The use of macrolides in treatment of upper respiratory tract infections

Antimicrobial resistance is a growing problem among upper respiratory tract pathogens. Resistance to β-lactam drugs among Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes is increasing. As safe and well-tolerated antibiotics, macrolides play a key role in the treatment of community-acquired upper respiratory tract infections (RTIs). Their broad spectrum of activity against gram-positive cocci, such as S. pneumoniae and S. pyogenes, atypical pathogens, H. influenzae (azithromycin and clarithromycin), and Moraxella catarrhalis, has led to the widespread use of macrolides for empiric treatment of upper RTIs and as alternatives for patients allergic to β-lactams. Macrolide resistance is increasing among pneumococci and recently among S. pyogenes, and is associated with increasing use of the newer macrolides, such as azithromycin. Ribosomal target modification mediated by erm(A) [erm(TR)] and erm(B) genes and active efflux due to mef(A) and mef(E) are the principal mechanisms of resistance in S. pneumoniae and S. pyogenes. Recently, ribosomal protein and RNA mutations have been found responsible for acquired resistance to macrolides in S. pneumoniae, S. pyogenes, and H. influenzae. Although macrolides are only weakly active against macrolide-resistant streptococci species producing an efflux pump (mef) and are inactive against pathogens with ribosomal target modification (erm), treatment failures are uncommon. Therefore, macrolide therapy, for now, remains a good alternative for treatment of upper RTIs; however, continuous monitoring of the local resistance patterns is essential.     

CT-guided interstitial single-fraction brachytherapy of lung tumors: phase I results of a novel technique

PURPOSES: To assess the safety of CT-guided brachytherapy of lung malignancies and to evaluate the initial therapeutic response. PATIENTS AND METHODS: Fifteen patients with 30 lung malignancies were included in this prospective phase I trial (metastases, 28; non-small cell lung cancers, 2). Pre-interventionally two patients had a vital capacity of < 80% (39% and 63%). These two patients, and one other, had FEV1 values of < 80% predicted (17%, 48%, and 64%). Tumors with a maximum diameter of 4 cm were treated with a single brachytherapy catheter that was positioned under CT-fluoroscopy. In two tumors with tumor diameters of 5.5 and 6.5 cm, two applicators were used. In one patient with an 11-cm irregularly shaped tumor, nine catheters were inserted. Treatment planning for 192Ir brachytherapy was performed using three-dimensional CT data that were acquired after percutaneous applicator positioning. All procedures were performed under local anesthesia. A follow-up CT was performed 6 weeks later and every 3 months pos-tintervention. RESULTS: The mean diameter of the 30 lung tumors was 2 cm (range, 0.6 to 11 cm; median diameter, 1.5 cm). The minimal dose within the tumor margin was 20 Gy in all 30 tumors treated. Except for nausea in one patient and focal hemorrhage detected on CT in two patients, no acute adverse events were recorded. One patient developed an abscess at the previous tumor location 9 months after treatment, which proved to be a local tumor recurrence. The median follow-up period was 5+ months with a local tumor control of 97%. CONCLUSION: The novel technique of CT-guided interstitial brachytherapy was safe for the treatment of lung tumors and yielded a very low complication rate. The initial data on therapeutic response are promising.     

Temperature homeostasis in transgenic mice lacking thyroid hormone receptor-alpha gene products

We studied temperature homeostasis in male mice lacking all thyroid hormone receptor-alpha gene products (TRalpha-0/0). As other TRalpha-deficient mice, TRalpha-0/0 mice have lower core body temperature (T(C)) than cognate wild-type controls. We found that obligatory thermogenesis is normal in TRalpha-0/0 and that the lower T(C) at room temperature (RT, 20-22 C) is caused by a down setting of the hypothalamic thermostat. However, TRalpha-0/0 mice are cold intolerant due to impaired facultative thermogenesis. Norepinephrine-induced brown adipose tissue (BAT) thermogenesis is blunted, even though BAT-relevant genes and T(4) deiodinase respond normally to cold stimulation, as do serum T(3), serum glycerol (marker of lipolysis), and heart rate. BAT normally contributes to maintain T(C) at RT, 9 C below thermoneutrality, yet TRalpha-0/0 mice do not show signs of being cold stressed at 20-22 C. Instead, oxygen consumption is greater in TRalpha-0/0 than in wild-type mice at RT, suggesting the recruitment of an alternate, cold-activated form of thermogenesis to compensate for the lack of BAT thermogenesis. These results indicate that TRalpha is necessary for T(3) to modulate the central control of T(C) and for an essential step in norepinephrine activation of BAT thermogenesis but not to sustain obligatory thermogenesis. In addition, the results provide evidence for an alternate form of facultative thermogenesis, which probably originates in skeletal muscle and that is less effective and more energy demanding than BAT thermogenesis.     

