Irinotecan-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses.

Irinotecan chemotherapy toxicities can be severe, and may result in treatment delay, morbidity and in some rare cases death. This systematic review of systematic reviews synthesises all meta-analyses on biomarkers for irinotecan toxicity across all genetic models for Asians, Caucasians, low dose, medium/high dose and regimens with and without fluorouracil. False-positive findings are a problem in pharmacogenetics, increasing the importance of systematic reviews. Four systematic reviews that investigated the effect of the polymorphisms UGT1A1*6 and/or*28 on neutropenia or diarrhoea toxicity were included. Both UGT1A1*6 and *28 were reliably demonstrated to be risk factors for irinotecan-induced neutropenia, with tests for both polymorphisms potentially being particularly useful in Asian cancer patients. UGT1A1*6 and *28 were also related to diarrhoea toxicity; however, at low doses of irinotecan there was evidence that UGT1A1*28 was not. In synthesising the best available evidence, this umbrella systematic review provides a novel reference for clinicians applying personalised medicine and identifies important research gaps.

Providing meaningful care for families experiencing stillbirth: a meta-synthesis of qualitative evidence.

OBJECTIVE: The objective of this study was to explore the meaningfulness of non-pharmacological care experienced by families throughout the experience of stillbirth from diagnosis onwards. STUDY DESIGN: A comprehensive systematic review was conducted. Multiple sources were searched for relevant studies including gray literature. Studies were included if they reported the experiences of families with the care they received throughout the experience of stillbirth, from diagnosis onwards. Studies were assessed for methodological quality prior to inclusion. Qualitative findings were extracted from included studies and pooled using a meta-aggregative approach. This paper reports the results of one meta-synthesis from the systematic review. RESULTS: Ten qualitative studies of moderate to high quality informed this meta-synthesis. The meta-aggregative synthesis included 69 findings that informed the development of 10 categories and one final, synthesized finding. Emerging themes that underpinned the meaningfulness of care provided to parents experiencing stillbirth included: information provision, the need for emotional support and appropriate maternity ward environments and systems. CONCLUSION: The results of this meta-synthesis revealed the elements of care that were experienced as meaningful from the perspective of parents who had experienced stillbirth. Exploration of these elements has provided important detail to underpin a growing understanding of how parents experience care and what may help or hinder parents' experience of distress, anxiety and grief throughout the experience of stillbirth.

Impact of subclinical and clinical mastitis on sensitivity to pain of dairy cows.

A total of 90 cows from three commercial farms were used to evaluate the relationship between subclinical mastitis and clinical mastitis and thermal nociceptive threshold. Milk strips from all udder quarters were tested for clinical mastitis with visual inspection of milk and udder alterations and for subclinical mastitis using California Mastitis Test. Milk yield was recorded, milk was sampled and further analyzed for somatic cells count (SCC). Cows were considered healthy when SCC200 000 cells/ml and no visual alterations in milk and/or udder, with moderate subclinical mastitis when SCC>500 000 cells/ml and no visual alterations in milk and/or udder and with clinical mastitis when visual alterations in milk and/or udder were detected. Nociceptive threshold was evaluated with the thermal threshold meter apparatus applied to the rear legs. Thermal threshold (TT) decreased when we compared healthy cows with cows presenting clinical mastitis and tended to decrease when we compare healthy cows with those with moderate subclinical mastitis. TT was lower at the ipsilateral rear leg compared with the contralateral leg to the infected mammary gland. TT linearly decreases as log10SCC increased and it showed sharp decrease as log10SCC exceed the value of 6.4. Increase in one unit of log10SCC increased the odds of low thermal threshold (lower than 55.8°C). Subclinical mastitis might be a welfare issue as it tended to decrease nociceptive thermal threshold.

Generation of memory T cells for adoptive transfer using clinical-grade anti-CD62L magnetic beads.

Pre-clinical studies of allogeneic stem cell transplantation suggest that depletion of naive T cells from donor lymphocytes will reduce the risk of GvHD but preserve immunity to infectious pathogens. In this study, we have established a clinical-grade protocol under good manufacturing practice conditions for purging CD62L(+) naive T cells from steady-state leukapheresis products using the CliniMACS system. The efficacy of immunomagnetic CD62L depletion was assessed by analysis of cell composition and functional immune responses. A median 2.9 log CD62L depletion was achieved with no evidence of CD62L shedding during the procedure and a mean T-cell yield of 47%. CD62L(-) cells comprised an equal mix of CD4(+) and CD8(+) T cells, with elimination of B cells but maintenance of regulatory T cells and natural killer cell populations. CD62L-depleted T cells were predominantly CD45RA(-) and CD45RA(+) effector memory (>90%) and contained the bulk of pentamer-staining antivirus-specific T cells. Functional assessment of CD62L(-) cells revealed the maintenance of antiviral T-cell reactivity and a reduction in the alloreactive immune response compared with unmanipulated cells. Clinical-grade depletion of naive T cells using immunomagnetic CD62L beads from steady-state leukapheresis products is highly efficient and generates cells suitable for adoptive transfer in the context of clinical trials.

