Muscle excitability testing.

Conventional electrophysiological methods, i.e. nerve conduction studies and electromyography are suitable methods for the diagnosis of neuromuscular disorders, however, they provide limited information about muscle fibre membrane properties and underlying disease mechanisms. Muscle excitability testing is a technique that provides in vivo information about muscle fibre membrane properties such as membrane potential and ion channel function. Since the 1960s, various methodologies have been suggested to examine muscle membrane properties but technical difficulties have limited its use. In 2009, an automated, fast and simple application, the so-called multi-fibre muscle velocity recovery cycles (MVRC) has accelerated the use of muscle excitability testing. Later, frequency ramp and repetitive stimulation protocols have been developed. Though this method has been used mainly in research for revealing disease mechanisms across a broad range of neuromuscular disorders, it may have additional diagnostic uses; value has been shown particularly in muscle channelopathies. This review will provide a description of the state-of-the art of methodological and clinical studies for muscle excitability testing.

Cortical inexcitability defines an adverse clinical profile in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: In amyotrophic lateral sclerosis, studies using threshold-tracking transcranial magnetic stimulation (TMS) have identified corticomotoneuronal dysfunction as a key pathogenic mechanism. Some patients, however, display no motor response at maximal TMS intensities, termed here an 'inexcitable' motor cortex. The extent to which this cortical difference impacts clinical outcomes remains unclear. The aim of this study was to determine the clinical profile of patients with inexcitability to TMS. METHODS: Motor cortex excitability was evaluated using TMS. Patients in whom a motor evoked potential could not be recorded in one or more limbs at maximal TMS intensities were classified as four-limb or partially inexcitable. Demographic information, clinical variables and survival data were analysed. RESULTS: From 133 patients, 40 were identified with inexcitability. Patients with four-limb inexcitability were younger (P = 0.03) and had lower-limb disease onset (64%), greater functional disability (P < 0.001) and faster disease progression (P = 0.02), particularly if inexcitability developed within 1 year of symptoms (P < 0.01). Patients with partial inexcitability had higher resting motor thresholds compared to the excitable cohort (P < 0.01), but averaged short-interval intracortical inhibition was similar (P = 0.5). Mean survival was reduced if inexcitability involved all limbs within 12 months of symptom onset (P = 0.04). CONCLUSION: Amyotrophic lateral sclerosis patients with inexcitability of all four limbs to TMS have a distinct clinical profile of younger age and lower-limb onset. Importantly, these patients display a more malignant disease trajectory, with faster progression, greater functional disability and reduced survival when occurring in early disease. This measure may provide an important prognostic marker in amyotrophic lateral sclerosis.

Conduction block in immune-mediated neuropathy: paranodopathy versus axonopathy.

BACKGROUND AND PURPOSE: Conduction block is a pathognomonic feature of immune-mediated neuropathies. The aim of this study was to advance understanding of pathophysiology and conduction block in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). METHODS: A multimodal approach was used, incorporating clinical phenotyping, neurophysiology, immunohistochemistry and structural assessments. RESULTS: Of 49 CIDP and 14 MMN patients, 25% and 79% had median nerve forearm block, respectively. Clinical scores were similar in CIDP patients with and without block. CIDP patients with median nerve block demonstrated markedly elevated thresholds and greater threshold changes in threshold electrotonus, whilst those without did not differ from healthy controls in electrotonus parameters. In contrast, MMN patients exhibited marked increases in superexcitability. Nerve size was similar in both CIDP groups at the site of axonal excitability. However, CIDP patients with block demonstrated more frequent paranodal serum binding to teased rat nerve fibres. In keeping with these findings, mathematical modelling of nerve excitability recordings in CIDP patients with block support the role of paranodal dysfunction and enhanced leakage of current between the node and internode. In contrast, changes in MMN probably resulted from a reduction in ion channel density along axons. CONCLUSIONS: The underlying pathologies in CIDP and MMN are distinct. Conduction block in CIDP is associated with paranodal dysfunction which may be antibody-mediated in a subset of patients. In contrast, MMN is characterized by channel dysfunction downstream from the site of block.

