Synthesis of imidazo-thiadiazole linked indolinone conjugates and evaluated their microtubule network disrupting and apoptosis inducing ability.

A series of imidazo[2,1-b][1,3,4]thiadiazole linked indolinone conjugates were synthesized and investigated for antiproliferative activity in different human cancer cell lines by changing various substitutions at indolinone and phenyl ring systems. Among them conjugates 7, 14 and 15 were exhibited potent antiproliferative activity with GI50 values from 0.13 to 3.8 µΜ and evaluated for cell cycle analysis, tubulin polymerization assay and apoptosis. Treatment with 7, 14 and 15 were resulted in accumulation of cells in G2/M phase, inhibition of tubulin assembly, disruption of microtubule network. Inhibition of tubulin polymerization was further supported by Western blot analysis. In addition, the conjugates (7, 14 and 15) also showed apoptosis in HeLa cell line, detailed biological studies such as Hoechst 33,258 staining, DNA fragmentation and caspase-3 assays suggested that these compounds induce cell death by apoptosis. Docking studies revealed that these compounds (7, 14 and 15) bind with αAsn101, αThr179, αSer178, ßCys241, ßLys254 and ßLys352 in the colchicine-binding site of the tubulin.

Design, synthesis and biological evaluation of new ß-carboline-bisindole compounds as DNA binding, photocleavage agents and topoisomerase I inhibitors.

A series of new ß-carboline-bisindole compounds were designed, synthesized and evaluated for their antiproliferative activity against human cancer cell lines, such as A549 (lung cancer), DU-145 (prostate cancer), HeLa (cervical cancer) and MCF-7 (breast cancer). All the compounds exhibited considerable antiproliferative activity. Among them, compounds 7g and 7r exhibited significant antiproliferative activity against DU-145 cells with IC50 values 1.86 and 1.80 µM respectively. Further, these compounds effectively inhibit DNA topoisomerase I activity and can also cleave the pBR322 plasmid upon irradiation with UV light. In addition, Annexin V-FITC assay suggested that these compounds induced apoptosis in DU- 145 cell line (prostate cancer). To know the binding mode of these compounds with DNA, spectroscopic studies were also carried out. These new compounds were showing a unique mode of binding with DNA, both biophysical studies such as UV-Visible, fluorescence, circular dichroism and molecular docking studies revealed that the ß-carboline-bisindole compounds exhibit combilexin type of interaction with DNA.

European and Mediterranean hydroclimate responses to tropical volcanic forcing over the last millennium.

Volcanic eruptions have global climate impacts, but their effect on the hydrologic cycle is poorly understood. We use a modified version of superposed epoch analysis, an eruption year list collated from multiple datasets, and seasonal paleoclimate reconstructions (soil moisture, precipitation, geopotential heights, and temperature) to investigate volcanic forcing of spring and summer hydroclimate over Europe and the Mediterranean over the last millennium. In the western Mediterranean, wet conditions occur in the eruption year and the following 3 years. Conversely, northwestern Europe and the British Isles experience dry conditions in response to volcanic eruptions, with the largest moisture deficits in post-eruption years 2 and 3. The precipitation response occurs primarily in late spring and early summer (April-July), a pattern that strongly resembles the negative phase of the East Atlantic Pattern. Modulated by this mode of climate variability, eruptions force significant, widespread, and heterogeneous hydroclimate responses across Europe and the Mediterranean.

Synthesis and biological evaluation of imidazo[2,1-b][1,3,4]thiadiazole-linked oxindoles as potent tubulin polymerization inhibitors.

A series of imidazo[2,1-b][1,3,4]thiadiazole-linked oxindoles composed of an A, B, C and D ring system were synthesized and investigated for anti-proliferative activity in various human cancer cell lines; test compounds were variously substituted at rings C and D. Among them, compounds 7 ((E)-5-fluoro-3-((6-p-tolyl-2-(3,4,5-trimethoxyphenyl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)indolin-2-one), 11 ((E)-3-((6-p-tolyl-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)indolin-2-one), and 15 ((E)-6-chloro-3-((6-phenyl-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)indolin-2-one) exhibited potent anti-proliferative activity. Treatment with these three compounds resulted in accumulation of cells in G2 /M phase, inhibition of tubulin assembly, and increased cyclin-B1 protein levels. Compound 7 displayed potent cytotoxicity, with an IC50 range of 1.1-1.6 µM, and inhibited tubulin polymerization with an IC50 value (0.15 µM) lower than that of combretastatin A-4 (1.16 µM). Docking studies reveal that compounds 7 and 11 bind with αAsn101, ßThr179, and ßCys241 in the colchicine binding site of tubulin.