Simulação da rentabilidade e viabilidade econômica de um modelo de produção de leite em free-stall / Simulation of economic feasibility and profitability of a free stall model milk production

Avaliaram-se a rentabilidade e a viabilidade econômica da implantação de um sistema de produção de leite em free-stall. Foi realizada uma pesquisa técnico-mercadológica para definir os investimentos necessários e determinar os custos de cada fator de produção. Considerou-se um modelo de produção composto por 100 vacas em lactação, com produção média total de 2595 litros de leite por dia. O custo operacional total mensal foi de R$27.787,39, tendo a nutrição como a variável de maior relevância, representando 62,7 por cento do custo. Para a receita bruta mensal, obteve-se o valor de R$43.817,50 e a consequente receita líquida mensal de R$16.030,11. Observou-se rentabilidade de 12,2 por cento ao ano, com valor presente líquido negativo de R$131.627,39. Concluiu-se que o modelo proposto mostrou-se economicamente inviável levando-se em consideração os preços estimados.

The economical profitability and viability of the implantation of a milk production system in free stall were evaluated. A technical-market analysis was done to define the necessary investment as well as to determine the costs of each production factor. A production model with 100 lactating cows averaging 2,595 liters of daily production was considered. The total monthly operational cost was R$27,781.39 showing that nutrition is the variable with higher relevance (62.7 percent of the cost). For the monthly gross income a value of R$43,817.50 was obtained and, consequently, the monthly net income (NI)was R$16,030.11. A 12.2 percent profitability per year from NI rendering a deficit net value of R$131,627.39. Considering the estimated prices it is concluded that the proposed model was economically unfeasible.

Searching for globally optimal functional forms for interatomic potentials using genetic programming with parallel tempering.

Molecular dynamics and other molecular simulation methods rely on a potential energy function, based only on the relative coordinates of the atomic nuclei. Such a function, called a force field, approximately represents the electronic structure interactions of a condensed matter system. Developing such approximate functions and fitting their parameters remains an arduous, time-consuming process, relying on expert physical intuition. To address this problem, a functional programming methodology was developed that may enable automated discovery of entirely new force-field functional forms, while simultaneously fitting parameter values. The method uses a combination of genetic programming, Metropolis Monte Carlo importance sampling and parallel tempering, to efficiently search a large space of candidate functional forms and parameters. The methodology was tested using a nontrivial problem with a well-defined globally optimal solution: a small set of atomic configurations was generated and the energy of each configuration was calculated using the Lennard-Jones pair potential. Starting with a population of random functions, our fully automated, massively parallel implementation of the method reproducibly discovered the original Lennard-Jones pair potential by searching for several hours on 100 processors, sampling only a minuscule portion of the total search space. This result indicates that, with further improvement, the method may be suitable for unsupervised development of more accurate force fields with completely new functional forms.

Effects of the Clarion Electrode Positioning System on auditory thresholds and comfortable loudness levels in pediatric patients with cochlear implants.

OBJECTIVE: To evaluate the effects of using the Electrode Positioning System on psychophysical auditory thresholds, most comfortable loudness levels, and electric auditory brainstem response (EABR) thresholds in children with the Clarion version 1.2 cochlear implant. DESIGN: Retrospective analysis. SETTING: Academic tertiary care center. PATIENTS AND METHODS: Clinical records of a series of 25 children who received the Clarion version 1.2 cochlear implant at the University of Minnesota, Minneapolis, between January 1997 and August 1999 were examined. Measures evaluated were psychophysical thresholds (T-levels) and most comfortable loudness levels (M-levels) obtained at the 3-month posthookup audiologic evaluation and EABR thresholds obtained during implant surgery. Relevant threshold measures were available for 24 patients, 11 of whom had received the Clarion spiral electrode and electrode positioner (EP group) and 13 of whom had received the spiral electrode without positioner (non-EP group). The 3 measures (T-levels, M-levels, and EABR thresholds) were compared across groups. In addition, EABR thresholds were compared with T-levels and M-levels within groups. RESULTS: Mean T-levels and M-levels were significantly lower for the EP group than for the non-EP group, and interpatient variability for these measures was considerably smaller in the EP group. Electric auditory brainstem response thresholds were not significantly different for EP vs non-EP patients; however, EABR data were available for only a few non-EP patients. CONCLUSIONS: Use of the electrode positioner results in lower T-levels and M-levels in children with the Clarion version 1.2 cochlear implant, consistent with results of previous studies in adults, and reduces across-patient variability for these measures. It is unclear from the present data whether use of the electrode positioner systematically reduces intraoperative EABR thresholds.

