Successful transcatheter pulmonary valve implantation in a dog: first clinical report.

Transcatheter pulmonary valve (TPV) implantation is a therapeutic approach approved by the United States Food and Drug Administration for human patients with failing pulmonary conduits in 2010 and for failing bioprosthetic surgical pulmonary valves in 2017. We report here the first successful transcatheter implantation of a stented valve in a pulmonary position in a dog with congenital pulmonary valve disease. A 3-year-old, 10.9 kg, client-owned Beagle dog was referred for a follow-up visit after a percutaneous balloon valvuloplasty performed 22 months before for treatment of a severe type A valvular pulmonary stenosis. The Doppler-derived peak pressure gradient was 348 mmHg before the procedure and 66 mmHg 24 h after. The dog was lethargic. Echocardiography revealed a mild pulmonary stenosis (pressure gradient-43 mmHg), severe pulmonary regurgitation, and secondary severe right ventricular and right atrial dilation. Worsening of right heart dilation was observed 2 months later despite medical therapy. A TPV implantation was performed using a prestented Melody bovine jugular bioprosthetic valve. The dog recovered uneventfully and was discharged 10 days after the procedure. Right heart dilation resolved within 15 days. The dog was doing well 7 months after valve implantation. This case demonstrates that TPV implantation with a stented valve is technically feasible in dogs with severe pulmonary valve disease. Stringent postoperative care, with particular attention to thrombosis and infectious endocarditis, and appropriate sizing and positioning of the valve stent are keys to the success of this procedure.

Exercise prehabilitation may lead to augmented tumor regression following neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

  Purpose: We evaluate the effect of an exercised prehabilitation programme on tumour response in rectal cancer patients following neoadjuvant chemoradiotherapy (NACRT). Patients and Methods: Rectal cancer patients with (MRI-defined) threatened resection margins who completed standardized NACRT were prospectively studied in a post hoc, explorative analysis of two previously reported clinical trials. MRI was performed at Weeks 9 and 14 post-NACRT, with surgery at Week 15. Patients undertook a 6-week preoperative exercise-training programme. Oxygen uptake (VO2) at anaerobic threshold (AT) wasmeasured at baseline (pre-NACRT), after completion of NACRT and at week 6 (post-NACRT). Tumour related outcome variables: MRI tumour regression grading (ymrTRG) at Week 9 and 14; histopathological T-stage (ypT); and tumour regression grading (ypTRG)) were compared. Results: 35 patients (26 males) were recruited. 26 patients undertook tailored exercise-training with 9 unmatched controls. NACRT resulted in a fall in VO2 at AT -2.0 ml/kg-1/min-1(-1.3,-2.6), p < 0.001. Exercise was shown to reverse this effect. VO2 at AT increased between groups, (post-NACRT vs. week 6) by +1.9 ml/kg-1/min-1(0.6, 3.2), p = 0.007. A significantly greater ypTRG in the exercise group at the time of surgery was found (p = 0.02). Conclusion: Following completion of NACRT, exercise resulted in significant improvements in fitness and augmented pathological tumour regression.

A systematic review of the safety and efficacy of aerobic exercise during cytotoxic chemotherapy treatment.

PURPOSE: Aerobic exercise improves prognosis and quality of life (QoL) following completion of chemotherapy. However, the safety and efficacy of aerobic exercise during chemotherapy is less certain. A systematic review was performed of randomised trials of adult patients undergoing chemotherapy, comparing an exercise intervention with standard care. METHOD: From 253 abstracts screened, 33 unique trials were appraised in accordance with PRISMA guidance, including 3257 patients. Interventions included walking, jogging or cycling, and 23 were of moderate intensity (50-80% maximum heart rate). RESULTS: Aerobic exercise improved, or at least maintained fitness during chemotherapy. Moderately intense exercise, up to 70-80% of maximum heart rate, was safe. Any reported adverse effects of exercise were mild and self-limiting, but reporting was inconsistent. Adherence was good (median 72%). Exercise improved QoL and physical functioning, with earlier return to work. Two out of four studies reported improved chemotherapy completion rates. Four out of six studies reported reduced chemotherapy toxicity. There was no evidence that exercise reduced myelosuppression or improved response rate or survival. CONCLUSIONS: Exercise during chemotherapy is safe and should be encouraged because of beneficial effects on QoL and physical functioning. More research is required to determine the impact on chemotherapy completion rates and prognosis.

