Effects of aging on cerebral blood flow, oxygen metabolism, and blood oxygenation level dependent responses to visual stimulation.
Calibrated functional magnetic resonance imaging (fMRI) provides a noninvasive technique to assess functional metabolic changes associated with normal aging. We simultaneously measured both the magnitude of the blood oxygenation level dependent (BOLD) and cerebral blood flow (CBF) responses in the visual cortex for separate conditions of mild hypercapnia (5% CO(2)) and a simple checkerboard stimulus in healthy younger (n = 10, mean: 28-years-old) and older (n = 10, mean: 53-years-old) adults. From these data we derived baseline CBF, the BOLD scaling parameter M, the fractional change in the cerebral metabolic rate of oxygen consumption (CMRO(2)) with activation, and the coupling ratio n of the fractional changes in CBF and CMRO(2). For the functional activation paradigm, the magnitude of the BOLD response was significantly lower for the older group (0.57 +/- 0.07%) compared to the younger group (0.95 +/- 0.14%), despite the finding that the fractional CBF and CMRO(2) changes were similar for both groups. The weaker BOLD response for the older group was due to a reduction in the parameter M, which was significantly lower for older (4.6 +/- 0.4%) than younger subjects (6.5 +/- 0.8%), most likely reflecting a reduction in baseline CBF for older (41.7 +/- 4.8 mL/100 mL/min) compared to younger (59.6 +/- 9.1 mL/100 mL/min) subjects. In addition to these primary responses, for both groups the BOLD response exhibited a post-stimulus undershoot with no significant difference in this magnitude. However, the post-undershoot period of the CBF response was significantly greater for older compared to younger subjects. We conclude that when comparing two populations, the BOLD response can provide misleading reflections of underlying physiological changes. A calibrated approach provides a more quantitative reflection of underlying metabolic changes than the BOLD response alone.


Negative repercussions of caregiving burden: Poor psychological well-being and depression.
To compare depression and psychological well-being between caregivers of schizophrenic patients and non-caregivers and to study the burden of caregiving as a relative risk for depression and psychological well-being. This cross sectional comparative study was conducted at International Islamic university Islamabad from January to September 2017. Fifty informal caregivers of schizophrenic patients from 19 to 55 years of age were included in the study. The control group consisted of age and socio-economic status matched healthy volunteers who did not have any psychological or medical patient at home needing care and assistance. For measurement of study variables i.e., burden of caregiving, depression and psychological well-being, instruments used were Zarit Burden Interview (ZBI), The Beck Depression Inventory (BDI) and Warwick-Edinburgh Mental Well-Being Scale (WEMWBS) respectively. Results were analyzed using MANOVA followed by One-Way ANOVA. Findings indicated that informal caregivers of schizophrenia have greater depression and poor psychological well-being in comparison to the non-caregiver controls. Association of caregiving burden with psychological well-being and depression was calculated using Chi Square test and relative risk. Caregiving adversely affects informal caregivers' mental health and wellbeing. Informal caregiving is a burden for the caregivers; health status of family members involved in caregiving should be routinely assessed to enhance their health-related quality of life.


Activation of sphingosine kinase by lipopolysaccharide promotes prostate cancer cell invasion and metastasis via SphK1/S1PR4/matriptase.
Gram-negative bacteria have been found to be a major population in prostatitis and prostate cancer (PCa) tissues. Lipopolysaccharide (LPS), a major compound of Gram-negative bacteria, with stimulatory activities in some cancer types, but has not been fully studied in PCa. In this study, we examined the effect of LPS on the invasion of PCa cells. Interestingly, LPS can enhance the invasiveness of PCa, but had no significant effect on PCa cell viability. Using protease inhibitor screening and biochemical analyses, matriptase, a member of the membrane-anchored serine protease family, is found to play a key role in LPS-induced PCa cell invasion. Mechanistically, Toll-like receptor 4 (TLR4, LPS receptor)-sphingosine kinase 1 (SphK1) signaling underlies LPS-induced matriptase activation and PCa cell invasion. Specifically, LPS induced the S225 phosphorylation of SphK1 and the translocation of SphK1 to plasma membrane, leading to the production of sphingosine 1-phosphate (S1P), ERK1/2 and matriptase activation via S1P receptor 4 (S1PR4). This phenomenon is further validated using the patient-derived explant (PDE) model. Indeed, there is a significant correlation among the elevated SphK1 levels, the Gleason grades of PCa specimens, and the poor survival of PCa patients. Taken together, this study demonstrates a potential impact of LPS on PCa progression. Our results provide not only a new finding of the role of bacterial infection in PCa progression but also potential therapeutic target(s) associated with PCa metastasis.