The in vitro evaluation of a local pedicled osteomyocutaneous mandibular flap for the reconstruction of composite mandibular defects.

PURPOSE: The purpose of this study was to develop and assess the potential feasibility of reconstructing composite defects of the mandible with a local pedicled osteomyocutaneous mandibular flap. MATERIALS AND METHODS: The flap design was established based on anatomic principles. A prospective evaluation of the flap was then performed in a fresh cadaver model, and, subsequently, its vascular integrity was documented with angiography. RESULTS: The pedicled osteomyocutaneous mandibular flap was technically simple to raise and had an exceptionally long arc of rotation, which should enable it to fill most compound segmental defects of the mandible. Angiographic studies of the harvested flaps done under fluoroscopic guidance confirmed that excellent vascularity of all components of the flap was present. CONCLUSIONS: The pedicled osteomyocutaneous mandibular flap appears to have a sound anatomic basis. Clinical evaluation is needed to fully elucidate its potential role in head and neck reconstruction.

The evolution of the clinician-scientist model of neurological rehabilitation.

Over the past three or four decades two treatment technologies have been evolving in parallel, recently to some extent merging. The first of these technologies is behaviour analysis, with its emphasis on identification and manipulation of variables external to the individual as controlling agents. The second is neurological rehabilitation, with a characteristic focus of resources on recovery of function following neurological damage. The histories of both of these technologies are similar in that they emerged from basic laboratory research with non-human subjects, followed by extension of findings to research with humans, culminating in widespread formal application of results. The past 5 years have seen a convergence of behaviour analytic and neurological rehabilitation techniques resulting in major shifts in treatment service delivery systems. We briefly chronicle the emergence of these two technologies from their basic underpinnings through world-wide use. Further, discussion is provided describing our and others' experience with the combining of behaviour and neurological rehabilitation. Finally, we give an account of an innovative neurological rehabilitation service delivery system designed to deliver effective cost-efficient treatment in the patient's natural environment. Implicit in the design and implementation of this real-world model of rehabilitation is the combination of behavioural technology and neurological rehabilitation towards the achievement of functional outcomes which endure. Our purpose in the above is to provide an introduction to present use and future potential of behaviour analytic methodologies and technologies in rehabilitation.

Multicenter evaluation of ondansetron use in hospitalized oncology patients.

An evaluation of ondansetron use in oncology patients in three hospitals is described. Criteria for the use of ondansetron were developed and approved by each hospital's pharmacy and therapeutics committee or medical staff executive committee. Ondansetron use was concurrently monitored in adult inpatients for four months. Nursing and physician notes were reviewed, and the patients were interviewed. Data were collected on patient demographics, medical history, dosage of ondansetron, outcome, adverse effects, and concurrent medications. The approved criteria were used to evaluate the appropriateness, effectiveness, and safety of ondansetron therapy. A total of 262 oncology patients were evaluated. Of these, 223 (85%) received ondansetron appropriately based on the emetic potential of their antineoplastic drug regimen. Ondansetron was correctly prescribed for acute-phase prophylaxis of nausea and vomiting in 252 patients (96%). Only 117 (45%) of the patients met the criterion for appropriate dosage. The mean +/- S.D. dose of ondansetron was 11.7 +/- 3.22 mg, and the mean +/- S.D. number of doses received per patient was 4.4 +/- 3.23. Of the 135 patients who received an inappropriate dosage, 106 (79%) were given a dose larger than currently recommended by the manufacturer. Positive outcomes, defined as no more than two episodes of vomiting, no more than two episodes of retching, and no more than two p.r.n. doses of antiemetics, were observed in 97%, 99.6%, and 94% of the 248 patients included in the outcome analysis, respectively. Chemotherapy was completed on schedule in all the patients, and there were no complications due to excessive vomiting or retching. Adverse reactions were reported by 21 patients (8%).(ABSTRACT TRUNCATED AT 250 WORDS)

Behaviour rehabilitation of the challenging client in less restrictive settings.

