Atubular glomeruli in a rat model of polycystic kidney disease

Atubular glomeruli in a rat model of polycystic kidney disease.BackgroundAutosomal-dominant polycystic kidney disease (ADPKD) is associated with a progressive decline in glomerular filtration rate (GFR) that often leads to end-stage renal disease. The basis for this decline in GFR is poorly understood.MethodsGlomeruli in heterozygous Han:SPRD rats with ADPKD and their normal litter mates were studied by light microscopy, using serial sectioning techniques. The connections of the renal corpuscles to proximal tubules were classified as normal, atrophied, or absent (atubular glomerulus). Renal corpuscles also were examined by scanning electron microscopy. Single nephron glomerular blood flows were determined using microspheres.ResultsIn the kidneys of six-month-old rats with ADPKD, 50% of the glomeruli were atubular and another 26% were associated with atrophied neck segments; these glomeruli were most often smaller in size than normal. About 16% of the glomeruli were hypertrophied and had normal connections to proximal tubules. Sclerotic changes in cystic kidney glomeruli were usually mild or moderate, and belied the failure of glomerular function. Glomerular blood flow in the cystic kidneys averaged half of normal and was markedly heterogeneous; the majority of small glomeruli displayed very low blood flows and a few showed relatively high blood flows. Fewer glomerular abnormalities were found in rats treated for five months with potassium citrate in their drinking water.ConclusionsThe diminished GFR in the rat with ADPKD can be accounted for largely by the formation of atubular glomeruli. Compensatory glomerular hypertrophy also is present and may contribute to the progression of the renal disease

A perpetual switching system in pulmonary capillaries

Of the 300 billion capillaries in the human lung, a small fraction meet normal oxygen requirements at rest, with the remainder forming a large reserve. The maximum oxygen demands of the acute stress response require that the reserve capillaries are rapidly recruited. To remain primed for emergencies, the normal cardiac output must be parceled throughout the capillary bed to maintain low opening pressures. The flow-distributing system requires complex switching. Because the pulmonary microcirculation contains contractile machinery, one hypothesis posits an active switching system. The opposing hypothesis is based on passive switching that requires no regulation. Both hypotheses were tested ex vivo in canine lung lobes. The lobes were perfused first with autologous blood, and capillary switching patterns were recorded by videomicroscopy. Next, the vasculature of the lobes was saline flushed, fixed by glutaraldehyde perfusion, flushed again, and then reperfused with the original, unfixed blood. Flow patterns through the same capillaries were recorded again. The 16-min-long videos were divided into 4-s increments. Each capillary segment was recorded as being perfused if at least one red blood cell crossed the entire segment. Otherwise it was recorded as unperfused. These binary measurements were made manually for each segment during every 4 s throughout the 16-min recordings of the fresh and fixed capillaries (>60,000 measurements). Unexpectedly, the switching patterns did not change after fixation. We conclude that the pulmonary capillaries can remain primed for emergencies without requiring regulation: no detectors, no feedback loops, and no effectors-a rare system in biology. NEW & NOTEWORTHY The fluctuating flow patterns of red blood cells within the pulmonary capillary networks have been assumed to be actively controlled within the pulmonary microcirculation. Here we show that the capillary flow switching patterns in the same network are the same whether the lungs are fresh or fixed. This unexpected observation can be successfully explained by a new model of pulmonary capillary flow based on chaos theory and fractal mathematics

Cardiac resynchronization therapy: mechanisms of action and scope for further improvement in cardiac function.

Aims: Cardiac resynchronization therapy (CRT) may exert its beneficial haemodynamic effect by improving ventricular synchrony and improving atrioventricular (AV) timing. The aim of this study was to establish the relative importance of the mechanisms through which CRT improves cardiac function and explore the potential for additional improvements with improved ventricular resynchronization. Methods and Results: We performed simulations using the CircAdapt haemodynamic model and performed haemodynamic measurements while adjusting AV delay, at low and high heart rates, in 87 patients with CRT devices. We assessed QRS duration, presence of fusion, and haemodynamic response. The simulations suggest that intrinsic PR interval and the magnitude of reduction in ventricular activation determine the relative importance of the mechanisms of benefit. For example, if PR interval is 201 ms and LV activation time is reduced by 25 ms (typical for current CRT methods), then AV delay optimization is responsible for 69% of overall improvement. Reducing LV activation time by an additional 25 ms produced an additional 2.6 mmHg increase in blood pressure (30% of effect size observed with current CRT). In the clinical population, ventricular fusion significantly shortened QRS duration (Δ-27 ± 23 ms, P < 0.001) and improved systolic blood pressure (mean 2.5 mmHg increase). Ventricular fusion was present in 69% of patients, yet in 40% of patients with fusion, shortening AV delay (to a delay where fusion was not present) produced the optimal haemodynamic response. Conclusions: Improving LV preloading by shortening AV delay is an important mechanism through which cardiac function is improved with CRT. There is substantial scope for further improvement if methods for delivering more efficient ventricular resynchronization can be developed. Clinical Trial Registration: Our clinical data were obtained from a subpopulation of the British Randomised Controlled Trial of AV and VV Optimisation (BRAVO), which is a registered clinical trial with unique identifier: NCT01258829, https://clinicaltrials.gov

Proteomic analysis of the Plasmodium male gamete reveals the key role for glycolysis in flagellar motility.

