International Regulatory Standards for the Qualitative Measurement of Deep Brain Stimulation in Clinical Research.

Deep brain stimulation (DBS) has progressed to become a promising treatment modality for neurologic and psychiatric disorders like epilepsy and major depressive disorder due to its growing personalization. Despite evidence pointing to the benefits of DBS if tested on these personalized qualitative metrics, rather than randomized-control trial quantitative standards, the evaluation of these novel devices appears to be based on the latter. This study surveyed the presence of this trend in the national regulatory guidelines of the prominent DBS researching countries. It was found that two governing bodies, in the European Union and Australia, acknowledged the option for qualitative measures. These findings support further development of national regulatory guidelines, so the neuroscientific community developing these neurotechnologies can better understand the impact their treatments have on patients.

Storage and export of microbial biomass across the western Greenland Ice Sheet.

The Greenland Ice Sheet harbours a wealth of microbial life, yet the total biomass stored or exported from its surface to downstream environments is unconstrained. Here, we quantify microbial abundance and cellular biomass flux within the near-surface weathering crust photic zone of the western sector of the ice sheet. Using groundwater techniques, we demonstrate that interstitial water flow is slow (~10-2 m d-1), while flow cytometry enumeration reveals this pathway delivers 5 × 108 cells m-2 d-1 to supraglacial streams, equivalent to a carbon flux up to 250 g km-2 d-1. We infer that cellular carbon accumulation in the weathering crust exceeds fluvial export, promoting biomass sequestration, enhanced carbon cycling, and biological albedo reduction. We estimate that up to 37 kg km-2 of cellular carbon is flushed from the weathering crust environment of the western Greenland Ice Sheet each summer, providing an appreciable flux to support heterotrophs and methanogenesis at the bed.

Ensemble asteroseismology of solar-type stars with the NASA Kepler mission.

In addition to its search for extrasolar planets, the NASA Kepler mission provides exquisite data on stellar oscillations. We report the detections of oscillations in 500 solar-type stars in the Kepler field of view, an ensemble that is large enough to allow statistical studies of intrinsic stellar properties (such as mass, radius, and age) and to test theories of stellar evolution. We find that the distribution of observed masses of these stars shows intriguing differences to predictions from models of synthetic stellar populations in the Galaxy.

How government policy decisions affect seniors' quality of life: findings from a participatory policy study carried out in Toronto, Canada.

Toronto seniors explored how government policy decisions were influencing their health and well-being. In this participatory policy study, emphasis was upon the lay and critical knowledge of highly informed seniors. Focus groups and interviews revealed that all three levels of governments were seen as not listening to seniors' voices. In nine key policy areas identified as influencing seniors' quality of life--hearing seniors' voices, housing, acute illness care, long-term care, income supports, transportation and mobility, promoting healthy lifestyles, access to information, and hearing voices from cultural communities--many concerns were raised. The gap between government rhetoric and government action on seniors' issues merits public health attention.

Cloning and differential expression of new calcium, calmodulin-dependent protein kinase II isoforms in Xenopus laevis oocytes and several adult tissues.

The different oligomers composing the high molecular weight calcium/calmodulin-dependent protein kinase II (CaMKII) holoenzyme, previously shown to be transiently activated during Xenopus oocyte maturation, migrate on SDS-PAGE as proteins of 83, 72, 62, 56, and 52 kDa and have all been cloned. The holoenzyme consists of the CaMKII isoforms gammaB, gammaC, and delta12, already described in other species, while gammaJ, gammaK, gammaL, gammaM, and gammaN are now described for the first time. The gamma-isoforms are splice variants of the gamma-gene, containing in their variable region different combinations of known exons and one, two or three novel exons. Semi-quantitative RT-PCR revealed that all isoforms identified in prophase oocytes are also expressed in adult tissues with a tissue-specific expression pattern. At least thirty different CaMKII isoforms could be identified in different Xenopus adult tissues, most of which are described here for the first time.

Diagnosis and treatment of Helicobacter pylori infection in children: a survey of WV primary care physicians.

Helicobacter pylori infection has been implicated in the development of peptic ulcer disease in children. Although clinical protocols for the diagnosis and treatment of this infection in children are available, the implementation of those guidelines by primary physicians are insufficient. In this study, we surveyed the clinical practices of 409 primary physicians who practice in West Virginia and treat children with H. pylori infection. Results showed in contradiction with the recommendation, primary physicians are still using serology as the preferred diagnostic method for this disease. Most of the physicians treat this disease with a combination of two antibiotics and anti-acid medication (H2 blockers or PPI) for at least one week. We conclude that an increase in knowledge of those guidelines among primary physicians may improve physicians' compliance with H. pylori guidelines.

