We present a detailed analysis of sexual HIV transmission from one source partner to two recipients. The HLA haplotypes between the source partner and one recipient were very similar with 7 out of 8 HLA alleles from four loci (HLA A, B C and DRB) shared, while the other recipient shared only one allele. The immunologic outcomes between the two recipients differed dramatically, despite the absence of apparent virologic differences in their inoculums. We suggest that non-viral factors, which might be related to differences in the HLA profile, played a role in determining different CD4+ T-cells dynamics for these two recipients.
human immunodeficiency virus; cellular immunity; HLA; evolution; transmission; disease progression; concordance
This study aims to examine the metabolic effects of intensification or initiation of insulin treatment with biphasic insulin 50/50, and determine the predictors of responders or non-responders to biphasic insulin 50/50.
A cohort of 2183 patients ≥18 years with diabetes, newly treated with biphasic insulin 50/50 between January 2000 and May 2012, were sourced from UK General Practices via The Health Improvement Network (THIN) database. Baseline clinical parameters of 1267 patients with suboptimal glycated hemoglobin (HbA1c) >7.5% (>58 mmol/mol) who had received background insulin regimens for at least 6 months preceding biphasic insulin 50/50 were compared against 12-month outcome data. Responders were defined as those with HbA1c <7.5% (58 mmol/mol) and/or HbA1c reduction of ≥1% (10.9 mmol/mol) at 12 months. Comparative analyses were carried out on subgroups of 237 patients initiating insulin therapy with biphasic insulin 50/50, and between users of the Humalog Mix50 (HM50) versus Insuman Comb 50 (IC50). Associations were examined using t tests and multivariate logistic regression techniques.
The overall mean HbA1c reduction at 12 months as a result of intensification and initiation with biphasic insulin 50/50 was 0.5% (5.5 mmol/mol) and 1.6% (17.5 mmol/mol), respectively. Adjusted ORs show obesity (body mass index >30 kg/m2), treatment duration for ≥9 months, and baseline HbA1c are independent determinants of responders. In addition, stratified for baseline HbA1c levels, HM50 was associated with better HbA1c outcome compared with IC50.
biphasic insulin 50/50 is effective for achieving glycemic control in suboptimal HbA1c levels, especially among obese patients with insulin-treated diabetes. Stratified for baseline HbA1c, HM50 was associated with improved HbA1c outcome compared with IC50.
We determined lung bioavailability of a fluticasone propionate (FP) pressurised metred-dose inhaler (Flovent® HFA; GlaxoSmithKline, Research Triangle Park, NC, USA) administered via AeroChamber Plus® (Monaghan Medical, Plattsburgh, NY, USA) with Facemask and Babyhaler® (GlaxoSmithKline) valved holding chambers (VHCs) using a population pharmacokinetic approach.
Children from 1 to <4 yrs of age with stable asthma but a clinical need for inhaled corticosteroid therapy were administered 88 µg FP hydrofluoroalkane (2 × 44 µg) twice daily delivered through the two devices in an open-label, randomised crossover manner for 8 days each. Patients were randomised to one of three sparse sampling schedules for blood collection throughout the 12-h dosing interval on the 8th day of each treatment for pharmacokinetic analysis. The area under the FP plasma concentration–time curve (AUC) was determined for each regimen.
17 children completed the study. The population mean AUC following FP with AeroChamber Plus® with Facemask was 97.45 pg·h·mL−1 (95% CI 85.49–113.32 pg·h·mL−1) and with Babyhaler® was 51.55 pg·h·mL−1 (95% CI 34.45–64.46 pg·h·mL−1). The relative bioavailability (Babyhaler®/AeroChamber Plus®) was 0.53 (95% CI 0.30–0.75).
Clinically significant differences in lung bioavailability were observed between the devices. VHCs are not interchangeable, as differences in drug delivery to the lung may occur. A population pharmacokinetic approach can be used to determine lung bioavailability of FP.
Asthma; inhaled corticosteroid; lung bioavailability; preschool children; valved holding chamber
Acute kidney injury (AKI) is increasingly prevalent in developing and developed countries and is associated with severe morbidity and mortality. Most etiologies of AKI can be prevented by interventions at the individual, community, regional and in-hospital levels. Effective measures must include community-wide efforts to increase an awareness of the devastating effects of AKI and provide guidance on preventive strategies, as well as early recognition and management. Efforts should be focused on minimizing causes of AKI, increasing awareness of the importance of serial measurements of serum creatinine in high risk patients, and documenting urine volume in acutely ill people to achieve early diagnosis; there is as yet no definitive role for alternative biomarkers. Protocols need to be developed to systematically manage prerenal conditions and specific infections. More accurate data about the true incidence and clinical impact of AKI will help to raise the importance of the disease in the community, increase awareness of AKI by governments, the public, general and family physicians and other health care professionals to help prevent the disease. Prevention is the key to avoid the heavy burden of mortality and morbidity associated with AKI.