Proactive multi-modality treatment of Pancreatic Neuroendocrine Tumours (PNETs): Potential survival benefits.

BACKGROUND/OBJECTIVES: Primary and metastatic pancreatic neuroendocrine tumours (PNET) can be treated with combination of surgery, locoregional and systemic therapy. Survival benefits from individual treatments have been well reported, however, the combined outcome from multimodal treatments are not well described in the literature. We report outcomes in a cohort of PNET patients treated with proactive, multimodality therapy. METHODS: 106 patients were identified from a single tertiary referral centre prospective database. Outcomes of treatment were studied, with the primary end point being death from any cause. RESULTS: Median follow-up was 71 months and overall 5-year survival of 62%. In patients with stage I-III disease (51 patients) estimated 5-year survival was 90%. Median survival in patients with stage IV disease was 51 months with an estimated 5-year survival of 40% in this group. A total of 80 patients (75%) had surgery of which 16% suffered complications requiring intervention. There was no perioperative mortality. CONCLUSIONS: This study demonstrates that proactive multimodal treatment is safe and may confer a survival benefit to patients in this cohort compared to historical data.

Neuroaxonal dystrophy in Merino-Border Leicester × Polled Dorset lambs.

CASE REPORT: The clinicopathological features of neuroaxonal dystrophy (NAD) in 2 lambs are described. Of 40 Merino-Border Leicester × Polled Dorset lambs on a property in north-eastern Victoria, 4 presented with marked ataxia and listlessness, and 2 affected animals (2 days and 2 weeks of age, respectively) of both sexes were necropsied. Numerous axonal swellings (spheroids) were found in the central nervous system, particularly in brainstem nuclei and spinal cord grey matter, and there was severe spinal cord demyelination. CONCLUSIONS: This is the first report of NAD in such crossbred lambs; the affected animals were much younger than in previously described cases of ovine NAD and myelin loss was of much greater magnitude than previously reported.

Should we implement 'opt-out' HIV testing for patients with lymphoma?

Patients with HIV are dying due to late diagnosis and physicians are being encouraged to increase HIV testing. The uptake of opt-in HIV screening for 113 lymphoma patients was audited at University College London Hospital. Of the 113 patients, 46 were not tested (41%). Previous research in the antenatal setting suggests that adopting opt-out screening would increase testing rates.

An extended outbreak of congenital chondrodysplasia in calves in South East Australia.

OBJECTIVE: To report an outbreak of congenital chondrodystrophy in calves in South East Australia. METHODS: District veterinarians investigated reported cases of calf deformities. Owners of affected herds were interviewed using a standard questionnaire to identify potential risk factors. Dams of several affected calves were serologically tested for Akabane virus, Aino virus, pestivirus and bluetongue, and affected calves were tested for pestivirus antigen and serum immunoglobulin concentrations. Gross and histopathological examinations of numerous calves were performed, concentrating on the musculoskeletal system. RESULTS: A case definition of distinctive skeletal deformities was established, and 89 property owners reported calves with chondrodystrophy in Spring 2003, 2004 or 2005. Some 14 property owners reported affected calves in more than one year. Prevalence and severity of deformity varied greatly between and within properties. None of breed, sex, age of dam, lineage, pasture type, supplementary feeding, fertiliser use or toxic plants was consistently associated with the disease. All dams experienced hot, dry conditions during the first trimester of pregnancy and were exposed to adverse conditions thereafter. Consistently dams were reported to have been grazing undulating to hilly terrain during early pregnancy. All serological tests were negative for Akabane virus, Aino virus, pestivirus and bluetongue. Histopathology of affected skeletal samples showed chondrodysplasia. CONCLUSION: The outbreak had similarities with previous outbreaks reported in the region. No specific aetiology could be determined. There is some evidence that the cause of the deformities could be a manganese deficiency during foetal development. Ongoing work to test this hypothesis is therefore warranted.