Interferon treatment is not associated with a worsening of psychiatric symptoms in patients with hepatitis C.

AIM: To study prospectively the psychiatric side effects of interferon-alpha in patients with hepatitis C. METHODS: Sixty-three consecutive patients at a hepatitis clinic were recruited. All were assessed using a psychiatric interview (SCID) and monitored using a self-reporting psychiatric symptom questionnaire (SCL-90). RESULTS: Patients on interferon did not suffer a drop in mood or an increase in anxiety or irritability. The subgroup with past depression also did not suffer an increase in depressive symptoms. No patients attempted suicide. CONCLUSIONS: The risk of serious psychiatric symptoms when being treated with interferon-alpha may not be high. Psychiatric illness or the possibility of psychiatric complications should not be used as a reason to refuse this treatment to patients with hepatitis C.

Identification of cyk, a cyclin B2 kinase, as a novel calcium/calmodulin-dependent protein kinase II and its role during Xenopus laevis oocyte maturation.

Recently, we have partially purified and characterized a specific cell cycle-regulated cyclin B2 kinase (cyk) from prophase oocytes of Xenopus laevis after an ATP-gamma-S activation step (R. Derua, I. Stevens, E. Waelkens, A. Fernandez, N. Lamb, W. Merlevede, and J. Goris, 1997, Exp. Cell Res. 230, 310-324). In the present paper we describe its purification to homogeneity. We could identify the kinase as a special form of calcium/calmodulin-dependent protein kinase II (CaMKII), consisting of five isoforms with molecular masses ranging from 52 to 83 kDa. At least three of them could be considered as novel. Using an in vivo assay with a synthetic peptide (cyktide), an activation of the kinase was shown at about 50% maturation. Further evidence for this observation came from the injection of the calcium chelator BAPTA and the specific cyk/CaMKII inhibitor AIP. A delay of oocyte maturation of at least 1 h was observed. Besides serine 53, a second cyk phosphorylation site in cyclin B2 was identified as threonine 41. Site-directed mutagenesis of these sites indicated that phosphorylation of these sites in Xenopus cyclin B2 was not required for the hallmark functions of cyclin B2.

Pharmacokinetics of clozapine and its metabolites in psychiatric patients: plasma protein binding and renal clearance.

AIMS: N-Desmethylclozapine and clozapine N-oxide are major metabolites of the atypical neuroleptic clozapine in humans and undergo renal excretion. The aim of this study was to investigate to what extent the elimination of these metabolites in urine contributes to the total fate of clozapine in patients and how they are handled by the kidney. METHODS: From 15 psychiatric patients on continuous clozapine monotherapy, blood and urine samples were obtained during four 2 h intervals, and clozapine and its metabolites were assayed in serum and urine by solid-phase extraction and h.p.l.c. Unbound fractions of the compounds were measured by equilibrium dialysis. RESULTS: The following unbound fractions in serum were found (geometric means): clozapine 5.5%, N-desmethylclozapine 9.7%, and clozapine N-oxide 24.6%. Renal clearance values calculated from unbound concentrations in serum and quantities excreted in urine were for clozapine on average 11% of the creatinine clearance, whereas those of N-desmethylclozapine and clozapine N-oxide amounted to 300 and 640%, respectively. The clearances of unbound clozapine and N-desmethylclozapine increased with increasing urine volume and decreasing pH. All renal clearance values exhibited large interindividual variations. The sum of clozapine and its metabolites in urine represented on average 14% of the dose. CONCLUSIONS: Clozapine, N-desmethylclozapine and clozapine N-oxide are highly protein-bound in serum. Clozapine is, after glomerular filtration, largely reabsorbed in the tubule, whereas the metabolites undergo net tubular secretion. Metabolic pathways alternative or subsequent to N-demethylation and N-oxidation must make major contributions to the total fate of clozapine in patients.

Growth hormone replacement does not improve psychological well-being in adult hypopituitarism: a randomized crossover trial.

In order to examine the effect of growth hormone (GH) on psychological parameters in adult hypopituitarism, 20 adults were studied, mean age 47 years (range 20-69) with hypopituitarism and confirmed GH deficiency (GH < 3 micrograms/l following clonidine 0.15 mg/m2). Subjects were randomly allocated to either GH-up to 0.25 U/kg per week in daily doses) or placebo for 3 months before crossover to the opposite treatment arm. Psychological parameters were assessed by self-reported questionnaires (Disease Specific Questionnaire (DSQ), the Symptom Checklist-90 (SCL-90), and the Social Adjustment Scale (SAS)) at baseline and monthly intervals to the end of the trial. Both SAS and SCL-90 total scores showed a significant decline with respect to time (p = .03 and .013 respectively), although this was not a function of active treatment. DSQ showed a trend to decline (p = .06), but no effect of active treatment. None of the subscale components of the SCL-90 showed any significant change on active treatment. Improvement in psychological parameters occurs as a function of enrolment to a clinical trial, rather than active GH replacement in adult hypopituitarism.

