UK Transfusion Laboratory Collaborative: minimum standards for staff qualifications, training, competency and the use of information technology in hospital transfusion laboratories 2014.

The SHOT Adverse Incident Reporting Scheme has consistently reported an unacceptably high level of errors originating in the laboratory setting. In 2006 an initiative was launched in conjunction with the IBMS, SHOT, RCPath, BBTS, UK NEQAS, the NHSE NBTC and the equivalents in Scotland, Wales and Northern Ireland that led to the formation of the UK TLC. The UK TLC in considering the nature and spread of the errors documented by SHOT concluded that a significant proportion of these errors were most likely to be related to either the use of information technology or staff education, staffing levels, skill mix, training and competency issues. In the absence of any formal guidance on these matters, the UK TLC developed a series of recommendations using the results of two laboratory surveys conducted in 2007 and 2008.

Eribulin mesylate pharmacokinetics in patients with solid tumors receiving repeated oral ketoconazole.

Purpose To study the influence of repeated oral administration of ketoconazole, a potent CYP3A4 inhibitor, on the plasma pharmacokinetics of eribulin mesylate administered by single-dose intravenous infusion. Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that is currently under development in phase I-III trials for the treatment of solid tumors. Experimental design A randomized, open-label, two treatments, two sequences, crossover phase I study was performed in patients with advanced solid tumors. Treatments were given on day 1 and day 15 and consisted of 1.4 mg/m(2) eribulin mesylate alone or 0.7 mg/m(2) eribulin mesylate plus 200 mg ketoconazole on the day of eribulin mesylate administration and the following day. Pharmacokinetic sampling for determination of eribulin plasma concentration was performed up to 144 h following administration of eribulin mesylate. Also safety and anti-tumor activity were determined. Results Pharmacokinetic sampling and analysis was completed in ten patients. Statistical analysis of dose-normalized log-transformed AUC0-∞ and Cmax indicated that single-dose exposure of eribulin was not statistically different when co-administered with ketoconazole (ratio of geometric least square means: 0.95 (90%CI: 0.80-1.12) and 0.97 (90%CI: 0.83-1.12), respectively) in patients with solid tumors. Ketoconazole had no effect on eribulin clearance and elimination half-life. The most frequently reported treatment related adverse events were fatigue and nausea, each reported in 8/12 patients. Seven patients (58.3 %) achieved stable disease as best overall response. Conclusions The results indicate that eribulin mesylate can be safely co-administered with ketoconazole. Drug-drug interactions are not expected with other CYP3A4 inhibitors.

Pharmacokinetics of eribulin mesylate in patients with solid tumors and hepatic impairment.

PURPOSE: The aim of this study was to determine the plasma pharmacokinetics of eribulin mesylate in patients with solid tumors with mild and moderate hepatic impairment. PATIENTS AND METHODS: A phase I, pharmacokinetic study was performed in patients with advanced solid tumors and normal hepatic function or Child-Pugh A (mild) or Child-Pugh B (moderate) hepatic impairment. Treatments were given on day 1 and 8 of a 21-day cycle and consisted of 1.4, 1.1 and 0.7 mg/m(2) eribulin mesylate, for normal hepatic function, Child-Pugh A and B hepatic impairment, respectively. Also safety and anti-tumor activity were determined. RESULTS: Hepatic impairment increased exposure to eribulin. In patients with Child-Pugh A (N = 7) and Child-Pugh B (N = 5), mean dose-normalized AUC(0-∞) was 1.75-fold (90 % confidence intervals (CI): 1.16-2.65) and 2.48-fold (90 % CI: 1.57-3.92) increased, respectively, compared with patients who have normal function (N = 6). The most frequently reported treatment-related events were alopecia (12/18) and fatigue (7/18) and these were observed across all groups. Nine patients (50 %) had stable disease as best response. CONCLUSIONS: A reduced dose of 1.1 and 0.7 mg/m(2) of eribulin mesylate is recommended for patients with Child-Pugh A or B hepatic impairment, respectively.

