Reduced Mitochondrial Respiration in Hybrid Asexual Lizards.

AbstractThe scarcity of asexual reproduction in vertebrates alludes to an inherent cost. Several groups of asexual vertebrates exhibit lower endurance capacity (a trait predominantly sourced by mitochondrial respiration) compared with congeneric sexual species. Here we measure endurance capacity in five species of Aspidoscelis lizards and examine mitochondrial respiration between sexual and asexual species using mitochondrial respirometry. Our results show reduced endurance capacity, reduced mitochondrial respiration, and reduced phenotypic variability in asexual species compared with parental sexual species, along with a positive relationship between endurance capacity and mitochondrial respiration. Results of lower endurance capacity and lower mitochondrial respiration in asexual Aspidoscelis are consistent with hypotheses involving mitonuclear incompatibility.

A multinational, prospective, observational study to estimate complete skin clearance in patients with moderate-to-severe plaque PSOriasis treated with BIOlogics in a REAL world setting (PSO-BIO-REAL).

BACKGROUND: Anti-tumour necrosis factor (TNF) and anti-interleukin (IL)-12/23 biologics revolutionized plaque psoriasis treatment by enabling ≥75% improvement in the Psoriasis Area and Severity Index (PASI 75) in clinical trials. Modern biologics are now reported to achieve PASI 100 (complete skin clearance) in clinical trials. However, real-world evidence of skin clearance rates with biologics is limited. PSO-BIO-REAL was conducted to understand the real-world burden of plaque psoriasis. OBJECTIVE: The primary objective of this observational study was to estimate the proportion of patients who achieved complete skin clearance at 6 months. Secondary objectives included maintenance of response and evaluation of complete skin clearance at 12 months. METHODS: PSO-BIO-REAL was a multinational, prospective, real-world, non-interventional study of skin clearance and patient-reported outcomes (PROs) with biologics. A total of 846 patients from the United States (32%), France (28%), Italy (22%), the United Kingdom (11%) and Germany (8%) were enrolled and followed for one year. Eligible patients were aged ≥18 years with moderate-to-severe plaque psoriasis who had initiated a biologic for plaque psoriasis. Patients could be biologic-naïve or switching biologics (biologic-experienced). Assessments were made at baseline and at months 6 and 12. RESULTS: At 6 and 12 months, 23% and 26% of patients achieved complete skin clearance, respectively. Prior to study entry, 60% were biologic-naïve. The proportion of patients achieving complete skin clearance was lower among biologic-experienced patients (20% at both months 6 and 12) compared with biologic-naïve patients (25% at month 6, 30% at month 12). The rate of complete skin clearance decreased as the number of prior biologics and baseline comorbidities increased. CONCLUSION: Only one in four patients achieved complete skin clearance after 6 months of treatment with biologics. The study indicates there still is an unmet need for more efficacious biologics for patients with psoriasis.

What Makes Health Care Special?: An Argument for Health Care Insurance.

While citizens in a liberal democracy are generally expected to see to their basic needs out of their own income shares, health care is treated differently. Most rich liberal democracies provide their citizens with health care or health care insurance in kind. Is this "special" treatment justified? The predominant liberal account of justice in health care holds that the moral importance of health justifies treating health care as special in this way. I reject this approach and offer an alternative account. Health needs are not more important than other basic needs, but they are more unpredictable. I argue that citizens are owed access to insurance against health risks to provide stability in their future expectations and thus to protect their capacities for self-determination.

Medical Need, Equality, and Uncertainty.

Many hold that distributing healthcare according to medical need is a requirement of equality. Most egalitarians believe, however, that people ought to be equal on the whole, by some overall measure of well-being or life-prospects; it would be a massive coincidence if distributing healthcare according to medical need turned out to be an effective way of promoting equality overall. I argue that distributing healthcare according to medical need is important for reducing individuals' uncertainty surrounding their future medical needs. In other words, distributing healthcare according to medical need is a natural feature of healthcare insurance; it is about indemnity, not equality.

Toll-like receptor 2 is present in the microenvironment of oral squamous cell carcinoma.

BACKGROUND: The aim of this study was to investigate the expression of toll-like receptor 2 (TLR2) on cells associated with oral squamous cell carcinoma, epithelial dysplasia and irritative hyperplasia, using immunohistochemistry. RESULTS: More immune cells expressed TLR2 in carcinoma and dysplasia than in hyperplasia (P<0.001). No hyperplastic samples showed positive TLR2 staining on keratinocytes, whereas keratinocytes in 64% of cases of carcinoma and 74% of cases of dysplasia were TLR2 positive. CONCLUSION: Positive TLR2 expression in the microenvironment suggests activation of immune surveillance against the altered epithelium, whereas TLR2 expression by malignant keratinocytes may be indicative of resistance to apoptosis as a pro-survival mechanism.

"Incident Teaching (IT)" Lecture Series - Incorporating Education Surrounding Clinical Incidents and Complaints into Foundation Year 1 (FY1) Doctors' Induction.

Patient safety incidents are any unintended or unexpected incidents which potentially could, or did, lead to harm to patients. Incident reports are crucial to improve patients' care and to identify further actions needed to prevent harm. A common view among the FY1 doctors in our local NHS Trust involved a fearful opinion surrounding being involved in clinical incidents. Significant anxiety in those situations prompted the need for a focus on the topic of "clinical incidents" during their induction to the Trust in two consecutive years of 2018 and 2019. A near-peer lecture series was delivered to new FY1 with qualitative pre- and post-lecture series feedbacks. Results from lecture series from two consecutive years showed all FY1 doctors agreed or strongly agreed that they had a good understanding of incidents following the lecture. Compared with their pre-course feedback, there was an increase of 6-fold (2018) and 8-fold (2019) in those that strongly agreed. Post-course, more than 90% of doctors reported that they would feel comfortable sharing with colleagues their involvement in an incident. In a growing culture of blame and litigation, it is important to address the harm associated with a blame-based culture. The process of investigating an incident has the potential to expose the areas of deficiency relating to an individual. Reducing stigma associated with incidents could theoretically reduce the second victim phenomenon. An open culture to incident reporting is a fundamental part of medical education and quality improvement. Encouraging this attitude amongst medical professionals and creating a supporting environment surrounding sharing of experiences will help to form a generation of doctors that see incident reporting in a positive light. Our model of lecture series could be utilised in other UK Foundation Programmes with the aim of enriching the FY1s' induction period.

Modulation of skeletal muscle sodium channels by human myotonin protein kinase.

In myotonic muscular dystrophy, abnormal muscle Na currents underlie myotonic discharges. Since the myotonic muscular dystrophy gene encodes a product, human myotonin protein kinase, with structural similarity to protein kinases, we tested the idea that human myotonin protein kinase modulates skeletal muscle Na channels. Coexpression of human myotonin protein kinase with rat skeletal muscle Na channels in Xenopus oocytes reduced the amplitude of Na currents and accelerated current decay. The effect required the presence of a potential phosphorylation site in the inactivation mechanism of the channel. The mutation responsible for human disease, trinucleotide repeats in the 3' untranslated region, did not prevent the effect. The consequence of an abnormal amount of the kinase would be altered muscle cell excitability, consistent with the clinical finding of myotonia in myotonic dystrophy.

Modulation of Xenopus oocyte-expressed phospholemman-induced ion currents by co-expression of protein kinases.

Phospholemman (PLM), the major sarcolemmal substrate for phosphorylation by cAMP-dependent kinase (PKA) protein kinase C (PKC) and NIMA kinase in muscle, induces hyperpolarization-activated anion currents in Xenopus oocytes, most probably by enhancing endogenous oocyte currents. PLM peptides from the cytoplasmic tail are phosphorylated by PKA at S68, by NIMA kinase at S63, and by PKC at both S63 and S68. We have confirmed the phosphorylation sites in the intact protein, and we have investigated the role of phosphorylation in the regulatory activity of PLM using oocyte expression experiments. We found: (1) the cytoplasmic domain is not essential for inducing currents in oocytes; (2) co-expression of PKA increased the amplitude of oocyte currents and the amount of PLM in the oocyte membrane largely, but not exclusively, through phosphorylation of S68; (3) co-expression of PKA had no effect on a PLM mutant in which all putative phosphorylation sites had been inactivated by serine to alanine mutation (SSST 62, 63, 68, 69 AAAA); (4) co-expression of PKC had no effect in this system; (5) co-expression of NIMA kinase increased current amplitude and membrane protein level, but did not require PLM phosphorylation. These findings point to a role for phosphorylation in the function of PLM.

Unusually high susceptibility of NZR/Gd rats to bladder cancer induction by low doses of nitrosomethylurea.

Inbred female rats of the NZR/Gd strain were exceptionally susceptible to nitrosomethylurea (NMU) toxicity after intravesical instillations. After only 1.0 mg NMU total given in 10 fractions, 100% of NZR rats developed malignant bladder tumours. Transitional cell carcinomas predominated (56%) when the NMU dose interval was 2 weeks, and most tumours were squamous carcinomas (57%) with a 1-week interval.

Quality assurance in the surgical intensive care unit. Where it came from and where it's going.