Acute Kidney Injury; Health; Morbidity; Mortality; Prevention and control
The role of the estrogen receptor β (ERβ) in the colon has received considerable interest, yet in vivo models are needed to better define its protective actions. In the present study, wild-type (WT), ERα and ERβ knockout (αERKO and βERKO) mice were injected with azoxymethane (AOM), a colon chemical carcinogen. Fourteen weeks after AOM exposure the incidence of aberrant crypt foci (ACF) was assessed by methylene blue staining. βERKO mice showed significantly higher incidence (P < 0.001) of ACF (15.0 ± 2.5) as compared to αERKO (3.4 ± 1.0) and WT (4.6 ± 1.0) mice. The colons in several βERKO mice had increased thickness and loss of normal morphology. It has been reported that ERβ plays a role in maintenance of the colonic crypt architecture; this may explain the loss of crypt organization in the colonic epithelium of βERKO mice. The presence of mucin depleted foci (MDF) has been shown, both in humans and in rodents, as an early event in colon cancer. Therefore, in order to surpass the limitations with ACF scoring, we performed alcian blue-neutral red staining to assess the presence of MDF. This assay allowed the assessment of precancerous lesions on all the βERKO mice colons (38.3 ± 4.0; P < 0.001), comparing to WT and αERKO mice (6.6 ± 1.5, and 10.0 ± 1.9, respectively), and served to confirm the ACF results. Together these data support the use of MDF staining as a biomarker for precancerous lesions and the protective role of ERβ in colon carcinogenesis.
Estrogen receptors; colon cancer; aberrant crypt foci; mucin depleted foci
Many chronic inflammatory diseases are associated with increased risk of developing cancer. In the colon, strong support for a link between chronic inflammation and cancer extends, in part, from population-based studies of persons with inflammatory bowel disease (IBD). Patients with IBD are at increased risk of developing colorectal cancer (CRC). The general consensus is that IBD results from the combined effects of genetics and environment factors known to affect the immune system. Vitamin D, an important regulator of the immune system, has been linked to IBD. Despite the strong potential reported for 1,25-dihydroxyvitamin D (1,25-OH)2D), its strong effects on calcium metabolism limits its potential value. Recently, less active vitamin D metabolites, cholecalciferol and 25-hydroxyvitamin D (25(OH)D), have gained considerable attention as promising agents against IBD-related colon cancer. Yet, their anti-proliferative properties and mechanism of action remain to be better defined. We present several signaling pathways commonly regulated by vitamin D compounds and highlight their regulation on TLR4. The efficacy of 25(OH)D and 1α-hydroxyviatmin D5 are defined using the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced IBD-related colon carcinogenesis model. In summary, vitamin D supplementation may provide a cost-effective approach to reduce IBD related colon cancer.
Vitamin D; inflammation; colon cancer
This study was to investigate the association between tCho and the clinical characteristics and biomarker status of breast cancer. Sixty-two patients with breast cancer which was 1.5 cm or larger in size on MR images were studied. The tCho concentration was correlated with the MR imaging features, the contrast enhancement kinetics, clinical variables, and biomarkers. Pair-wise two-tailed Spearman’s non-parametric test was used for the statistical analysis. The tCho was higher in high grade than moderate/low grade tumor (p=0.04) and in tumors with higher Ktrans and kep (p<0.001 for both). The association of tCho with age (p=0.05) and triple negative biomarker (p=0.09) approached significance. tCho was not detected in 17 patients, including 15 invasive ductal cancer and 2 infiltrating lobular cancer. Fifteen of the 17 patients had moderate to low grade cancers, and 11 had HER-2 negative cancer, suggesting these two factors might lead to false negative choline. Higher tCho in high grade tumors and tumors with higher Ktrans and kep indicates choline is associated with cell proliferation and tumor angiogenesis. Higher choline level in younger women may be due to their more aggressive tumor type. The results presented here may aid in better interpretation of 1H MRS for diagnosis of breast lesions.