Synthesis of ß-carboline-benzimidazole conjugates using lanthanum nitrate as a catalyst and their biological evaluation.

A series of ß-carboline-benzimidazole conjugates bearing a substituted benzimidazole and an aryl ring at C3 and C1 respectively were designed and synthesized. The key step of their preparation was determined to involve condensation of substituted o-phenylenediamines with 1-(substituted phenyl)-9H-pyrido[3,4-b]indole-3-carbaldehyde using La(NO3)3·6H2O as a catalyst and their cytotoxic potential was evaluated. Conjugates 5a, 5d, 5h and 5r showed enhanced cytotoxic activity (GI50 values range from 0.3 to 7.1 µM in most of the human cancer cell lines) in comparison to some of the previously reported ß-carboline derivatives. To substantiate the cytotoxic activity and to understand the nature of interaction of these conjugates with DNA, spectroscopy, DNA photocleavage and DNA topoisomerase I inhibition (topo-I) studies were performed. These conjugates (5a, 5d and 5r) effectively cleave pBR322 plasmid DNA in the presence of UV light. In addition, the effect of these conjugates on DNA Topo I inhibition was studied. The mode of binding of these new conjugates with DNA was also examined by using both biophysical as well as molecular docking studies, which supported their multiple modes of interaction with DNA. Moreover, an in silico study of these ß-carboline-benzimidazole conjugates reveals that they possess drug-like properties.

Synthesis and biological evaluation of imidazopyridine-oxindole conjugates as microtubule-targeting agents.

A library of imidazopyridine-oxindole conjugates was synthesised and investigated for anticancer activity against various human cancer cell lines. Some of the tested compounds, such as 10 a, 10 e, 10 f, and 10 k, exhibited promising antiproliferative activity with GI50 values ranging from 0.17 to 9.31 µM. Flow cytometric analysis showed that MCF-7 cells treated by these compounds arrested in the G2 /M phase of the cell cycle in a concentration-dependent manner. More particularly, compound 10 f displayed a remarkable inhibitory effect on tubulin polymerisation. All the compounds depolarised mitochondrial membrane potential and caused apoptosis. These results are further supported by the decreased phosphorylation of Akt at Ser473. Studies on embryonic development revealed that the lead compounds 10 f and 10 k caused delay in the development of zebra fish embryos. Docking of compound 10 f with tubulin protein suggested that the imidazo[1,2-a]pyridine moiety occupies the colchicine binding site of tubulin.

Anti-tubercular agents. Part 7: a new class of diarylpyrrole-oxazolidinone conjugates as antimycobacterial agents.

In an effort to discover new anti-tubercular agents, a series of new diarylpyrrole-oxazolidinone conjugates have been designed and synthesized. The anti-tubercular activity of these new conjugates (4a-n and 5a-d) against Mycobacterium tuberculosis H37Rv and drug resistance strains such as M. tuberculosis Rif(R) and M. tuberculosis XDR are discussed, wherein compound 4i has been found to be the most potent amongst the series. MTT assay was performed on the active conjugates of the series (4b-f, 4i and 5c) against mouse macrophage (J-774) cells to evaluate cytotoxic effects and selective index values. In addition, these conjugates (4a-n and 5a-d) are also tested against a panel of Gram-positive and Gram-negative bacterial strains. The docking studies have been carried out to provide some insight into the mechanism of action for this class of compounds.

Synthesis, biological evaluation of new oxazolidino-sulfonamides as potential antimicrobial agents.

A number of linezolid-like oxazolidino-sulfonamides (7a-y and 8a-b) were designed and synthesized with a view to develop antimicrobial agents with improved properties. Most of the synthesized compounds showed good to moderate activity against a panel of standard Gram-positive and Gram-negative bacteria and fungal strains. The compounds 7i and 7v exhibited significant activity, with a MIC value of 2.0-6.0 µg/mL against a panel of Gram-positive and Gram-negative bacteria. These compounds also showed activity against Candida albicans, with a MIC value of 4.0 µg/mL. A correlation of the antimicrobial activity with calculated lipophilicity values (C log P) is also presented.

Health insurance as a requirement to undergo cardiac transplantation: a national survey of transplant program practices.

