Contribution of specific binding to the central benzodiazepine site to the brain concentrations of two novel benzodiazepine site ligands

The in vivo occupancy of brain benzodiazepine binding sites by compounds A and B was measured using a [(3)H]Ro 15-1788 binding assay and related to plasma and brain drug concentrations. The plasma concentration associated with 50% occupancy was higher for compound A than compound B (73 and 3.7 nM, respectively), however, there was little difference in the brain concentrations required (73 and 63 nM). Both compounds showed a non-linear relationship between plasma and brain concentrations such that above brain concentrations of approximately 100 nM increasing plasma concentrations did not result in a concomitant increase in brain concentrations. This is consistent with brain concentrations being dependent on a saturable compartment which was postulated to be the benzodiazepine binding site-containing GABA(A) receptors. This hypothesis was tested in alpha1H101R mice, in which the alpha1 subunit of the GABA(A) receptor is rendered insensitive to benzodiazepine binding resulting in an approximate 50% reduction in the total benzodiazepine-containing GABA(A) receptor population. It was shown that the Occ(50) brain concentrations in the alpha1H101R animals was lower (17 nM) than in wild type mice (63 nM), as was the plateau concentration in the brain (105 and 195 nM, respectively). These data suggest measured concentrations of compounds A and B in brain tissue are dependent on receptor expression with a minimal contribution from unbound and non-specifically bound compound.     

HER2/neu in systemic therapy for women with breast cancer: a systematic review

BACKGROUND: Amplification and/or overexpression of the HER2/neu gene is associated with a poor prognosis in breast cancer. Many studies have suggested that this gene may be associated with the relative efficacy of chemotherapy and endocrine therapy options. METHODS: A systematic review of the evidence was conducted. MEDLINE, EMBASE, the Cochrane Library, the American Society of Clinical Oncology annual meeting proceedings, and the San Antonio Breast Cancer Symposia proceedings were all searched to November 2006 for reports of analysis by HER2/neu status of the relative efficacy of the treatment arms in randomized controlled trials. RESULTS: Thirty-five trials were identified. A meta-analysis of trials of tamoxifen versus observation found no significant interaction between treatment and HER2/neu status, although one trial not included in the meta-analysis did find interaction. A meta-analysis of adjuvant anthracycline-based chemotherapy trials found a significant interaction (difference in disease-free survival log-hazard ratios -0.31, 95% confidence interval -0.50 to -0.13; difference in overall survival log-hazard ratios -0.34, 95% confidence interval -0.53 to -0.14). Significant interaction was also found in a meta-analysis of disease-free survival in trials of adjuvant taxane therapy versus non-taxane therapy (difference in disease-free survival log-hazard ratios -0.36, 95% confidence interval -0.68 to -0.04). HER2/neu overexpression and/or amplification was associated with greater efficacy of the anthracycline or taxane regimen. CONCLUSIONS: Current evidence supports the conclusion that the benefit of both anthracycline-based and taxane-based adjuvant chemotherapy is associated on HER2/neu status, with patients with HER2/neu-positive cancers benefiting more from these therapies than those with HER2/neu-negative cancers.     

Accuracy of surgeon prediction of appendicitis severity in pediatric patients

PurposeClinical prediction of disease severity is important as one considers nonoperative management of simple appendicitis. This study assesses the accuracy of surgeons' prediction of appendicitis severity.MethodsFrom February to August 2016, pediatric surgeons at a single institution were asked to predict whether patients had simple or complex appendicitis preoperatively based on clinical data, imaging, and general assessment. Receiver operating characteristic curves were generated to determine area under the curve (AUC) and optimal cutoff points of clinical findings for diagnosing simple appendicitis. Outcomes included sensitivity and specificity of variables to identify simple appendicitis. Predictions were compared to operative findings using χ². A p-value < 0.05 was considered statistically significant.ResultsOf 125 cases (median age 9 years [IQR 7–13], 58% male), simple appendicitis was predicted in 77 (62%) and complex appendicitis in 48 (38%). Predictions were accurate in 59 (77%) simple cases and 45 (94%) complex cases. Although surgeon prediction was more accurate than individual imaging or clinical findings and was highly sensitive (95%) for diagnosing simple appendicitis, specificity was only 71%.Lower WBC (< 15.5 × 10³/μL, AUC 0.61, p = 0.05), afebrile (< 100.4 °F, AUC 0.86, p < 0.01), and shorter symptom duration (≤ 1.5 days, AUC 0.71, p < 0.001) were associated with simple appendicitis. Of 18 complex cases (14%) inaccurately predicted as simple, 17 (94%) lacked diffuse tenderness, 15 (83%) were well-appearing, 11 (61%) had ultrasound findings of simple appendicitis, 11 (61%) had ≤ 2 days of symptoms, and 8 (44%) were afebrile (< 100.4 °F).ConclusionWhile surgeon prediction of simple appendicitis is more accurate than ultrasound or clinical data alone, diagnostic accuracy is still limited.Type of studyProspective survey.Level of evidenceII     

HHV‐8‐related visceral Kaposi’s sarcoma following allogeneic HSCT: Report of a pediatric case and literature review

Sala I, Faraci M, Magnano GM, Sementa A, di Marco E, Garaventa A, Micalizzi C, Lanino E, Morreale G, Moroni C, Castagnola E. HHV‐8‐related visceral Kaposi’s sarcoma following allogeneic HSCT: Report of a pediatric case and literature review.
Pediatr Transplantation 2011: 15:E8–E11. © 2010 John Wiley & Sons A/S. Abstract: An HHV‐8‐related visceral KS was diagnosed in a 10‐yr‐old boy after partially matched allogeneic HSCT. This complication occurred 463 days after HSCT and involved tonsils, lymph nodes, hard palate, lung, skin, and paranasal sinuses. Treatment with pegylated liposomal doxorubicin induced long‐term remission (33 months) of this disease. HHV‐8 infection is quite frequent after HSCT, but KS, and especially its visceral form, is a very rare complication, and its association with HHV‐8 has been documented even less frequently. However, our observation suggests that HHV‐8‐related KS should be taken into consideration in the differential diagnosis of late post‐HSCT complications.     

Relationship between serum uric acid levels and urinary albumin excretion in patients with heart failure

OBJECTIVES: Hyperuricaemia is a constant finding in patients with heart failure (HF). Upregulated xanthine-oxidase activity seems to contribute to progression of the disease through the production of oxidative stress and the development of vascular and endothelial dysfunction. On this basis we speculated that in HF serum uric acid levels correlated with a reliable marker of endothelial dysfunction as urinary albumin excretion. METHODS: Fifty-three patients with HF underwent assessment of serum uric acid, N-terminal probrain natriuretic peptide (NT-proBNP), glomerular filtration rate (GFR), other metabolic parameters and determination of urinary albumin concentration (UAC) in a morning urine sample. RESULTS: In univariate analysis there is a direct correlation between serum uric acid levels and log UAC (r = 0.43, P < 0.01); uric acid correlates also positively with log NT-proBNP (r = 0.31, P < 0.05) and negatively with log-GFR (r = -0.38, P < 0.01). In stepwise regression analysis serum uric acid emerged as the only predictor of increased UAC (standardized coefficient = 0.42, P = 0.001) independent of other clinical determinants and metabolic factors. CONCLUSION: Serum uric acid represents the strongest predictor of elevated UAC in HF. Regression of albuminuria may be a simple target to verify the efficacy of xanthine-oxidase inhibition in these patients.