Lanosterol induces mitochondrial uncoupling and protects dopaminergic neurons from cell death in a model for Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder marked by the selective degeneration of dopaminergic neurons in the nigrostriatal pathway. Several lines of evidence indicate that mitochondrial dysfunction contributes to its etiology. Other studies have suggested that alterations in sterol homeostasis correlate with increased risk for PD. Whether these observations are functionally related is, however, unknown. In this study, we used a toxin-induced mouse model of PD and measured levels of nine sterol intermediates. We found that lanosterol is significantly (∼50%) and specifically reduced in the nigrostriatal regions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice, indicative of altered lanosterol metabolism during PD pathogenesis. Remarkably, exogenous addition of lanosterol rescued dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+)-induced cell death in culture. Furthermore, we observed a marked redistribution of lanosterol synthase from the endoplasmic reticulum to mitochondria in dopaminergic neurons exposed to MPP+, suggesting that lanosterol might exert its survival effect by regulating mitochondrial function. Consistent with this model, we find that lanosterol induces mild depolarization of mitochondria and promotes autophagy. Collectively, our results highlight a novel sterol-based neuroprotective mechanism with direct relevance to PD.

Increased expression of acyl-coenzyme A: cholesterol acyltransferase-1 and elevated cholesteryl esters in the hippocampus after excitotoxic injury.

Significant increases in levels of cholesterol and cholesterol oxidation products are detected in the hippocampus undergoing degeneration after excitotoxicity induced by the potent glutamate analog, kainate (KA), but until now, it is unclear whether the cholesterol is in the free or esterified form. The present study was carried out to examine the expression of the enzyme involved in cholesteryl ester biosynthesis, acyl-coenzyme A: cholesterol acyltransferase (ACAT) and cholesteryl esters after KA excitotoxicity. A 1000-fold greater basal mRNA level of ACAT1 than ACAT2 was detected in the normal brain. ACAT1 mRNA and protein were upregulated in the hippocampus at 1 and 2 weeks after KA injections, at a time of glial reaction. Immunohistochemistry showed ACAT1 labeling of oligodendrocytes in the white matter and axon terminals in hippocampal CA fields of normal rats, and loss of staining in neurons but increased immunoreactivity of oligodendrocytes, in areas affected by KA. Gas chromatography-mass spectrometry analyses confirmed previous observations of a marked increase in level of total cholesterol and cholesterol oxidation products, whilst nuclear magnetic resonance spectroscopy showed significant increases in cholesteryl ester species in the degenerating hippocampus. Upregulation of ACAT1 expression was detected in OLN93 oligodendrocytes after KA treatment, and increased expression was prevented by an antioxidant or free radical scavenger in vitro. This suggests that ACAT1 expression may be induced by oxidative stress. Together, our results show elevated ACAT1 expression and increased cholesteryl esters after KA excitotoxicity. Further studies are necessary to determine a possible role of ACAT1 in acute and chronic neurodegenerative diseases.

The effect of APOE genotype on brain levels of oxysterols in young and old human APOE epsilon2, epsilon3 and epsilon4 knock-in mice.

Despite apolipoprotein E's important role in cholesterol transport and metabolism in the brain as well as its influence on Alzheimer's disease, the impact of the human APOE genotype on cholesterol metabolism in brain has not been fully examined. This study was carried out to investigate APOE genotype effects on oxysterols measured. In this study the measurement of cholesterol and several oxysterols in the brains of human APOE epsilon2, epsilon3 and epsilon4 knock-in mice at 8 weeks and 1 year of age using gas chromatography mass spectrometry (GC-MS) demonstrated no APOE genotype or age effect on total brain cholesterol and the oxysterol 24-hydroxycholesterol. The level of 27-hydroxycholesterol was elevated in 1 year old animals for all APOE genotypes. Interestingly, lathosterol an indicator of cholesterol synthesis was significantly reduced in the 1 year old animals for all APOE genotypes. APOE epsilon4 expressing mice exhibited statistically lower levels of lathosterol compared to APOE epsilon2 in both the young and old mice. Oxidized cholesterol metabolites were significantly lower in APOE epsilon2 mice compared to other genotypes at 8 weeks old. Although minimal differences were observed between APOE E3 and E4 knock-in (KI) mice, these findings indicate that there are some clear APOE genotype specific effects on brain cholesterol synthesis and associated metabolic pathways, particularly in APOE epsilon2 KI mice.