Targeted lung cancer screening selects individuals at high risk of cardiovascular disease.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in populations eligible for lung cancer screening. The aim of this study was to determine whether a brief CV risk assessment, delivered as part of a targeted community-based lung cancer screening programme, was effective in identifying individuals at high risk who might benefit from primary prevention. METHODS: The Manchester Lung Screening Pilot consisted of annual low dose CT (LDCT) over 2 screening rounds, targeted at individuals in deprived areas at high risk of lung cancer (age 55-74 and 6-year risk ≥1.51%, using PLCOM2012 risk model). All participants of the second screening round were eligible to take part in the study. Ten-year CV risk was estimated using QRISK2 in participants without CVD and compared to age (±5 years) and sex matched Health Survey for England (HSE) controls; high risk was defined as QRISK2 score ≥10%. Coronary artery calcification (CAC) was assessed on LDCT scans and compared to QRISK2 score. RESULTS: Seventy-seven percent (n=920/1,194) of screening attendees were included in the analysis; mean age 65.6 ± 5.4 and 50.4% female. QRISK2 and lung cancer risk (PLCOM2012) scores were correlated (r = 0.26, p < 0.001). Median QRISK2 score was 21.1% (IQR 14.9-29.6) in those without established CVD (77.6%, n = 714/920), double that of HSE controls (10.3%, IQR 6.6-16.2; n = 714) (p < 0.001). QRISK2 score was significantly higher in those with CAC (p < 0.001). Screening attendees were 10-fold more likely to be classified high risk (OR 10.2 [95% CI 7.3-14.0]). One third (33.7%, n = 310/920) of all study participants were high risk but not receiving statin therapy for primary CVD prevention. DISCUSSION: Opportunistic CVD risk assessment within a targeted lung cancer screening programme is feasible and is likely to identify a very large number of individuals suitable for primary prevention.

A structured, group-based diabetes self-management education (DSME) programme for people, families and whanau with type 2 diabetes (T2DM) in New Zealand: an observational study.

BACKGROUND: Group-based diabetes self-management education (DSME) programmes have been shown to be effective. A programme tailored for the unique social and ethnic environment of New Zealand (NZ) was developed using concepts from internationally developed programmes. AIM: To assess the effectiveness of a 6 week New Zealand specific DSME programme. METHODS: In this observational study people with type 2 diabetes (aged 18-80 years) from diverse cultural backgrounds were recruited from primary care. Seventeen groups of six education sessions were run. Clinical data were collected from primary care at baseline, 3, 6 and 9 months. Participants also completed a self-administered questionnaire on diabetes knowledge, and self-management behaviours. RESULTS: 107 participants, mean age 56.7±11.3 years and mean duration of diabetes 7.5±7 years (NZ European (44%), Maori (24%), Pacific (16%) and Indian (16%)), were enrolled. Confidence in self-managing diabetes, regular examination of feet, physical activity levels and smoking rates all improved. Glycaemic control improved between baseline and 6 months (HbA1C 64.9±20.0 mmol/mol to 59.9±13.9 mmol/mol (p<0.05) (baseline 8.07%±1.80, 6 months 7.62%±1.25)), but was no different to baseline at 9 months. Systolic BP reduced from 131.9±16.4 to 127.4±18.2 mmHg (p<0.05) at 6 months, but increased to baseline levels by 9 months. Diastolic BP, triglycerides and urine microalbumin:creatinine ratio were significantly reduced at 3, 6 and 9 months. CONCLUSION: A group-based DSME programme designed specifically for the NZ population was effective at improving aspects of diabetes care at 6 months. The attenuation of these improvements after 6 months suggests a refresher course at that time may be beneficial.

Colobronchial fistula: a late complication of childhood radiotherapy.

We present the case of a colobronchial fistula in a 41-year-old man who underwent radiotherapy for nephroblastoma as an infant. He attended for barium enema, which demonstrated a fistula between colon and bronchial tree. Following right hemicolectomy and pathological examination of the resected bowel, no active disease process was identified to explain the development of this rare fistula. Radiotherapy was deemed the most probable aetiology. We are unaware of this having been previously described.

Toxicological response of a bioluminescent microbial assay to Zn, Pb and Cu in an artificial soil solution: relationship with total metal concentrations and free ion activities.

The relationship between toxicological response and both total concentrations and free ion activities of Pb, Cu and Zn in an artificial soil solution has been investigated using lux-marked Escherichia coli HB101 (pUCD607) as a bioassay. SO4(2-) (as K2SO4) was added as an inorganic complexing agent up to 0.01 M representing the range of ionic strengths found in soil solutions and giving a wide range of free metal ion activities. EC50 values expressed in terms of concentration, varied significantly with K2SO4 molarity for all metals. However, when EC50 values were expressed in terms of free ion activity they were not significantly different for Pb and Zn, supporting the free ion activity model. Conversely, EC50 values expressed as free Cu activity did vary significantly with K2SO4 molarity, possibly due to a greater degree of adsorption of Cu onto inactive sites on the cell surfaces than for Zn and Pb. Linear regression analysis of bioluminescence on free ion activity revealed significant correlations for each metal above the toxicity threshold. In conclusion, lux-marked E. coli is suitable for investigating the toxicity of metal ions and complexes in non saline systems although cell surface adsorption effects could be important for some metals, e.g. Cu.

