from this study that some serogroups of V. cholerae can cause diarrhea by a mechanism quite different from that of toxigenic V. cholerae O1 and O139, and we have proposed the nomenclature of enteropathogenic V. cholerae to include these serogroups.