Rapid Resolution of Donor-Derived Glomerular Fibrin Thrombi After Deceased Donor Kidney Transplantation.

The aim of this study was to determine the clinical and histologic outcomes related to transplanting kidneys from deceased donors with glomerular fibrin thrombi (GFT). We included all cases transplanted between October 2003 and October 2014 that had either a preimplantation biopsy or an immediate postreperfusion biopsy showing GFT. The study cohort included 61 recipients (9.9%) with GFT and 557 in the control group without GFT. Delayed graft function occurred in 49% of the GFT group and 39% in the control group (p = 0.14). Serum creatinine at 1, 4, and 12 months and estimated GFR at 12 months were similar in the two groups. Estimated 1-year graft survival was 93.2% in the GFT group and 95.1% in the control group (p = 0.22 by log-rank). Fifty-two of the 61 patients in the GFT group (85%) had a 1-month protocol biopsy, and only two biopsies (4%) showed residual focal glomerular thrombi. At the 1-year protocol biopsy, the prevalence of moderate to severe interstitial fibrosis and tubular atrophy was 24% in the GFT group and 30% in the control group (p = 0.42). We concluded that GFT resolves rapidly after transplantation and that transplanting selected kidneys from deceased donors with GFT is a safe practice.

Transplanting Kidneys from Deceased Donors With Severe Acute Kidney Injury.

Our aim was to determine outcomes with transplanting kidneys from deceased donors with acute kidney injury, defined as a donor with terminal serum creatinine ≥2.0 mg/dL, or a donor requiring acute renal replacement therapy. We included all patients who received deceased donor kidney transplant from June 2004 to October 2013. There were 162 AKI donor transplant recipients (21% of deceased donor transplants): 139 in the standard criteria donor (SCD) and 23 in the expanded criteria donor (ECD) cohort. 71% of the AKI donors had stage 3 (severe AKI), based on acute kidney injury network (AKIN) staging. Protocol biopsies were done at 1, 4, and 12 months posttransplant. One and four month formalin-fixed paraffin embedded (FFPE) biopsies from 48 patients (24 AKI donors, 24 non-AKI) underwent global gene expression profiling using DNA microarrays (96 arrays). DGF was more common in the AKI group but eGFR, graft survival at 1 year and proportion with IF/TA>2 at 1 year were similar for the two groups. At 1 month, there were 898 differentially expressed genes in the AKI group (p-value <0.005; FDR <10%), but by 4 months there were no differences. Transplanting selected kidneys from deceased donors with AKI is safe and has excellent outcomes.

Addition of Fentanyl to Ropivacaine Infusion in Continuous Thoracic Paravertebral Infusion Does Not Improve Its Analgesic Effect Following Modified Radical Mastectomy: A Randomized Controlled Trial.

A randomized controlled trial was conducted to evaluate pain scores in patients given continuous thoracic paravertebral (TPV) block with ropivacaine alone or with fentanyl in modified radical mastectomy (MRM). Forty female patients ASA classes 1 and 2, aged 18 to 60 years, undergoing MRM were recruited. Preanesthesia with 0.5% ropivacaine, 20 mL, was injected at the T4 TPV space. After 2 hours, patients were randomly assigned to receive a 0.1 mL/kg/h infusion of either 0.2% ropivacaine (group R) or 0.19% ropivacaine plus fentanyl, 2 µg/mL (group RF). Postoperatively, patient-controlled analgesia (PCA) with fentanyl was provided. Visual analog scale (VAS) pain scores at rest and movement were significantly less in group RF at 8 AM on postoperative day 1 (R vs RF: rest: 2 [interquar-tile range, 0-7] vs 1 [0-6]; P = .016; movement: 2.5 [1-8] vs 2 [1-8], P= .042) and on movement 60 minutes postoperatively (R vs RF: 2 [0-9] vs 2 [1-2]; P = .01). Mean total fentanyl consumed via PCA in group R was significantly more (206 ± 31.68 µg vs RF 82.5 ± 35.07 µg, P < .001). Mean total fentanyl consumed via PCA plus TPV infusion was comparable (R: 206 ± 31.68 µg vs RF: 211 ± 25.52 µg, P < .2). Because the mean VAS score was below 3 in all timeframes, addition of fentanyl to ropivacaine in continuous TPV infusion in MRM had no clinical advantage.

Comparison of the effects of three different toxin genes and their levels of expression on cell growth and bystander effect in lung adenocarcinoma.