Non-collinear ferrimagnetism in a Fe64Er19B17 metallic glass.

Polarized neutron beam measurements on a Fe(64)Er(19)B(17) metallic glass have shown directly that it has a non-collinear magnetic structure. It can be described using a model in which the magnetic moments on the iron atoms point in a random cone that is ferrimagnetically coupled to a random cone of erbium moments, in the manner suggested from bulk measurements. The spin-flip cross-sections were successfully calculated using an optimized choice of the values of the magnetic moments µ(Fe), µ(Er) and the random cone angles θ(Fe), θ(Er). The non-spin-flip cross-sections have an unusual variation with the scattering vector Q, which has not been observed before with transition metal-metalloid glasses. At 1.5 and 60 K the [Formula: see text] cross-section contains a pre-peak at a smaller value of Q (1.3 Å(-1)) than the pre-peaks which have been observed in the structure factors of some transition metal glasses. At 180 K the form of these cross-sections remains the same but the two channels have interchanged, so [Formula: see text] contains the pre-peak. This interchange shows that a complete inversion of the magnetic structure occurs between 60 and 180 K-presumably at the compensation temperature T(comp)≈120 K. Attempts to simulate these cross-sections using the methods applied to (Fe,Tb)B glasses were unsuccessful because none of the known partial structure factors contains a pre-peak which can imitate the observed one. The possible origins of the pre-peak are discussed.

Better informed: an overview of health informatics.

Healthcare informatics is increasing in importance both for healthcare administrators and medical and dental practitioners. Governments across the developed world are initiating major national health IT programmes. At the same time, future best medical and dental practice will increasingly depend on computer-based support tools, although disagreement remains about the effectiveness of current support tools. Over the longer term, future informatics tools, combined with other medical and dental technology modalities, promise more adaptive, patient-focused and efficient healthcare and education for the practitioner and the patient.

A phase I study of intravenous TZT-1027 administered on day 1 and day 8 of a three-weekly cycle in combination with carboplatin given on day 1 alone in patients with advanced solid tumours.

BACKGROUND: TZT-1027 is a tubulin-binding drug and synthetic derivative of dolastatin-10 with cytotoxic and antivascular activity in vitro and in vivo. Studies have demonstrated anti-tumour activity in several tumour types. METHODS: Patients were treated with escalating doses of TZT-1027 and carboplatin at doses from 1.6 to 2.0 mg/m2 and AUC 4 and 5 respectively. For pharmacokinetic analysis, plasma sampling was done during the first course using a high-performance liquid chromatographic assay. RESULTS: 14 patients received a total of 55 cycles at three dose levels. Dose limiting toxicities (DLTs) were first observed with 1.6 mg/m2 TZT-1027 and carboplatin AUC 5; 1 patient had grade 4 neutropenia and a delay in day 8 treatment occurred in two patients (gr 2 fatigue, gr 3 diarrhoea). At TZT-1027 2 mg/m2 and carboplatin AUC 5, one patient experienced grade 3 paralytic ileus. The most frequent toxicities were neutropenia, anaemia, fatigue, constipation, infection and vomiting. Peripheral neuropathy was reported in 36% of patients. One patient (pancreatic adenocarcinoma) achieved a partial response lasting 181 days. Pharmacokinetic analysis did not demonstrate any interaction between TZT-1027 and carboplatin. CONCLUSIONS: The recommended phase II dose is TZT-1027 1.6 mg/m2 and carboplatin AUC 5. No evidence of a PK interaction between these agents was observed.

The personal dental service as a setting for an undergraduate clinical programme.