Effect of bone meal (calcium phosphate) amendments on metal release from contaminated soils--a leaching column study.

Metal-contaminated soil may be remediated in situ by the formation of highly insoluble metal phosphates if an appropriate phosphorus (P) source can be found. Leaching column experiments have been carried out to assess the suitability of bone meal as such a source. Bone meal additions reduced metal release from a contaminated soil, increased soil and leachate pH and decreased soil leachate toxicity. Minimal P leaching occurred from the soil. The data are consistent with a proton consuming bone meal (calcium phosphate) dissolution reaction followed by the formation of metal phosphates. Although, no metal phosphates were observed to form using X-ray diffraction of scanning electron microscopy this could be due to their low concentration. Relatively low (1:50 bone meal:soil) concentrations of fine (90-500 microns) bone meal would appear to be an effective treatment for metal-contaminated soils.

Creating knowledge structures in the pharmaceutical industry: the increasing significance of virtual organisation.

This paper explores the specific trend and challenges facing the pharmaceutical industry regarding the exploitation of Internet e-commerce technology and virtual organisation to develop and maintain competitive advantage. There are two important facets of the current trend. One is the rapid development of a complex network of alliances between the established pharmaceutical companies and the specialised biotechnology company start-ups. The other is the rapid growth of internet e-commerce companies dedicated to developing specialised technological platforms for acquiring and selling genetic and biochemical knowledge. The underlying challenge is how big pharmaceutical companies can emulate some of the innovation processes of smaller biotechnology company start-ups, and how they can appropriate and applied new technological knowledge on the development of new drugs. Pharmaceutical companies in order to retain competitive advantage need to continuously monitor all aspects of knowledge management with regard to the R&D and manufacturing process (as well as customer management and marketing). Technological change and organisational restructuring should be aimed at boosting the capacity of large firms to innovate rapidly.

Lead mineral transformation by fungi.

Pyromorphite (Pb5(PO4)3Cl), the most stable lead mineral under a wide range of geochemical conditions [1], can form in urban and industrially contaminated soils [2] [3] [4] [5]. It has been suggested that the low solubility of this mineral could reduce the bioavailability of lead, and several studies have advocated pyromorphite formation as a remediation technique for lead-contaminated land [3] [5] [6], if necessary using addition of phosphate [6]. Many microorganisms can, however, make insoluble soil phosphate bioavailable [7] [8] [9] [10], and the solubilisation of insoluble metal phosphates by free-living and symbiotic fungi has been reported [11] [12] [13] [14] [15]. If pyromorphite can be solubilised by microbial phosphate-solubilising mechanisms, the question arises of what would happen to the released lead. We have now clearly demonstrated that pyromorphite can be solubilised by organic-acid-producing fungi, for example Aspergillus niger, and that plants grown with pyromorphite as sole phosphorus source take up both phosphorus and lead. We have also discovered the production of lead oxalate dihydrate by A. niger during pyromorphite transformation, which is the first recorded biogenic formation of this mineral. These mechanisms of lead solubilisation, or its immobilisation as a novel lead oxalate, have significant implications for metal mobility and transfer to other environmental compartments and organisms. The importance of considering microbial processes when developing remediation techniques for toxic metals in soils is therefore emphasised.

Administration of time-expired yellow fever vaccine: public health response and results of a serological investigation.

The discovery that a local travel clinic had administered 101 doses of time-expired yellow fever vaccine over a six month period prompted an immediate investigation in order to advise vaccinees about to travel to areas where yellow fever is endemic. No data were available to provide adequate reassurance about the potential efficacy of time-expired vaccine, so a rapid serological investigation was conducted, which provided evidence that the yellow fever vaccine had remained potent beyond its expiry date.

Barriers to hepatitis C transmission within breathing systems: efficacy of a pleated hydrophobic filter.

It has been suggested that breathing circuits contaminated with body fluids may provide a route of nosocomial patient-to-patient transmission of the hepatitis C virus. Thus, a number of authorities have recommended the use of breathing circuit filters to minimize such risks. The present study sought to simulate a humidified breathing circuit and evaluate two different designs of breathing circuit filters to determine their efficacy in preventing passage of the hepatitis C virus. A hydrophobic pleated-membrane filter consistently prevented the passage of hepatitis C virus while a large-pore "electret" filter design was ineffective. We conclude that not all filter types are equally suited to preventing the passage of viruses and we therefore consider it essential that, if filters are intended to prevent the passage of named pathogens in a humidified breathing circuit, they should be evaluated in a similar experimental system to that described in order to prove their efficacy.

