Gene Replacement Strategies for Lung Cancer

Advances in our understanding of the molecular genetics of cancer present an opportunity to develop prevention and treatment strategies based on the reversal of specific genetic lesions. This strategy is analogous to the classic concept of gene therapy for replacement of defective or nonfunctioning genes. The gene families implicated in carcinogenesis include dominant oncogenes and tumor suppressor genes. Regional administration of viral vectors expressing wildtype p53 and antisense K-ras prevents tumor growth for tumors with the specific genetic lesions in orthotopic tumor models and mediates regression of large established tumors. These studies provide a rationale for a new clinical protocol recently approved by the National Institutes of Health Recombinant DNA Advisory Committee and Food and Drug Administration to replace a defective p53 gene with intratumor injection of recombinant retrovirus expressing wild-type p53 or elimination of activated K-ras by expression of antisense K-ras messenger RNA. If these agents are efficacious, their lack of toxicity may provide a sufficiently high therapeutic index such that they could be used as an adjuvant to surgery to treat patients with earlier stages of cancer or as prevention for second primary cancers for individuals with genetic abnormalities in premalignant lesions. Although much research needs to be done, the possibility of specific gene targeting with a high therapeutic index makes this a promising area of investigation.     

Desensitization of human breast-cancer cells by interferon-alpha

Continuous exposure of human breast cancer cells, MCF-7, to interferon-alpha (IFN) induces a state.of non-responsiveness termed as desensitization. mRNA 561 is transiently induced by IFN-alpha in MCF-7 cells, peak cytoplasmic levels are reached by six to twelve hours; the mRNA level declines steadily and is reduced to uninduced levels by forty eight hours. Induction of mRNA 561 was used as an index of responsiveness of cells to IFN-alpha and desensitization was characterized in MCF-7 cells and in MCF-7 cells transfected by the v-H-ras oncogene (MCF-7ras). The kinetics and degree of IFN-mediated induction of mRNA 561 was comparable in both the cell lines. Desensitization was observed in MCF-7 cells and not in MCF-7ras. It was a reversible event, requiring de novo protein synthesis as inclusion of cycloheximide inhibited desensitization. The cellular elements that mediate such a phenomena are elicited by IFNs during the initial phases of IFN action and may be polypeptides. The refractory period, the time after which MCF-7 cells become responsive, was determined to be five days. In conclusion, we demonstrate the use of mRNA 561 induction in evaluating desensitization. Inhibition of protein synthesis or transfection with ras blocks desensitization in MCF-7 cells.     

Evaluation of endometrial changes and p53 expression in tamoxifen treated women: Comparision of various methods.

Objective: To compare transvaginal sonography (TVS), sonohysterography (SHG), hysteroscopy and endometrial aspiration (EA) and p53 expression in assessing endometrial abnormalities in women on tamoxifen. Methods: In a cross sectional study of 50 pre- and post-menopausal women receiving tamoxifen for > 2 years, all participants underwent TVS and EA. Those with endometrial thickness > 4 mm on TVS underwent hysteroscopy and SHG. Serum p53 antibody and p53 immunohistochemistry were tested in all women. Results: The sensitivity and specificity when compared with histopathology as the reference standard were as follows: TVS 100% and 33.3%, SHG 85.7% and 50%, hysteroscopy 92.8% and 80.8%, serum p53 50% and 83.3%, and p53 immunohistochemistry 57.1% and 61.1%. Prevalence of endometrial abnormalities was not significantly different in asymptomatic and symptomatic women. Conclusion: Tamoxifen-users require routine testing for endometrial evaluation. TVS followed by hysteroscopy and biopsy is an effective option. p53 expression correlates with histological abnormalities. Key words: Tamoxifen, Sonography, Sonohysterography, Hysteroscopy, Endometrium, p53.     

Burkholderia pseudomallei in Environment of Adolescent Siblings with Melioidosis,Kerala, India, 2019

In 2019, Burkholderia pseudomallei was isolated from the backyard of 2 siblings with melioidosis in Kerala, India. This finding highlights the value of healthcare providers being aware of risk for melioidosis in febrile patients, of residents taking precautions when outside, and of increasing environmental surveillance for B. pseudomallei in this region.     

Maternal mortality in India: a 20-year study from a large referral medical college hospital, West Bengal

Aim:  The present study was carried out to analyze the maternal death rate and its changing trends over a 20-year period in a large referral/teaching institution in Eastern India.
Methods:  A retrospective analysis of maternal deaths was carried out from January 1986 to December 2005 at the Department of Obstetrics and Gynaecology, R. G. Kar Medical College and Hospital, Kolkata, India. Records were divided into four 5-yearly periods: 1986–1990; 1991–1995; 1996–2000; and 2001–2005, for comparison of the trends. The initial interval from 1986 to 1990 was chosen as the reference period.
Results:  The cumulative maternal mortality ratio (MMR) was 599.3 per 100 000 live births. Comparison between the first 5-year period (1986–1991) and the last (2001–2005) showed a statistical significant downward trend in MMR (683.6 vs 474.3; P  < 0.001). Deaths due to direct causes are still the leading cause, accounting for 82.09% of total deaths. Hypertensive disorders (36.14%), hemorrhage (21.91%) and sepsis (19.54%) were still the major causes of direct obstetric deaths throughout the study period. Hypertensive disorders alone showed a substantial decline after the introduction of magnesium sulphate.
Conclusion:  The fall in maternal mortality has been very slow.     