Characterization and physiological importance of a novel cell cycle regulated protein kinase in Xenopus laevis oocytes that phosphorylates cyclin B2.

We have partially purified a specific cyclin B2 kinase (cyk) from prophase oocytes of Xenopus laevis after an ATP-gamma-S activation step. Phosphopeptide analysis identified Ser53 as the major in vitro phosphorylation site for cyk in cyclin B2. Using a synthetic peptide derived from cyclin B2 encompassing Ser53 (cyktide) as a substrate, cyk was shown to be activated during progesterone-induced maturation, with a peak of activity between 40 and 50% maturation. A sustained high cyk activity was observed in oscillating egg extracts. Microinjection of cyk-phosphorylated cyclin B2 into prophase oocytes accelerated progesterone-induced maturation by about 2 h, indicating that cyclin B2 is a relevant substrate for cyk and that the function of cyk is situated upstream of cdc2-cyclin B activation. Microinjection of cyk-phosphorylated cyktide or a combination of cyk and cyclin B1 into G2 fibroblasts induced significant changes in cell morphology, reminiscent of a premature prophase-like phenotype. Similarly, addition of cyk-phosphorylated cyktide in cyclin B1-dependent interphase extracts resulted in histone H1 kinase activation.

The variable subunit associated with protein phosphatase 2A0 defines a novel multimember family of regulatory subunits.

Two protein phosphatase 2A (PP2A) holoenzymes were isolated from rabbit skeletal muscle containing, in addition to the catalytic and PR65 regulatory subunits, proteins of apparent molecular masses of 61 and 56 kDa respectively. Both holoenzymes displayed low basal phosphorylase phosphatase activity, which could be stimulated by protamine to an extent similar to that of previously characterized PP2A holoenzymes. Protein micro-sequencing of tryptic peptides derived from the 61 kDa protein, termed PR61, yielded 117 residues of amino acid sequence. Molecular cloning by enrichment of specific mRNAs, followed by reverse transcription-PCR and cDNA library screening, revealed that this protein exists in multiple isoforms encoded by at least three genes, one of which gives rise to several splicing variants. Comparisons of these sequences with the available databases identified one more human gene and predicted another based on a rabbit cDNA-derived sequence, thus bringing the number of genes encoding PR61 family members to five. Peptide sequences derived from PR61 corresponded to the deduced amino acid sequences of either alpha or beta isoforms, indicating that the purified PP2A preparation was a mixture of at least two trimers. In contrast, the 56 kDa subunit (termed PR56) seems to correspond to the epsilon isoform of PR61. Several regulatory subunits of PP2A belonging to the PR61 family contain consensus sequences for nuclear localization and might therefore target PP2A to nuclear substrates.

Elevated norharman plasma levels in alcoholic patients and controls resulting from tobacco smoking.

Plasma norharman and harman levels were measured by solvent extraction and HPLC with fluorescence detection in alcohol-dependent patients undergoing in-patient abstinence treatment and in control subjects. In both groups, randomly collected samples from smokers contained higher mean norharman levels than those from non-smokers. In three volunteers norharman concentrations rose sharply after smoking of one or two cigarettes and declined to near-basal levels within one hour after one cigarette. When 12 patients kept a smoking-free interval of at least 6 h, they had similarly low plasma norharman concentrations (20 +/- 8 pg/ml) as 18 non-smoking control subjects (17 +/- 8 pg/ml) or as 13 smoking controls who had abstained from smoking (20 +/- 6 pg/ml). Ten of the patients smoked one cigarette and within 5-10 min attained norharman levels of 177 +/- 147 pg/ml plasma. The high prevalence of smokers among chronic alcoholics probably explains the previous finding of elevated norharman plasma levels in these patients.

Molecular cloning and developmental regulation of expression of two isoforms of the catalytic subunit of protein phosphatase 2A from Xenopus laevis.