Validated capillary electrophoretic method for the quantitative analysis of histamine acid phosphate and/or benzalkonium chloride.

A novel capillary electrophoresis method has been developed and validated for the quantitative determination of histamine acid phosphate (HAP) and/or benzalkonium chloride (BKC). The solutes were separated using a pH 2.5 phosphate electrolyte with detection at 200 nm. Acceptable precision was obtained using internal standardisation. The method was also acceptable for determining levels of histidine which is an impurity in HAP. Profiling of BKC homologues was demonstrated for batch identity purposes. This method is used routinely and it is intended to register this method in the British Pharmacopoeia to supplement current test methods of TLC and HPLC.

Rapid diagnosis and determination of duration of viraemia in dengue fever using a reverse transcriptase polymerase chain reaction.

A rapid, simple diagnostic polymerase chain reaction (PCR) method for the diagnosis of dengue fever was developed using a pair of consensus oligonucleotide primers and validated with laboratory-derived strains of dengue serotypes 1-4 and other common flaviviruses. A cluster of 13 patients with clinical dengue fever admitted to a single infectious diseases unit over a period of 3 months allowed evaluation of this technology. The PCR was positive in all 11 acute dengue cases and negative in 2 convalescent cases and 10 febrile patients recently returned from the tropics in whom an alternative diagnosis was established. In some of the acute cases, viraemia was detected before the development of a diagnostic antibody response (indirect immunoglobulin (Ig) G enzyme-linked immunosorbent assay (ELISA) and capture IgM ELISA). In patients from whom sequential sera were taken, defervescence and recovery from thrombocytopenia coincided with the disappearance of dengue ribonucleic acid from the blood. Nucleotide sequencing of the PCR products was undertaken in 2 cases (from India and Guyana) and the results showed a close match with previously reported serotype 2 sequencies, suggesting a potential for use of this region of the genome in epidemiological studies.

Lead phosphate formation in soils.

Pyromorphite (Pb5(PO4)3Cl) is one of the most thermodynamically stable lead minerals under the geochemical conditions prevailing in the surface environment. It is therefore expected to form in soils contaminated with Pb if sufficient phosphorus is available. Pyromorphite has previously been identified in mine-waste and industrially contaminated soils but has not previously been identified in urban soils. This paper reports on the presence of a Pb phosphate in urban and roadside soils. This phase has formed in the soil as a weathering product of Pb-bearing grains. Quantitative EDX analyses indicated that the Pb phosphate phase is pyromorphite with Ca frequently substituting for Pb between 21-31 atomic percent. However, positive identification of this phase by XRD was hindered by the deviation from pure end-member and possibly also by the poorly crystalline nature of the phase. Pyromorphite accounted for less than 2% of the total Pb in these soils. However, phosphate amendments to the soil could induce further formation of pyromorphite. As pyromorphite is a highly insoluble mineral, this may be effective in reducing the bioavailability of Pb in urban soils.

Lead contamination of UK dusts and soils and implications for childhood exposure: An overview of the work of the Environmental Geochemistry Research Group, Imperial College, London, England 1981-1992.

Over the course of the last decade, research conducted by the Imperial College Environmental Geochemistry Research Group has focused on the nature and effects of lead in UK dusts and soils. An initial nationwide reconnaissance survey demonstrated that approximately 10% of the population is exposed to lead levels in excess of 2,000 µg g(-1) in house-hold dust. Subsequent exposure studies revealed that for 2 year old children in the UK urban environment, approximately 50% of lead intake was from dust ingested as a result of hand-to-mouth activity. Follow-up computer controlled scanning electron microscopy (CCSEM) analysis of urban household dust and particulate material wiped from children's hands showed that important sources of dust lead include lead-based paint, road dust and soils. CCSEM identification of specific soil lead tracer particles (from minewaste contaminated soils) in dusts and on children's hands further documented the important role of soil as a source of exposure. Speciation studies of soil lead of this origin indicated that the form of the lead, which is largely influenced by the soil environment, is the primary control on bioavailability. It appears that although lead of minewaste origin may be present at elevated levels in dusts and soils, it does not necessarily contribute to elevated blood lead levels when the lead is present in relatively insoluble form.