Myosteatosis at diagnosis is adversely associated with 2-year survival in women with estrogen receptor-negative metastatic breast cancer

Breast Cancer Research and Treatment - To examine the relationship between skeletal muscle (SM) and cancer-specific outcomes for women with estrogen receptor-negative (ER?) metastatic breast...     

Compartmental Pharmacokinetics and Tissue Drug Distribution of the Pradimicin Derivative BMS 181184 in Rabbits

The pharmacokinetics of the antifungal pradimicin derivative BMS 181184 in plasma of normal, catheterized rabbits were characterized after single and multiple daily intravenous administrations of dosages of 10, 25, 50, or 150 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of BMS 181184 were determined by a validated high-performance liquid chromatography method, and plasma data were modeled into a two-compartment open model. Across the investigated dosage range, BMS 181184 demonstrated nonlinear, dose-dependent kinetics with enhanced clearance, reciprocal shortening of elimination half-life, and an apparently expanding volume of distribution with increasing dosage. After single-dose administration, the mean peak plasma BMS 181184 concentration (C_max) ranged from 120 μg/ml at 10 mg/kg to 648 μg/ml at 150 mg/kg; the area under the concentration-time curve from 0 to 24 h (AUC_0–24) ranged from 726 to 2,130 μg · h/ml, the volume of distribution ranged from 0.397 to 0.799 liter/kg, and the terminal half-life ranged from 4.99 to 2.31 h, respectively (P < 0.005 to P < 0.001). No drug accumulation in plasma occurred after multiple daily dosing at 10, 25, or 50 mg/kg over 15 days, although mean elimination half-lives were slightly longer. Multiple daily dosing at 150 mg/kg was associated with enhanced total clearance and a significant decrease in AUC_0–24 below the values obtained at 50 mg/kg (P < 0.01) and after single-dose administration of the same dosage (P < 0.05). Assessment of tissue BMS 181184 concentrations after multiple dosing over 16 days revealed substantial uptake in the lungs, liver, and spleen and, most notably, dose-dependent accumulation of the drug within the kidneys. These findings are indicative of dose- and time-dependent elimination of BMS 181184 from plasma and renal accumulation of the compound after multiple dosing.     

Effect of cortisone treatment on the active transport of calcium by the small intestine

It is generally recognized that glucocorticoid administration may diminish calcium absorption in vivo as well as the active transport of calcium by the intestine in vitro. Recent studies by others have emphasized the possibility of an alteration in the metabolism of vitamin D to 25-hydroxycholecalciferol in accounting for the steroid effects on calcium absorption. The results obtained in the present studies fail to support this hypothesis.The present studies confirm that the administration of cortisone or other glucocorticoids to the rat interferes with the active transport of calcium by duodenal gut sacs in vitro. This abnormality is not due to an alteration in the permeability of the intestine to calcium, and it cannot be corrected by the administration of either massive doses of vitamin D(2) or modest doses of 25-hydroxycholecalciferol. Experiments concerned with the effects of cortisone on the level of the vitamin D-dependent duodenal calcium-binding protein, the amount of bioassayable vitamin D activity in the mucosa, and the distribution and metabolism of (3)H-vitamin D(3), did not provide evidence in favor of a harmone-related defect in either the localization of vitamin D or its metabolism to 25-hydroxycholecalciferol. Alterations in the transport of iron and D-galactose, not dependent on vitamin D, suggest that cortisone treatment may be responsible for more than a simple antagonism to the effects of vitamin D.The results of the present studies indicate that cortisone administration affects the cellular mechanisms mediating calcium transport in a manner that is opposite to the effects of vitamin D, but seems to be independent of any direct interaction with the parent vitamin or its metabolites. If a disorder in vitamin D metabolism is at all involved, it is at a step subsequent to 25-hydroxylation.     