Transduction of malignant cells with toxin genes provides a novel means to promote tumor cell destruction. The efficacy of a toxin gene is dependent on the cell type targeted, the quantity of exogenous protein synthesized, and the mechanisms of growth inhibition and bystander killing. To develop gene therapy for targeting metastatic lung adenocarcinoma, the toxic activity of herpes simplex virus type 1-thymidine kinase, Escherichia coli cytosine deaminase, and human deoxycytidine kinase were investigated in metastatic human lung adenocarcinoma cell lines H1437 and H2122. Cells were transduced stably with retroviral vectors containing the toxin gene cDNA under the control of either a strong [cytomegalovirus (CMV) immediate early promotor and enhancer] or an intermediate strength (Moloney murine leukemia virus long terminal repeat) promotor. A comparison of toxin gene efficacy was based on the level of specific enzyme activity, the concentration of prodrug required to inhibit cell growth by 50%, and the magnitude of the bystander effect. In lung adenocarcinoma cell lines, cytosine deaminase, driven by the CMV promoter, was superior to thymidine kinase and deoxycytidine kinase in its ability to achieve high levels of specific enzyme activity, to induce growth inhibition, and to affect neighboring cell growth. Therefore, cytosine deaminase expressed from the CMV promotor seems to be the most promising toxin gene for human lung adenocarcinoma gene therapy.

Central bronchial carcinoid: Management of a case and anesthetic perspectives.

Obstructing lesions of the central airways present with a variety of symptoms and are often associated with pneumonia or asthma-like states. Anesthesia to these patients often presents challenges right from the preoperative stabilization of underlying lung condition, mask ventilation in the supine position to maintaining oxygenation and ventilation in the intraoperative and postoperative period. We present here a case of a young woman with a central bronchial tumor with significant airway obstruction with potential for major bleeding and subsequent anesthetic management without lung sacrificing measures and cardiopulmonary bypass assistance.

Measles Outbreak in High Risk Areas of Delhi: Epidemiological Investigation and Laboratory Confirmation.

OBJECTIVE: To describe epidemiological and laboratory characteristics of the measles outbreaks recorded in the urban slums of Delhi (designated as high risk areas under the Polio program), from February through July 2014. METHODS: As a part of surveillance and containment measures, an extensive field investigation for measles case search (WHO definition) through 'house to house survey' was conducted by district health teams and field volunteers of National Polio Surveillance Project (NPSP), WHO, Delhi from February through July, 2014. The data generated by the health teams was collected and analyzed. RESULTS: About 1.1 million households in the high risk areas of Delhi were surveyed for epidemiological investigations. A total of 1337 suspected measles cases were reported. The case fatality rate (CFR) was 1.2 %. Statistical analysis showed significant relation between age of the child (measles case) and immunization status. Higher numbers of reported cases were above 5 y and less than 9 mo of age. Measles IgM was detected in 132 cases and D8 strain was isolated on genotyping. CONCLUSIONS: The outbreak was predominantly localized to the high risk areas (urban slums) of the city. Low CFR was reported during the outbreaks. The outbreaks highlight the need to extend the reach of immunization services to urban slums and strengthen measles surveillance including laboratory based surveillance.

Toxin gene-mediated growth inhibition of lung adenocarcinoma in an animal model of pleural malignancy.

Transduction of malignant cells with toxin genes provides a novel strategy by which to promote tumor cell destruction. Whereas the capacity of the toxin gene/prodrug combination cytosine deaminase/fluorocytosine to inhibit growth of human metastatic pulmonary adenocarcinoma cell lines in vitro is established, the in vivo efficacy of this binary system has not yet been determined. For the development of toxin gene therapy for the treatment of lung adenocarcinoma metastatic to the pleural space, a reliable, disease-specific model is required. The serosa of the rat small intestine resembles the basal lamina of the pleura and provides the basis for a more convenient model than direct injection of tumor into the pleural space. Adenocarcinoma cells are inoculated into everted denuded rat intestine configured as a sac. Immunocytochemical and histological analyses show rapid cell growth with characteristics that mimic nodular metastatic intrapleural disease. In the context of this model, systemically delivered fluorocytosine significantly inhibits the growth of cytosine deaminase-expressing human lung adenocarcinoma cells. The dosing schedule required 30 days; neither addition of an enzyme inhibitor that increases the half-life of fluorocytosine nor intralumenal drug delivery is effective in shortening (to 15 days) the protocol. We conclude that CD continues to hold promise as a toxin gene for lung adenocarcinoma gene therapy, and that prolonged prodrug administration may be required for maximum efficacy.

Intratumoral administration of adenoviral interleukin 7 gene-modified dendritic cells augments specific antitumor immunity and achieves tumor eradication.

