A review on current status of antiviral siRNA

Viral diseases like influenza, AIDS, hepatitis, and Ebola cause severe epidemics worldwide. Along with their resistant strains, new pathogenic viruses continue to be discovered so creating an ongoing need for new antiviral treatments. RNA interference is a cellular gene‐silencing phenomenon in which sequence‐specific degradation of target mRNA is achieved by means of complementary short interfering RNA (siRNA) molecules. Short interfering RNA technology affords a potential tractable strategy to combat viral pathogenesis because siRNAs are specific, easy to design, and can be directed against multiple strains of a virus by targeting their conserved gene regions. In this review, we briefly summarize the current status of siRNA therapy for representative examples from different virus families. In addition, other aspects like their design, delivery, medical significance, bioinformatics resources, and limitations are also discussed.     

Depression among women with obstetric fistula in Kenya

Objective

To establish the prevalence of depression and describe associated factors among fistula patients attending an obstetric fistula surgical camp in Kenya.

Methods

A cross-sectional study was conducted focusing on obstetric fistula patients attending a national fistula camp held in August 2008 at Kenyatta National Hospital, Nairobi, Kenya. A structured questionnaire was used to obtain sociodemographic data and medical histories for all consenting patients before surgery. Depression measures were obtained using the Patient Health Questionnaire-9.

Results

Of the 70 women interviewed, 2 (2.9%) and 12 (17.1%) reported a history of psychiatric illness and suicidal ideations, respectively. Depression was present in 51 (72.9%) patients, with 18 (25.7%) meeting criteria for severe depression. Depression was significantly associated with women older than 20 years of age (P = 0.01), unemployment (P = 0.03), lack of social support following fistula (P = 0.04), and living with fistula for over 3 months (P = 0.01).

Conclusion

Women with obstetric fistula are predisposed to high levels of depression. A holistic management approach, including mental health care and family support, is recommended.     

Rapidly Progressive Congenital Rhabdomyosarcoma Presenting with Multiple Cutaneous Lesions: An Uncommon Diagnosis and a Therapeutic Challenge

Congenital rhabdomyosarcomas (RMSs) are rare tumors with variable clinical presentations. A 2 month-old, term male neonate (37 weeks, 4 days), weighing 3.2 kg, born to a 24 year-old primigravida, by simple vaginal delivery presented with multiple erythematous papulonodular lesions over his trunk that progressed to his whole body, on the first day of delivery. Prior to conception, his mother was treated for polycystic ovarian disease. On the tenth day, his chest computed tomogram scans revealed multiple, heterogeneously enhancing, bilateral pleural-based soft tissue density nodular lesions, along with multiple soft tissue density lesions, involving skeletal muscles of all his body parts. Microsections from two biopsies (on 10th day and after 2 months) revealed a malignant round cell tumor with cells arranged in a diffuse, solid pattern, comprising embryonal and solid alveolar components. Immunohistochemically, the tumor cells were diffusely positive for desmin, myoD1 and myogenin. Diagnosis of embryonal and alveolar (mixed type) RMS was offered. Further molecular cytogenetic analysis was negative for PAX3-FKHR and PAX7-FKHR. The patient was induced on chemotherapy as per intergroup rhabdomyosarcoma study IV protocol. There was treatment response with near total remission after 8 weeks of treatment. Thereafter, new lesions started appearing that also disappeared after modification of the chemotherapy drugs. However, after 16 months, the baby died of brain metastasis. The present case forms the fourth case report of an aggressive form of a congenital RMS with extensive cutaneous involvement and brain metastasis. A review of previously diagnosed cases of congenital RMSs is discussed herewith.     

Role of HPV DNA testing in predicting cervical intraepithelial lesions: comparison of HC HPV and ISH HPV

