Implementation of emergency obstetric care training in Bangladesh: lessons learned

The Women's Right to Life and Health project aimed to reduce maternal morbidity and mortality in Bangladesh through provision of comprehensive emergency obstetric care (EmOC) in the country's district and sub-district hospitals. Human resources development was one of the project's major activities. This paper describes the project in 2000-2004 and lessons learned. Project documents, the training database, reports and training protocols were reviewed. Medical officers, nurses, facility managers and laboratory technicians received training in the country's eight medical college hospitals, using nationally accepted curricula. A 17-week competency-based training course for teams of medical officers and nurses was introduced in 2003. At baseline in 1999, only three sub-district hospitals were providing comprehensive EmOC and 33 basic EmOC, mostly due to lack of trained staff and necessary equipment. In 2004, 105 of the 120 sub-district hospitals had become functional for EmOC, 70 with comprehensive EmOC and 35 with basic EmOC, while 53 of 59 of the district hospitals were providing comprehensive EmOC compared to 35 in 1999. The scaling up of competency-based training, innovative incentives to retain trained staff, evidence-based protocols to standardise practice and improve quality of care and the continuing involvement of key stakeholders, especially trainers, will all be needed to reach training targets in future.     

DOES SQUATTING REDUCE PELVIC FLOOR DESCENT DURING DEFAECATION?

Neurogenic faecal and urinary incontinence result from a stretch-induced injury to the pelvic nerves, from difficult childbirth or from chronic straining at stool. It has been suggested that the condition occurs less frequently in societies where the squatting position is used during defaecation, and that squatting may minimize pelvic floor descent. This is a prospective study which evaluates the position of the pelvic floor during defaecation straining in 52 patients. The position of the perineum was measured at rest and during maximal defaecation straining using a perineometer, with the patient in the left lateral, sitting and squatting positions. There was a significant difference in the position of the perineum at rest and on straining between the left lateral position and both the sitting and squatting positions. However, there was no significant difference at rest or on straining between the sitting and squatting positions. These results show that squatting does not reduce pelvic floor descent during defaecation straining, and imply that squatting would not help reverse stretch-induced pudendal nerve damage.     

Alteration of pulse configuration affects the pain response during diode laser photocoagulation

Background and Objective: The shape of the treatment pulse of the diode laser (810 nm) can be easily altered electronically in contrast to ion laser photocoagulators. We investigated whether changes in laser pulse shape influenced the subjective pain response in patients undergoing retinal photocoagulation when only topical anesthesia was used. Study Design/Materials and Methods: Twenty consecutive patients required peripheral retinal photocoagulation for proliferative diabetic retinopathy or extensive retinal breaks. Three diode pulse waveforms including a square wave, shaped-wave, and an envelope of micropulses were compared to one another. Power was adjusted so that each waveform delivered the same total energy. The patients subjectively ranked the intensity of any pain they experienced for each group of lesions. Responses were compared to one another using an analysis of variance. Results: 40% of patients found the standard square wave pulse to be significantly more painful (P < 0.05) than the shaped pulse mode and 30% found the square wave significantly more painful (P < 0.05) than the micropulse mode. Conclusion: Modification of the laser pulse waveform may ameliorate pain induced by diode laser photocoagulation of the retinal periphery. © 1995 Wiley-Liss, Inc.     

Analysis of glutathione <Emphasis Type=Italic>S</Emphasis>-transferase Pi isoform (GSTP1) single-nucleotide polymorphisms and macular telangiectasia type 2

Recent imaging studies have suggested that macular pigment is decreased centrally in macular telangiectasia type 2 (MT2). The uptake of xanthophyll pigment into the macula is thought to be facilitated by a xanthophyll-binding protein (XBP). The Pi isoform of glutathione S-transferase (GSTP1) represents one such XBP with high binding affinity. This case–control study aimed to determine whether two common single-nucleotide polymorphisms (SNPs) of GSTP1 were associated with MT2. DNA samples from 39 cases and 21 controls were collected. Two polymorphic sites of Ile105Val and Ala114Val in exons 5 and 6 respectively, of the GSTP1 gene were analysed. Comparison of alleles and genotypes between cases and controls indicated that there were no statistically significant differences for either the Ile105Val SNP (P = 0.43) or the Ala114Val SNP (P = 0.85), or for any combinations; however, the homozygous at-risk genotype (GG) of the Ile105Val SNP was present in 8% of cases but absent in controls. This study found no statistically significant association between two common GSTP1 SNPs and MT2; however, a trend towards a greater frequency of the GG genotype of the Ile105Val SNP in cases is of great interest. The biological plausibility of disturbed macular pigment uptake in MT2 makes GSTP1 an excellent candidate gene. Further investigation is warranted in future studies of MT2.     