The relevance of somatosensory auras in refractory temporal lobe epilepsies

The purpose of this study is to look at the prevalence, characteristics, and prognostic value of somatosensory auras (SSAs) in patients who have undergone temporal lobe epilepsy (TLE) surgery to treat drug‐resistant focal epilepsy. We retrospectively reviewed all patients with drug‐resistant epilepsy who underwent TLE surgery at Cleveland Clinic between 2005 and 2010 (n = 333) to study the prevalence, characteristics, and prognostic implications of SSA in the context of TLE surgery. Analyses were performed using two seizure outcome definitions: complete seizure freedom and Engel classification. Of the 333 patients, 26 (7.8%) had SSA. Almost half (12 patients) had unilateral sensory symptoms, whereas the rest had bilateral symptoms. Tingling and numbness were the most frequently reported sensations. Compared to their non‐SSA counterparts, patients with SSA had the same clinical and imaging characteristics, but had a higher rate of breakthrough seizures (p = 0.03), although most (54%) were still able to achieve Engel class of I (p = 0.02). Based on our results we would encourage detailed presurgical testing, which may include an invasive evaluation to analyze the extent of the epileptogenic zone in patients with SSA and suspected TLE.     

Increasing incidence of HIV‐ associated tuberculosis in Romanian injecting drug users

Background

A high prevalence of tuberculosis (TB) among HIV‐positive injecting drug users (IDUs) may fuel the TB epidemic in the general population of Romania. We determined the frequency and characteristics of TB in HIV‐infected IDUs referred to a national centre.

Methods

Prospective observational cohort study of all newly‐diagnosed HIV‐positive IDUs admitted to Victor Babes Hospital, Bucharest, between January 2009 and December 2014. Socio‐demographics, clinical characteristics and outcomes of HIV/TB co‐infected IDUs were compared to HIV‐positive IDUs without TB.

Results

170/598 (28.5%) HIV‐infected IDUs were diagnosed with TB. The prevalence increased from 12.5% in 2009 to 32.1% in 2014 (P < 0.001). HIV/TB co‐infected individuals had lower median CD4 cell counts 75 (vs. 450/mm³, P < 0.0001) and higher median HIV viral loads 5.6 log₁₀ (vs. 4.9 log₁₀, P < 0.0001) when presenting to healthcare services. 103/170 (60.6%) HIV/TB co‐infected IDUs were diagnosed with pulmonary TB. Resistant Mycobacterium tuberculosis strains were common, with 18/105 (17.1%) of patients having Multi‐Drug Resistant (MDR) disease. Higher mortality rate was associated with TB co‐infection (P < 0.0001), extra‐pulmonary TB (P = 0.0026) and extensively drug resistant TB (P = 0.024).

Conclusions

Tuberculosis (TB) is an increasing problem in HIV‐infected IDUs in Romania. Presentation is often with advanced HIV, significant TB drug resistance and consequent outcomes are poor.

     

Acceptability of condom promotion and distribution among 10 to 19 year-old adolescents in Mpwapwa and Mbeya rural districts, Tanzania

ABSTRACT: BACKGROUND: The HIV/AIDS pandemic remains a leading challenge for global health. Although condoms are acknowledged for their key role on preventing HIV transmission, low and inappropriate use of condoms persists in Tanzania and elsewhere in Africa. This study assesses factors affecting acceptability of condom promotion and distribution among Tanzanian adolescents. METHODS: Data were collected in 2011 as part of a larger cross-sectional survey on condom use among 10-19 year-olds in Mpwapwa and Mbeya rural districts of Tanzania using a structured questionnaire. Associations between acceptability of condom promotion and distribution and each of the explanatory variables was tested using Chi Square. Multivariate logistic regression model was used to examine independent predictors of the acceptability of condom promotion and distribution using STATA (11) statistical software at 5% significance level. RESULTS: Mean age of the 1,327 adolescent participants (50.5% being males) was 13.5 years (SD=1.4). Acceptance of condom promotion and distribution was found among 37% of the adolescents. Being sexually active and aged 15-19 was the strongest predictor of the acceptability of condom promotion and distribution (OR=7.78, 95% CI 4.65-12.99). Others were; not agreeing that a condom is effective in preventing transmissions of STIs including HIV (OR=0.34, 95% CI 0.20-0.56), being a resident of Mbeya rural district (OR=1.67, 95% CI 1.28-2.19), feeling comfortable being seen by parents/guardians holding/buying condoms (OR=2.20, 95% CI 1.40-3.46) and living with a guardian (OR=1.48, 95% CI 1.08-2.04). CONCLUSION: Acceptability of condom promotion and distribution among adolescents in Mpwapwa and Mbeya rural is low. Effect of sexual activity on the acceptability of condom promotion and distribution is age-dependent and was the strongest. Feeling comfortable being seen by parents/guardians buying or holding condoms, perceived ability of condoms to offer protection against HIV/AIDS infections, district of residence and living arrangements also offered significant predictive effect. Knowledge of these factors is vital in designing successful and sustainable condom promotion and distribution programs in Tanzania. Key words Acceptability, condom promotion and distribution, adolescents, Tanzania.     

