Piperidinols that show anti-tubercular activity as inhibitors of arylamine N-acetyltransferase: an essential enzyme for mycobacterial survival inside macrophages

Latent M. tuberculosis infection presents one of the major obstacles in the global eradication of tuberculosis (TB). Cholesterol plays a critical role in the persistence of M. tuberculosis within the macrophage during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into cell-wall lipids. Arylamine N-acetyltransferase (NAT) is encoded within a gene cluster that is involved in the cholesterol sterol-ring degradation and is essential for intracellular survival. The ability of the NAT from M. tuberculosis (TBNAT) to utilise propionyl-CoA links it to the cholesterol-catabolism pathway. Deleting the nat gene or inhibiting the NAT enzyme prevents intracellular survival and results in depletion of cell-wall lipids. TBNAT has been investigated as a potential target for TB therapies. From a previous high-throughput screen, 3-benzoyl-4-phenyl-1-methylpiperidinol was identified as a selective inhibitor of prokaryotic NAT that exhibited antimycobacterial activity. The compound resulted in time-dependent irreversible inhibition of the NAT activity when tested against NAT from M. marinum (MMNAT). To further evaluate the antimycobacterial activity and the NAT inhibition of this compound, four piperidinol analogues were tested. All five compounds exert potent antimycobacterial activity against M. tuberculosis with MIC values of 2.3-16.9 µM. Treatment of the MMNAT enzyme with this set of inhibitors resulted in an irreversible time-dependent inhibition of NAT activity. Here we investigate the mechanism of NAT inhibition by studying protein-ligand interactions using mass spectrometry in combination with enzyme analysis and structure determination. We propose a covalent mechanism of NAT inhibition that involves the formation of a reactive intermediate and selective cysteine residue modification. These piperidinols present a unique class of antimycobacterial compounds that have a novel mode of action different from known anti-tubercular drugs

Changing use of surgical antibiotic prophylaxis in Thika Hospital, Kenya: a quality improvement intervention with an interrupted time series design.

INTRODUCTION: In low-income countries, Surgical Site Infection (SSI) is a common form of hospital-acquired infection. Antibiotic prophylaxis is an effective method of preventing these infections, if given immediately before the start of surgery. Although several studies in Africa have compared pre-operative versus post-operative prophylaxis, there are no studies describing the implementation of policies to improve prescribing of surgical antibiotic prophylaxis in African hospitals. METHODS: We conducted SSI surveillance at a typical Government hospital in Kenya over a 16 month period between August 2010 and December 2011, using standard definitions of SSI and the extent of contamination of surgical wounds. As an intervention, we developed a hospital policy that advised pre-operative antibiotic prophylaxis and discouraged extended post-operative antibiotics use. We measured process, outcome and balancing effects of this intervention in using an interrupted time series design. RESULTS: From a starting point of near-exclusive post-operative antibiotic use, after policy introduction in February 2011 there was rapid adoption of the use of pre-operative antibiotic prophylaxis (60% of operations at 1 week; 98% at 6 weeks) and a substantial decrease in the use of post-operative antibiotics (40% of operations at 1 week; 10% at 6 weeks) in Clean and Clean-Contaminated surgery. There was no immediate step-change in risk of SSI, but overall, there appeared to be a moderate reduction in the risk of superficial SSI across all levels of wound contamination. There were marked reductions in the costs associated with antibiotic use, the number of intravenous injections performed and nursing time spent administering these. CONCLUSION: Implementation of a locally developed policy regarding surgical antibiotic prophylaxis is an achievable quality improvement target for hospitals in low-income countries, and can lead to substantial benefits for individual patients and the institution

Topography as a modifier of breeding habitats and concurrent vulnerability to malaria risk in the western Kenya highlands