Recurrent unicystic maxillary ameloblastoma presenting as unilateral proptosis

Unicystic Ameloblastoma (UA) is a rare variant of ameloblastoma which is an odontogenic epithelial neoplasm, typically affecting mandibular ramus. Maxillary ameloblastoma is a rare entity with a more disastrous consequence. Although extremely rare, their highly recurrent and locally aggressive behavior can lead to invasion of vital structures surrounding maxilla (orbit, cranium) even after several years of conservative surgical management (limited resection, curettage). We report a case of 16-year-old girl presenting with proptosis of left eye, UA left maxilla, who was treated initially with limited resection (enucleation) and curettage and the lesion recurred after two years with a more aggressive behavior, causing destruction floor of orbit. To this date there are only 23 documented cases of orbital invasion and only three of the reports are in ophthalmic literature. The ophthalmologists need to be aware of this type of rare lesion presenting as proptosis.     

Capsaicin exerts therapeutic effects by targeting tNOX-SIRT1 axis and augmenting ROS-dependent autophagy in melanoma cancer cells

Although considered a sporadic type of skin cancer, malignant melanoma has regularly increased internationally and is a major cause of cancer-associated death worldwide. The treatment options for malignant melanoma are very limited. Accumulating data suggest that the natural compound, capsaicin, exhibits preferential anticancer properties to act as a nutraceutical agent. Here, we explored the underlying molecular events involved in the inhibitory effect of capsaicin on melanoma growth. The cellular thermal shift assay (CETSA), isothermal dose-response fingerprint curves (ITDRF_CETSA), and CETSA-pulse proteolysis were utilized to confirm the direct binding of capsaicin with the tumor-associated NADH oxidase, tNOX (ENOX2) in melanoma cells. We also assessed the cellular impact of capsaicin-targeting of tNOX on A375 cells by flow cytometry and protein analysis. The essential role of tNOX in tumor- and melanoma-growth limiting abilities of capsaicin was evaluated in C57BL/6 mice. Our data show that capsaicin directly engaged with cellular tNOX to inhibit its enzymatic activity and enhance protein degradation capacity. The inhibition of tNOX by capsaicin was accompanied by the attenuation of SIRT1, a NAD⁺-dependent deacetylase. The suppression of tNOX and SIRT1 then enhanced ULK1 acetylation and induced ROS-dependent autophagy in melanoma cells. Capsaicin treatment of mice implanted with melanoma cancer cells suppressed tumor growth by down-regulating tNOX and SIRT1, which was also seen in an in vivo xenograft study with tNOX-depleted melanoma cells. Taken together, our findings suggest that tNOX expression is important for the growth of melanoma cancer cells both in vitro and in vivo, and that inhibition of the tNOX-SIRT1 axis contributes to inducting ROS-dependent autophagy in melanoma cells.     

Enterohepatic recirculation model of irinotecan (CPT-11) and metabolite pharmacokinetics in patients with glioma

Background  Enterohepatic recirculation of irinotecan and one of its metabolites, SN-38, has been observed in pharmacokinetic data sets from previous studies. A mathematical model that can incorporate this phenomenon was developed to describe the pharmacokinetics of irinotecan and its metabolites. Patients and methods  A total of 32 patients with recurrent malignant glioma were treated with weekly intravenous administration of irinotecan at a dose of 125 mg/m². Plasma concentrations of irinotecan and its three major metabolites were determined. Pharmacokinetic models were developed and tested for simultaneous fit of parent drug and metabolites, including a recirculation component. Results  Rebound in the plasma concentration suggestive of enterohepatic recirculation at approximately 0.5–1 h post-infusion was observed in most irinotecan plasma concentration profiles, and in some plasma profiles of the SN-38 metabolite. A multi-compartment model containing a recirculation chain was developed to describe this process. The recirculation model was optimal in 22 of the 32 patients compared to the traditional model without the recirculation component. Conclusion  A recirculation chain incorporated in a multi-compartment pharmacokinetic model of irinotecan and its metabolites appears to improve characterization of this drug’s disposition in patients with glioma.     