Medical student teaching in the UK: how well are newly qualified doctors prepared for their role caring for patients with cancer in hospital?

A number of studies have identified problems with undergraduate oncology teaching. We have investigated how well prepared newly qualified doctors (first foundation year, or FY1 doctors) are for treating patients with cancer. Twenty-five FY1 doctors and 15 senior doctors participated in interviews. We turned the emergent themes into a questionnaire for all 5143 UK FY1 doctors in 2005. The response rate was 43% (2062 responses). Sixty-one percent of FY1 doctors had received oncology teaching at medical school, but 31% recalled seeing fewer than 10 patients with cancer. Forty percent of FY1 doctors felt prepared for looking after patients with cancer. Sixty-five percent felt prepared for diagnosing cancer, 15% felt they knew enough about chemotherapy and radiotherapy, and 11% felt prepared for dealing with oncological emergencies. Respondents believed medical students should learn about symptom control (71%) and communication skills (41%). Respondents who had received oncology teaching were more likely to feel prepared for looking after patients with cancer (OR 1.52; 95% CI 1.14-2.04). Preparedness also correlated with exposure to patients with cancer (OR 1.48; 95% CI 1.22-1.79). We have found worryingly low levels of exposure of medical students to patients with cancer. First foundation year doctors lack knowledge about cancer care and symptom control. Oncologists should maintain involvement in undergraduate teaching, and encourage greater involvement of patients in this teaching.

Can assisted reproductive technologies help to offset population ageing? An assessment of the demographic and economic impact of ART in Denmark and UK.

Governments worldwide are searching for ways to cope with ageing populations as the demographic shift towards fewer and later births takes hold. The potential contribution of assisted reproductive technologies (ART) to increasing fertility rates has not yet been explored. This paper describes a preliminary study into the impact ART policies might have on population ageing. A deterministic model is developed to quantify the effects of ART policies on total fertility rate (TFR), and tested using data from the UK and Denmark. The population structure for 2050 is modelled to translate fertility rates into time-dependent population dynamics, and the costs of potential ART policies are investigated. If access to ART in the UK were increased to the level of Denmark, the TFR would increase by 0.04, from 1.64 to 1.68. The cumulative effect on the population structure would be a 1.7% decrease in old-age dependency ratio in 2050. Although the empirical models do not include behavioural components, the results demonstrate that ART does have potential to contribute to TFR and influence population structure, and that the direct costs associated with adopting ART as a population policy are comparable with those of existing policies commonly used by governments to influence fertility.

Chondrodysplastic calves in Northeast Victoria.

Outbreaks of chondrodysplasia in calves occur sporadically every 10-15 years, particularly following prolonged drought conditions, throughout Northeastern Victoria and the Southern Tablelands of New South Wales, Australia. An outbreak spanning 2 calving seasons (2003-2004) involving numerous losses through stillbirth, perinatal loss, and poor growth was investigated. Investigations of 4 representative cases are presented here with a definition of the gross and histopathologic defects and an overview of epidemiologic data gathered from affected farms. Calves showed variable disproportionate dwarfism without arthrogryposis. Long bones were shortened and showed axial rotation. Articular surfaces were distorted with misshapen weight-bearing surfaces associated with variable thickness of articular cartilage. Physes were distorted and variable in thickness with occasional foci of complete closure. The major histologic abnormality in the physes was disorderly development of the zones of cartilage hypertrophy, with reduced number and irregular arrangement of hypertrophic chondrocytes; similar less severe changes were present in the zones of cartilage proliferation. Histochemical staining of the cartilage matrix was variable in intensity, and there was evidence of abnormal resorption of cartilage matrix at the level of the primary spongiosa. Osteoid formation and subsequent bone remodelling seemed unaffected, and diaphyseal cortical bone appeared normal at the gross and light microscopic level. No infectious agents were identified, and other known causes for chondrodysplasia in calves were excluded. The most likely cause for the syndrome was considered to be congenital manganese deficiency. Further surveys of tissue and blood manganese levels from cows and calves with and without clinical signs from the region are planned.