Individuals who have sustained traumatic brain injury may provide friends, family, and rehabilitation professionals with challenges through an increased likelihood of their engaging in socially inappropriate behaviours. At extremes the inappropriate behaviours include vocal and physical assault, non-compliance, self-injurious behaviours, elopement, and property destruction. While these maladaptive behaviours are by themselves troublesome, for some individuals they provide severe barriers to rehabilitation. One option for the challenging rehabilitation client is a neurobehavioural programme, typically offering an access-limited or otherwise secure physical environment and which focuses on behaviour reduction. While outcomes from neurobehavioural programmes are typically positive, their expense and the negative connotations of this type of programme will at times dissuade family members from enrolling the client. We describe an alternative, less restrictive behavioural programme operated in the physical and social context of a larger, more typical community-based rehabilitation programme for traumatically brain-injured individuals. This programme has been in operation for nearly three years, successfully serving more than 200 clients, of which approximately 20% posed behaviour management problems. Identified variables accounting for these successes include: formal guidelines for programme development, staff training and monitoring, data collection, integration of an interdisciplinary team, discharge planning and post-discharge follow-up. We provide a general programme description followed by discussions of four brief case studies to illustrate basic principles of the programme. Programme strengths are discussed, as are constraints placed on the programme by the physical and social environments in which it operates.

Is there a role for fluconazole in the treatment of vulvovaginal candidiasis?

OBJECTIVE: To review the data describing the use of fluconazole in the treatment of vulvovaginal candidiasis (VVC). DATA IDENTIFICATION: A MEDLINE search of the English-language literature and a bibliographic review of pertinent articles examining the use of fluconazole in the treatment of VVC. STUDY SELECTION AND DATA EXTRACTION: Relevant open and controlled studies reporting on the efficacy, associated adverse effects, or both of fluconazole for the treatment of VVC are reviewed. Appropriate conclusions and/or data are extracted from each article and described. DATA SYNTHESIS: Studies comparing fluconazole with ketoconazole and topical antifungal agents such as clotrimazole and miconazole have shown fluconazole to be equally efficacious with minimal adverse effects. Most of these trials used single-dose fluconazole, which would theoretically lead to a high degree of medication compliance. Fluconazole also has shown promise at diminishing VVC relapse or recurrence, possibly because of more complete vaginal and rectal eradication of Candida species. Pharmacoeconomically, single-dose fluconazole therapy is cost-effective; however, the recent approval of miconazole and clotrimazole by the Food and Drug Administration for over-the-counter use may limit this potential advantage. CONCLUSIONS: Until additional data are available, fluconazole may be considered a treatment alternative for women with VVC who experience frequent relapses or recurrences, or for those who are noncompliant with standard therapy.

Clomipramine: an antiobsessional tricyclic antidepressant.

The chemistry, pharmacology, pharmacokinetics, adverse effects, and dosage of clomipramine hydrochloride are described, and clinical studies of the use of clomipramine in treating obsessive-compulsive disorder (OCD), other psychiatric conditions, and chronic pain are reviewed. Clomipramine hydrochloride, a tricyclic antidepressant, is a potent inhibitor of serotonin reuptake and may affect dopaminergic neurotransmission, suppress rapid eye movement sleep, produce changes in electrocardiograms, and elevate plasma prolactin. The drug is well absorbed from the gastrointestinal tract and undergoes extensive first-pass metabolism. Peak plasma concentrations occur three to four hours after a 150-mg oral dose. The mean elimination half-life is 39 hours. Some 66% of a dose is excreted in the urine, the remainder being eliminated in the feces. In clinical trials, clomipramine was significantly more effective than placebo, clorgiline, amitriptyline, imipramine, and doxepin in ameliorating the symptoms of OCD. Initial effects are seen at four weeks; improvement may continue for up to 18 weeks. Clomipramine may also be effective in treating panic attacks, phobias, depression, and chronic pain. The most common adverse effects of clomipramine are anticholinergic; others include nausea, seizures, and sexual difficulties. Interactions between clomipramine and barbiturates, haloperidol, monoamine oxidase inhibitors, and cigarette smoking have been documented. The usual initial adult dosage is 25-50 mg/day, titrated gradually to 250 mg/day if necessary. Clomipramine hydrochloride is a welcome new agent for the treatment of obsessive-compulsive disorder. Although its adverse-effect profile is like that of other tricyclic antidepressants, sexual dysfunction and seizures may be more frequent with this agent and limit its use.