Neonatal encephalopathy: Focus on epidemiology and underexplored aspects of etiology.

Neonatal Encephalopathy (NE) is a neurologic syndrome in term and near-term infants who have depressed consciousness, difficulty initiating and maintaining respiration, and often abnormal tone, reflexes and neonatal seizures in varying combinations. Moderate/severe NE affects 0.5-3/1000 live births in high-income countries, more in low- and middle-income countries, and carries high risk of mortality or disability, including cerebral palsy. Reduced blood flow and/or oxygenation around the time of birth, as with ruptured uterus, placental abruption or umbilical cord prolapse can cause NE. This subset of NE, with accompanying low Apgar scores and acidemia, is termed Hypoxic-Ischemic Encephalopathy. Other causes of NE that can present similarly, include infections, inflammation, toxins, metabolic disease, stroke, placental disease, and genetic disorders. Aberrant fetal growth and congenital anomalies are strongly associated with NE, suggesting a major role for maldevelopment. As new tools for differential diagnosis emerge, their application for prevention, individualized treatment and prognostication will require further systematic studies of etiology of NE.

The tactile motion aftereffect suggests an intensive code for speed in neurons sensitive to both speed and direction of motion.

Neurophysiological studies in primates have found that direction-sensitive neurons in the primary somatosensory cortex (SI) generally increase their response rate with increasing speed of object motion across the skin and show little evidence of speed tuning. We employed psychophysics to determine whether human perception of motion direction could be explained by features of such neurons and whether evidence can be found for a speed-tuned process. After adaptation to motion across the skin, a subsequently presented dynamic test stimulus yields an impression of motion in the opposite direction. We measured the strength of this tactile motion aftereffect (tMAE) induced with different combinations of adapting and test speeds. Distal-to-proximal or proximal-to-distal adapting motion was applied to participants' index fingers using a tactile array, after which participants reported the perceived direction of a bidirectional test stimulus. An intensive code for speed, like that observed in SI neurons, predicts greater adaptation (and a stronger tMAE) the faster the adapting speed, regardless of the test speed. In contrast, speed tuning of direction-sensitive neurons predicts the greatest tMAE when the adapting and test stimuli have matching speeds. We found that the strength of the tMAE increased monotonically with adapting speed, regardless of the test speed, showing no evidence of speed tuning. Our data are consistent with neurophysiological findings that suggest an intensive code for speed along the motion processing pathways comprising neurons sensitive both to speed and direction of motion.

Spatial structuring of arbuscular mycorrhizal communities in benchmark and modified temperate eucalypt woodlands.

Arbuscular mycorrhizal fungi (AMF) are crucial to the functioning of the plant-soil system, but little is known about the spatial structuring of AMF communities across landscapes modified by agriculture. AMF community composition was characterized across four sites in the highly cleared south-western Australian wheatbelt that were originally dominated by forb-rich eucalypt woodlands. Environmentally induced spatial structuring in AMF composition was examined at four scales: the regional scale associated with location, the site scale associated with past management (benchmark woodlands with no agricultural management history, livestock grazing, recent revegetation), the patch scale associated with trees and canopy gaps, and the fine scale associated with the herbaceous plant species beneath which soils were sourced. Field-collected soils were cultured in trap pots; then, AMF composition was determined by identifying spores and through ITS1 sequencing. Structuring was strongest at site scales, where composition was strongly related to prior management and associated changes in soil phosphorus. The two fields were dominated by the genera Funneliformis and Paraglomus, with little convergence back to woodland composition after revegetation. The two benchmark woodlands were characterized by Ambispora gerdemannii and taxa from Gigasporaceae. Their AMF communities were strongly structured at patch scales associated with trees and gaps, in turn most strongly related to soil N. By contrast, there were few patterns at fine scales related to different herbaceous plant species, or at regional scales associated with the 175 km distance between benchmark woodlands. Important areas for future investigation are to identify the circumstances in which recolonization by woodland AMF may be limited by fungal propagule availability, reduced plant diversity and/or altered chemistry in agricultural soils.

The effect of hand-arm vibration syndrome on quality of life.

