Bovine aortic arch: a novel association with thoracic aortic dilation.

AIM: To investigate whether there is a link between bovine arch and thoracic aortic aneurysm. MATERIALS AND METHODS: Computed tomography (CT) and magnetic resonance imaging (MRI) images of the thorax of 191 patients with dilated thoracic aortas and 391 consecutive, unselected patients as controls were retrospectively reviewed. Bovine arch was considered present if either a shared origin of the left common carotid and innominate arteries or an origin of the left common carotid from the innominate artery was identified. A chi-square test was used to evaluate the significance of differences between subgroups. RESULTS: A trend towards increased prevalence of bovine arch was seen in patients with dilated aortas (26.2%) compared to controls (20.5%, p=0.12). The association was statistically significant in patients over 70 years old (31.9%, p=0.019) and when dilation involved the aortic arch (47.6%, p=0.003). CONCLUSIONS: An association between bovine arch and aortic dilation is seen in older patients, and when dilation involves the aortic arch. Bovine arch should be considered a potential risk factor for thoracic aortic aneurysm.

Concomitant mutations and splice variants in KRAS and BRAF demonstrate complex perturbation of the Ras/Raf signalling pathway in advanced colorectal cancer.

BACKGROUND AND AIMS: KRAS and BRAF mutations occur in colorectal cancers (CRCs) and are considered mutually exclusive methods of activating the RAS/RAF/MEK/ERK pathway. This pathway is a therapeutic target and KRAS mutation may predict tumour responsiveness. The purpose of this study was to investigate the relationship between KRAS and BRAF mutations in 24 CRC cell lines and 29 advanced CRCs. METHODS: KRAS and BRAF mutations were detected using high resolution melting and sequencing. Expression of mutations was confirmed by reverse transcription- PCR (RT-PCR) and sequencing. CpG island methylator phenotype (CIMP) was tested by methylation-specific PCR. RESULTS: KRAS or BRAF mutation occurred in 79% of cell lines and 59% of CRCs. In the cell lines, KRAS mutations occurred in 54% of cases (with 62% in codons 12/13 and 38% in other codons). Four cell lines had a homozygous mutation. Only heterozygous BRAF mutations were detected in 29% cell lines. The V600E mutation occurred most commonly and was associated with CIMP+ status (p = 0.005). Mutations at codons 529 and 581 were also found and, in one case, BRAF and KRAS mutation co-occurred. Unexpectedly, BRAF splice variants (with a predicted kinase-dead protein) were found in 5/24 (21%) cell lines. In advanced CRCs, KRAS mutations occurred in 48% of cases (64% codons 12/13, 36% other codons) and BRAF mutations in 10% (66% V600E, 33% exon 11). A compound KRAS/BRAF mutation was not seen. CONCLUSIONS: Disrupted Ras/Raf signalling is common in CRC. Homozygous KRAS mutations and concomitant KRAS/BRAF mutations may be indicative of a gene dosage effect. The significance of BRAF splice variants is uncertain but may represent another layer of complexity. Finally, if KRAS mutation is to be used for predictive testing, then the whole gene may need to be screened as mutations occur outside codons 12/13.

The putative tumour modifier gene ATP5A1 is not mutated in human colorectal cancer cell lines but expression levels correlate with TP53 mutations and chromosomal instability.

BACKGROUND: Both the putative modifier gene ATP5a1 and the tumour suppressor gene TP53 are involved in the regulation of apoptosis and may be involved in the development of colorectal cancers. AIMS: To investigate the relationship between these genes in 16 colorectal cancer cell lines. METHODS: Each gene was screened for mutation using high resolution melting analysis and sequencing. Expression of ATP5a1 mRNA was tested by quantitative PCR. RESULTS: Sequence changes in ATP5a1 were found in 9/16 (56%) cell lines and consisted of mainly novel single nucleotide polymorphisms (SNPs) found in the 5' UTR, introns 4/5/9 and exon 7. TP53 mutations were also found in 9/16 (56%) cell lines; these were consistent with previous reports. High levels of ATP5a1 expression were seen in cell lines with TP53 mutation compared with those with wild type TP53 (p = 0.02). Furthermore, an A-->G change at the -18 position in intron 4 of ATP5a1 was significantly associated with increased gene expression (p = 0.0391). Comparison with genotype showed that cell lines with chromosomal instability (CIN) had significantly higher levels of ATP5a1 expression than those with microsatellite instability (MSI) (p = 0.02). CONCLUSION: Higher levels of ATP5a1 expression are associated with certain SNPs and with TP53 mutation. High expression also occurs in CIN and may facilitate tumour development along this pathway. Conversely, low levels of ATP5a1 expression may facilitate development of tumours with MSI.

A model of activity-dependent changes in dendritic spine density and spine structure.

Recent evidence indicates that the morphology and density of dendritic spines are regulated during synaptic plasticity. See, for instance, a review by Hayashi and Majewska [9]. In this work, we extend previous modeling studies [27] by combining a model for activity-dependent spine density with one for calcium-mediated spine stem restructuring. The model is based on the standard dimensionless cable equation, which represents the change in the membrane potential in a passive dendrite. Additional equations characterize the change in spine density along the dendrite, the current balance equation for an individual spine head, the change in calcium concentration in the spine head, and the dynamics of spine stem resistance. We use computational studies to investigate the changes in spine density and structure for differing synaptic inputs and demonstrate the effects of these changes on the input-output properties of the dendritic branch. Moderate amounts of high-frequency synaptic activation to dendritic spines result in an increase in spine stem resistance that is correlated with spine stem elongation. In addition, the spine density increases both inside and outside the input region. The model is formulated so that this long-term potentiation-inducing stimulus eventually leads to structural stability. In contrast, a prolonged low-frequency stimulation paradigm that would typically induce long-term depression results in a decrease in stem resistance (correlated with stem shortening) and an eventual decrease in spine density.

A variant of pseudospectral method for activity-dependent dendritic branch model.

A new variant of the pseudospectral method for an activity-dependent dendritic branch model is proposed. This algorithm incorporates the Neumann boundary conditions in a more efficient way than in the algorithms proposed before for similar problems. Numerical experiments indicate that the new algorithm is more efficient than the previous algorithms discussed in the literature on the subject.

Fine-scale mapping of a locus for severe bipolar mood disorder on chromosome 18p11.3 in the Costa Rican population.

We have searched for genes predisposing to bipolar disorder (BP) by studying individuals with the most extreme form of the affected phenotype, BP-I, ascertained from the genetically isolated population of the Central Valley of Costa Rica (CVCR). The results of a previous linkage analysis on two extended CVCR BP-I pedigrees, CR001 and CR004, and of linkage disequilibrium (LD) analyses of a CVCR population sample of BP-I patients implicated a candidate region on 18p11.3. We further investigated this region by creating a physical map and developing 4 new microsatellite and 26 single-nucleotide polymorphism markers for typing in the pedigree and population samples. We report the results of fine-scale association analyses in the population sample, as well as evaluation of haplotypes in pedigree CR001. Our results suggest a candidate region containing six genes but also highlight the complexities of LD mapping of common disorders.

Etanercept combined with conventional treatment in Wegener's granulomatosis: a six-month open-label trial to evaluate safety.

OBJECTIVE: To evaluate the safety of etanercept (Enbrel) in patients receiving conventional treatment for Wegener's granulomatosis (WG). METHODS: We performed a 6-month open-label trial of etanercept (25 mg subcutaneously twice weekly) which was added to standard therapies for WG (glucocorticoids, methotrexate, cyclophosphamide, azathioprine, cyclosporine) and prescribed according to disease severity. Evaluations of clinical response were determined by the Birmingham Vasculitis Activity Score for WG (BVAS/WG) in 20 patients with persistently active disease or with new flares of previously established WG. Fourteen of the 20 patients (70%) had etanercept added as the only new therapeutic variable. RESULTS: Injection site reactions (ISRs) were the most common adverse event related to etanercept (8 episodes in 5 patients [25%]; < 1% of all injections). All ISRs were mild. Two patients had a combined total of 5 hospitalizations (1 patient had 4), but no hospitalizations were attributable solely to etanercept-related adverse events. One patient with severe subglottic stenosis developed pneumococcal tracheobronchitis and subsequently had a localized Herpes zoster infection. Nineteen patients (95%) were still taking etanercept at 6 months, the single exception being a patient who developed progression of orbital (retro-bulbar) disease at 4 months. There were no deaths. The mean BVAS/WG at entry was 3.6 (range 1-8), which decreased at 6 months to 0.6 (P < 0.001, 95% confidence interval [95% CI] -4.0 to -2.1). Among the 14 patients in whom etanercept was the only new treatment variable, the mean daily prednisone dose decreased from 12.9 mg at entry to 6.4 mg at 6 months. This comparison did not achieve statistical significance (difference -6.5; P = 0.19, 95% CI -16.6 to +3.6). Sixteen of the patients (80%) achieved BVAS/WG scores of 0 at some point. However, intermittently active disease was observed in 15 patients (75%). CONCLUSION: In this open-label trial, etanercept used in combination with standard treatments was well-tolerated in patients with WG. Adverse events were few. BVAS/WG scores improved at 6 months, but intermittently active WG (occasionally severe) was common. A randomized, double-masked trial to assess the efficacy of etanercept in WG has begun.

A district survey of vaccine cold chain protection in general practitioners' surgeries.

Failure to ensure that vaccines are kept within a prescribed temperature range at all times can reduce their potency and cause primary vaccine failure. A postal survey of 103 general practices in a health district to assess vaccine handling and storage yielded 75 responses (73%). Poor practice was identified in receipt and storage of vaccines, temperature monitoring and control, management of vaccines during immunisation sessions, and disposal of partly used vaccines. The data suggest that the vaccine cold chain is not maintained with the degree of care necessary for safe practice. National guidelines need to be implemented conscientiously by all those involved with immunisation programmes if the effectiveness of vaccines is to be guaranteed.

Minor surgery in general practice--setting the standards.

BACKGROUND: A self-assessment tool was trialled to set a baseline for control of infection in general practice and to assess the nature and adequacy of infection control precautions in primary care settings with particular reference to minor surgery. METHODS: A request for volunteers was included in a flier sent out periodically by the Communicable Disease Unit to all general practices in the county (n = 114). Eleven practices (9.6 per cent) volunteered to take part and an audit of infection control precautions was undertaken with the practice nurse and/or manager. RESULTS: Of the 11 general practices audited, nine did not have a written policy for control of infection, did not have a separate, dedicated room for minor surgery, did not use protective clothing appropriately, used terry towels for hand-drying and reprocessed single-use only items. Ten used inappropriate methods to decontaminate heat labile items, seven did not record sterilizer processing cycles and five did not comply with HTM 2010 with regard to sterilizer maintenance. Following the survey, minimum infection control requirements have been developed for future applications to provide extended minor surgery within general practice and these will be monitored at subsequent surgery inspection visits and through audit. CONCLUSIONS: Results suggest that there is little room for complacency with regard to standards of infection control in general practice. In view of the increasing shift towards primary care based minor surgery it would be helpful if minimum standards were to be agreed nationally.

Dendritic and synaptic effects in systems of coupled cortical oscillators.

We explore the influence of synaptic location and form on the behavior of networks of coupled cortical oscillators. First, we develop a model of two coupled somatic oscillators that includes passive dendritic cables. Using a phase model approach, we show that the synchronous solution can change from a stable solution to an unstable one as the cable lengthens and the synaptic position moves further from the soma. We confirm this prediction using a system of coupled compartmental models. We also demonstrate that when the synchronous solution becomes unstable, a bifurcation occurs and a pair of asynchronous stable solutions appear, causing a phase lag between the cells in the system. Then using a variety of coupling functions and different synaptic positions, we show that distal connections and broad synaptic time courses encourage phase lags that can be reduced, eliminated, or enhanced by the presence of active currents in the dendrite. This mechanism may appear in neural systems where proximal connections could be used to encourage synchrony, and distal connections and broad synaptic time courses could be used to produce phase lags that can be modulated by active currents.

A portable system for closed loop control of the paralysed hand using functional electrical stimulation.

A portable and closed-loop system is described for the paralysed hand using transcutaneous electrical stimulation. It is implemented using a modest microprocessor which receives data from force sensors mounted in a glove on the users hand. A display shows parameter values and a menu for the user to sequentially select controller states. For the grip state, the control loop is basically proportional plus a two stage integral response (gain adaptation). Eight channels can be accommodated in the stimulator. The system was evaluated with the help of a tetraplegic who managed to hold everyday objects in a stable grip.

Spike frequency adaptation affects the synchronization properties of networks of cortical oscillations.

Oscillations in many regions of the cortex have common temporal characteristics with dominant frequencies centered around the 40 Hz (gamma) frequency range and the 5-10 Hz (theta) frequency range. Experimental results also reveal spatially synchronous oscillations, which are stimulus dependent (Gray & Singer, 1987; Gray, Konig, Engel, & Singer, 1989; Engel, Konig, Kreiter, Schillern, & Singer, 1992). This rhythmic activity suggests that the coherence of neural populations is a crucial feature of cortical dynamics (Gray, 1994). Using both simulations and a theoretical coupled oscillator approach, we demonstrate that the spike frequency adaptation seen in many pyramidal cells plays a subtle but important role in the dynamics of cortical networks. Without adaptation, excitatory connections among model pyramidal cells are desynchronizing. However, the slow processes associated with adaptation encourage stable synchronous behavior.

Passive immunotherapy in advanced HIV infection and therapeutic plasmapheresis in asymptomatic HIV-positive individuals: a four-year clinical experience.

We have been treating patients with advanced HIV disease using passive immunotherapy (PIT). Earlier studies of PIT which have been published concerned relatively short periods of treatment: our study is by far the longest and reports also on the long-term effects of plasmapheresis on healthy HIV-infected individuals. Fifty-nine patients with an average CD4+ T-cell count of 55 per cu.mm. at baseline were transfused at monthly intervals with 500 ml of hyperimmune plasma. No disease progression or death occurred among the 8 asymptomatic patients under the treatment, which lasted for 36.25 months on average. Seven of the 15 ARC patients progressed to AIDS but none died in an average period of 25.9 months. Seven of the 36 symptomatic AIDS patients with advanced disease died in an average period of 19.6 months. PIT appears to be nontoxic and to have beneficial effects lasting at least four years under continuous treatment. It probably delays disease progression in ARC and AIDS patients, and almost certainly does so in asymptomatic late HIV infection with a very low CD4+ T-cell count. None of the 51 donors suffered adverse effects, nor did any progress to ARC or AIDS in an average period of 30.1 months. Their laboratory parameters indicated a nearly stable condition: in particular, their average CD4+ T-cell count rose from 478 to 498. The study of our plasma donors indicated that repeated and frequent plasma donation by asymptomatic HIV-infected individuals could delay disease progression, although further studies are needed to investigate this.

The role of axonal delay in the synchronization of networks of coupled cortical oscillators.

Coupled oscillator models use a single phase variable to approximate the voltage oscillation of each neuron during repetitive firing where the behavior of the model depends on the connectivity and the interaction function chosen to describe the coupling. We introduce a network model consisting of a continuum of these oscillators that includes the effects of spatially decaying coupling and axonal delay. We derive equations for determining the stability of solutions and analyze the network behavior for two different interaction functions. The first is a sine function, and the second is derived from a compartmental model of a pyramidal cell. In both cases, the system of coupled neural oscillators can undergo a bifurcation from synchronous oscillations to waves. The change in qualitative behavior is due to the axonal delay, which causes distant connections to encourage a phase shift between cells. We suggest that this mechanism could contribute to the behavior observed in several neurobiological systems.

An outbreak of Vero cytotoxin producing Escherichia coli O157 infection associated with takeaway sandwiches.

An outbreak of food poisoning due to Escherichia coli O157 phage type 2 Vero cytotoxin 2 affected 26 people in southern counties of England in May and June 1995. The organism was isolated from faecal specimens from 23 patients, 16 of whom lived in Dorset and seven in Hampshire. Isolates were indistinguishable by phage typing, Vero cytotoxin gene typing, restriction fragment length polymorphism, and pulsed field gel electrophoresis. Three associated cases, linked epidemiologically to the outbreak, were confirmed serologically by detection of antibodies to E. coli O157 lipopolysaccharide. Twenty-two of the 26 patients were adults: four were admitted to hospital with haemorrhagic colitis. Four cases were children: two were admitted to hospital with haemolytic uraemic syndrome (HUS). There were no deaths. Although E. coli O157 was not isolated from any food samples, illness was associated with having eaten cold meats in sandwiches bought from two sandwich producers, in Weymouth and in Portsmouth. Both shops were supplied by the same wholesaler, who kept no records and obtained cooked meats from several sources in packs that did not carry adequate identification marks. It was, therefore, impossible to trace back to the original producer or to investigate further to determine the origin of contamination with E. coli O157. To protect the public health it is essential that all wholesale packs of ready-to-eat food carry date codes and the producer's identification mark. Detailed record keeping should be part of hazard analysis critical control point (HACCP) systems and should be maintained throughout the chain of distribution from the producer to retail outlets.

Waterborne cryptosporidiosis associated with a borehole supply.