We describe the changes in the prevalence of overweight and obesity in 4606 students that applied to a Mexican University during 1994 to 2008. The mean (± standard deviation [SD]) age was 17.7 ± 1.2 years-old. Progressive and significant increments of bodyweight (female [F] = 2.6, P = 0.03), body mass index (BMI) (F = 4.4, P = 0.001), and waist circumference (F = 30.08, P < 0.0001) in women, and bodyweight (male [M] = 8.9, P < 0.001), BMI (M = 10.4, P < 0.001), and waist circumference (M = 13.01, P < 0.001) in men were observed. A significant increment (P < 0.05) in the prevalence of overweight since 1994 (n = 87, 12.1%) throughout 1997 (n = 102, 14.1%), 1998 (n = 133, 18.4%), 1999 (n = 1993, 26.8%), and 2008 (n = 206, 19.9%) was documented. Similarly, the prevalence of obesity had a significant increment in all students evaluated (P < 0.0001) since 1994 (n = 29, 13.2%) through 1997 (n = 11, 5.0%), 1998 (n = 45, 20.5%), 1999 (n = 53, 24.1%), and 2008 (n = 82, 37.3%). The increment was significant in both women (P = 0.02) and men (P < 0.001). In summary, we report a significant increment in the prevalence of overweight and obesity in Mexican students living in an urban setting over a time period of 14 years.
body mass index; adolescents; weight problems; obese
Clinical and experimental studies showing lung damage associated with biologically active neutrophil derivatives suggests the possibility that intrauterine neutrophil activation may predispose to the development of pulmonary haemorrhage in extremely low birthweight infants early after birth.
To assess neutrophil functional activity in cord blood from extremely low birthweight infants who subsequently developed severe pulmonary haemorrhage.
Neutrophil functional activity was evaluated in the cord blood of preterm neonates (gestational age <28 weeks and weight <800 g) who developed pulmonary haemorrhage (n = 6) and in controls who did not (n = 6). Infants with congenital abnormalities and noteworthy maternal complications such as diabetes, pre‐eclampsia, haemorrhagic disorders, and connective tissue disease were excluded. Neutrophils isolated from cord blood immediately after delivery were tested to evaluate neutrophil chemotaxis, random motility, and chemiluminescence. Standard methodology was used.
Chemotaxis and chemiluminescence of neutrophils from cord blood of infants with pulmonary haemorrhage was higher than in the controls (34.8 (2.0) v 28.6 (0.8) μm, p<0.001, and 95.8 (8.5) v 73.2 (3.6) cpm ×103, p<0.001 respectively). Random motility of cord blood neutrophils was comparable in the two groups (28.6 (1.2) v 25.3 (1.2) μm, p<0.09).
Intrauterine induction of chemotactic activity and metabolic oxygenation of neutrophils may predispose to the development of pulmonary haemorrhage in extremely low birthweight infants with respiratory distress early after birth.
preterm; neutrophil functional activity; pulmonary haemorrhage; lungs
To identify in a prospective observational study the cardiac structural and functional abnormalities and mortality in patients with end stage renal disease (ESRD) with a raised cardiac troponin T (cTnT) concentration.
126 renal transplant candidates were studied over a two year period. Clinical, biochemical, echocardiographic, coronary angiographic, and dobutamine stress echocardiographic (DSE) data were examined in comparison with cTnT concentrations dichotomised at cut off concentrations of < 0.04 μg/l and < 0.10 μg/l.
Left ventricular (LV) size and filling pressure were significantly raised and LV systolic and diastolic function parameters significantly impaired in patients with raised cTnT, irrespective of the cut off concentration. The proportions of patients with diabetes and on dialysis were higher in both groups with raised cTnT. With a cut off cTnT concentration of 0.04 μg/l but not 0.10 μg/l, significantly more patients had severe coronary artery disease and a positive DSE result. The total ischaemic burden during DSE was similar in cTnT positive and negative patients, irrespective of the cut off concentration used. LV end systolic diameter index and E:Ea ratio were independent predictors of cTnT rises ⩾ 0.04 μg/l and ⩾ 0.10 μg/l, respectively. Diabetes was independently associated with cTnT at both cut off concentrations. Mortality was higher in all patients with raised cTnT.