Limb lengthening over plate

Background:

The limb lengthening over plate eliminates the associated risk of infection with limb lengthening over intramedullary nail. We present our experience of limb lengthening in 15 patients with a plate fixed on the proximal segment, followed by corticotomy and application of external fixator.

Materials and Methods:

15 patients (7 females, 8 males) were included in this consecutive series. The average age was 18.1 years (range 8–35 years). Fifteen tibiae and one femur were lengthened in 15 patients. Lengthening was achieved at 1 mm/day followed by distal segment fixation with three or four screws on reaching the target length.

Results:

The preoperative target length was successfully achieved in all patients at a mean of 4.1 cm (range 1.8–6.5 cm). The mean duration of external fixation was 75.3 days (range 33–116 days) with the mean external fixation index at 19.2 days/cm (range 10.0–38.3 days/cm). One patient suffered deep infection up to the plate, three patients had mild procurvatum deformities, and one patient developed mild tendo achilles contracture.

Conclusion:

Lengthening over a plate allows early removal of external fixator and eliminates the risk of creating deep intramedullary infection as with lengthening over nail. Lengthening over plate is also applicable to children with open physis.     

Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that is frequently associated with activating mutations in NOTCH1 and dysregulation of MYC. Here, we performed 2 complementary screens to identify FDA-approved drugs and drug-like small molecules with activity against T-ALL. We developed a zebrafish system to screen small molecules for toxic activity toward MYC-overexpressing thymocytes and used a human T-ALL cell line to screen for small molecules that synergize with Notch inhibitors. We identified the antipsychotic drug perphenazine in both screens due to its ability to induce apoptosis in fish, mouse, and human T-ALL cells. Using ligand-affinity chromatography coupled with mass spectrometry, we identified protein phosphatase 2A (PP2A) as a perphenazine target. T-ALL cell lines treated with perphenazine exhibited rapid dephosphorylation of multiple PP2A substrates and subsequent apoptosis. Moreover, shRNA knockdown of specific PP2A subunits attenuated perphenazine activity, indicating that PP2A mediates the drug’s antileukemic activity. Finally, human T-ALLs treated with perphenazine exhibited suppressed cell growth and dephosphorylation of PP2A targets in vitro and in vivo. Our findings provide a mechanistic explanation for the recurring identification of phenothiazines as a class of drugs with anticancer effects. Furthermore, these data suggest that pharmacologic PP2A activation in T-ALL and other cancers driven by hyperphosphorylated PP2A substrates has therapeutic potential.     

Host Biomarkers of Invasive Pulmonary Aspergillosis To Monitor Therapeutic Response

Invasive pulmonary aspergillosis (IPA) is a life-threatening disease of immunocompromised patients that requires aggressive therapy. Detection of the disease and monitoring of the therapeutic response during IPA are complex, and current molecular diagnostics are not suitably robust. Here, we explored proteomic profiles of bronchoalveolar lavage fluid (BALF) specimens from a persistently neutropenic rabbit model of IPA. Three experimental arms, uninfected control animals, infected untreated animals, and animals infected and treated with ravuconazole/amphotericin B, were studied. Total proteins were evaluated by two-dimensional (2D) gel electrophoresis, followed by matrix-assisted laser desorption ionization–time of flight/time of flight (MALDI-TOF/TOF) mass spectrometry (MS) and quantified by enzyme-linked immunosorbent assay (ELISA). Host-derived proteins haptoglobin (Hp), C-reactive protein (CRP), and annexin A1 (Anx A1) were prominently found in BALF during the IPA infection and showed significant changes in response to antifungal therapy (P < 0.0001). In serum, differences in Hp (P = 0.0001) between infected and treated rabbits were observed. Preliminary in vitro studies revealed that Aspergillus fumigatus-secreted proteases may contribute to the cleavage of Anx A1 during IPA. In summary, host protein biomarkers Hp, CRP, and Anx A1 may have value in monitoring therapeutic response to antifungal agents in IPA patients with confirmed disease.