Two types of PP2A catalytic subunit cDNA clones were isolated from a Xenopus oocyte library. One type corresponds to the Xenopus C36 alpha (XC36 alpha) isoform as published by Cormier et al. (1991) and another type encodes for a novel isoform of PP2AC36 (XC36 beta), more homologous to the C36 beta isoform cloned from Mammalia. Northern blot analysis with isoform specific probes showed that the XC36 alpha mRNA transcript of 2 kb is more abundant than the XC36 beta mRNA of 1.9 kb during embryogenesis and in adult tissues. Both transcripts are highly expressed in ovary and heart relative to the other adult tissues examined. The high expression levels of both XC36 alpha and XC36 beta transcripts in the ovary decrease during the first mitotic embryonic divisions. Resumption of zygotic expression starts at about the same time for both mRNAs, during the tailbud stage, but the XC36 beta transcript shows only a moderate and transient increase and declines again during the tadpole stage whereas expression of XC36 alpha increases further during the same period until the onset of metamorphosis.

Patients' opinions on respiratory care: do doctors fulfill their needs?

To date, guidelines and consensus reports on quality care for asthma and chronic obstructive pulmonary disease (COPD) are mainly based on research and opinions of care providers. Patients' viewpoints on good medical care have rarely been studied. We designed a postal questionnaire to study the needs of patients with asthma or COPD for medical care provided by general practitioners and lung physicians. A total of 121 patients filled out the questionnaire, which included 111 items about needs. Although generally satisfied, patients reported several unfulfilled needs. Main topics were the need for information about diagnostic tests, prognosis, and long-term use of medication. In addition, patients wanted more written information about the nature of their disease. One-third of patients wanted more participation in decisions about their treatment. These results suggest the quality of medical care for patients with asthma or COPD can be improved by adjusting provided care to needs expressed by patients.

Tryptophan metabolites, pyridoxine (vitamin B6) and their influence on the recurrence rate of superficial bladder cancer. Results of a prospective, randomised phase III study performed by the EORTC GU Group. EORTC Genito-Urinary Tract Cancer Cooperative Group.

This double-blind randomised phase III trial was designed to assess the effect of pyridoxine administration on the recurrence of Ta and T1 transitional cell tumours of the bladder. The trial accrued 291 patients and showed no significant difference between the pyridoxine and placebo treatment groups with respect to the time to first recurrence or the recurrence rate. Adjustment for the main prognostic factors, namely the recurrence rate prior to entry, the number of tumours at entry, the G grade and the levels of the tryptophan metabolites kynurenine plus acetyl kynurenine at entry do not change the overall conclusions.

Haloperidol and lorazepam combined: clinical effects and drug plasma levels in the treatment of acute schizophrenic psychosis.

In 61 acute schizophrenic patients the effects of haloperidol (HPL) and lorazepam combined vs. HPL alone and the interaction between these drugs were evaluated. Patients were assigned to groups randomly. The study design was open. Study duration was 28 days. Psychopathology was evaluated on the basis of BPRS scores. Extrapyramidal side-effects were rated according to Simpson and Angus (1970). Pharmacological parameters included serum levels of lorazepam, HPL, and reduced HPL. Mean daily lorazepam dosage was 0.05 mg/kg, mean HPL dosage 0.5 mg/kg. None of the patients treated with lorazepam and HPL achieved better BPRS total or subscores, nor did their condition improve faster than in patients treated with HPL alone. A significant linear relationship between lorazepam serum levels and oral dosage was found, but none between lorazepam serum levels and BPRS total score, subscore reduction, or extrapyramidal side-effects. The authors conclude that beneficial effects of lorazepam in the treatment of acute psychosis are scant and may not justify the risks incurred with routine comedication of lorazepam.

Superficial siderosis of the central nervous system. A 37-year follow-up of a case and review of the literature.

The course of a patient suffering from superficial siderosis of the central nervous system for 37 years is presented and diagnostic and therapeutic approaches are evaluated. The syndrome is clinically defined by slowly progressing deafness, cerebellar ataxia, myelopathy and neuropsychological deficits in combination with recurrent xanthochromia of the cerebrospinal fluid with siderophages. The diagnosis may be confirmed by computed tomography, which shows degeneration of the cerebellar vermis, and by magnetic resonance imaging, demonstrating iron deposits on the surface of brain, brain stem and spinal cord. Therapy should seek to identify and remove the source of bleeding, since pharmacotherapy with iron-depleting drugs is of limited effectiveness.

Neuroleptically induced dystonia in Huntington's disease: a case report.

A patient with Huntington's disease developed acute dystonia whilst treated with tiapride. Sulpiride and tetrabenazine also induced dystonia. The anticholinergic biperiden depressed the syndrome but worsened psychopathology. Finally a combination of tetrabenazine and clozapine was successful in treatment of both chorea and dystonia. According to this observation, acute dystonia may occur in Huntington's disease as a consequence of neuroleptic treatment.