A method for preparation, storage, and activation of large populations of immotile sea urchin sperm.
Reversible protein phosphorylation is associated with initiation and modulation of sperm flagellar motility. Many studies aimed at examining the signal transduction mechanisms underlying the expression of motility have relied on detergent-permeabilized sperm reactivated with exogenous 32P-ATP. However, the reactivation conditions allow variable levels of motility to be expressed and phosphorylation of many proteins that appear to be unrelated to sperm motility. Thus, identification of the few relevant proteins is difficult. We have developed a method to collect and keep sperm immotile until reactivated for analysis to normal motility levels. Artificial sea water (ASW) buffered with 5 mM 2-[N-morpholino]ethanesulfonic acid at pH 6.0 and containing 50 mM KCl allows collection and storage of immotile sea urchin sperm for up to 96 h at 4-5 degrees C. Motility under these conditions is essentially zero, but sperm is rapidly reactivated to normal motility by diluting with ASW to standard pH (8.0) and KCl concentration (10 mM).


Diplopia and diarrhea: ileal carcinoid metastatic to the central nervous system.
The case of a patient with metastatic ileal carcinoid is reported. The peculiarities of this case were as follows: 1) The patient presented with symptoms attributable to a mass lesion in the brain which was proven to be a carcinoid tumor by biopsy. 2) The patient had symptoms attributable to carcinoid syndrome without radiologic evidence of hepatic metastasis. 3) No bony or pulmonary metastasis was evident, which suggests that the metastatic spread from the ileum occurred through the spinous venous plexus of Batson. The patient's symptoms were managed with cyproheptadine with good effect. A review of the carcinoid syndrome and the determinants of its metastatic spread is presented.


Effect of radiation, heat, and aging on in vitro wear resistance of polyethylene.
Radiation cross-linking increases the wear resistance of polyethylene used in total hip replacement. Radiation also generates residual free radicals, which are detrimental to long-term properties of polyethylene. Two approaches are used to stabilize the residual free radicals and terminally sterilize the components. One is postirradiation annealing with gas sterilization and the other is postirradiation melting with gamma sterilization in nitrogen. The hypothesis of the current study is that postirradiation annealing followed by gamma sterilization in nitrogen will result in more free radicals in polyethylene than gamma sterilization either in air or in nitrogen alone. To test this hypothesis, concentration of residual free radicals was quantified in polyethylene that was annealed and gamma sterilized in nitrogen and control polyethylenes gamma sterilized in air versus in nitrogen. Three crosslinked polyethylenes that were melted and gas sterilized also were included in the study. The effects of residual free radicals were studied by accelerated aging. Oxidation levels and weight loss in bidirectional pin-on-disk tests were determined before and after aging. Polyethylene that was subjected to postirradiation annealing and gamma sterilization resulted in 58% more residual free radicals than control polyethylenes. Weight loss of the annealed polyethylene increased by 16-fold on accelerated aging and had three times higher oxidation levels than that measured in control polyethylenes after aging. In contrast, polyethylenes that were stabilized with postirradiation melting and terminally gas sterilized showed no detectable residual free radicals. Accelerated aging did not affect the weight loss and oxidation levels of melted polyethylenes.


Anchoring the Self to the Body in Bilateral Vestibular Failure.
Recent findings suggest that vestibular information plays a significant role in anchoring the self to the body. Out-of-body experiences of neurological origin are frequently associated with vestibular sensations, and galvanic vestibular stimulation in healthy participants anchors the self to the body. Here, we provide the first objective measures of anchoring the self to the body in chronic bilateral vestibular failure (BVF). We compared 23 patients with idiopathic BVF to 23 healthy participants in a series of experiments addressing several aspects of visuo-spatial perspective taking and embodiment. In Experiment 1, participants were involved in a virtual "dot-counting task" from their own perspective or the perspective of a distant avatar, to measure implicit and explicit perspective taking, respectively. In both groups, response times increased similarly when the avatar's and participant's viewpoint differed, for both implicit and explicit perspective taking. In Experiment 2, participants named ambiguous letters (such as "b" or "q") traced on their forehead that could be perceived from an internal or external perspective. The frequency of perceiving ambiguous letters from an internal perspective was similar in both groups. In Experiment 3, participants completed a questionnaire measuring the experienced self/body and self/environment "closeness". Both groups reported a similar embodied experience. Altogether, our data show that idiopathic BVF does not change implicit and explicit perspective taking nor subjective anchoring of the self to the body. Our negative findings offer insight into the multisensory mechanisms of embodiment. Only acute peripheral vestibular disorders and neurological disorders in vestibular brain areas (characterized by strong multisensory conflicts) may evoke disembodied experiences.