In two murine lung cancer models adenoviral interleukin 7-transduced dendritic cells (DC-AdIL-7) were administered intratumorally, resulting in complete tumor regression. Intratumoral DC-AdIL-7 therapy was as effective as DCs pulsed with specific tumor peptide antigens. Comparison with other intratumoral therapies including recombinant IL-7, AdIL-7 vector alone, unmodified DCs, IL-7-transduced fibroblasts, or DCs pulsed with tumor lysates revealed DC-AdIL-7 therapy to be superior in achieving antitumor responses and augmenting immunogenicity. Mice with complete tumor eradication as a result of either DC-AdIL-7 or AdIL-7 therapy were rechallenged with parental tumor cells 30 days or more after complete tumor eradication. All the DC-AdIL-7-treated mice completely rejected a secondary rechallenge, whereas the AdIL-7-treated mice had sustained antitumor effects in only 20-25% of the mice. DC-AdIL-7 therapy was more effective than AdIL-7 in achieving systemic antitumor responses and enhancing immunogenicity. After complete tumor eradication, those mice treated with DC-AdIL-7 evidenced significantly greater release of splenocyte GM-CSF and IFN-gamma than did controls or AdIL-7-treated mice. After intratumoral injection, gene-modified DCs trafficked from the tumor to lymph node sites and spleen. DCs were detected in nodal tissues for up to 7 days after intratumoral injection. We report that intratumoral DC-AdIL-7 leads to significant systemic immune responses and potent antitumor effects in murine lung cancer models.

Molecular conjugate vectors mediate efficient gene transfer into gastrointestinal epithelial cells.

Transfer of genes to the gastrointestinal epithelium would be advantageous from investigational and therapeutic standpoints. Efficient transfer of DNA to the intestinal epithelial cells, however, has been problematic with conventional viral and nonviral vectors. As an alternative, we have utilized molecular conjugate vectors to transfer DNA to enterocytes via the receptor-mediated endocytosis pathway. We were able to achieve efficient transfection of transformed (Caco2 cells) and nontransformed gastrointestinal cells derived from neonatal piglets utilizing molecular conjugate vectors. Analysis of heterologous gene expression revealed that enterocytes could serve as a secretory cellular source of alpha 1-antitrypsin and factor IX. Transient expression of heterologous DNA persisted for up to 2 weeks following transfection. Our observations suggest that molecular conjugate vectors may represent a promising strategy in the transfer of genes to cells of the gastrointestinal tract.

Ectopic expression of the thyroperoxidase gene augments radioiodide uptake and retention mediated by the sodium iodide symporter in non-small cell lung cancer.

Radioiodide is an effective therapy for thyroid cancer. This treatment modality exploits the thyroid-specific expression of the sodium iodide symporter (NIS) gene, which allows rapid internalization of iodide into thyroid cells. To test whether a similar treatment strategy could be exploited in nonthyroid malignancies, we transfected non-small cell lung cancer (NSCLC) cell lines with the NIS gene. Although the expression of NIS allowed significant radioiodide uptake in the transfected NSCLC cell lines, rapid radioiodide efflux limited tumor cell killing. Because thyroperoxidase (TPO) catalyzes iodination of proteins and subsequently causes iodide retention within thyroid cells, we hypothesized that coexpression of both NIS and TPO genes would overcome this deficiency. Our results show that transfection of NSCLC cells with both human NIS and TPO genes resulted in an increase in radioiodide uptake and retention and enhanced tumor cell apoptosis. These findings suggest that single gene therapy with only the NIS gene may have limited efficacy because of rapid efflux of radioiodide. In contrast, the combination of NIS and TPO gene transfer, with resulting TPO-mediated organification and intracellular retention of radioiodide, may lead to more effective tumor cell death. Thus, TPO could be used as a therapeutic strategy to enhance the NIS-based radioiodide concentrator gene therapy for locally advanced lung cancer.

Gene therapy for lung cancer.

Gene therapy has received considerable attention and some speculation as to its value. Although few patients have been treated, the preliminary results of the phase I lung cancer gene therapy clinical trials are very promising. Clinically relevant basic research in the molecular pathogenesis and immunology of lung cancer is progressing. As improved vector technologies are developed, new opportunities will be available to initiate lung cancer gene therapy trials that are based on a more detailed understanding of lung cancer biology. In conclusion, although important biologic and technical questions remain unanswered, recent research suggests that gene therapy will have a profound impact on lung cancer treatment.

Initial experience with day case laparoscopic cholecystectomy at a tertiary care hospital in India.