BACKGROUND: It is important to determine how hand-arm vibration syndrome (HAVS), a common occupational condition, affects quality of life (QOL). AIMS: To measure the physical (SF12-P) and mental (SF12-M) components of QOL in workers with HAVS, using the SF12 questionnaire, and to determine the effect of the vascular, sensorineural and musculoskeletal components of HAVS on QOL. METHODS: Subjects were recruited consecutively from workers with HAVS attending an occupational medicine clinic. They were assessed to determine the Stockholm vascular and sensorineural scale stages as well as an upper extremity pain score, measured by the Borg scale, as an indication of musculoskeletal problems associated with the use of vibrating tools. The SF12-P and SF12-M were both compared with Canadian population normal values after adjusting for age and sex. Multiple linear regression was used to determine the effect of the various HAVS components on SF12-P and SF12-M as well as the effects of age and carpal tunnel syndrome. RESULTS: One hundred and forty-one subjects were recruited and 139 (99%) agreed to participate, including 134 men and 5 women. The SF12-P and SF12-M scores were significantly below the Canadian population mean values (P < 0.001), indicating lower QOL. In the multiple regression analysis, the predictor with the largest partial R (2) value for both the SF12-P and SF12-M was the upper extremity pain score. CONCLUSIONS: Both the physical and the mental QOL in workers with HAVS were below Canadian population normal values and subjects' upper extremity pain score had the greatest effect on their QOL.

DASH work module in workers with hand-arm vibration syndrome.

BACKGROUND: The Disabilities of the Arm, Shoulder and Hand work module (DASH-W) questionnaire has not previously been described in relation to hand-arm vibration syndrome (HAVS). AIMS: To measure work-related disability in workers with HAVS using the DASH-W questionnaire and to determine how the various components of HAVS affect the DASH-W score. METHODS: Workers with HAVS from a variety of industries were assessed over a 2-year period at the occupational health clinic, St Michael's Hospital, Toronto. Subjects completed the DASH-W questionnaire and were assessed by an occupational physician to determine their Stockholm sensorineural and vascular stages and upper extremity pain score measured by the Borg scale, as an indication of musculoskeletal problems associated with HAVS. The average DASH-W score was compared with the average value for the US population. Multiple linear regression was used to determine the contribution of the various components of HAVS to the DASH-W score. RESULTS: There were 139 (134 men and 5 women) participants. The subjects with HAVS had a mean DASH-W score of 54.7 (95% CI: 50.3-59.1), which was considerably higher than the average for the US population (P < 0.001). Statistically significant HAVS variables in the multiple linear regression included the Stockholm sensorineural stage (P < 0.05) and the upper extremity pain score (P < 0.001) with the pain score having the highest partial R (2) value. CONCLUSIONS: Workers with HAVS reported significant upper extremity work-related disability as measured by the DASH-W questionnaire, and the upper extremity pain score made the largest contribution to the DASH-W scores in these subjects.

Nature and quality of antipsychotic prescribing practice in UK psychiatry of intellectual disability services.

BACKGROUND: Antipsychotics are perceived to be over-used in the management of behavioural problems in people with an intellectual disability (ID). Published guidelines have set good practice standards for the use of these drugs for behavioural indications. We sought to identify the range of indications for which antipsychotic drugs are prescribed in people with ID and to audit clinical practice against the standards. METHOD: Data were collected from the clinical records of individuals with ID who were under the care of mental health services in the UK, and prescribed an antipsychotic drug. RESULTS: The sample comprised 2319 patients from 39 clinical services. Twenty-seven per cent of the patients had a diagnosis of a psychotic illness (ICD-10 F20-29) and 27% an affective illness (ICD-10 F30-39). The proportion who did not have a psychiatric diagnosis ranged from 6% of those with borderline/mild ID to 21% of those with severe/profound ID. Overall, the most common indications for prescribing an antipsychotic drug were comorbid psychotic illness, anxiety and agitation, and a range of behavioural disturbances. The prevalence of use of antipsychotic drugs to manage challenging behaviour in the absence of concomitant mental illness increased with the severity of ID and accounted for almost half of prescriptions in those with severe/profound ID. Adherence to the audit standards related to documentation of clinical indications and review of efficacy was high. Side effect monitoring was less assiduous. CONCLUSIONS: In clinical practice, most prescriptions for antipsychotic drugs in people with ID are consistent with the evidence base and the overall quality of prescribing practice, as measured against recognised standards, is good, although in some patients potentially remedial side effects may not be detected and treated.