OBJECTIVE: To investigate the feasibility and benefits of placing dental undergraduates into a general dental practice setting for part of their clinical programme. SETTING: Two six-surgery general dental practices in the North West of England operating within the personal dental service of the NHS. METHOD: Six volunteer final year students worked within the practices for one-day-per week for 11 weeks. Evaluation included patients', practitioners' and students' views obtained from questionnaires and/or interviews and an analysis of students' clinical records. RESULTS: The students saw a large positive impact from: working alongside a dental nurse; developing their clinical skills; working in a busy practice environment; and developing interpersonal skills. Patients were very positive with 98% (44/45) being complimentary about the treatment they received, and commenting that they would be willing to participate in future student training programmes. The practice principals would also welcome continuation of the programme. CONCLUSION: The programme was both feasible and educationally beneficial. The financial implications need further research.

Phase I and pharmacokinetic study of TZT-1027, a novel synthetic dolastatin 10 derivative, administered as a 1-hour intravenous infusion every 3 weeks in patients with advanced refractory cancer.

BACKGROUND: TZT-1027 is a synthetic dolastatin 10 analog with antineoplastic properties in various cell lines and tumor xenografts. The purpose of this phase I study was to evaluate the safety and toxicity, maximum tolerated dose, pharmacokinetics and pharmacodynamics, clinical and metabolic antitumor activity of TZT-1027 when given as a 1-h intravenous infusion every 3 weeks in patients with refractory solid tumors. PATIENTS AND METHODS: Patients had a histologically verified refractory tumor with measurable disease, were > or = 18 years old, had an Eastern Cooperative Oncology Group performance status <2 and adequate bone marrow, liver, renal and cardiac function. Dose-limiting toxicity was defined as platelets <25 x 10(9)/l, neutrophils <0.5 x 10(9)/l for >5 days, febrile neutropenia > or = 38.5 degrees C with grade 4 (National Cancer Institute-common toxicity criteria) neutropenia, or grade 3/4 non-hematological toxicity excluding nausea and vomiting. The last dose was the dose where > or = 2 out of six patients experienced dose-limiting toxicity in cycle one. The maximum tolerated dose was one dose level below with less than two of six patients with dose-limiting events. RESULTS: Twenty-one non-selected, fully evaluable patients were enrolled. The majority were male (19) and the median age was 55 years (range 39-67). Dose levels of TZT-1027 ranged from 1.35 to 3.0 mg/m(2). The median number of cycles was two (range 1-4). Dose-limiting toxicities were observed in three patients at the 3.0 mg/m(2) dose level, including neutropenia, fatigue and a short lasting, reversible peripheral neurotoxic syndrome. The most common toxicities per patient were fatigue, anorexia, alopecia, nausea, constipation, leukopenia and neutropenia. Based on RECIST criteria, the best response was stable disease in seven patients. The pharmacokinetic evaluation revealed a T(1/2) of approximately 7 h and linear kinetics. CONCLUSIONS: The recommended dose of TZT-1027 for the 3-weekly administration is 2.7 mg/m(2). Neutropenia, fatigue and a reversible peripheral neurotoxic syndrome are dose-limiting with this schedule. TZT-1027 may be associated with neurological side-effects in patients previously exposed to neurotoxic compounds such as oxaliplatin.

[Acral skin necrosis in a patient with malaria]. / Necrose cutânea distal em doente com malária.

A case of acral skin necrosis in a 21-year-old farm workman, associated with Plasmodium falciparum malaria is reported. Patient presented jaundice, disorientation and delirium, high parasitemia, hypoglycemia, anemia, low platelets, and dark necrotic maculae surrounded by an erythematous halo, circumscribed to toes. After malaria treatment, the clinical evolution was uneventful and the skin lesions also improved without sequels. The possibility that some of the skin changes, eventually observed in malaria patients, may be related with responses to Plasmodium infection is emphasized.

Neurobiological studies of reading and reading disability.

