Body weight in patients with Parkinson's disease.

There is some evidence suggesting that Parkinson's disease (PD) patients exhibit lower body weight when compared to age-matched healthy subjects. Low body mass index (BMI) is correlated with low bone mineral density, both of which are major risk factors for hip fractures. Possible determinants of weight loss in PD patients include hyposmia, impaired hand-mouth coordination, difficulty chewing, dysphagia, intestinal hypomotility, depression, decreased reward processing of dopaminergic mesolimbic regions, nausea, and anorexia as the side effects of medication, and increased energy requirements due to muscular rigidity and involuntary movements. It is unclear whether PD patients in general, or only a subgroup of those affected, definitely show lower BMI in the advanced stages of the disease. We therefore recommend that the body weight of PD patients be monitored monthly as the disease progresses, and that a patient's nutrition should be supplemented with sufficient amounts of vitamin D and calcium to reduce the risk of hip fractures and strengthen bone density. Because meal times may coincide with unpredictable off periods associated with akinesia and impaired hand-mouth coordination, PD patients also need flexible food schedules that accommodate the associated symptoms of this disease.     

Peritoneal morphology in children treated by continuous ambulatory peritoneal dialysis

Fifty peritoneal biopsies (PB) from 35 patients with end-stage renal disease, treated by continuous ambulatory peritoneal dialysis (CAPD) and aged 2 months to 18 years, were examined by light microscopy (n=50) and/or scanning electron microscopy. PB were performed during surgical procedures immediately before the start of, during, or after the cessation of CAPD treatment. PB from 15 children without renal disease undergoing laparatomy were examined similarly. Before the start of CAPD, a scarcity and shortening of the mesothelial microvilli was observed by scanning electron microscopy. During and after CAPD, variable alterations of mesothelium, interstitium and capillaries were found. The mesothelial layer was absent in all 5 PB obtained during episodes of active peritonitis. In patients treated by CAPD for longer than 6 months, mesothelial denudation was observed more frequently (6/11) than in children treated for shorter periods (1/7) (P<0.08). Fibrosis of the peritoneal membrane was present in about 50% of patients during or after the cessation of CAPD without impairment of peritoneal function. No correlation was found between the presence of fibrosis and the frequency of peritonitis or the duration of CAPD treatment.     

Patients' experience of epilepsy and health care

OBJECTIVE: The aim of this study was to assess the severity of epilepsy and its effect on patients lives, and to describe patients' use of and attitudes to health care. METHOD: A questionnaire was sent to 595 people with epilepsy identified from 14 general practices in north-west Bristol. All patients aged 16 years and over receiving anti-epileptic medication for their epilepsy were included in the study. Areas investigated included severity of epilepsy and its effect on quality of life, anti-epileptic medication and its perceived effect, health care utilization and preferences for health care. RESULTS: Seizure frequency was strongly associated with adverse effects of epilepsy. Attacks of epilepsy were experienced at least monthly by 20.4% (95% confidence intervals (Cl) 17.0-23.7%) of patients, 29.4% (25.4-33.4%) took more than one anti-epileptic drug, 56.1% (50.1-62.2%) reported drug side effects, 74.1% (70.3-77.8%) would prefer to receive all or most of their epilepsy care in a general practice setting, and 69.8% (63.5- 76.2%) would like contact with a primary care-based epilepsy specialist nurse. During the previous year 42.4% (35.9-48.8%) of patients had not seen a doctor about their epilepsy. Of patients who had attended the general practice only 13.4% (9.6-17.2%) had regular arrangements to see their GP about epilepsy. Patients receiving both primary and secondary care had the greatest needs and wants for improved care. CONCLUSIONS: Structured care, including regular appointments, co-ordination of primary and secondary care, and increased monitoring and discussion, may improve the quality of life of people with epilepsy, but requires evaluation.      

Role for interleukin-1 (IL-1) in benzene-induced hematotoxicity: inhibition of conversion of pre-IL-1 alpha to mature cytokine in murine macrophages by hydroquinone and prevention of benzene-induced hematotoxicity in mice by IL-1 alpha

Chronic exposure of humans to benzene (BZ), a myelotoxin, causes aplastic anemia and acute leukemia. The stromal macrophage that produces interleukin-1 (IL-1), a cytokine essential for hematopoiesis, is a target of BZ's toxicity. Monocyte dysfunction and decreased IL-1 production have been shown to be involved in aplastic anemia in humans. Hydroquinone (HQ), a toxic bone marrow (BM) metabolite of BZ, causes time- and concentration-dependent inhibition of processing of the 34-Kd pre-interleukin-1 alpha (IL-1 alpha) to the 17-Kd mature cytokine in murine P388D1 macrophages and BM stromal macrophages, as measured by Western immunoblots of cell lysate proteins using a polyclonal rabbit antimurine IL-1 alpha antibody. HQ over a 10-fold concentration range had no effect on the lipopolysaccharide (LPS)-induced production of pre- IL-1 alpha precursor or on cell viability or DNA and protein synthesis. Stromal macrophages obtained from the femoral BM of C57Bl/6 mice exposed to BZ (600 or 800 mg/kg body weight) for 2 days were incapable of processing the 34-Kd pre-IL-1 alpha to the mature 17-Kd cytokine when stimulated in culture with LPS. Stromal macrophages from mice coadministered BZ and indomethacin, a prostaglandin H synthase (PHS) inhibitor that has been shown to prevent BZ-induced myelotoxic and genotoxic effects in mice when coadministered with benzene were able to convert the pre-IL-1 alpha to mature cytokine. Administration of recombinant murine IL-1 alpha (rMuIL-1 alpha) to mice before a dose of BZ that causes severe depression of BM cellularity completely prevents BM depression, most probably by bypassing the inability of the stromal macrophage in BZ-treated animals to process pre-IL-1 alpha to the mature cytokine.     