Patients with ESRD with raised cTnT concentrations have increased mortality. Raised concentrations are strongly associated with diabetes, LV dilatation, and impaired LV systolic and diastolic function, but not with severe coronary artery disease.
end stage renal disease; cardiac troponin T; renal failure; cardiac structure
A simple, specific, accurate and stability indicating reversed phase high performance liquid chromatographic method was developed for the simultaneous determination of atorvastatin calcium and amlodipine besylate in tablet dosage forms. A phenomenex Gemini C-18, 5 μm column having 250×4.6 mm i.d. in isocratic mode, with mobile phase containing 0.02 M potassium dihydrogen phosphate:acetonitrile:methanol (30:10:60, v/v/v) adjusted to pH 4 using ortho phosphoric acid was used. The flow rate was 1.0 ml/min and effluents were monitored at 240 nm. The retention times of atorvastatin calcium and amlodipine besylate were 11.6 min and 4.5 min, respectively. The calibration curves were linear in the concentration range of 0.08-20 μg/ml for atorvastatin calcium and 0.1-20 μg/ml for amlodipine besylate. Atorvastatin calcium and amlodipine besylate stock solutions were subjected to acid and alkali hydrolysis, chemical oxidation and dry heat degradation. The degraded product peaks were well resolved from the pure drug peak with significant difference in their retention time values. The proposed method was validated and successfully applied to the estimation of atorvastatin calcium and amlodipine besylate in combined tablet dosage forms.
Atorvastatin calcium; amlodipine besylate; degradation; reversed phase liquid chromatography; stability indicating; validation
A simple, specific, accurate and stability indicating reversed phase liquid chromatographic method was developed for the determination of nebivolol hydrochloride in tablet dosage forms. A phenomenex Gemini C-18, 5 μm column having 250×4.6 mm i.d., with mobile phase containing methanol: acetonitrile: 0.02 M potassium dihydrogen phosphate (60:30:10, v/v/v; pH 4.0) was used. The retention time of nebivolol hydrochloride was 2.6 min. The linearity for nebivolol hydrochloride was in the range of 0.2-10 μg/ml. The recovery was found to be in the range of 98.68-100.86%. The detection limit and quantification limit were found to be 0.06 μg/ml and 0.2 μg/ml, respectively. Nebivolol stock solutions were subjected to acid, alkali and neutral hydrolysis, chemical oxidation and dry heat degradation. The degraded product peaks were well resolved from the pure drug peak with significant difference in their retention time values. The proposed method was validated and successfully applied to the estimation of nebivolol hydrochloride in tablet formulations.
Nebivolol hydrochloride (NEB); degradation; reversed phase liquid chromatography; stability indicating; validation
A simple, specific, accurate, and precise reverse phase liquid chromatographic method was developed and validated for the estimation of risperidone in tablet dosage forms. A Phenomenex Gemini C-18, 5 μm column having 250×4.6 mm i.d. in isocratic mode, with mobile phase containing methanol: acetonitrile: 50 mM potassium dihydrogen orthophosphate (80:10:10 v/v) was used. The flow rate was 1.3 ml/min and effluents were monitored at 234 nm. Clozapine was used as an internal standard. The retention time of risperidone and clozapine were 2.5 min and 3.3 min, respectively. The method was validated for linearity, accuracy, precision, specificity, limit of quantification, limit of detection, robustness and stability. The limit of detection and limit of quantification for estimation of risperidone was found to be 500 ng/ml and 990 ng/ml, respectively. Recovery of risperidone was found to be in the range of 99.02-101.68%. Proposed method was successfully applied for the quantitative determination of risperidone in tablet formulations.
Reverse phase liquid chromatography; risperidone; RP-HPLC; specificity; validation
A simple, specific, accurate, and precise reverse phase high performance liquid chromatographic method was developed and validated for the estimation of venlafaxine hydrochloride in tablet dosage forms. A Phenomenex Gemini C-18, 5 μm column having 250 × 4.6 mm i.d. in isocratic mode, with mobile phase containing methanol: 0.05 M potassium dihydrogen orthophosphate (70:30, v/v; pH 6.2) was used. The flow rate was 1.0 ml/min and effluents were monitored at 226 nm. Carbamazepine was used as an internal standard. The retention time of venlafaxine hydrochloride and carbamazepine were 3.7 min and 5.3 min, respectively. The method was validated for specificity, linearity, accuracy, precision, limit of quantification, limit of detection, robustness and solution stability. Limit of detection and limit of quantification for estimation of venlafaxine hydrochloride were found to be 100 ng/ml and 300 ng/ml, respectively. Recoveries of venlafaxine hydrochloride in tablet formulations were found to be in the range of 99.02-101.68%. Proposed method was successfully applied for the quantitative determination of venlafaxine hydrochloride in tablet dosage forms.
Venlafaxine hydrochloride; carbamazepine; antidepressant; RP-HPLC; validation