From 1 April to 31 May 1993, 64 cases of cryptosporidiosis were diagnosed within one district health authority. Forty were classified as primary cases, 35 of whom were clustered in an area supplied by a discrete public water supply that supplied the majority of homes in a large town. Most of the water in this supply is abstracted from boreholes and some is filtered before distribution. Households that received mains water from this supply were 15 times more likely to be affected than households nearby that received water from other sources. A case control study demonstrated a dose response relationship between consumption of water obtained from the town supply and risk of illness. Very low concentrations of cryptosporidial oocysts were detected in the water supply on four occasions several weeks after the outbreak. Environmental investigation failed to reveal a likely mechanism for contamination of the water supply.

The effect of permethrin-impregnated wall-curtains on malaria transmission and morbidity in the suburbs of Maputo, Mozambique.

The effect of nylon-netting wall-curtains impregnated with 0.5 g permethrin/m2 upon the biting rate of malaria vectors (Anopheles gambiae s.l. and An. funestus) and on the Plasmodium falciparum parasite rate, and morbidity due to malaria in children under five and between five and fourteen years was tested in the Maputo area. The curtains significantly lowered biting rates of both vector species inside curtained houses, but reduced inside resting and outside biting only in An. funestus. The percentage of children with falciparum parasitaemia fell significantly in curtained houses, and among their neighbours. However, parasite load and malaria morbidity in under fives was unaffected but malaria morbidity fell throughout the experimental area in 5 to 14-year-olds. This led to the speculation that malaria vectors inhibited from feeding in the vicinity of the curtains might have gone to feed in the adjacent control area.

Worms, wells and water in western Madagascar.

This study of schistosomiasis and intestinal parasites was carried out on 496 children in the Firaisana (District) of Ankilivalo in Western Madagascar. The prevalence of these parasites was determined and data collected on nutrition, agriculture and the use of water in order to gain an understanding of the transmission and effects of these parasites. Recommendations for their control are suggested. In two schools within the area of a major irrigation scheme the prevalence of urinary schistosomiasis was 69%, and 50% suffer from at least one intestinal worm. In a school outside the main irrigation area, the prevalence of schistosomiasis was much lower (7%). Ultimately the control of schistosomiasis will depend on improvements to the irrigation and drainage infrastructure, and in standards of sanitation. However, chemotherapy is the only method of bringing the disease under control in the short term.

Practical low cost stand/sit system for mid-thoracic paraplegics.

The use of functional electrical stimulation (FES) to enable paraplegics to stand is not new or indeed difficult to undertake under laboratory conditions. However, there are substantial problems to overcome before such systems can be used routinely by patients without professional supervision. The overriding consideration has to be one of safety, i.e. the system must be 'fail safe'. Secondly, the system must be quick and easy to use in a wide variety of locations, otherwise it will not provide any increase in function. Finally, it must be inexpensive enough to be available to a large number of paraplegics. The primary aim of our work was to provide such a system to enable mid-thoracic lesion paraplegics to stand wherever they wish. This involved the development of a microprocessor-based stimulator to enable the stimulating envelope to be individually tailored to a given patient's requirements and the provision of closed loop control to minimize fatigue. A folding standing frame was also designed which replaces the arm rests on a standard wheelchair. Using this system, the user is able to stand within 30 s of stopping and can remain standing for up to 10 min. Cosmetic calipers (knee-ankle-foot orthoses) are also being used for paraplegics who require to stand for longer periods. It is hoped that such a system will provide stable standing for a large number of paraplegics at a unit cost of approximately 750 pound.

A randomized double blind controlled trial comparing two amoxycillin regimens in the treatment of acute exacerbations of chronic bronchitis.

A randomized double blind trial comparing two amoxycillin regimens in the treatment of acute exacerbations of chronic bronchitis was performed. Forty-one patients were entered into the study. Twenty patients received amoxycillin sachets 3g twice daily for three days and 21 patients received amoxycillin capsules 500 mg three times daily for seven days. There was no significant difference between the two groups in terms of duration of hospital admission, reduction in sputum volume, clearance of pus from the sputum or the number of treatment failures. No patient developed unwanted effects from the treatment with high dose amoxycillin. Twenty-eight patients were followed for one year and there was no difference in the number of exacerbations experienced by patients treated with short course high dose therapy compared with low dose therapy. It is concluded that short course high dose amoxycillin may be as effective as conventional course amoxycillin in the treatment of acute exacerbations of chronic bronchitis.