BACKGROUND: Cholecystectomy is one of the commonest general surgical operations. Laparoscopic cholecystectomy is currently the most favoured approach. As it is associated with less postoperative pain and ileus, it allows early discharge of patients from the hospital. Studies from the West have reported that 'day case laparoscopic cholecystectomy' is feasible and safe. In India, the current practice is to admit patients for laparoscopic cholecystectomy 24-48 hours prior to surgery and to discharge most patients within one to two days of surgery. There is no report from any Indian centre describing 'day case laparoscopic cholecystectomy'. We conducted a prospective study to assess the feasibility, safety and patients' acceptance of 'day case laparoscopic cholecystectomy' in a tertiary care hospital. METHODS: Eighty-four patients with symptomatic cholelithiasis, aged less than 65 years with ASA grade I and II, were offered day case laparoscopic cholecystectomy. Seventy-four patients consented to be included in the study. The nature of operation and likely postoperative course were explained in detail to the patients. Conventional 4-port laparoscopic cholecystectomy was attempted in all patients. The main outcome measures assessed were successful management of patients on day case basis and its acceptance by the patients. RESULTS: Sixty-eight (92%) patients underwent successful laparoscopic cholecystectomy. Fifty-five of these (81%) were successfully managed as day case procedures. There were no major complications. Three of the 55 patients (5.4%) needed re-admission and could be managed conservatively. Fifty-three (96%) patients described their experience as 'pleasant'. None of them described their experience to be 'unpleasant' or 'bad'. Fifty-four (98%) patients stated that they would recommend day case laparoscopic cholecystectomy to close friends and relatives. CONCLUSION: In selected patients, day case laparoscopic cholecystectomy is safe and feasible in a developing country.

VAC Therapy in Large Infected Sacral Pressure Ulcer Grade IV-Can Be an Alternative to Flap Reconstruction?

Vacuum-assisted closure (VAC) therapy is a new entrant in wound care after growth factors and alginate or hydrocolloid dressing, in the treatment of pressure ulcers. We have been using this technique for diabetic foot ulcers. A young nondiabetic man presented with a large sacral bed sore after high doses of ionotropes in an intensive care unit for treating severe hypotension. His wound was debrided, and instead of flap surgery in such infected wound, he was treated with VAC therapy. The complete wound healing was achieved in 6 weeks and at half the cost of flap surgery. Moreover, the chances of flap failure and its related complications were eliminated.

Cryosurgery and ligation (Cryo-plication) of symptomatic hemorrhoids - "an ideal procedure". Initial experience and review of literature.

Haemorrhoidal disease has been in limelight again due to emerging newer modalities of treatment over the last decade. The range varies from simple rubber band ligation to stapled rectopexy. But a rational and ideal approach is still unclear. This study aims to analyze the ideal modality in today's scenario of managing haemorrhoidal disease. A prospective study on 12 patients, was carried out over 24 months in a surgical unit of a tertiary care hospital. The pain, bleeding, rectal discharge, anal stenosis were observed. Results show that the Cryoplication procedure had no anal stenosis, minimal bleeding, less pain and cost was effective. When compared with other contemporary modalities it has lesser complications and short and easy learning curve.

CCL19 reduces tumour burden in a model of advanced lung cancer.

Epstein-Barr virus-induced molecule 1 ligand chemokine (CCL19) is a CC chemokine that chemoattracts both dendritic cells (DC) and T lymphocytes. We evaluated the antitumour efficacy of CCL19 in a murine model of spontaneous bronchoalveolar cell carcinoma. These transgenic mice (CC-10 TAg) express the SV40 large T antigen under the Clara Cell promoter, develop bilateral, multifocal, pulmonary carcinomas and die at 4 months owing to progressive pulmonary tumour burden. To mimic therapy in late-stage disease, 3-month-old transgenic mice were treated with recombinant CCL19 (0.5 microg dose(-1)) by intranodal (axillary lymph node region) injection three times per week for 4 weeks. CCL19 treatment led to a marked reduction in tumour burden with extensive mononuclear infiltration of the tumours compared to diluent treated controls. Flow cytometric analyses showed significant increases in CD4 and CD8T cell subsets as well as DC in the lungs of CCL19-treated mice. Lung tissue cytokine profiles showed a shift towards immune stimulatory molecules with a decrease in the immunosuppressive cytokine TGF-beta. Our findings show that CCL19 may serve as a potential immune stimulator and provide a strong rationale for the evaluation of CCL19 in cancer immunotherapy.

A study of 'social network' in schizophrenia.

An attempt was made to investigate the social network of thirty two first admission cases of Schizophrenia, vis-a-vis thirty one non-schizophrenic psyhiatric patients. The social network of the two groups did not differ significantly. The findings are discussed in relation to the nature of sample and the control group.