BACKGROUND: Recent limitations in Medicaid coverage of transplantation in Arizona jeopardized transplantation of potential recipients in that state and called attention to financial barriers inherent in the present organ allocation system. Policies of cardiac transplant centers regarding insurance requirements for transplantation have not been previously assessed. We sought to determine the policies of adult cardiac transplant programs nationwide regarding insurance requirements for evaluation and listing for cardiac transplantation. METHODS: From December 15, 2008 to November 16, 2010, all active adult cardiac transplant programs in the United States were surveyed regarding insurance requirements for evaluation and listing for cardiac transplantation. RESULTS: Surveys were completed by 62 of 101 programs, accounting for 71% of adult cardiac transplants in 2007. Only 2% of recipients were uninsured. Insurance was required by 48% of programs to evaluate and 84% to list for transplantation. For uninsured patients, 81% of programs required a large amount of money upfront (median, $200,000; interquartile range, $10,000-$300,000) to list for transplantation and often (84%) educated patients about fundraising to acquire these resources. CONCLUSIONS: Adult cardiac transplant programs generally require candidates to have adequate health insurance to undergo transplantation. Uninsured patients typically need a significant amount of money upfront to be listed for transplantation and often are advised to fundraise to gather such resources.

Simultaneous recording of rat auditory cortex and thalamus via a titanium-based, microfabricated, microelectrode device.

Direct recording from sequential processing stations within the brain has provided opportunity for enhancing understanding of important neural circuits, such as the corticothalamic loops underlying auditory, visual, and somatosensory processing. However, the common reliance upon microwire-based electrodes to perform such recordings often necessitates complex surgeries and increases trauma to neural tissues. This paper reports the development of titanium-based, microfabricated, microelectrode devices designed to address these limitations by allowing acute recording from the thalamic nuclei and associated cortical sites simultaneously in a minimally invasive manner. In particular, devices were designed to simultaneously probe rat auditory cortex and auditory thalamus, with the intent of recording auditory response latencies and isolated action potentials within the separate anatomical sites. Details regarding the design, fabrication, and characterization of these devices are presented, as are preliminary results from acute in vivo recording.

Titanium-based dielectrophoresis devices for microfluidic applications.

To date, materials selection in microfluidics has been restricted to conventional micromechanical materials systems such as silicon, glass, and various polymers. Metallic materials offer a number of potential advantages for microfluidic applications, including high fracture toughness, thermal stability, and solvent resistance. However, their exploitation in such applications has been limited. In this work, we present the application of recently developed titanium micromachining and multilayer lamination techniques for the fabrication of dielectrophoresis devices for microfluidic particle manipulation. Two device designs are presented, one with interdigitated planar electrodes defined on the floor of the flow channel, and the other with electrodes embedded within the channel wall. Using these devices, two-frequency particle separation and Z-dimensional flow visualization of the dielectrophoresis phenomena are demonstrated.

Dorsal onlay buccal mucosal graft urethroplasty in long anterior urethral stricture.

OBJECTIVE: To assess the success of buccal mucosal graft (BMG) urethroplasty by the dorsal onlay technique in long anterior urethral stricture (> 2 cm long) through the midline perineal incision. MATERIALS AND METHODS: From January 1998 to December 2003, 43 patients with long anterior urethral strictures were managed by dorsal onlay BMG urethroplasty. After voiding trial, they were followed up at 3 months with uroflowmetry, retrograde urethrogram (RGU) and American Urological Association symptoms score (AUA symptoms scores). Successful outcome was defined as normal voiding with a maximum one attempt of visual internal urethrotomy (VIU) after catheter removal. Patients were further followed-up with uroflowmetry at 3 months interval and RGU every 6 months interval. RESULTS: Mean stricture length was 4.8 cm (range 3 to 9 cm) and mean follow up was 48 months (range 12 to 84 months). Only five patients were found to develop stricture at anastomotic site, during follow-up. Two of them voided normally after single attempt of VIU. Other three patients (6.9%) required further open surgery or repeat VIU during follow up and were considered as failure. CONCLUSION: Dorsal onlay BMG urethroplasty is a simple technique with good surgical outcome.