Randomised comparative trial of thermal balloon ablation and levonorgestrel intrauterine system in patients with idiopathic menorrhagia

AIMS: To compare the effectiveness of thermal balloon ablation (TBA) and levonorgestrel intrauterine system (LNG-IUS) in the management of idiopathic menorrhagia and changes in pictorial blood loss assessment chart (PBAC) scores in patients who had failed on oral medical treatment. METHODS: Phase III, single-centre, open randomised controlled trial. Following full screening and evaluation of 104 women, 33 were randomised to TBA and 33 to LNG-IUS. Primary outcomes were changes in PBAC scores from baseline to 12 months. Secondary outcomes were changes in haemoglobin and serum ferritin, at six months, continuation with treatment and hysterectomy rates at two years and changes in PBAC scores at three, six and nine months. RESULTS: All patients randomised had a PBAC score of > or = 120. At all assessment times, median PBAC scores were less than baseline, the greatest reductions being seen at 12 months for both treatments. When the median PBAC for the LNG-IUS (26 (0-68)) was significantly different to the median PBAC for the TBA cohort (62 (0-142)) P < 0.001. Irregular bleeding problems were the most common reason for discontinuation of the LNG-IUS and resulted in more women (39.8%) seeking other treatment by two years than the TBA (23.1%) (P < 0.05) and more undergoing a hysterectomy (20.7% vs 13.3%, respectively) (p > 0.05). Patient acceptability of the LNG-IUS and TBA was similar at 12 and 24 months in terms of their perceived satisfaction of effect on menorrhagia. CONCLUSIONS: Both TBA and LNG-IUS achieved significant decreases in PBAC scores, with those for the LNG-IUS being significantly greater at 12 months. However, prolonged days of bleeding resulted in fewer women continuing with the LNG-IUS at two years.     

A framework for web based geographical information systems for country wide antimicrobial resistance monitoring

Drug resistance—arising from the misuse and overuse of antimicrobial agents—is becoming a major concern as new strains of resistant microorganisms are emerging and fewer new antimicrobial drugs are in development. This paper presents an idea of implementing a Real Time Web Based Information System to monitor changes in the antibiotic sensitivity of microorganisms, located at different areas and time periods based on data collected from accredited laboratories. This pattern can be mapped over geographical map of the area and can be interpreted by clinicians/policy makers. The authors demonstrate the use of such information system using cross sectional data obtained from a nasopharyngeal swab survey of 151 children affected with HIV. Such system can aid physicians to improve the choice of antibiotic to be administered using real time data.     

Prevalence and Predictors of Left Ventricular Diastolic Dysfunction in a Hispanic Patient Population

Minimal data exist on attributes of diastolic dysfunction in the Hispanic population. The purpose of this study was to evaluate the prevalence and predictors of diastolic dysfunction in a Hispanic patient population. We performed a retrospective review of 166 consecutive echocardiograms in a southwestern Texas Hospital that caters to a large Hispanic patient population. We identified all echocardiograms that met criteria for diastolic dysfunction and assessed baseline demographics and comorbidities in the cohort of Hispanic patients. A multivariate analysis was performed to identify the independent predictors of diastolic dysfunction. A total of 129 out of 166 patients (77.8%) were of Hispanic origin. Out of the 129 patients, 87 (67.4%) had some degree of diastolic dysfunction in this population suggesting a high prevalence in the study cohort. In the diastolic dysfunction group, the mean age was 64.5 ± 13.9, 37% were male and 63% female, 78% had diabetes, 85% had hypertension, and 49% had some degree of renal insufficiency (stages 3–5). A logistic multivariate analysis showed that diabetes was an independent predictor of diastolic dysfunction with odds ratio of 2.69 (95% confidence interval [CI], 1.06–6.28; p = 0.038). Similarly age (per year increase) and chronic kidney disease were independent predictors of diastolic dysfunction. We demonstrated that older age, presence of diabetes, and renal dysfunction are independent predictors of diastolic dysfunction in the Hispanic patient population. Strategies geared toward reducing diabetes and preventing renal dysfunction are likely to decrease prevalence of diastolic dysfunction and heart failure in this community.     

Percutaneous coronary intervention versus coronary artery bypass grafting in diabetic patients

Revascularization with CABG or angioplasty in diabetic patients is associated with a less favor-able outcome. The value of early intervention will be assessed in the ongoing BARI 2D trial. It remains to be determined whether the widespread use of GP IIb/IIIa drugs and prolonged dual antiplatelet therapy in diabetic patients who receive stents, and possibly drug-eluting stents, will alter results significantly so that outcomes become comparable or even better than CABG (Fig. 3). It seems prudent to consider CABG with LIMA grafting in diabetic patients who have severe multi-vessel disease and to consider angioplasty in selected patients who have more discrete and less severe disease.     

Aortic dissection--an update

Acute aortic dissection is a medical emergency with high morbidity and mortality requiring emergent diagnosis and therapy. Rapid advances in noninvasive imaging technology have facilitated the early diagnosis of this condition and should be considered in the differential diagnosis of any patient with chest, back, or abdominal pain. Emergent surgery is the treatment for patients with type A dissection while optimal medical therapy is appropriate in patients with uncomplicated type B dissection. Adequate beta-blockade is the cornerstone of medical therapy. Patients who survive acute aortic dissection need long-term medical therapy with beta-blockers and statins and appropriate serial imaging follow-up. Future advances in this field include biomarkers in the early diagnosis of acute aortic dissection and presymptomatic diagnosis with genetic screening. Overall patients with aortic dissection are at high risk for an adverse outcome and need to be managed aggressively in hospital and long term with frequent follow-up.