Mortalities in bobby calves associated with long distance transport.

OBJECTIVE: To investigate how distance of transportation and time of year affects mortality of bobby calves. METHOD: The overall mortality of bobby calves transported by road to an abattoir in Northern Victoria was investigated by the analysis of mortality data from 1998 to 2000 from the abattoir records. RESULTS: Mortality of bobby calves increased exponentially with distance of transportation to the abattoir. The association between distance travelled and mortality was greatest in August. The increased mortality associated with greater distance travelled occurred during transportation rather than after arrival at the abattoir. The highest mortality of bobby calves was seen in October, followed by September, and the lowest was observed in August. CONCLUSION: Limits on the distance of transportation of bobby calves should be incorporated into future codes of practice to reduce the mortality of bobby calves.

Solution nuclear magnetic resonance structure of a protein disulfide oxidoreductase from Methanococcus jannaschii.

The solution structure of the protein disulfide oxidoreductase Mj0307 in the reduced form has been solved by nuclear magnetic resonance. The secondary and tertiary structure of this protein from the archaebacterium Methanococcus jannaschii is similar to the structures that have been solved for the glutaredoxin proteins from Escherichia coli, although Mj0307 also shows features that are characteristic of thioredoxin proteins. Some aspects of Mj0307's unique behavior can be explained by comparing structure-based sequence alignments with mesophilic bacterial and eukaryotic glutaredoxin and thioredoxin proteins. It is proposed that Mj0307, and similar archaebacterial proteins, may be most closely related to the mesophilic bacterial NrdH proteins. Together these proteins may form a unique subgroup within the family of protein disulfide oxidoreductases.

Antibiotics for acute bacterial conjunctivitis.

BACKGROUND: There are concerns regarding whether antibiotic therapy confers significant benefit in the treatment of acute bacterial conjunctivitis. OBJECTIVES: The aim of this review is to assess the benefit and harm of antibiotic therapy in the management of acute bacterial conjunctivitis. SEARCH STRATEGY: We searched the Cochrane Eyes and Vision Group specialised register, the Cochrane Controlled Trials Register - Central, MEDLINE and the reference lists of identified trial reports. We used the Science Citation Index to look for articles that cited the relevant studies, and we contacted investigators and pharmaceutical companies for information about additional trials. The most recent searches were carried out in September 1998. SELECTION CRITERIA: We included double masked randomised controlled trials in which any form of antibiotic treatment had been compared with placebo in the management of acute bacterial conjunctivitis. This included topical, systemic and combination (for example, antibiotics and steroids) antibiotic usage. DATA COLLECTION AND ANALYSIS: One reviewer extracted data and the accuracy was checked by a second reviewer. Relative risks were summarised. We tested for heterogeneity between studies. MAIN RESULTS: Six published trials were identified of which three fulfilled the eligibility criteria for inclusion in this review. One trial was single masked and therefore excluded. A second report, when translated, was found to have no placebo group and was therefore excluded. One trial is currently 'awaiting assessment'. This has been published in abstract form and has yet to be fully reported. All the trials thus far identified appear to have been conducted on a selected specialist care patient population. The trials were heterogeneous in terms of their inclusion and exclusion criteria, the nature of the intervention, and the outcome measures assessed. Meta-analysis indicates that acute bacterial conjunctivitis is frequently a self-limiting condition, as clinical remission (cure or significant improvement) occurred by days two to five in 64% (95% confidence interval (CI) 57% to 71%) of those treated with placebo. Treatment with antibiotics was, however, associated with significantly better rates of clinical remission (days two to five: relative risk (RR) 1.31 95% CI 1.11 to 1.55, NNT=5) with a suggestion that this benefit was maintained for late clinical remission (days six to 10: RR 1.27 95% CI 1.00 to 1.61, NNT=5). Antibiotic treatment was associated with rates of microbiological remission (pathogen eradication or reduction). No serious outcomes were reported in either the active or placebo arms of these trials, indicating that important sight-threatening complications are an infrequent occurrence. REVIEWER'S CONCLUSIONS: Acute bacterial conjunctivitis is frequently a self-limiting condition but the use of antibiotics is associated with significantly improved rates of early clinical remission and early and late microbiological remission. Since trials to-date have been conducted in selected specialist care patient populations these results may not necessarily be generalisable to a primary care based population. A trial based in primary care designed to assess the cost-effectiveness of commonly prescribed antibiotic(s) versus placebo in acute bacterial conjunctivitis is warranted.