Comparison of clinical evaluation of genitourinary symptoms in female adolescents among primary care versus emergency department physicians.

OBJECTIVE: To compare clinical approaches to assessment and treatment of female adolescents with genitourinary symptoms among primary care and emergency department (ED) physicians. DESIGN: A chart review was performed of the evaluation and treatment of 472 patients presenting between July 1, 2005, and June 30, 2006. SETTING: Suburban and tertiary care EDs and primary care settings. PARTICIPANTS: Female patients age 13-21 years with genitourinary symptoms. INTERVENTIONS: None. OUTCOME MEASURES: Physician assessment of sexual history, performance of pelvic exam and sexually transmitted infection (STI) tests, empiric treatment of suspected STIs. RESULTS: Patients seen in primary care settings were more likely to be asked about sexual history, including contraceptive use, than patients in the ED (P<0.001). After adjustment for age and race, there was no statistically significant difference between the ED and primary care sites in performance of pelvic exams or gonorrhea and chlamydia tests. However, there was a higher likelihood that older adolescents would undergo pelvic exams (P=0.001), and STI testing (P=0.002) than younger patients. There was no significant difference in empiric treatment of patients with positive STI tests between ED and primary care sites or across the age spectrum. CONCLUSIONS: ED physicians should obtain sexual histories on patients with genitourinary symptoms. Both primary care and ED clinicians should consistently test for STIs in sexually active patients who have genitourinary symptoms. Physicians in both settings should have a low threshold for testing and empirically treating adolescents with symptoms or physical exam findings consistent with STIs.

Mass spectrometry tools and metabolite-specific databases for molecular identification in metabolomics.

The chemical identification of mass spectrometric signals in metabolomic applications is important to provide conversion of analytical data to biological knowledge about metabolic pathways. The complexity of electrospray mass spectrometric data acquired from a range of samples (serum, urine, yeast intracellular extracts, yeast metabolic footprints, placental tissue metabolic footprints) has been investigated and has defined the frequency of different ion types routinely detected. Although some ion types were expected (protonated and deprotonated peaks, isotope peaks, multiply charged peaks) others were not expected (sodium formate adduct ions). In parallel, the Manchester Metabolomics Database (MMD) has been constructed with data from genome scale metabolic reconstructions, HMDB, KEGG, Lipid Maps, BioCyc and DrugBank to provide knowledge on 42,687 endogenous and exogenous metabolite species. The combination of accurate mass data for a large collection of metabolites, theoretical isotope abundance data and knowledge of the different ion types detected provided a greater number of electrospray mass spectrometric signals which were putatively identified and with greater confidence in the samples studied. To provide definitive identification metabolite-specific mass spectral libraries for UPLC-MS and GC-MS have been constructed for 1,065 commercially available authentic standards. The MMD data are available at http://dbkgroup.org/MMD/.

Evaluation of a new Staphylococcus aureus latex agglutination kit, Prolex Staph Xtra, against other third-generation kits.

Staphylococcus aureus, including methicillin-resistant strains, continues to be a common cause of infection/colonisation, which necessitates accurate and prompt diagnosis in the laboratory. Several rapid agglutination tests that aid this function are available, and some have been modified to improve their performance. One such kit, Prolex Staph Xtra, has been released recently. This study aims to compare this kit with other improved kits (i.e., Pastorex Staph-Plus, Staphaurex Plus and Staphytect Plus) and investigate their ability to confirm the identity of 100 strains of S. aureus. Results showed that 50 were resistant to methicillin. Specificity was checked against 30 strains of coagulase-negative staphylococci and 20 Enterococcus species isolates. Of the four kits tested, Prolex Staph Xtra and Pastorex Staph-Plus proved superior in terms of sensitivity and speed.

Methicillin-resistant Staphylococcus aureus detection using chromogenic media: the Sheffield experience.

