Water immersion increases urinary excretion of aquaporin-2 in healthy humans

Many previous studies have shown that aquaporin-2 (AQP2), the vasopressin-regulated water channel, is excreted in the urine and that the excretion increases in response to vasopressin. Moreover, recently a close correlation between AQP2 excretion in urine and kidney AQP2 expression has been demonstrated, showing that urinary excretion of AQP2 is a reliable indicator for AQP-2 function. As head-out water immersion causes an expansion in the central vascular volume equal to that induced by 2 liters of saline, without modifying plasma composition, we used immersion in water to evaluate if the response to acute expansion of the central vascular volume could involve vasporessin (AVP) and AQP2. In healthy subjects, concentrations of plasma atrial natriuretic factor (ANF) and AVP, and urinary AQP2 were measured during a 2-hour immersion period. In all subjects, immersion caused a prompt and marked increase in immunoreactive ANF (23.0 +/- 2.12 pg/ml at second hour vs. 2.17 +/- 0.42 pg/ml at baseline) and in urinary excretion of AQP2 (23.9 +/- 2. 69 pmol/mg creatinine at second hour vs. 4.42 +/- 0.14 pmol/mg creatinine at baseline), while a significant decrease was found in plasma AVP. Recovery was associated with a prompt return to pre-study levels. These findings demonstrate that heat-out water immersion stimulates urinary excretion of AQP2 in absence of an increase in plasma AVP.     

Doxorubicin pharmacokinetics: the effect of abnormal liver biochemistry tests

We studied variability in doxorubicin pharmacokinetics in 24 patients with abnormal liver biochemistry tests. Blood samples were collected after the first cycle of single-agent doxorubicin given as an i.v. bolus and plasma levels were measured by high-performance liquid chromatography. The relationship between doxorubicin clearance (dose/AUC) and liver biochemistry tests (AST, bilirubin, albumin, alkaline phosphatase and indocyanine green clearance) was investigated. Patients with a raised bilirubin level had reduced doxorubicin clearance, but there was no clear relationship between the extent of this elevation and the reduction in doxorubicin clearance. Doxorubicin clearance was lower in patients with an isolated increase in AST than in those with normal liver biochemistry, but this difference was not statistically significant. Nevertheless, there was a significant correlation between reduced doxorubicin clearance and both raised serum AST levels and low indocyanine green clearance. These pharmacokinetic data suggest that current dose reductions based solely on the extent to which bilirubin is elevated may not be optimal. Received: 20 October 1997 / Accepted: 20 January 1998     

Social difficulties and victimization in children with SLI at 11 years of age.

Specific language impairment is sometimes thought to be associated with concurrent difficulties in the area of social and behavioral development (N. Botting and G. Conti-Ramsden, 2000; D. P. Cantwell and L. Baker, 1987; M. Fujiki, B. Brinton, and C. Todd, 1996; S. Redmond and M. Rice, 1998). The present study follows a group of 242 children, initially studied at age 7 years when they attended language units in England, and assesses their social and behavioral status at age 11 years. In total, 64% of the children were found to have scores on the Rutter behavioral questionnaire (M. Rutter, 1967) of 9 or above (clinical threshold); 34% scored over the threshold for the Strengths and Difficulties questionnaire (R. Goodman, 1997); and 39% scored below average on the Peer Competence subscale of the Harter Perceived Competence Scale (S. Harter and R. Pike, 1984). On further analysis, these generalized difficulties were characterized mainly by poor social competence. In addition, 36% of the cohort were at risk of being regular targets for victimization compared to 12% of a comparison sample of typically developing peers. Few associations were found between social outcome and other measures, including nonverbal intelligence, overall linguistic skill, gender, and longitudinal measures taken previously. Importantly, however, pragmatic language difficulties measured on the Children's Communication Checklist (D. V. M. Bishop, 1998) were most strongly related to poor social outcome and to expressive language related to victimization.     