BACKGROUND: Gametogenesis and fertilization play crucial roles in malaria transmission. While male gametes are thought to be amongst the simplest eukaryotic cells and are proven targets of transmission blocking immunity, little is known about their molecular organization. For example, the pathway of energy metabolism that power motility, a feature that facilitates gamete encounter and fertilization, is unknown. METHODS: Plasmodium berghei microgametes were purified and analysed by whole-cell proteomic analysis for the first time. Data are available via ProteomeXchange with identifier PXD001163. RESULTS: 615 proteins were recovered, they included all male gamete proteins described thus far. Amongst them were the 11 enzymes of the glycolytic pathway. The hexose transporter was localized to the gamete plasma membrane and it was shown that microgamete motility can be suppressed effectively by inhibitors of this transporter and of the glycolytic pathway. CONCLUSIONS: This study describes the first whole-cell proteomic analysis of the malaria male gamete. It identifies glycolysis as the likely exclusive source of energy for flagellar beat, and provides new insights in original features of Plasmodium flagellar organization

Long-term survival of cancer patients compared to heart failure and stroke: A systematic review

<p>Abstract</p> <p>Background</p> <p>Cancer, heart failure and stroke are among the most common causes of death worldwide. Investigation of the prognostic impact of each disease is important, especially for a better understanding of competing risks. Aim of this study is to provide an overview of long term survival of cancer, heart failure and stroke patients based on the results of large population- and hospital-based studies.</p> <p>Methods</p> <p>Records for our study were identified by searches of Medline via Pubmed. We focused on observed and relative age- and sex-adjusted 5-year survival rates for cancer in general and for the four most common malignancies in developed countries, i.e. lung, breast, prostate and colorectal cancer, as well as for heart failure and stroke.</p> <p>Results</p> <p>Twenty studies were identified and included for analysis. Five-year observed survival was about 43% for all cancer entities, 40-68% for stroke and 26-52% for heart failure. Five-year age and sex adjusted relative survival was 50-57% for all cancer entities, about 50% for stroke and about 62% for heart failure. In regard to the four most common malignancies in developed countries 5-year relative survival was 12-18% for lung cancer, 73-89% for breast cancer, 50-99% for prostate cancer and about 43-63% for colorectal cancer. Trend analysis revealed a survival improvement over the last decades.</p> <p>Conclusions</p> <p>The results indicate that long term survival and prognosis of cancer is not necessarily worse than that of heart failure and stroke. However, a comparison of the prognostic impact of the different diseases is limited, corroborating the necessity for further systematic investigation of competing risks.</p

Co-resident Parents and Young People Aged 15–34: Who Does What Housework?

Young adults are now more likely to co-reside with their parents than previous generations, but domestic work patterns among this family type are largely unexplored. This study addresses this issue using Australian Bureau of Statistics Time Use Surveys (1992, 1997, 2006) and Poisson–Gamma regression analyses. It examines patterns in and correlates of domestic labor in two-generation households in which young people aged 15–34 co-reside with their parents (n = 1,946 households comprised of 2,806 young people and 5,129 parents). It differentiates between routine indoor tasks (cooking, cleaning, laundry), non-routine tasks (outdoor work, household management and maintenance, car care) and grocery shopping. Predictors of more time in some domestic activities by young people include being in neither employment nor education/training (NEET), being older, having a single parent and being in a non-English speaking household (young women). Young people being NEET, or female, are associated with less cooking time for mothers, but in the main when young people do perform domestic activities, they do not relieve their parents of those same activities, suggesting more time is spent by the household in total

A G358S mutation in the Plasmodium falciparum Na⁺ pump PfATP4 confers clinically-relevant resistance to cipargamin

Diverse compounds target the Plasmodium falciparum Na(+) pump PfATP4, with cipargamin and (+)-SJ733 the most clinically-advanced. In a recent clinical trial for cipargamin, recrudescent parasites emerged, with most having a G358S mutation in PfATP4. Here, we show that PfATP4(G358S) parasites can withstand micromolar concentrations of cipargamin and (+)-SJ733, while remaining susceptible to antimalarials that do not target PfATP4. The G358S mutation in PfATP4, and the equivalent mutation in Toxoplasma gondii ATP4, decrease the sensitivity of ATP4 to inhibition by cipargamin and (+)-SJ733, thereby protecting parasites from disruption of Na(+) regulation. The G358S mutation reduces the affinity of PfATP4 for Na(+) and is associated with an increase in the parasite’s resting cytosolic [Na(+)]. However, no defect in parasite growth or transmissibility is observed. Our findings suggest that PfATP4 inhibitors in clinical development should be tested against PfATP4(G358S) parasites, and that their combination with unrelated antimalarials may mitigate against resistance development

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder