Skin oxygen tension is improved by immersion in oxygen-enriched water.

OBJECTIVE: The perceived health and physiologic functioning of skin depends on adequate oxygen availability. Economical and easily used therapeutic approaches to increase skin oxygenation could improve the subjective appearance of the skin as well as support the management of some cutaneous conditions related to chronic hypoxic ischaemia (e.g. ulcerative wounds). We have tested the hypothesis that the O2 partial pressure of skin (PskO2 ) increases during immersion in water enriched with high levels of dissolved oxygen. METHODS: A commercially available device was used to produce water containing 45 to 65 mg L(-1) of dissolved O2 . Young adults (YA; n = 7), older adults (OA; n = 13) and older adults with diabetes (OAD; n = 11) completed different experiments that required them to immerse their feet in tap water (<2 mg L(-1) of O2 ; control) or O2 -enriched water (O2 -H2 O; experimental) for 30 min. Transcutaneous oximetry was used to measure PskO2 for 20 min pre- and post-immersion. RESULTS: Pre-immersion mean (standard deviation) PskO2 on the plantar surface of the big toe was 75 (10), 67 (10) and 65 (10) mmHg in YA, OA and OAD, respectively. Post-immersion PskO2 was 244 (25), 193 (28) and 205 (28) mmHg for the same groups. We also show that post-immersion PskO2 varies by location and with advancing age. CONCLUSION: Water is an effective vehicle for transporting dissolved O2 across the skin surface and could be used as a basis for development of economical therapeutic approaches that improve skin oxygen tension to support skin health and function.

Factors associated with time to initiation of a PCSK9 inhibitor after hospital discharge for acute myocardial infarction.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) lower atherosclerotic cardiovascular disease (ASCVD) event risk. OBJECTIVE: Analyze patient characteristics associated with time to PCSK9i initiation following an acute myocardial infarction (AMI). METHODS: We analyzed characteristics of patients ≥21 years of age in the Marketscan or Medicare databases who initiated a PCSK9i 0-89 days, 90-179 days, or 180-365 days after an AMI between July 2015 and December 2018 (n=1,705). We estimated the cumulative incidence of recurrent ASCVD events before PCSK9i initiation. RESULTS: Overall, 42%, 25%, and 33% of patients who initiated a PCSK9i did so 0-89 days, 90-179 days, and 180-365 days following AMI hospital discharge, respectively. Taking ezetimibe prior to AMI hospitalization and initiating ezetimibe within 30 days after AMI hospital discharge were each associated with a higher likelihood of PCSK9i initiation in the 0-89 days versus 180-365 days post-discharge (adjusted odds ratio [OR] 1.83, 95% confidence interval [95%CI] 1.35-2.49 and 1.76, 95%CI 1.11-2.80, respectively). Statin use before and statin initiation within 30 days after AMI hospitalization were associated with a lower likelihood of PCSK9i initiation 0-89 days versus 180-365 days post-discharge (adjusted OR 0.64, 95%CI 0.49-0.84 and 0.39, 95%CI 0.28-0.54, respectively). Overall, 8.0%, 10.5%, and 12.5% of patients had an ASCVD event at 90, 180, and 365 days following AMI hospital discharge and before initiating a PCSK9i, respectively. CONCLUSION: Among patients initiating a PCSK9i after AMI, a low proportion did so within 89 days of hospital discharge. Many patients had a recurrent ASCVD event before treatment initiation.

Midwife-led assessment of non-catastrophic obstetric emergencies; work activity and patient attitudes.

SUMMARY: A high proportion of pregnant women attending for urgent assessment do not need emergency care and they have lower clinical priority compared with women who have serious complications in labour. We are aware that this results in a high number of complaints about waiting times. We set up a midwife-led service founded on the introduction of integrated care pathways for the six commonest conditions, based on national recommendations. A review of the case notes of 100 consecutive women who attended the maternity assessment centre was undertaken, of which 99 were suitable for analysis. On average, eight new patients were seen each day. The study found that 60% of the sample were cared for by a midwife alone and just one in three underwent direct medical assessment. The proportion cared for by midwives alone varied widely according to the presenting condition; more than 90% of those with reduced fetal movement but just one in three of those attending with antepartum haemorrhage. On average, women waited for a total of 80 min (range 35-290 min). More than 80% were in the unit for less than 120 min. On average, the wait times appeared to be longer for those women presenting with hypertension, probably because of the greater need for laboratory testing. Of a subset of 20 women surveyed by telephone questionnaire, only one (5%) was surprised to have been seen by a midwife; 17 (85%) said the counselling was excellent or good; 18 (90%) said they would be content to see a midwife for any future visit but two women said they would prefer to see a doctor at a future visit.

A multicentre longitudinal observational study of changes in self reported health status in people with Parkinson's disease left untreated at diagnosis.

BACKGROUND: The issue of when to start treatment in Parkinson's disease (PD) remains controversial. Some favour treatment at diagnosis while others opt for a "wait and watch" policy. The effect of the latter policy on the self reported health status of people with PD is unknown. AIMS: To record self reported health status through longitudinal use of a validated PD specific questionnaire (PDQ-39) in untreated PD patients in multiple centres in the UK. To compare patients who were left untreated with those who were offered treatment during follow-up. METHODS: A multicentre, prospective, "real life" observational audit based study addressing patient reported outcomes in relation to self reported health status and other sociodemographic details. RESULTS: 198 untreated PD were assessed over a mean period of 18 months. During two follow-up assessments, the self reported health status scores in all eight domains of the PDQ-39 and the overall PDQ-39 summary index worsened significantly (p<0.01) in patients left untreated. In a comparative group in whom treatment was initiated at or soon after diagnosis, there was a trend towards improvement in self reported health status scores after treatment was started. CONCLUSIONS: This study addresses for the first time self reported health status, an indicator of health related quality of life, in untreated PD. The findings may strengthen the call for re-evaluation of the policy to delay treatment in newly diagnosed patients with PD.

The effects of lisinopril on renal function in proteinuric renal transplant recipients.

Renal transplantation is frequently accompanied by systemic hypertension. In the present study we evaluated the effect of 2.5 mg lisinopril in 12 hypertensive and proteinuric renal graft recipients with stable graft function over 3 months. Only patients with absence of renal artery stenosis, at least as judged by technetium-scan imaging, were included. Lisinopril was effective in lowering systemic blood pressure. Mean arterial pressure was unchanged despite reduction of concomitant antihypertensive medication. Mean serum creatinine was unchanged during the study (1.95 +/- 0.8 mg/dl in the pretreatment period vs. 1.77 +/- 0.76 mg/dl in the intervention period, n.s.). Glomerular filtration rate remained stable (62.75 +/- 21.96 vs. 60.17 +/- 18.27 ml/min/1.73 m2, n.s.) whereas renal plasma flow increased (224.75 +/- 91.66 vs. 244.92 +/- 94.13 ml/min/1.73m2, P < 0.01), leading to a drop in filtration fraction (31.4 +/- 12.4 vs. 26.8 +/- 8.6, n.s.). Renal vascular resistance was significantly reduced following angiotensin-converting enzyme (ACE) inhibitor therapy (26,447 +/- 14,574 vs. 23,425 +/- 12,430 dyne sec cm-5/1.73 m2, P < 0.01). Mean daily proteinuric decreased significantly (2.98 +/- 2.06 vs. 2.06 +/- 2.29 g, P < 0.01) whereas in a group of patients with comparable blood pressure but without ACE inhibitor therapy and similar degree of proteinuria, 24-hr proteinuria remained stable. No severe side effects were observed--in particular, mean serum potassium showed only a slight increase and no clinically significant hyperkalemic condition was observed. When lisinopril therapy was withdrawn after 3 months, blood pressure increased in all patients, requiring reinstitution of additional antihypertensive medication. Renal hemodynamic parameters and daily proteinuria returned to baseline values. We conclude that 2.5 mg lisinopril daily was safe and effective in this group of renal transplant recipients and showed a good antihypertensive as well as antiproteinuric effect.

No interaction between the APOE and the alpha-1-antichymotrypsin genes on risk for Alzheimer's disease.

It is now known that possession of one of the three common forms of the apolipoprotein E gene (allele epsilon 4) confers an increased risk for Alzheimer's disease (AD), both familial and sporadic, and that this risk is dose-dependent. Other genes that may play a role in AD, either through independent association with the disease or through modification of, or interaction with, the existing apolipoprotein E (APOE) risk, are now under investigation including the alpha-1-antichymotrypsin (ACT) gene, the very low density lipoprotein receptor (VLDL-R) gene, and the presenilin-1 (PS-1) gene. Kamboh et al. [1995] reported that a polymorphism in the alpha-1-antichymotrypsin gene could modify the risk for AD conferred by the APOE locus, specifically by increasing the risk for AD among epsilon 4 homozygotes. The ACT gene, which is found on chromosome 14, has previously been proposed as a candidate for AD due to the presence of the ACT protein in senile plaques and the reported elevation of the protein in the cerebro-spinal fluid (CSF) and serum of AD cases. We have investigated this reported association within our familial and sporadic AD dataset, where we find no independent association between ACT and the occurrence of AD. Logistic regression analysis excludes ACT or the interaction between ACT and APOE as significant contributors in the prediction of disease status. By this analysis, ACT genotyping does not provide additional information about an individual's risk of Alzheimer's disease beyond the risk information conferred by APOE genotype alone.

Increasing the efficiency of virus infectivity assays: small inoculum volumes are as effective as centrifugal enhancement.

Improving the virus particle:infectious unit ratio is a continuing goal for animal virologists. It is demonstrated for an influenza A virus that decreasing the size of the inoculum volume to 10 microl per well of a 96-well plate was as effective as using centrifugal force with inoculum up to 250 microl. Both achieved a 7.5-fold increase in infectivity in monolayers of MDCK cells compared with standard conditions. The underlying principle of both methods is to bring virus particles into close contact with cell receptors.

A simple and accurate mathematical method for calculation of the EC50.

A simple, accurate, and speedy noncomputational technique for the calculation of the EC50 or any other concentration-related parameter of concentration-effect curves is presented. It avoids the necessity for graph construction or computational curve-fitting programs and allows accurate calculation of the EC50, where the value falls between two known concentrations The technique has been applied to a concentration-response curve constructed to hepatic arterial (HA) vasoconstrictor responses to HA injections of noradrenaline in an isolated dual-perfused rat liver preparation. EC50 values calculated by the new technique were compared to those calculated by conventional, established, noncomputational techniques. The new technique is faster, more accurate, and simpler to perform than other established noncomputational techniques used for the calculation of the EC50 and can be widely applied to many other pharmacological investigations.

Palliation of a malignant gastrocolic fistula by endoscopic human fibrin sealant injection.

We report the case of a female patient with Hodgkin's disease resistant to therapy who developed a gastrocolic fistula as a consequence of her disease, leading to distressing faeculent vomiting. This was not considered to be amenable to surgical resection and her symptoms were successfully palliated endoscopically using injection of human fibrin sealant into the gastric and colonic aspect of the fistula tract. Both mechanical sealing and promotion of healing by human fibrin sealant are likely to be responsible for its efficacy.

The effects of binder film characteristics on granule and tablet properties.

The physical properties of cast films of four polymers, which are used as binders in tableting, have been determined. Films were equilibrated at different relative humidities and tested both in tension, at three rates of strain, and by the use of indentation to determine creep compliance and hardness of the film under load. Granules and compacts have also been made using the four polymers as binders and the properties of these have been measured. One of the polymers, starch, formed a paste that was difficult to mix adequately. With the other three polymers a positive correlation was found between compact crushing strength and the creep compliance, the ultimate tensile strength and the elongation at fracture of the cast films. A negative correlation was found between the compact crushing strength and the Brinell Hardness of the films.

Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study.

Reliable detection of JAK2-V617F is critical for accurate diagnosis of myeloproliferative neoplasms (MPNs); in addition, sensitive mutation-specific assays can be applied to monitor disease response. However, there has been no consistent approach to JAK2-V617F detection, with assays varying markedly in performance, affecting clinical utility. Therefore, we established a network of 12 laboratories from seven countries to systematically evaluate nine different DNA-based quantitative PCR (qPCR) assays, including those in widespread clinical use. Seven quality control rounds involving over 21,500 qPCR reactions were undertaken using centrally distributed cell line dilutions and plasmid controls. The two best-performing assays were tested on normal blood samples (n=100) to evaluate assay specificity, followed by analysis of serial samples from 28 patients transplanted for JAK2-V617F-positive disease. The most sensitive assay, which performed consistently across a range of qPCR platforms, predicted outcome following transplant, with the mutant allele detected a median of 22 weeks (range 6-85 weeks) before relapse. Four of seven patients achieved molecular remission following donor lymphocyte infusion, indicative of a graft vs MPN effect. This study has established a robust, reliable assay for sensitive JAK2-V617F detection, suitable for assessing response in clinical trials, predicting outcome and guiding management of patients undergoing allogeneic transplant.

Neutralization of animal virus infectivity by antibody.

Neutralization is the ability of antibody to bind to and inactivate virus infectivity under defined conditions in vitro. Most neutralizing antibodies also protect animals in vivo, but protection is more complex as it also involves interaction of antibody with cells and molecules of the innate immune system. Neutralization by antibody can be mediated by a number of different mechanisms: by aggregation of virions, destabilization of the virion structure, inhibition of virion attachment to target cells, inhibition of the fusion of the virion lipid membrane with the membrane of the host cell, inhibition of the entry of the genome of non-enveloped viruses into the cell cytoplasm, inhibition of a function of the virion core through a signal transduced by an antibody, transcytosing IgA, and binding to nascent virions to block their budding or release from the cell surface. The mechanism of neutralization is determined by the properties of both a virion epitope and the antibody that reacts with it. Further, since a virus has at least several unique epitopes sited in different locations on the virion, and since the paratope and other properties of the reacting antibody can vary, this means that a virus can be neutralized by several different mechanisms. Understanding the processes of neutralization informs the creation of modern vaccines, and gives valuable insights into virus-cell interactions.