Dorsal onlay buccal mucosal graft urethroplasty in long anterior urethral stricture

OBJECTIVE: To assess the success of buccal mucosal graft (BMG) urethroplasty by the dorsal onlay technique in long anterior urethral stricture (> 2 cm long) through the midline perineal incision. MATERIALS AND METHODS: From January 1998 to December 2003, 43 patients with long anterior urethral strictures were managed by dorsal onlay BMG urethroplasty. After voiding trial, they were followed up at 3 months with uroflowmetry, retrograde urethrogram (RGU) and American Urological Association symptoms score (AUA symptoms scores). Successful outcome was defined as normal voiding with a maximum one attempt of VIU after catheter removal. Patients were further followed-up with uroflowmetry at 3 months interval and RGU every 6 months interval. RESULTS: Mean stricture length was 4.8 cm (range 3 to 9 cm) and mean follow up was 48 months (range 12 to 84 months). Only five patients were found to develop stricture at anastomotic site, during follow-up. Two of them voided normally after single attempt of VIU. Other three patients (6.9 percent) required further open surgery or repeat VIU during follow up and were considered as failure. CONCLUSION: Dorsal onlay BMG urethroplasty is a simple technique with good surgical outcome.

A decade's experience with vesicovaginal fistula in India.

A retrospective analysis of 252 cases of vesicovaginal fistulae was done to analyse its etio-pathology and management in an Indian population. After a thorough evaluation, different techniques of fistula closure were used for repair and the results were listed. The main outcome measures were the etiology of the fistula, need for tissue interposition and cure rate per repair as well as the overall cure rate. We compared our results with literature and concluded that simple and small fistulae should be repaired with layered closure. All complicated fistulae should be repaired with tissue interposition or tissue graft. This is the first study from India compiling 10 years of experience on vesicovaginal fistula.

A survey of physicians' attitudes to transfusion practice in critically ill patients in the UK.

This study aimed to examine the attitudes of intensivists and haematologists to the use of blood and blood products using a scenario-based postal questionnaire. One hundred and sixty-two intensivists and 77 haematologists responded to the survey. In four scenarios, the baseline haemoglobin thresholds for red cell transfusion ranged from 6 to 12 g.dl(-1). There was significant variation between scenarios (p <0.005). Increasing age, high Acute Physiology and Chronic Health Status II score, surgery, acute respiratory distress syndrome, septic shock and lactic acidosis significantly (p <0.005) modified the transfusion threshold. There were greater variations in the baseline threshold for platelet transfusion. The majority of respondents (72.3%) selected a baseline haemoglobin threshold between 9 and 10 g.dl(-1). The thresholds for platelet transfusion were far less consistent.

Blood component use in critically ill patients.

This prospective observational study was conducted to assess the current transfusion practice in critically ill patients. One thousand two hundred and forty-seven consecutive critically ill patients admitted between February 1999 and October 1999 were included in the study. Overall 666 (53%) patients were administered red cells. Transfused patients had significantly higher intensive care unit mortality but also had higher Acute Physiology and Chronic Health Evaluation II scores and longer durations of stay. The average pretransfusion haemoglobin concentration was < 9 g.dl(-1) in 75% of transfusion episodes. The common indications for transfusion were low haemoglobin (72%) and haemorrhage (25%). Overall, 202 (16%) and 281 (22%) of the patients were transfused platelets and fresh frozen plasma, respectively. The indications for transfusion were haemorrhage, low platelet counts, prolonged prothrombin time or to provide cover for invasive interventions. Most platelet transfusions were given at values in the order of 50-100 x 10(9).l(-1). The pretransfusion platelet count varied according to the indications for transfusion. This study showed that transfusion practice is consistent and that in general there does not seem to be an excessive use of blood components in critically ill patients.

A re-classification of ayurvedic herbs indicated in skin diseases (kustha).

Several drugs are prescribed for a single disease in Ayurveda. Often one drug is indicated in many diseases, with this type of information, the drugs indicated in a disease can be reclassified on the basis of pathogenesis, in order to understand the intensity of the efficacy and mode of action on par with ayurvedic methodology. Besides the pathological basis, the terminologies used to explain the effect of the drug should also be considered while working on the gradation of efficiency. Considering those points of view, the drugs indicated in skin diseases (KUSTHAS) have been reclassified in a newer way.

Combining the von Langenbeck and the Wardill-Kilner operations in certain clefts of the palate.

The rationale for combining two standard cleft palate procedures is set forth. The circumstances in which this combination is recommended are outlined and diagrammed. By joining the positive qualities of two established and popular methods, it is possible in certain cases to facilitate palate closure while reducing common minor complications by incorporating the good qualities of each procedure and reducing the negative.