<p>Abstract</p> <p>Background</p> <p>Topographic parameters such as elevation, slope, aspect, and ruggedness play an important role in malaria transmission in the highland areas. They affect biological systems, such as larval habitats presence and productivity for malaria mosquitoes. This study investigated whether the distribution of local spatial malaria vectors and risk of infection with malaria parasites in the highlands is related to topography.</p> <p>Methods</p> <p>Four villages each measuring 9 Km²lying between 1400-1700 m above sea level in the western Kenya highlands were categorized into a pair of broad and narrow valley shaped terrain sites. Larval, indoor resting adult malaria vectors and infection surveys were collected originating from the valley bottom and ending at the hilltop on both sides of the valley during the rainy and dry seasons. Data collected at a distance of ≤500 m from the main river/stream were categorized as valley bottom and those above as uphill. Larval surveys were categorized by habitat location while vectors and infections by house location.</p> <p>Results</p> <p>Overall, broad flat bottomed valleys had a significantly higher number of anopheles larvae/dip in their habitats than in narrow valleys during both the dry (1.89 versus 0.89 larvae/dip) and the rainy season (1.66 versus 0.89 larvae/dip). Similarly, vector adult densities/house in broad valley villages were higher than those within narrow valley houses during both the dry (0.64 versus 0.40) and the rainy season (0.96 versus 0.09). Asymptomatic malaria prevalence was significantly higher in participants residing within broad than those in narrow valley villages during the dry (14.55% vs. 7.48%) and rainy (17.15% vs. 1.20%) season. Malaria infections were wide spread in broad valley villages during both the dry and rainy season, whereas over 65% of infections were clustered at the valley bottom in narrow valley villages during both seasons.</p> <p>Conclusion</p> <p>Despite being in the highlands, local areas within low gradient topography characterized by broad valley bottoms have stable and significantly high malaria risk unlike those with steep gradient topography, which exhibit seasonal variations. Topographic parameters could therefore be considered in identification of high-risk malaria foci to help enhance surveillance or targeted control activities in regions where they are most needed.</p

Preparation and in vitro evaluation of 177Lu-iPSMA-RGD as a new heterobivalent radiopharmaceutical

This study aimed to synthesize a new 177Lu-iPSMA-RGD heterobivalent radiopharmaceutical, as well as to assess the in vitro radiopharmaceutical potential to target cancer cells overexpressing PSMA and a(v) b(3) integrins. The radiotracer prepared with a radiochemical purity of 98.8 ± 1.0% showed stability in human serum, specific recognition with suitable affinity to PSMA and a(v)b(3) integrins, and capability to inhibit cancer cell proliferation and VEGF signaling (antiangiogenic effect). Results warrant further preclinical studies to establish the 177Lu-iPSMA-RGD potential as a dual therapeutic radiopharmaceutical.CONACyT-CB-2016-01-28152

Hypothesis: primary antiangiogenic method proposed to treat early stage breast cancer

<p>Abstract</p> <p>Background</p> <p>Women with Down syndrome very rarely develop breast cancer even though they now live to an age when it normally occurs. This may be related to the fact that Down syndrome persons have an additional copy of chromosome 21 where the gene that codes for the antiangiogenic protein Endostatin is located. Can this information lead to a primary antiangiogenic therapy for early stage breast cancer that indefinitely prolongs remission? A key question that arises is when is the initial angiogenic switch thrown in micrometastases? We have conjectured that avascular micrometastases are dormant and relatively stable if undisturbed but that for some patients angiogenesis is precipitated by surgery. We also proposed that angiogenesis of micrometastases very rarely occurs before surgical removal of the primary tumor. If that is so, it seems possible that we could suggest a primary antiangiogenic therapy but the problem then arises that starting a therapy before surgery would interfere with wound healing.</p> <p>Results</p> <p>The therapy must be initiated at least one day prior to surgical removal of the primary tumor and kept at a Down syndrome level perhaps indefinitely. That means the drug must have virtually no toxicity and not interfere meaningfully with wound healing. This specifically excludes drugs that significantly inhibit the VEGF pathway since that is important for wound healing and because these agents have some toxicity. Endostatin is apparently non-toxic and does not significantly interfere with wound healing since Down syndrome patients have no abnormal wound healing problems.</p> <p>Conclusion</p> <p>We propose a therapy for early stage breast cancer consisting of Endostatin at or above Down syndrome levels starting at least one day before surgery and continuing at that level. This should prevent micrometastatic angiogenesis resulting from surgery or at any time later. Adjuvant chemotherapy or hormone therapy should not be necessary. This can be continued indefinitely since there is no acquired resistance that develops, as happens in most cancer therapies.</p

Trends in upper gastrointestinal diagnosis over four decades in Lusaka, Zambia: a retrospective analysis of endoscopic findings