The early history of QA is one of stunning achievements. Men and women led by a vision of what hospital health care should be brought about fundamental changes in the structure of hospitals and medical schools. These successes required lifetimes of work and enormous capital (Flexner's war chest would have amounted to billions of 1990 dollars). A second wave of reform included the creation of credentialing committees, tissue committees, and infection control efforts. Although less dramatic in their impact, these efforts have had measurable influence on the outcome of health care and, under the joint administration of local hospitals and the JCAHO, continue to guarantee excellence in health care. The most recent attempts at quality assurance, driven at least in part by a federal mandate to control costs, have been much more modest in their success. Committed groups working within a sound theoretical framework have had great difficulty monitoring and evaluating centrally a process as decentralized as health care. The regularity with which new fashions in QA have appeared underscores the frustration felt with this approach. If the quality of health care is to be monitored centrally, reliable measures of quality will be required. No one knows if such measures actually exist. The absence of objective evidence that quality has been improved by these efforts suggests that little has been accomplished, perhaps because all easily attainable improvements had already been implemented. The basic concept of a centrally monitored hospital structure within which provision is made for ongoing observation and innovation by those actually involved in the care of patients retains the advantages of central monitoring and local invention. It is a model that will be hard to improve on. We should persist in our efforts, but fundamental advances are unlikely. In the end, quality is only doing everything the best it can be done. The best quality assurance requires an excellent hospital in which a well-trained and committed staff has a central mandate and local purview to do the best possible job. Two thousand years after Hammurabi's minions busied themselves determining the appropriate punishment for various medical misadventures, the Greek Hippocrates advocated a less complex approach to the same problem. He suggested that the quality of health care could be best guaranteed by administering an oath to physicians, exhorting them simply to do what was best for their fellow men. This approach has seen us through two millennia and, however variable its results, may not be easily improved on.

Mutagenic activation of dialkylnitrosamines by intact urothelial cells.

Intact urothelial cells isolated from bladders of untreated inbred NZO/BIGd or NZC/BIGd mice and NZR/Gd rats activated dimethyl, diethyl, dipropyl, and dibutyl nitrosamines in a liquid culture mutagenesis fluctuation assay using Salmonella typhimurium TA100 as target organism. Rat and mouse urothelial cells were highly effective at 1.5 X 10(5) cells/ml, in O2 gas phase, and no cofactors were required. Relative mutagenic activities were estimated at equitoxic (LD50) concentrations of the 4 nitrosamines. Nitrosamines with odd-carbon chain substitutents were more active than the C-even compounds. Although dibutylnitrosamine is a powerful bladder carcinogen in both rats and mice while the other 3 compounds very rarely cause bladder tumours, the most active promutagens were dipropyl and dimethyl, followed by diethyl and dibutyl nitrosamines. None were active in absence of urothelial cells. Mouse bladder cells were more active than those from NZR rats. There were sex differences in the mice with NZC males and NZO females predominating, but in NZR rats urothelial cells from male and female animals were equally active. These dialkylnitrosamines are widely distributed in the environment, and our results indicate that direct mutagenic activation in the urothelium could be one factor contributing to the incidence of bladder cancer.

Enhancement of recall of cardiopulmonary resuscitation (CPR): Use of moving-image card to review the dynamics of CPR.

Since victims of cardiac arrest have a more favorable outcome when CPR is immediately applied, it is important to continue to motivate individuals to learn proper technique. It is equally important to ensure that individuals who have learned CPR maintain adequate recall of the procedure. With the intent of enhancing recall of the principles of CPR, a wallet-size plastic card was developed which, when tilted, creates the illusion of movements. Thus, the card enables a viewer to review the dynamic aspects of CPR and reinforces the essential steps of establishing an airway and maintaining breathing and circulation.

Intraarticular heterotopic ossification in the knee following intramedullary nailing of the fractured femur using a retrograde method.

The cases of a forty-five-year-old woman and a twenty-year-old man who developed severe intraarticular and periarticular heterotopic ossification around the knee following intramedullary nailing of a femur fracture using a retrograde technique. The association of musculoskeletal heterotopic ossification with closed head injuries seems well established and can occur in and around the knee following retrograde intramedullary nailing. This complication may occur more often than has been reported.

Psychological disturbance and child sexual abuse: a follow-up study.

OBJECTIVE: The aim of this prospective study was to identify risk factors for the development of psychological disturbance in sexually abused children, enabling recognition of the need for appropriate psychological intervention and provision. METHOD: A city-wide study of children aged 16 or under was carried out, with all cases of CSA requiring investigation within 12 months included. Data were collected on 144 children from police, social services, and pediatricians. Follow-up was by questionnaire and interview with involved professionals at 4 weeks, 9 months, and 2 years post investigation. RESULTS: Initially, two-thirds of children showed emotional or behavioral indicators of disturbance, commonly sleep disturbance, temper tantrums, and depression. Over time, there was a substantial increase, with anxiety and depression, suicide attempts, substance abuse, lack of interaction with peers and sexualized behavior showing increases over the study's duration. Age, gender, abuse, and perpetrator characteristics did not show strong effects initially. Children involved in criminal proceedings were at particular risk. No improvement was evident over time. CONCLUSIONS: In the absence of clear risk factors other than initial disturbance, process models involving cognitive factors may be helpful in explaining disturbance, and the need for early identification of disturbance and intervention is highlighted.

