Reduced apoptosis and proliferation and increased Bcl-2 in residual breast cancer following preoperative chemotherapy

Experimental laboratory data suggest that tumour growth is a balance between apoptosis and proliferation and that suppression of drug-induced apoptosis by oncogenes such as bcl-2 may be an important cause of intrinsic chemoresistance. The aims of this study were to assess the in vivo relationship of apoptosis to proliferation and Bcl-2 protein in human breast tumours both prior to chemotherapy and in the residual resistant cell population at the completion of treatment. We examined apoptotic index (AI), Ki67 and Bcl-2 protein expression in the tissue of 40 patients with operable breast cancer immediately before ECF preoperative chemotherapy, and in 20 of these patients with residual tumour, at the completion of treatment. There was a significant positive association between AI and Ki67 both before and after chemotherapy, and in their percentage change with treatment. In the residual specimens AI and Ki67 were significantly reduced compared with pre-treatment biopsies, while Bcl-2 expression showed a significant increase. No differences were seen in the pre-treatment levels of any of the variables measured between patients obtaining pathological complete response and those who did not, although numbers were small. These data suggest that apoptosis and proliferation are closely related in vivo. It is possible that the phenotype of reduced apoptosis and proliferation, and increased Bcl-2 may be associated with breast cancer cells resistant to cytotoxic chemotherapy, although this can only be proven by assessing larger numbers of patients in relation to pathological response.     

Glutamatergic drugs exacerbate symptomatic behavior in a transgenic model of comorbid Tourette's syndrome and obsessive-compulsive disorder

We previously created a transgenic mouse model of comorbid Tourette's syndrome and obsessive-compulsive disorder (TS+OCD), by expressing a neuropotentiating cholera toxin (CT) transgene in a subset of dopamine D1 receptor-expressing (D1+) neurons thought to induce cortical and amygdalar glutamate output. To test glutamate's role in the TS+OCD-like disorder of these transgenic mice (D1CT-7 line), the effects of glutamate receptor-binding drugs on their behavior were examined. MK-801, a non-competitive NMDA receptor antagonist that indirectly stimulates cortical-limbic glutamate output, aggravated a transgene-dependent abnormal behavior (repetitive climbing and leaping) in the D1CT-7 mice at doses insufficient to induce stereotypies, and more readily induced stereotypies and limbic seizure behaviors at high doses. NBQX, a seizure-inhibiting AMPA receptor antagonist, reduced only the MK-801-dependent stereotypic and limbic seizure behavior of D1CT-7 mice, but not their transgene-dependent behaviors. These data imply that TS+OCD-like behavior is mediated by cortical-limbic glutamate, but that AMPA glutamate receptors are not an essential part of this behavioral circuit. Our findings lead to the prediction that the symptoms of human Tourette's syndrome and obsessive-compulsive disorder are elicited by excessive forebrain glutamate output.     

Don’t Have No Time: Daily Rhythms and the Organization of Time for Low‐Income Families*

Using ethnographic data from Welfare, Children, and Families: A Three‐City Study, we examined time obligations and resource coordination of low‐income mothers. Longitudinal data from 75 African American, Hispanic, and non‐Hispanic White families residing in Chicago, including information on daily routines, perceptions of time, and access to resources, were gathered via participant observation and intensive semistructured interviews over 4 years. Results indicated that families constantly improvised daily rhythms to obtain and sustain resources, including child care, transportation, and social services. Participants were proactive in identifying and coordinating resources to transition from welfare to work or to maintain paid employment. Strategies used to coordinate resources and the cost associated with the inability to do so are discussed. Policy and social service recommendations are offered.     

The incidence of inherited metabolic disorders in the West Midlands, UK.

BACKGROUND: Inherited metabolic disorders (IMDs) are a heterogeneous group of genetic conditions mostly occurring in childhood. They are individually rare but collectively numerous, causing substantial morbidity and mortality. AIMS: To obtain up-to-date estimates of the birth prevalence of IMDs in an ethnically diverse British population and to compare these estimates with those of other published population-based studies. METHODS: Retrospective data from the West Midlands Regional Diagnostic Laboratory for Inherited Metabolic Disorders (Birmingham, UK) for the 5 years (1999-2003) were examined. The West Midlands population of 5.2 million is approximately 10% of the UK population. Approximately 11% of the population of the region is from black and ethnic minority groups compared with approximately 8% for the the UK. RESULTS: The overall birth prevalence was 1 in 784 live births (95% confidence interval (CI) 619 to 970), based on a total of 396 new cases. The most frequent diagnoses were mitochondrial disorders (1 in 4929; 95% CI 2776 to 8953), lysosomal storage disorders (1 in 5175; 95% CI 2874 to 9551), amino acid disorders excluding phenylketonuria (1 in 5354; 95% CI 2943 to 9990) and organic acid disorders (1 in 7962; 95% CI 3837 to 17 301). Most of the diagnoses (72%) were made by the age of 15 years and one-third by the age of 1 year. CONCLUSIONS: These results are similar to those of the comparison studies, although the overall birth prevalence is higher in this study. This is probably due to the effects of ethnicity and consanguinity and increasing ascertainment. This study provides useful epidemiological information for those planning and providing services for patients with IMDs, including newborn screening, in the UK and similar populations.     