Methicillin-resistant Staphylococcus aureus (MRSA) continues to cause major problems, both in hospitals and the community. Microbiology departments need to review their methodology regularly to ensure that they are contributing in the most appropriate manner to the battle against MRSA. Media employing chromogenic enzymes to aid the isolation and identification of MRSA is a relatively new approach. In this study, 192 swabs from 112 different patients were inoculated on two chromogen-containing media and four other commonly used solid MRSA media to determine which gave the appropriate combination of sensititivity, specificity and speed of result. Methicillin-resistant S. aureus was isolated on at least one of the six media from 102 of the 192 swabs. Both chromogenic media proved to be statistically significantly more sensitive than the other media after overnight incubation and had a sensitivity of 96% after 48 hours' incubation. The recent introduction of chromogen-containing MRSA media offers microbiology laboratories the opportunity to isolate and confirm the majority of MRSA infections/colonisations in 24 hours, which should result in better patient care. The possible slight increase in costs should not provide a valid excuse for using inferior methodologies.

Impacts of livestock grazing and tree clearing on birds of woodland and riparian habitats.

We investigated the impact of pastoral management on birds in subtropical grassy eucalypt woodland in southeastern Queensland, Australia, where the patterns of land management have made it possible to disentangle the effects of livestock grazing from those of tree clearing. We recorded changes in bird species composition, density, and relative abundance across two woodland habitat types (riparian and nonriparian) and two levels of clearing (wooded and nonwooded) and three levels of livestock grazing (low, moderate, and high) replicated over space (1000 km(2)) and time (2001-2002). We predicted that species that depend on understory vegetation would be most negatively affected by livestock grazing. A Bayesian generalized linear model showed that the level of grazing had the greatest effect when trees were present. When trees were absent, the impact of grazing was overshadowed by the effects of a lack of trees. Over 65% of species responded to different levels of grazing, and the abundance of 42% of species varied markedly with habitat and grazing. The most common response to grazing was high species relative abundance under low levels of grazing (28% of species), species absence at high levels of grazing (20%), and an increase in abundance with increasing grazing (18%). Despite having similar bird assemblages, the effect of grazing was stronger in riparian habitat than in adjacent woodland habitat. Our results suggest that any level of commercial livestock grazing is detrimental to some woodland birds, particularly the understory-dependant species, as predicted. Nevertheless, provided trees are not cleared, a rich and abundant bird fauna can coexist with moderate levels of grazing. Habitats with high levels of grazing, on the other hand, resulted in a species-poor bird assemblage dominated by birds that are increasing in abundance nationally.

A comparison of goal attainment scaling and the Canadian Occupational Performance Measure for paediatric rehabilitation research.

PURPOSE: To investigate the relative utility of Canadian Occupational Performance Measure (COPM) (adapted for children) and Goal Attainment Scaling (GAS) as outcome measures for paediatric rehabilitation. METHODS: A two-group pre-post design investigated the impact of a 3-month programme. Forty-one children with spastic hemiplegic cerebral palsy (mean 3.9 years; GMPM level 1; 21 boys, 10 girls) were randomized to occupational therapy only and occupational therapy plus one Botulinum Toxin A injection. The latter was considered a 'proven' intervention for the purpose of this instrumentation study. Intervention impact was investigated using GAS and COPM. Instrument sensitivity, convergent validity, goal/problem profiles and administration were evaluated. RESULTS: Both instruments were sensitive to within group change and detected significant between group change. Likert scale coding for GAS scores was more sensitive than the traditional weighted GAS or COPM. Different constructs were measured by each instrument. COPM was more time efficient in training, development and administration. CONCLUSION: Study aim, logistic and resource factors should guide the choice of COPM and/or GAS instruments as both are sensitive to change with a proven intervention and both evaluate different constructs.

Clinical pathways in total knee arthroplasty: a New Zealand experience.