Human papillomavirus (HPV) is widely accepted as the primary agent involved in the development of squamous intraepithelial neoplasia and cervical carcinoma. Several commercial tests are available for detecting HPV DNA. This study compares the efficacy of INFORM HPV (in situ hybridization [ISH] HPV) and HCII (HC HPV) in predicting cervical lesions. A total of 762 sequential Papanicolaou (Pap) smears determined by cytologic examination to be either atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL) were tested by both Hybrid Capture (HC) HPV and ISH HPV; 250 follow-up biopsies were reviewed as the reference standard for presence or absence of a lesion. ISH HPV and HC HPV differed significantly in accurately predicting biopsy findings from ASC-US and LSIL cases. The overall sensitivity and specificity of ISH HPV were 97% (28/29) and 86% (191/221); and HC HPV was 79% (23/29) and 56% (123/221). The positive predictive value (PPV) of ISH HPV was 48% (28/58) vs HC HPV value of 19% (23/121). Negative predictive value (NPV) was also better with ISH HPV at 99% (191/192) and HC HPV at 95% (123/129). Of equal importance, ISH HPV demonstrated a lower false-positive rate compared to HC HPV, 12% (30/250) vs 39% (98/250), as well as having a slightly lower false-negative rate 0.4% (1/250) vs 2.4% (6/250). ISH HPV is more predictive of biopsy histopathology in patients with detectable cervical lesions than is HC HPV. Effective triage of patients by HPV analysis using ISH HPV as compared to HC HPV has the potential of significant public health impact by reducing unnecessary colposcopies, as well as adverse medical, social, and psychological patient consequences.     

Duodenal perforation in a 14-year-old boy with abdominal tuberculosis despite being on antituberculous treatment

We are presenting a case of a 14-year-old male patient with known history of abdominal tuberculosis on medication for 4 months with frank peritonitis and air under the diaphragm found to have primary perforation of the duodenum due to tuberculosis. Tuberculosis is common in the third world but affects iliocaecal junction commonly. Cases with tuberculous duodenal are rarely reported in the literature.     

Simplified risk stratification criteria for identification of patients with MRSA bacteremia at low risk of infective endocarditis: implications for avoiding routine transesophageal echocardiography in MRSA bacteremia

The aim of this study was to identify patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia with low risk of infective endocarditis (IE) who might not require routine trans-esophageal echocardiography (TEE). We retrospectively evaluated 398 patients presenting with MRSA bacteremia for the presence of the following clinical criteria: intravenous drug abuse (IVDA), long-term catheter, prolonged bacteremia, intra-cardiac device, prosthetic valve, hemodialysis dependency, vertebral/nonvertebral osteomyelitis, cardio-structural abnormality. IE was diagnosed using the modified Duke criteria. Of 398 patients with MRSA bacteremia, 26.4 % of cases were community-acquired, 56.3 % were health-care-associated, and 17.3 % were hospital-acquired. Of the group, 44 patients had definite IE, 119 had possible IE, and 235 had a rejected diagnosis. Out of 398 patients, 231 were evaluated with transthoracic echocardiography (TTE) or TEE. All 44 patients with definite IE fulfilled at least one criterion (sensitivity 100 %). Finally, a receiver operator characteristic (ROC) curve was obtained to evaluate the total risk score of our proposed criteria as a predictor of the presence of IE, and this was compared to the ROC curve of a previously proposed criteria. The area under the ROC curve for our criteria was 0.710, while the area under the ROC curve for the criteria previously proposed was 0.537 (p?<?0.001). The p-value for comparing those 2 areas was less than 0.001, indicating statistical significance. Patients with MRSA bacteremia without any of our proposed clinical criteria have very low risk of developing IE and may not require routine TEE.     

Atopic dermatitis is not independently associated with nonfatal myocardial infarction or stroke among US women

We aimed to determine the association between atopic dermatitis (AD) and cardiovascular events in the Nurses' Health Study 2, a cohort of US women. We used logistic regression models to calculate age‐ and multivariate‐adjusted odds ratios (OR) and 95% confidence intervals (CI) for the associations between history of AD and nonfatal MI and nonfatal stroke. Of the 78 702 participants in our analysis, 7916 (10%) had a history of AD. There were 392 and 391 cases of nonfatal MI and stroke, respectively. AD was not associated with MI in age‐ or multivariate‐adjusted analyses. AD was significantly associated with stroke in the age‐adjusted analysis (OR 1.38, 95% CI 1.03–1.85). This was no longer significant in multivariate models that adjusted for hypertension, hypercholesterolemia and diabetes (OR 1.31, 95% CI 0.98–1.76) and atopic comorbidities (OR 1.17, 95% CI 0.86–1.58). AD was not independently associated with nonfatal MI or stroke in this study.     