Randomized placebo-controlled study of low-dose warfarin for the prevention of central venous catheter-associated thrombosis in patients with cancer.

PURPOSE: In this multicenter, randomized, placebo-controlled clinical trial, we studied whether warfarin 1 mg daily reduces the incidence of symptomatic central venous catheter (CVC) -associated thrombosis in patients with cancer. PATIENTS AND METHODS: Two hundred fifty-five patients with cancer who required a CVC for at least 7 days were randomly assigned to receive warfarin 1 mg or placebo. RESULTS: There were 11 (4.3%) symptomatic CVC-associated thromboses among 255 patients, with no difference in the incidence of symptomatic CVC-associated thrombosis between patients taking warfarin 1 mg daily (six of 130 patients; 4.6%) and patients taking placebo (five of 125 patients; 4.0%; hazard ratio, 1.20; 95% CI, 0.37 to 3.94). Warfarin had no effect on CVC life span (84 days v 63 days in control and warfarin groups, respectively; 95% confidence limit, -16 to 55 days; P = .09), and it did not affect the number of premature CVC removals (23.2% v 25.4% in control and warfarin groups, respectively; 95% confidence limit of difference -8.34 to 12.71; P = .68) or the frequency of major bleeding episodes (2% v 0% in control and warfarin groups, respectively; P = .5, Fisher's exact test). CONCLUSION: Symptomatic CVC-associated thrombosis in patients with cancer, although significant, is less common than previously reported. In this study, the administration of warfarin 1 mg daily did not reduce the incidence of symptomatic CVC-associated thrombosis in patients with cancer. However, the low rate of symptomatic CVC-associated thrombosis means that a much larger trial is required to address this issue definitively.     

Differences in morphine-induced antinociception and locomotor activity in mature adult and aged mice

Mature adult (3-6 months old) and aged (24-27 months old) male ICR mice were injected with 10 to 100 mg/kg morphine, SC. The ED50 values for locomotor behavior representing 5 times control activity were 7.5 mg/kg for aged mice and 17.8 mg/kg for the mature adults. There were striking age- and dose-dependent differences in both intensities and durations of morphine-induced locomotor activity. The ED50 values for antinociception 1 hour after morphine administration were 70 mg/kg for the aged mice and 13 mg/kg for the mature adults. One hour after injecting 30 and 100 mg/kg morphine tagged with 3H-morphine, 0.13 and 0.14 percent of the doses appeared in brains of aged and mature adult mice, respectively. Distribution of morphine among brain regions was the same for both age groups. The results suggest that the differences in response to morphine by the two age groups were due to age-related differences in affinities, numbers and/or functioning of opioid receptors and not to pharmacokinetic differences.     

Inertial Flywheel Resistance Training in Tendinopathy Rehabilitation: A Scoping Review

BackgroundInertial Flywheel Resistance Training (IFRT) has recently emerged as a beneficial rehabilitation option for some musculoskeletal disorders. Although the use of resistance training as treatment for tendinopathy has become widespread, it is unclear if IFRT has efficacy as a treatment option for tendinopathies.ObjectiveTo identify current evidence on IFRT in the treatment of tendinopathy, evaluating intervention parameters and outcomes.MethodsThis scoping review was reported in accordance with the PRISMA Extension for Scoping Reviews (PRISMA-ScR). Databases searched included MEDLINE, CINAHL, AMED, EMBase, SPORTDiscus, Cochrane library (Controlled trials, Systematic reviews), and five trial registries. Two independent reviewers screened studies at title, abstract and full text. Following screening, data were extracted and charted, and presented as figures and tables alongside a narrative synthesis. Any study design conducted on adults, investigating the effects of IFRT for tendinopathy were included. Data were extracted on intervention parameters and outcomes of IFRT interventions.ResultsFour studies on patellar tendinopathy were included. A variety of outcomes were assessed, including pain, function, strength, power, and tendon morphological and mechanical properties, particularly changes in tendon thickness. IFRT intervention parameters were largely homogenously prescribed, with slight variances.ConclusionDespite a paucity of studies to date on the effects of IFRT for treating tendinopathy, preliminary evidence for beneficial effects of IFRT on clinical outcomes in patellar tendinopathy is encouraging. As IFRT is a relatively new and unexplored method in tendinopathy rehabilitation, definitive conclusions, and recommendations cannot be made at present, which should be addressed in future research, due to the potential therapeutic benefits highlighted in this review.     

Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy: the Boyd collection revisited.

OBJECTIVE: We sought to determine morphologically when the maternal uterine circulation to the human placenta is established. STUDY DESIGN: We performed a histologic review of 12 early-pregnancy hysterectomy specimens contained within the Boyd Collection, ranging from 43 to 130 days' gestation. RESULTS: Before the eighth week of pregnancy, maternal arterial connections with the intervillous space are restricted to tortuous networks of intercellular spaces. Only after this period can direct channels be observed. Initially, these are of small caliber, but they become sizable and clearly delineated after 11 to 12 weeks. CONCLUSION: The maternal circulation to the placenta must be extremely sluggish before the eighth week of pregnancy but will be gradually established over the next few weeks. It is unlikely to be substantial until at least 12 weeks. The implication is that development of the human fetoplacental unit during most of the first trimester takes place in a low-oxygen environment.