Perception of risk of HIV infection from regular attenders to an industrial dental service.

The advent of the HIV pandemic has necessitated the introduction of consistent cross-infection procedures for dentistry. Suprisingly little is known of patient reactions to some of these changes. A structured questionnaire was administered (in 1988/9, n = 613) to regular-attending patients of an industrial dental service to assess their views towards cross-infection procedures. Approximately a third of the study sample believed that there was a slight risk or more of contracting HIV infection at the dentist. This risk perception attenuated with further visits to the dentist. Some patients (13%) claimed to be aware from the media of someone having been cross-infected with the HIV virus from a dental visit. The majority of patients prefer the dentist to adopt the barrier methods of mask and glove wearing. Over 60% of patients would like their dentist to wear a mask when in fact a mask had not been worn. Accuracy of recall by patients for mask wearing was only 70% and for glove wearing 88%. The possibility that drawing the patient's attention to cross-infection control may be reassuring for the patient was not supported with some evidence to suggest that in instances where the dentist provided treatment, the patient's perception of risk was increased.

No more wakeful nights. Helping elderly people to sleep properly.

Lack of sleep can cause untold misery, particularly in elderly people, whose sleep routines are subject to age-related change. A range of practical steps can be taken to minimise the effects of these changes on the quality and quantity of elderly people's sleep.

Development of a broad spectrum polymer-released antimicrobial coating for the prevention of resistant strain bacterial infections.

More than 400,000 primary hip and knee replacement surgeries are performed each year in the United States. From these procedures, approximately 0.5-3% will become infected and when considering revision surgeries, this rate has been found to increase significantly. Antibiotic-resistant bacterial infections are a growing problem in patient care. This in vitro research investigated the antimicrobial potential of the polymer released, broad spectrum, Cationic Steroidal Antimicrobial-13 (CSA-13) for challenges against 5 × 10(8) colony forming units (CFU) of methicillin-resistant Staphylococcus aureus (MRSA). It was hypothesized that a weight-to-weight (w/w) concentration of 18% CSA-13 in silicone would exhibit potent bactericidal potential when used as a controlled release device coating. When incorporated into a polymeric device coating, the 18% (w/w) broad-spectrum polymer released CSA-13 antimicrobial eliminated 5 × 10(8) CFU of MRSA within 8 h. In the future, these results will be utilized to develop a sheep model to assess CSA-13 for the prevention of perioperative device-related infections in vivo.

Isolation of hepatocellular lipid droplets: the separation of distinct subpopulations.

A new method for the isolation of lipid droplets from rat liver has been devised. The procedure involves tissue homogenization and discontinuous density gradient centrifugation. Six discrete bands of lipid particles, rich in triglyceride and cholesterol, are visible following 30 min of centrifugation at 25,770 g (max) in a swinging bucket rotor. An entire rat liver can be processed in 1-2 hr. Differences in the density of these liver lipid particles correlate with their triglyceride, sterol, phospho-lipid, and protein contents. The separation of these distinct populations of intracellular particulate neutral lipids provides an approach to the study of their origin and metabolism. This procedure may also be useful in the isolation of various populations of lipid-rich particles from other tissues.

Correlation of human bladder tumor recurrence with changes in clonogenicity of urothelial cells.

Over a 2-year period 340 cystoscopies were performed on 174 patients (126 men and 48 women) followed up for previously treated transitional cell tumor of the bladder or new cases suspected of having bladder tumor. Bladder washings taken at cystoscopy in 66% yielded cells for clonogenic assay. Patients with transitional cell tumors had an average clonogenic index (CI) of 14 (+/- 5) colonies per 10(5) viable urothelial cells, whereas previously tumorous patients with tumor-free bladders had an average CI of 6 +/- 1 colonies (P less than 0.001, Student's t test). Patients with hematuria but no bladder tumor had an average CI of 8 (not significant). In serial examinations with consecutive successful clonogenic assay, 11 of 16 patients remaining tumor-free had constant or falling CI whereas 9 of 12 patients with recurrent tumor had rising CI values (Fisher; P less than 0.025). Changes in the clonogenic index of cells taken from bladder washings paralleled the changes in tumor status at cystoscopy and might have predictive value in this disease.