PURPOSE: To ascertain the effects of a clinical pathway in our institution. METHODS: This retrospective and comparative study was performed on all patients undergoing total knee arthroplasty over a 5-year period. This period covered the 30 months prior to the introduction of the pathway (group 1), and the 30 months following its introduction (group 2). RESULTS: There was a significant reduction in the duration of hospital stay of group 2 patients (p<0.0001), with 62.8% of these patients staying less than 8 postoperative days. There was a reduction in the number of patients with thromboembolic complications (p<0.05) and no increase in overall complications or readmission rate. There was a trend to increased use of rehabilitation services among group 2 patients. CONCLUSION: Clinical pathway implementation resulted in a significant reduction in the length of stay, and achieved a more efficient management of hospitalised patients without compromising outcome.

Streptococcus grouping latex kits: evaluation of five commercially available examples.

This study compares a recently introduced latex agglutination test for the serogrouping of beta-haemolytic streptococci against four internationally used commercial kits. The new kit is Prolex-Blue (Pro-Lab Diagnostics) and the comparators are Streptex (Murex), PathoDx (DPC), Streptococcus Grouping kit (Oxoid) and Prolex-White (Pro-Lab Diagnostics). A total of 302 consecutive clinical isolates are tested against all five kits, following the individual manufacturer's protocol, for both accuracy and speed. In addition, the data produced permits determination of the strengths or weaknesses of the kits against individual serotypes. Prolex-Blue proved to be both accurate and rapid, with a sensitivity of 99% and a specificity of 100%. Furthermore, average time to agglutination was substantially less than achieved by three of the other four kits evaluated.

Decrease in beta-cell mass leads to impaired pulsatile insulin secretion, reduced postprandial hepatic insulin clearance, and relative hyperglucagonemia in the minipig.

Most insulin is secreted in discrete pulses at an interval of approximately 6 min. Increased insulin secretion after meal ingestion is achieved through the mechanism of amplification of the burst mass. Conversely, in type 2 diabetes, insulin secretion is impaired as a consequence of decreased insulin pulse mass. beta-cell mass is reported to be deficient in type 2 diabetes. We tested the hypothesis that decreased beta-cell mass leads to decreased insulin pulse mass. Insulin secretion was examined before and after an approximately 60% decrease in beta-cell mass achieved by a single injection of alloxan in a porcine model. Alloxan injection resulted in stable diabetes (fasting plasma glucose 7.4 +/- 1.1 vs. 4.4 +/- 0.1 mmol/l; P < 0.01) with impaired insulin secretion in the fasting and fed states and during a hyperglycemic clamp (decreased by 54, 80, and 90%, respectively). Deconvolution analysis revealed a selective decrease in insulin pulse mass (by 54, 60, and 90%) with no change in pulse frequency. Rhythm analysis revealed no change in the periodicity of regular oscillations after alloxan administration in the fasting state but was unable to detect stable rhythms reliably after enteric or intravenous glucose stimulation. After alloxan administration, insulin secretion and insulin pulse mass (but not insulin pulse interval) decreased in relation to beta-cell mass. However, the decreased pulse mass (and pulse amplitude delivered to the liver) was associated with a decrease in hepatic insulin clearance, which partially offset the decreased insulin secretion. Despite hyperglycemia, postprandial glucagon concentrations were increased after alloxan administration (103.4 +/- 6.3 vs. 92.2 +/- 2.5 pg/ml; P < 0.01). We conclude that an alloxan-induced selective decrease in beta-cell mass leads to deficient insulin secretion by attenuating insulin pulse mass, and that the latter is associated with decreased hepatic insulin clearance and relative hyperglucagonemia, thereby emulating the pattern of islet dysfunction observed in type 2 diabetes.

Direct measurement of pulsatile insulin secretion from the portal vein in human subjects.