UNLABELLED: Evidence from neuroimaging studies, including our own, suggest that skilled word identification in reading is related to the functional integrity of two consolidated left hemisphere (LH) posterior systems: a dorsal (temporo-parietal) circuit and a ventral (occipito-temporal) circuit. This posterior system appears to be functionally disrupted in developmental dyslexia. Relative to nonimpaired readers, reading-disabled individuals demonstrate heightened reliance on both inferior frontal and right hemisphere posterior regions, presumably in compensation for the LH posterior difficulties. We propose a neurobiological account suggesting that for normally developing readers, the dorsal circuit predominates at first, and in conjunction with premotor systems, is associated with analytic processing necessary for learning to integrate orthographic with phonological and lexical semantic features of printed words. The ventral circuit constitutes a fast, late-developing, word form system, which underlies fluency in word recognition. LEARNING OUTCOMES: As a result of this activity, (1) the participant will learn about a model of lexical processing involving specific cortical regions. (2) The participant will learn about evidence which supports the theory that two dorsal LH systems may be disrupted in developmental dyslexia. (3) The participant will learn that individuals with reading impairment may rely on other regions of the brain to compensate for the disruption of posterior function.

A clinical minimum data set for primary dental care.

OBJECTIVE: To achieve consensus within primary dental care on the contents of a clinical minimum data set to measure oral health status. DESIGN: Using the Delphi process a simple random sample of 30 LDCs and 10 CDS services in England were asked to rank a list of existing clinical indicators in order of their perceived importance as a means of measuring oral health. A nominated panel representing the stakeholder organisations of primary dental care reviewed this ranking and identified a core group of clinical indicators to be included in a clinical minimum data set. RESULTS: An 80 percent response rate to the Delphi process was achieved. Consensus was reached on a core group of 10 indicators, which can provide information on patient's perceptions of pain, function and appearance, and professional measurements of caries, teeth present, periodontal disease, oral sepsis, presence of mucosal pathology and tooth wear. CONCLUSIONS: A representative sample of primary care dentists in England and the key representative organisations of primary dental care achieved consensus on the contents of a clinical minimum data set to record oral health status in primary dental care. This is a first step in standardising the measurement of oral health status across primary care.

6-hydroxydopamine increases hydroxyl free radical production and DNA damage in rat striatum.

Oxidative damage is considered to be an important factor of 6-hydroxydopamine (6-OHDA) toxicity. To address this issue, microdialysis probes were implanted into the striatum of Wistar rats and perfused with 6-OHDA. Salicylate was included in the perfusion fluid to measure 2,3-dihydroxybenzoic acid (2,3-DHBA) as a marker of hydroxyl radical formation using HPLC with electrochemical detection. Additionally, striatal tissue was analysed for DNA base alterations using gas chromatography-mass spectrometry. 6-OHDA administration resulted in a rapid and substantial 6.6-fold increase in 2,3-DHBA formation and also increased levels of the modified DNA bases 5-hydroxycytosine, hypoxanthine and 2,6-diamino-4-hydroxy-5-formamidopyrimidine. Hydroxyl radical formation and DNA base alterations are early phenomena of 6-OHDA toxicity and provide clues to the processes that may be involved in the initiation of cell death in Parkinson's disease.

Management information failings and future requirements for dental commissioning groups.

OBJECTIVE: To examine existing secondary care management information systems for dental specialities, and to determine their completeness and suitability for supporting effective primary care led purchasing decisions. DESIGN: An observational cross-sectional study of current information systems in selected secondary care provider units and the applicability of their data for contracting dental services. A comparative study of two information systems in two settings (primary and secondary care) and the utility of the data gathered for contracting for dental services. SUBJECTS: Secondary care activity data was sought from the key secondary dental care providers (hospitals) in two dental total purchasing localities. Referral data were also collected directly from general dental practitioners. MAIN OUTCOME MEASURES: The integrity, quality and accuracy of current secondary care activity data in dental specialities, in comparison to data supplied from primary dental care. RESULTS: The secondary care activity data was found to be incomplete, inadequate and inaccurate. It was found that due to data retrieval insufficiency, indicative budgets for secondary providers may be reduced to less than half of their actual entitlement. The data inflated individual dental outpatient attendance by 3.3 times between 1995/6 and by 2.5 times between 1996/7. CONCLUSION: Existing management information systems within secondary care providers are not structured in a way which will adequately inform future commissioning by the dental profession. Communication between primary and secondary care must be increased and data inputting methods in secondary care provider units must be substantially improved.