Backbone dynamics of sequence specific recognition and binding by the yeast Pho4 bHLH domain probed by NMR.

Backbone dynamics of the basic/helix-loop-helix domain of Pho4 from Saccharomyces cerevisae have been probed by NMR techniques, in the absence of DNA, nonspecifically bound to DNA and bound to cognate DNA. Alpha proton chemical shift indices and nuclear Overhauser effect patterns were used to elucidate the secondary structure in these states. These secondary structures are compared to the co-crystal complex of Pho4 bound to a cognate DNA sequence (Shimizu T. Toumoto A, Ihara K, Shimizu M, Kyogou Y, Ogawa N, Oshima Y, Hakoshima T, 1997, EMBO J 15: 4689-4697). The dynamic information provides insight into the nature of this DNA binding domain as it progresses from free in solution to a specifically bound DNA complex. Relative to the unbound form, we show that formation of either the nonspecific and cognate DNA bound complexes involves a large change in conformation and backbone dynamics of the basic region. The nonspecific and cognate complexes, however, have nearly identical secondary structure and backbone dynamics. We also present evidence for conformational flexibility at a highly conserved glutamate basic region residue. These results are discussed in relation to the mechanism of sequence specific recognition and binding.

Should weaker study designs ever be preferred over randomised controlled trials.

Randomised controlled trials are typically cited as the 'best' form of study design to be used when comparing the efficacy or effectiveness of different devices such as pressure-redistributing beds and mattresses. This article presents a RCT that compared two forms of alternating pressure air mattress. No statistically significant differences were found between the incidence of sores upon the two mattresses. However the study was under-powered, and so was unlikely to identify differences in efficacy should they have existed. In discussion it is suggested that randomised controlled trials may be less useful to those purchasing mattresses than 'weaker' study designs that capture the experience of the users of such devices.

Cation-dependence of the self-association behavior of guanylyl-(3'-5')-guanosine.

The aggregation behavior of guanylyl-(3'-5')-guanosine, GpG, in the form of the tetramethylammonium (TMA), Li, Na, and K salts in aqueous solution has been investigated by NMR and FTIR techniques. The salts were prepared by a cation-exchange method. The ability of the cations to induce aggregate formation is TMA+ < Li+ < Na+ < K+, where TMA+ has only a weakly promoting action and K+ has a very strong effect. Three types of aggregates have been observed: (a) small aggregates which are in rapid exchange with respect to the NMR time scale; (b) intermediate-sized aggregates which are slow to exchange; (c) very large aggregates which can only be observed by FTIR. In all cases the aggregated species are held together by base stacking and guanine-guanine hydrogen bonding. A stoichiometry of 2 GpG per K+ has been determined by a 1H NMR titration of TMAGpG with KCl. Models have been proposed for the various-sized species. These include stacked dimers, stacked tetramers (similar to G-tetrads), and species in which K+ ion bridges between phosphates in separate tetramers.

A narrow window of intracellular calcium concentration is optimal for neurite outgrowth in rat sensory neurones.

We have examined neurite outgrowth in rat sensory neurones when cytosolic free calcium concentration ([Ca2+]i) was varied in the range 0-60 nM. Neurite outgrowth was maximal at 35 nM [Ca2+]i and was reduced at higher and lower values of [Ca2+]i. These results provide direct evidence for Mattson and Kater's suggestion of an optimal calcium range for growth cone function.