Applying core theory and spatial analysis to identify hepatitis C virus infection “core areas” in British Columbia,Canada

“Core areas” of transmission for bacterial sexually transmitted infections have been identified. However, it is unclear whether core areas apply to viral infections, such as hepatitis C virus (HCV). We used geographic mapping and spatial analysis to identify distinct core areas of HCV infection in British Columbia (BC) using the BC Hepatitis Testers Cohort (BC‐HTC), 1990‐2013. The BC‐HTC includes all BC residents tested for HCV (~1.5 million; 1990‐2013). Core HCV infection areas were identified spatially and temporally for five time periods (1990‐1993, 1994‐1998, 1999‐2003, 2004‐2008 and 2009‐2013) through thematic mapping, Kernel Density Estimation, Hotspot analysis and cluster analysis at the Census dissemination area level in ArcGIS and SatScan. HCV infection core areas were consistently identified. HCV core areas expanded from the downtown of major cities in different regions of BC (Metro Vancouver, Vancouver Island, and Northern BC; 1990‐1998), to smaller cities in Metro Vancouver and Interior BC (2000 onwards). Statistically significant clusters, or hotspots, were also observed for downtown Vancouver, Northern BC (Prince George) and Vancouver Island from 1990 to 2008 with expansion to other urban areas in Metro Vancouver from 1990‐2013. Statistically significant clusters persisted after adjustment for injection drug use, number of HCV tests, age, sex, material and social deprivation. Persistence of areas with high HCV diagnoses rates in Vancouver and Prince George supports the theory of core areas of HCV transmission. Identification of core areas can inform prevention, care and treatment programme interventions and evaluate their impact over time.     

Predictive factors for not undergoing RNA testing in patients found to have hepatitis C serology and impact of an automatic alert

The process of diagnosis and linkage to care in cases of hepatitis C virus (HCV) infection remains an obstacle to disease control. The aims of this study were to evaluate predictive factors for not undergoing RNA testing among patients with positive HCV serology and impact of incorporating an automated electronic alert with recommendations in clinical practice. We collected HCV antibody tests requested from October 2011 to September 2014 to evaluate the rate of RNA testing and predictive factors for not undergoing RNA testing. Since October 2014, an automated alert notification has been implemented to remind physicians for testing RNA after a positive HCV test and referral to specialist care. 41 403 HCV antibody tests were requested from 34 073 patients. 870 (2.55%) patients tested positive. After a median of follow‐up of 57.0 months (range 45.6‐82.1), 37.6% did not have RNA testing. The independent predictors for not undergoing RNA testing were primary care serology requests (P < 0.001), no history of drug use (P = 0.005) and a lack of social support (P = 0.015). The intervention impact was evaluated in a pre‐alert cohort (October 2011‐September 2014) and a post‐alert cohort (October 2014‐September 2015). After the incorporation of the alert, the rate of RNA testing increased from 62.4% to 77.7% (P < 0.001). Incomplete assessment of HCV infection is a challenge in primary care. The implementation of an automated alert for recommending RNA testing after a positive HCV antibody test is feasible in clinical practice and increases the rate of patients with RNA testing.     

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models,once tauopathy is initiated,by restoring the autophagic flux

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTau^P301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTau^P301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.     

Cost of care of arterial hypertension and its impact on the budget assigned to health in Mexico

OBJECTIVE: To assess the medical care costs of hypertension and their impact on the health care expenditures and on Mexico's Gross National Product (GNP). MATERIAL AND METHODS: An ecological study was conducted from June to November 1999, at Instituto Mexicano del Seguro Social (Mexican Institute of Social Security, IMSS), in Monterrey, Nuevo Leon, Mexico. A random sample of medical charts of patients with hypertension was selected, to extract data on utilization of health services and unitary costs per care episode. The cost per care episode and per hypertensive patient was calculated by adjusting the unitary cost as a function of standard and extreme utilization of IMSS health services. The resulting figure was then projected to the total population of hypertensive patients and compared to the annual health care expenditures of Mexico. RESULTS: The annual cost per patient with hypertension was $1,067 in the standard scenario and $3,913 in the extreme scenario. The annual expenditures from hypertension corresponded to 13.95% of the budget allocated to health care and to 0.71%, of Mexico's GNP. These figures changed to 51.17% and 2.61% in the extreme scenario, respectively. CONCLUSIONS: The costs of hypertension medical care account for a good portion of healthcare resources. This problem should be analyzed by multidisciplinary health teams in search of more efficient medical care alternatives.     

The involvement of the renin-angiotensin system gene polymorphisms in coronary heart disease

INTRODUCTION AND OBJECTIVES: Previous studies angiotensin-converting enzyme gene insertion/deletion polymorphism ACE (I/D), angiotensinogen gene polymorphism, and angiotensin II AT1 receptor polymorphism in relation to coronary heart disease controversial results. This study was designed to analyze the association between these gene polymorphisms and the first coronary event in individuals residing on Grand Canary Island, Spain. PATIENTS AND METHOD: Case-control study. Case subjects (n = 304) were recruited at the first coronary event; age-matched controls (n = 315) were randomly selected from the Grand Canary population. Participants were examined for the usual risk factors. Blood samples were obtained for biochemical analyses and DNA extraction. Genotyping was performed by PCR and restriction analysis. RESULTS: Neither ACE (I/D) nor AT1 receptor polymorphism was associated with coronary heart disease, whereas the frequency distribution of AGT M235T genotypes among patients and control subjects (TT: 29% and 19%; MT: 48% and 50%; MM: 22% and 31%, respectively) was statistically different (p = 0.003). Multiple logistic regression analysis identified the TT genotype of the angiotensinogen gene (OR = 1.9; 95% CI 1.1-3.4), diabetes (OR = 4.4; 95% CI 2.0-9.4) and hypertension (OR = 2.1; 95% CI 1.3-3.3) as risk factors predicting the coronary event. CONCLUSIONS: Our results provide no evidence of an association between ACE (I/D) or AT1 receptor polymorphism and coronary heart disease. However, homozygosity for the T allele of the angiotensinogen gene, diabetes and hypertension independently place individuals at higher risk of experiencing a coronary event on Grand Canary Island.