A comparison of normative and subjective assessment of the child prevalence of developmental defects of enamel amongst 12-year-olds living in the North West Region, UK.

Analysis of data from a 1996-97 cross sectional epidemiological study of the dental health of a sample of 12-y-old children living in Crewe, in north west England was used to compare normative and subjective assessment of developmental defects of enamel. Five hundred and twenty two 12-y-old children from secondary schools in Crewe were examined. One hundred and eighty two children (34.8%), had home post codes within the optimally fluoridated part of Crewe. Using the Developmental Defects of Enamel Index, 178 children (34%) in Crewe were normatively identified as having enamel defects present on their upper incisors. Thirty five children (6.7%), were unhappy with the appearance of their upper incisors because of marks that would not brush off. Neither the normative nor the subjective assessment of enamel defects demonstrated any difference in prevalence between the fluoridated and non-fluoridated areas. In Crewe, one in 20 children normatively diagnosed as being free from enamel defects were unhappy with the appearance of their upper incisors because of marks that would not brush off. There are differences in perception between dental professionals and 12-y-old children over the presence and relevance of developmental defects of enamel. Further research is required if we are to understand the difference in professional and lay perceptions of developmental defects affecting upper incisor teeth.

Connectivity of ectopic neurons in the molecular layer of the somatosensory cortex in autoimmune mice.

Approximately 50% of New Zealand Black mice (NZB/BINJ) and 80% of NXSM-D/EiJ mice prenatally develop neocortical layer I ectopias, mostly in somatosensory cortices. These cortical anomalies are similar to those seen in the brains of individuals with dyslexia. Neurofilament staining revealed a radial column of tightly packed fiber bundles in the layers underlying ectopias. This suggested that the connectivity of the ectopic neurons was aberrant. The present study used the tracers 1,1'-dioctadecyl- 3,3,3',3'-tetramethylindo- carbocyanine perchlorate (DiI) and biotinylated dextran amine (BDA) to more thoroughly explore the cortical and thalamic connectivity of the ectopias. DiI placement into ectopias again revealed a distinct bundle of fibers extending from the ectopic neurons to the deep cortical layers. This bundle split in the white matter with some fibers traveling to the corpus callosum and others to the internal capsule. Thalamic connections were concentrated in the ventrobasal com- plex (VB) and posterior thalamic nucleus group (Po). Injections of BDA into VB revealed reciprocal connections between VB and the ectopic cortical neurons. Ipsilateral corticocortical projections were seen between ectopias in primary somatosensory and motor and secondary somatosensory cortices, but no contralateral connections of the ectopic neurons were seen. These findings confirm the notion that layer I ectopias are anomalously connected by comparison to neurons in homologous cortex, which may underlie widespread dysfunction of brains containing ectopias.

Functional neuroimaging studies of reading and reading disability (developmental dyslexia).

Converging evidence from a number of neuroimaging studies, including our own, suggest that fluent word identification in reading is related to the functional integrity of two consolidated left hemisphere (LH) posterior systems: a dorsal (temporo-parietal) circuit and a ventral (occipito-temporal) circuit. This posterior system is functionally disrupted in developmental dyslexia. Reading disabled readers, relative to nonimpaired readers, demonstrate heightened reliance on both inferior frontal and right hemisphere posterior regions, presumably in compensation for the LH posterior difficulties. We propose a neurobiological account suggesting that for normally developing readers the dorsal circuit predominates at first, and is associated with analytic processing necessary for learning to integrate orthographic features with phonological and lexical-semantic features of printed words. The ventral circuit constitutes a fast, late-developing, word identification system which underlies fluent word recognition in skilled readers.