Comparative investigation of the influence of nizatidine, ranitidine, and cimetidine on the steady-state pharmacokinetics of theophylline in COPD patients.

The influence of usual regimens of the H2 blocking drugs, cimetidine, ranitidine, and nizatidine on the steady-state plasma concentrations and pharmacokinetic characteristics of theophylline was studied in seventeen patients with chronic obstructive pulmonary disease (COPD). Patients were dosed to steady-state with an oral, sustained-release formulation of theophylline given in therapeutic doses twice daily for 2 weeks. Over the next 4 weeks, each patient received a week-long regimen of each H2 blocker concomitantly with theophylline, and a week-long regimen of theophylline alone (control). At the end of each of the latter 4 weeks the steady-state pharmacokinetics of theophylline were assessed. Neither ranitidine nor nizatidine treatment altered the steady-state pharmacokinetics of theophylline relative to the control phase (i.e. no H2 blocker treatment). Values for theophylline C(ave), Cssmax, AUC0-12, and CLoral were significantly different during cimetidine treatment compared with all other treatments (ranitidine, nizatidine, and control). Cimetidine increased theophylline Cssmax, AUC0-12 and Cave by approximately 32%, and decreased theophylline oral clearance by approximately 23%. The authors conclude that cimetidine alters the steady-state pharmacokinetics of theophylline in COPD patients, whereas ranitidine and nizatidine are without effect.     

In vivo evidence that ethosuximide is a substrate for cytochrome P450IIIA.

The role of various subfamilies of rat hepatic cytochrome P450 in the oxidation of ethosuximide was evaluated by comparing ethosuximide clearance in control rats and those pretreated with relatively selective P450 inducers and/or inhibitors. Clotrimazole pretreatment increased ethosuximide clearance threefold (p less than 0.005). Dexamethasone increased ethosuximide clearance twofold (p less than 0.001), and the dexamethasone effect was completely abolished by a single dose of triacetyloleandomycin. These results suggest a prominent role for cytochrome P450IIIA in ethosuximide metabolism in the rat. Isoniazid increased ethosuximide clearance twofold (p less than 0.001), and this effect was abolished by a single dose of diallylsulfide, suggesting that ethosuximide is also processed by cytochrome P450IIE1 in rats. Phenobarbital pretreatment increased ethosuximide clearance 2-2.7 fold (p less than 0.001); an effect that was only partially reversed by orphenadrine, an inhibitor of cytochrome P450IIB/IIC enzymes. This suggests a quantitatively less important role for the IIB/IIC subfamilies in processing ethosuximide, since phenobarbital is an inducer of P450 subfamilies IIB, IIC, IIE, and IIIA. Neither the cytochrome P450IA inducer, beta-naphthoflavone, nor the inhibitor, alpha-naphthoflavone altered ethosuximide clearance. Ajmaline, an inhibitor of cytochrome P450IID, had no effect on ethosuximide clearance. Together, these findings suggest that ethosuximide is principally oxidized by cytochrome P450IIIA, and that cytochrome P450IIE may play an important role. Cytochromes P450IIB/C play less prominent roles in ethosuximide oxidation, and neither cytochrome P450IA nor cytochrome P450IID is involved.     

Integrating children's services in England: national evaluation of children's trusts

Background Poor co‐ordination of services can have severe consequences for disadvantaged children with complex needs. Since 2003 national and local governments in England embarked on sweeping reforms aimed at improving and integrating local health, education and social services for children. These were to be organized locally by children's trusts and piloted by 35 children's trust pathfinders. Methods This study described and compared the experience of integrating children's services in all 35 children's trust pathfinders, covering 20% of children in England. It had a prospective mixed‐methods design. Over 3 years we interviewed 147 managers and professionals working in the children's trusts, including 172 semi‐structured interviews, carried out two questionnaire surveys of the 35 children's trusts and analysed official documents. Results In most areas different agencies jointly commissioned children's services, especially for mental health, disabilities and multi‐purpose children's centres, and increasingly pooled finances. Provision of multi‐agency and multi‐professional services was increasing. Professionals generally supported these changes but found them stressful. All children's trusts appointed directors of children's services and established boards representing multiple agencies. Systems for sharing information about individual children were mostly in place but were still underused. Health services were generally less involved in joint work than were local authorities' education and social care services, with notable exceptions. Areas where local authorities and health authorities shared geographical boundaries made most progress. Some children's trusts made few changes beyond their statutory obligations. Conclusion Children's trusts enabled major changes to services in areas where local actors and organizations were motivated and empowered. In other areas the remit of children's trusts was often too broad and vague to overcome entrenched organizational and professional divisions and interests. Policymakers need to balance facilitation of change in areas with dynamic change agents with methods for ensuring that dormant areas and agencies are not left behind.