School vision screening, ages 5–16 years: the evidence-base for content, provision and efficacy

The optometric profession in the UK has a major role in the detection, assessment and management of ocular anomalies in children between 5 and 16 years of age. The role complements a variety of associated screening services provided across several health care sectors. The review examines the evidence-base for the content, provision and efficacy of these screening services in terms of the prevalence of anomalies such as refractive error, amblyopia, binocular vision and colour vision and considers the consequences of their curtailment. Vision screening must focus on pre-school children if the aim of the screening is to detect and treat conditions that may lead to amblyopia, whereas if the aim is to detect and correct significant refractive errors (not likely to lead to amblyopia) then it would be expedient for the optometric profession to act as the major provider of refractive (and colour vision) screening at 5-6 years of age. Myopia is the refractive error most likely to develop during primary school presenting typically between 8 and 12 years of age, thus screening at entry to secondary school is warranted. Given the inevitable restriction on resources for health care, establishing screening at 5 and 11 years of age, with exclusion of any subsequent screening, is the preferred option.     

Temozolomide pharmacodynamics in patients with metastatic melanoma: dna damage and activity of repair enzymes O6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1.

PURPOSE: Temozolomide, a DNA methylating agent used to treat melanoma, induces DNA damage, which is repaired by O6-alkylguanine alkyltransferase (ATase) and poly(ADP-ribose) polymerase-1 (PARP-1)-dependent base excision repair. The current study was done to define the effect of temozolomide on DNA integrity and relevant repair enzymes as a prelude to a phase I trial of the combination of temozolomide with a PARP inhibitor. EXPERIMENTAL DESIGN: Temozolomide (200 mg/m2 oral administration) was given to 12 patients with metastatic malignant melanoma. Peripheral blood lymphocytes (PBL) were analyzed for PARP activity, DNA single-strand breakage, ATase levels, and DNA methylation. PARP activity was also measured in tumor biopsies from 9 of 12 patients and in PBLs from healthy volunteers. RESULTS: Temozolomide pharmacokinetics were consistent with previous reports. Temozolomide therapy caused a substantial and sustained elevation of N7-methylguanine levels, a modest and sustained reduction in ATase activity, and a modest and transient increase in DNA strand breaks and PARP activity in PBLs. PARP-1 activity in tumor homogenates was variable (828 +/- 599 pmol PAR monomer/mg protein) and was not consistently affected by temozolomide treatment. CONCLUSIONS: The effect of temozolomide reported here are consistent with those documented in previous studies with temozolomide and similar drug, dacarbazine, demonstrating that a representative patient population was investigated. Furthermore, PARP activity was not inhibited by temozolomide treatment and this newly validated pharmacodynamic assay is therefore suitable for use in a proof-of-principle phase I trial a PARP-1 inhibitor in combination with temozolomide.     

A realist qualitative study to explore how low‐income pregnant women use Healthy Start food vouchers

Healthy Start is the UK government's food voucher programme for low‐income pregnant women and young children. It was introduced in 2006, but the impact of the programme on nutritional outcomes remains understudied. This study sought to explore potential outcomes of the Healthy Start programme (including intended and unintended outcomes) and develop explanations for how and why these outcomes might occur. A realist review preceded this study, in which programme theories were developed and tested using existing evidence. This qualitative study aimed to further refine and consolidate the programme theories from the realist review while remaining open to new and emerging theories (or hypotheses) about how low‐income pregnant women use Healthy Start vouchers. Semistructured interviews were conducted with 11 low‐income women from North West England, who received Healthy Start vouchers during pregnancy. A realist logic of analysis was applied to generate clear and transparent linkages between outcomes and explanations. The findings suggested that some women used the vouchers to improve their diets during pregnancy (intended outcome), whereas some women were diverted towards alternative or unintended outcomes. Women's circumstances, values, beliefs, and motivations influenced how they perceived and responded to the vouchers. This paper presents four evidence‐based programme theories to explain four contrasting (and potentially overlapping) outcomes: dietary improvements (theory refined from review), shared benefits (new theory), financial assistance (theory refined from review), and stockpiling formula (new theory). It considers how the Healthy Start programme could be improved, to increase the possibilities for low‐income women to experience the intended outcome of dietary improvements.