A heterozygote phenotype is present in the jvs +/- mutant mouse livers

The juvenile visceral steatosis (jvs) mouse, having a mutation in the carnitine transporter gene Octn2, is a model of primary systemic carnitine deficiency in humans (SCD, OMIM 212140). Like humans with SCD, homozygous jvs -/- mice have hepatic and cardiac steatoses, reduced plasma and tissue carnitines, and increased urinary carnitine clearance. Because symptomatic heterozygotes have been reported for some fatty acid oxidation disorders, including SCD, we compared the jvs heterozygotes to normal control mice. We measured the free and esterified carnitine, total cholesterol, and triglycerides in adult liver samples, myocardium, and skeletal muscle. Our results indicate significant differences between the livers of nonfasting adult normal (n = 8) vs jvs heterozygotes (n = 8) (means +/- SEM, p < 0.01) for the following parameters: free carnitine, 2.28 +/- 0.36 nmol/mg protein vs 0.41 +/- 0.13; total carnitine, 3.48 +/- 0.36 vs 1.27 +/- 0.25; triglycerides, 0.14 +/- 0.04 vs 0.39 +/- 0.02; and total cholesterol, 0.21 +/- 0.02 vs 0.39 +/- 0.04, but not for esterified carnitine, 1.18 +/- 0.17 vs 0.90 +/- 0.17 (p > 0.05). There is also a negative correlation between hepatic free carnitine and triglycerides from jvs heterozygotes (p < 0.05). Similar results were obtained with myocardium and skeletal muscle. We conclude that free and total carnitine levels are significantly lower in the heterozygote mouse liver and heart while triglyceride and total cholesterol levels are significantly higher. We speculate that in situations of lipolytic stress, some SCD heterozygotes might develop clinical symptoms of carnitine deficiency.     

A murine model of dual infection with cytomegalovirus and Pneumocystis carinii: effects of virus-induced immunomodulation on disease progression

Despite the use of antimicrobial prophylaxis, cytomegalovirus (CMV) and Pneumocystis carinii (PC) pneumonia (PCP) are both leading causes of morbidity and mortality in immunocompromised patients. It has previously been reported that CMV infection modulates host immune responses with a variety of mechanisms which include the suppression of helper T cell functions and antigen presenting cell (APC) functions, both of which are critical for PCP resolution. However, the mechanisms of these interactions and other possible immune regulatory effects are not clearly understood. In this study, we investigated the impact of murine CMV (MCMV) induced immunomodulation on the progression of PCP in a co-infection model. Initial results show that dually infected mice had evidence of more severe PC disease, which include a greater loss of body weight, an excess lung PC burden and delayed clearance of PC from lungs, compared to mice with PC infection alone. At day 7 post-infection, dually infected mice had reduced numbers of MHC-II expressing cells in the lung interstitium and lymph nodes and reduced migration of CD11c+ cells to both the tracheobronchial lymph nodes and alveolar spaces. Dual infected mice showed elevated numbers of specific CD8 responses concomitant with a decrease in activated CD4+ T cells in both the lymph nodes and in alveolar spaces when compared to mice infected with MCMV alone. These data suggest that MCMV infection inhibits the immune responses generated against PC which contribute to the delayed clearance of the organism.     

Prevalence and predictors of anthracycline cardiotoxicity in children treated for acute myeloid leukaemia: retrospective cohort study in a single centre in the United Kingdom

Background

Anthracycline cardiomyopathy is of concern in children treated for acute myeloid leukaemia (AML), but there are few data on the incidence and natural history of cardiotoxicity after AML treatment in the United Kingdom, where regimens have included high anthracycline exposure.

Procedure

Prevalence and predictors of cardiotoxicity were retrospectively reviewed in 124 children treated on the MRC AML 10 and AML 12 trials in a single, large centre from November 1987 to September 2004. Subclinical cardiotoxicity was defined as a shortening fraction of less than 28% and clinical cardiomyopathy as evidence of heart failure, and both were classified as late cardiotoxicity 1 year after completing first line therapy.

Results

Cumulative survival was 61% at 10 years. The prevalence of early and late cardiotoxicity was 13.7% (95%‐CI: 8.2–22.0%) and 17.4% (95%‐CI: 10.9–26.8%), respectively. Early cardiotoxicity was a strong predictor (OR = 9.18; 95%‐CI: 2.10–40.11; P < 0.005) and children who received salvage therapy following relapse showed a trend towards increased late cardiotoxicity (OR = 3.53; 95%‐CI: 0.86–14.48; P < 0.08). Subclinical cardiotoxicity resolved spontaneously in all but one case, but clinical cardiomyopathy always required continuing therapy. Two children died of cardiomyopathy and six remained on medical therapy.

Conclusions

Anthracycline cardiotoxicity remains a major concern for survivors of childhood AML and correlates with early cardiotoxicity and treatment intensity. Long‐term follow‐up is required to fully determine the outcome for children with subclinical cardiotoxicity. Pediatr Blood Cancer 2011;56:625–630. © 2011 Wiley‐Liss, Inc.