Insulin is secreted in a high frequency pulsatile manner. These pulses are delivered directly into the portal vein and then undergo extraction and dilution before delivery into the systemic circulation. The reported frequency of these insulin pulses estimated in peripheral blood varies from an interpulse interval of 4-20 min. We postulated that this discrepancy is due to the attenuation of the pulse signal in the systemic circulation vs. the portal circulation. In the present study we measured pulsatile insulin release directly in the portal circulation of human subjects who had indwelling transjugular intrahepatic portasystemic stent shunts (TIPSS) to decompress portal hypertension. We quantitated pulsatile insulin secretion in both the overnight fasted state (fasting) and during a hyperglycemic clamp (8 mmol/L). Direct portal vein sampling established that pulsatile insulin secretion in humans has an interval (periodicity) of approximately 5 min. The amplitude (and mass) of the insulin concentration oscillations observed in the portal vein was approximately 5-fold greater than that observed in the arterialized vein and was similar to that observed in the dog. Increased insulin release during hyperglycemia was achieved through amplification of the insulin pulse mass. In conclusion, direct portal vein sampling in humans revealed that the interpulse interval of insulin pulses in humans is about 5 min, and this frequency is also observed when sampling from the systemic circulation using a highly specific insulin assay and 1-min sampling, but is about 4-fold greater than the frequency observed at this site using single site RIAs. We confirm that enhanced insulin release in response to hyperglycemia is achieved by amplification of these high frequency pulses.

Phase II trial of escalated dose of tirapazamine combined with cisplatin in advanced malignant melanoma.

A phase II study was undertaken to determine the efficacy of tirapazamine combined with cisplatin in patients with metastatic melanoma between April 1996 and April 1997. Tirapazamine 390 mg/m2, administered i.v. over 2 h, followed in 1 h by cisplatin 75 mg/m2 over 1 h, were used every 21 days to treat chemotherapy-naive patients with metastatic melanoma. Objective tumor measurements were used to assess efficacy of the regimen. NCI common toxicity criteria were used to grade toxicities. Forty-eight patients with metastatic melanoma of cutaneous or mucosal origin, none with symptomatic brain metastasis, were treated. Nine patients had a partial response, with an overall response rate of 20% (95% confidence interval: 9-33%). The median duration of response was 6 months. Grade 3 nausea, vomiting, anorexia, muscle cramps and fatigue occurred in fewer than 10% of patients. Neutropenia and thrombocytopenia were rare. This outpatient single-day administered tirapazamine-cisplatin regimen has definite activity in chemotherapy-naive patients with metastatic melanoma. Further studies in combination with other agents active against this disease are warranted.

The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles.

NIDDM is characterized by islet amyloid deposits and decreased beta-cell mass. Islet amyloid is derived from the locally expressed protein islet amyloid polypeptide (IAPP). While it is now widely accepted that abnormal aggregation of IAPP has a role in beta-cell death in NIDDM, the mechanism remains unknown. We hypothesized that small IAPP aggregates, rather than mature large amyloid deposits, are cytotoxic. Consistent with this hypothesis, freshly dissolved human (h)-IAPP was cytotoxic when added to dispersed mouse and human islet cells, provoking the formation of abnormal vesicle-like membrane structures in association with vacuolization and cell death. Human islet cell death occurred by both apoptosis and necrosis, predominantly between 24 and 48 h after exposure to h-IAPP. In contrast, the addition to dispersed islet cells of matured h-IAPP containing large amyloid deposits of organized fibrils was seldom associated with vesicle-like structures or features of cell death, even though the cells were often encased in the larger amyloid deposits. Based on these observations, we hypothesized that h-IAPP cytotoxicity is mediated by membrane damage induced by early h-IAPP aggregates. Consistent with this hypothesis, application of freshly dissolved h-IAPP to voltage-clamped planar bilayer membranes (a cell-free in vitro system) also caused membrane instability manifested as a marked increase in conductance, increased membrane electrical noise, and accelerated membrane breakage, effects that were absent using matured h-IAPP or rat IAPP solutions. Light-scattering techniques showed that membrane toxicity corresponded to h-IAPP aggregates containing approximately 25-6,000 IAPP molecules, an intermediate-sized amyloid particle that we term intermediate-sized toxic amyloid particles (ISTAPs). We conclude that freshly dissolved h-IAPP is cytotoxic and that this cytotoxicity is mediated through an interaction of ISTAPs with cellular membranes. Once ISTAPs mature into amyloid deposits comprising >10(6) molecules, the capacity of h-IAPP to cause membrane instability and islet cell death is significantly reduced or abolished. These data may have implications for the mechanism of cell death in other diseases characterized by local amyloid formation (such as Alzheimer's disease).