Retrospective observational study of HER2 immunohistochemistry in borderline breast cancer patients undergoing neoadjuvant therapy,with an emphasis on Group 2 (HER2/CEP17 ratio ≥2.0, HER2 copy number <4.0 signals/cell) cases

Background The ASCO/CAP guidance on HER2 testing in breast cancer (BC) has recently changed. Group 2 tumours with immunohistochemistry score 2+ and HER2/CEP17 ratio ≥2.0 and HER2 copy number <4.0 signals/cell were re-classified as HER2 negative. This study aims to examine the response of Group 2 tumours to neoadjuvant chemotherapy (NACT).Methods 749 BC cases were identified from 11 institutions. The association between HER2 groups and pathological complete response (pCR) was assessed.Results 54% of immunohistochemistry HER2 positive (score 3+) BCs showed pCR, compared to 19% of immunohistochemistry 2+ FISH amplified cases. 27% of Group 2 treated with HER2 targeted therapy achieved pCR, compared to 19 and 11% in the combined Groups 1 + 3 and Groups 4 + 5, respectively. No difference in pCR rates was identified between Group 2 and Group 1 or combined Groups 1 + 3. However, Group 2 response rate was higher than Groups 4 + 5 (p = 0.017).Conclusion No difference in pCR was detected in tumours with a HER2/CEP17 ratio ≥2.0 and a HER2 score 2+ by IHC when stratified by HER2 gene copy number. Our data suggest that ASCO/CAP HER2 Group 2 carcinomas should be evaluated further with respect to eligibility for HER2 targeted therapy.Subject terms: Breast cancer, Breast cancer     

Radiographic and neuro-SPECT imaging in an immature third ventricle teratoma: case report.

We report a case of an immature teratoma of the third ventricle, which was preoperatively thought to be a choroid plexus papilloma. The diagnosis was made by biopsy since the radiographic (CT, MRI), angiographic and scintigraphic findings ([99mTc]pertechnetate, 99mTc-DTPA, 99mTc-HMPAO brain SPECT) were nonspecific. Disruption of the blood-brain barrier is the mechanism for radionuclidic and contrast tumoral uptake and is demonstrated by marked contrast enhancement on CT and focal concentration on [99mTc]pertechnetate and 99mTc-DTPA images. No suppression of [99mTc]pertechnetate tumor uptake was observed following the administration of potassium perchlorate. Increased concentration of tumor protein is suggested by the increased signal on the T1-weighted magnetic resonance images and high [99mTc]pertechnetate uptake. The tumor's detection on the 99mTc-HMPAO brain SPECT was due to its intraventricular location. A number of potential mechanisms for brain tumor localization of 99mTc-HMPAO are discussed.     

Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide

Glioblastoma multiforme (GBM) has a poor prognosis with an overall survival of 14–15 months after surgery, radiation and chemotherapy using temozolomide (TMZ). A major problem is that the tumors acquire resistance to therapy. In an effort to improve the therapeutic efficacy of TMZ, we performed a genome-wide RNA interference (RNAi) synthetic lethality screen to establish a functional gene signature for TMZ sensitivity in human GBM cells. We then queried the Connectivity Map database to search for drugs that would induce corresponding changes in gene expression. By this approach we identified several potential pharmacological sensitizers to TMZ, where the most potent drug was the established antipsychotic agent Thioridazine, which significantly improved TMZ sensitivity while not demonstrating any significant toxicity alone. Mechanistically, we show that the specific chemosensitizing effect of Thioridazine is mediated by impairing autophagy, thereby preventing adaptive metabolic alterations associated with TMZ resistance. Moreover, we demonstrate that Thioridazine inhibits late-stage autophagy by impairing fusion between autophagosomes and lysosomes. Finally, Thioridazine in combination with TMZ significantly inhibits brain tumor growth in vivo, demonstrating the potential clinical benefits of compounds targeting the autophagy-lysosome pathway. Our study emphasizes the feasibility of exploiting drug repurposing for the design of novel therapeutic strategies for GBM.