BACKGROUND AND AIMS: There a shortage of robust information about profiles of gastrointestinal disease in sub-Saharan Africa. The endoscopy unit of the University Teaching Hospital in Lusaka has been running without interruption since 1977 and this 38-year record is largely intact. We report an analysis of endoscopic findings over this period. METHODS: Written endoscopy records from 29th September 1977 to 16th December 2014 were recovered, computerised, coded by two experienced endoscopists and analysed. Temporal trends were analysed using tables, graphs, and unconditional logistic regression, with age, sex of patient, decade, and endoscopist as independent variables to adjust for inter-observer variation. RESULTS: Sixteen thousand nine hundred fifty-three records were identified and analysed. Diagnosis of gastric ulcer rose by 22 %, and that of duodenal ulcer fell by 14 % per decade. Endoscopically diagnosed oesophageal cancer increased by 32 % per decade, but gastric cancer rose only in patients under 60 years of age (21 % per decade). Oesophageal varices were the commonest finding in patients presenting with haematemesis, increasing by 14 % per decade in that patient group. Two HIV-related diagnoses, oesophageal candidiasis and Kaposi’s sarcoma, rose from almost zero to very high levels in the 1990s but fell substantially after 2005 when anti-retroviral therapy became widely available. CONCLUSIONS: This useful dataset suggests that there are important trends in some endoscopic findings over four decades. These trends are not explained by inter-observer variation. Reasons for the divergent trends in incidence of peptic ulceration and apparent trends in diagnosis of upper gastrointestinal cancers merit further exploration

Copy Number Variation Affecting the Photoperiod-B1 and Vernalization-A1 Genes Is Associated with Altered Flowering Time in Wheat (Triticum aestivum)

The timing of flowering during the year is an important adaptive character affecting reproductive success in plants and is critical to crop yield. Flowering time has been extensively manipulated in crops such as wheat (Triticum aestivum L.) during domestication, and this enables them to grow productively in a wide range of environments. Several major genes controlling flowering time have been identified in wheat with mutant alleles having sequence changes such as insertions, deletions or point mutations. We investigated genetic variants in commercial varieties of wheat that regulate flowering by altering photoperiod response (Ppd-B1 alleles) or vernalization requirement (Vrn-A1 alleles) and for which no candidate mutation was found within the gene sequence. Genetic and genomic approaches showed that in both cases alleles conferring altered flowering time had an increased copy number of the gene and altered gene expression. Alleles with an increased copy number of Ppd-B1 confer an early flowering day neutral phenotype and have arisen independently at least twice. Plants with an increased copy number of Vrn-A1 have an increased requirement for vernalization so that longer periods of cold are required to potentiate flowering. The results suggest that copy number variation (CNV) plays a significant role in wheat adaptation

The positive impact of a facilitated peer mentoring program on academic skills of women faculty

<p>Abstract</p> <p>Background</p> <p>In academic medicine, women physicians lag behind their male counterparts in advancement and promotion to leadership positions. Lack of mentoring, among other factors, has been reported to contribute to this disparity. Peer mentoring has been reported as a successful alternative to the dyadic mentoring model for women interested in improving their academic productivity. We describe a facilitated peer mentoring program in our institution's department of medicine.</p> <p>Methods</p> <p>Nineteen women enrolled in the program were divided into 5 groups. Each group had an assigned facilitator. Members of the respective groups met together with their facilitators at regular intervals during the 12 months of the project. A pre- and post-program evaluation consisting of a 25-item self-assessment of academic skills, self-efficacy, and academic career satisfaction was administered to each participant.</p> <p>Results</p> <p>At the end of 12 months, a total of 9 manuscripts were submitted to peer-reviewed journals, 6 of which are in press or have been published, and another 2 of which have been invited to be revised and resubmitted. At the end of the program, participants reported an increase in their satisfaction with academic achievement (mean score increase, 2.32 to 3.63; <it>P </it>= 0.0001), improvement in skills necessary to effectively search the medical literature (mean score increase, 3.32 to 4.05; <it>P </it>= 0.0009), an improvement in their ability to write a comprehensive review article (mean score increase, 2.89 to 3.63; <it>P </it>= 0.0017), and an improvement in their ability to critically evaluate the medical literature (mean score increased from 3.11 to 3.89; <it>P </it>= 0.0008).</p> <p>Conclusions</p> <p>This facilitated peer mentoring program demonstrated a positive impact on the academic skills and manuscript writing for junior women faculty. This 1-year program required minimal institutional resources, and suggests a need for further study of this and other mentoring programs for women faculty.</p