Effect of high-pressure homogenization on the physical and antioxidant properties of Quercus resinosa infusions encapsulated by spray-drying.
Quercus resinosa leaves are used in northern Mexico as a refreshing beverage rich in polyphenolic compounds. These leaves show astringency and hence need taste masking for incorporating in a food product. They also interact with many other food components and are not very stable to food processing environments, thus it is important to protect them and a common way is by encapsulation. In the present study the use of encapsulation by spray-drying of Quercus resinosa leaves infusions was evaluated. Q. resinosa leaves were collected, air dried, and milled prior to infusion preparation. Lactose-sodium caseinate blends at 3 different proportions (11 : 4%, 9 : 6%, and 7 : 8%) were dispersed with a constant amount of lyophilized infusion (0.075%) and processed under high-pressure homogenization (0, 100, 200, 300 MPa). Total phenolic content, DPPH kinetic analysis, deoxy-D-ribose oxidation inhibition, rheological evaluation, and particle size analysis were performed to evaluate the obtained capsules. High antioxidant activity was shown by capsules despite their very low concentration when inhibiting deoxy-D-ribose oxidation. Chain breaking rate was related to polyphenolic concentration in capsules. Using lactose-caseinate blends produces capsules of submicron to nanometer size that retain the good antioxidant capacities of original infusions.


Three-dimensional imaging of cell and extracellular matrix elasticity using quantitative micro-elastography.
Recent studies in mechanobiology have revealed the importance of cellular and extracellular mechanical properties in regulating cellular function in normal and disease states. Although it is established that cells should be investigated in a three-dimensional (3-D) environment, most techniques available to study mechanical properties on the microscopic scale are unable to do so. In this study, for the first time, we present volumetric images of cellular and extracellular elasticity in 3-D biomaterials using quantitative micro-elastography (QME). We achieve this by developing a novel strain estimation algorithm based on 3-D linear regression to improve QME system resolution. We show that QME can reveal elevated elasticity surrounding human adipose-derived stem cells (ASCs) embedded in soft hydrogels. We observe, for the first time in 3-D, further elevation of extracellular elasticity around ASCs with overexpressed TAZ; a mechanosensitive transcription factor which regulates cell volume. Our results demonstrate that QME has the potential to study the effects of extracellular mechanical properties on cellular functions in a 3-D micro-environment.


Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice.
Tissue kallikrein is a serine protease thought to be involved in the generation of bioactive peptide kinins in many organs like the kidneys, colon, salivary glands, pancreas, and blood vessels. Low renal synthesis and urinary excretion of tissue kallikrein have been repeatedly linked to hypertension in animals and humans, but the exact role of the protease in cardiovascular function has not been established largely because of the lack of specific inhibitors. This study demonstrates that mice lacking tissue kallikrein are unable to generate significant levels of kinins in most tissues and develop cardiovascular abnormalities early in adulthood despite normal blood pressure. The heart exhibits septum and posterior wall thinning and a tendency to dilatation resulting in reduced left ventricular mass. Cardiac function estimated in vivo and in vitro is decreased both under basal conditions and in response to beta-adrenergic stimulation. Furthermore, flow-induced vasodilatation is impaired in isolated perfused carotid arteries, which express, like the heart, low levels of the protease. These data show that tissue kallikrein is the main kinin-generating enzyme in vivo and that a functional kallikrein-kinin system is necessary for normal cardiac and arterial function in the mouse. They suggest that the kallikrein-kinin system could be involved in the development or progression of cardiovascular diseases.


Contralateral hamstring autografts do not provide benefit compared to ipsilateral hamstring autografts in primary or revision anterior cruciate ligament reconstruction: a systematic review.
To evaluate the clinical outcomes of primary or revision ACL reconstruction (ACLR) after contralateral hamstring autografts versus ipsilateral hamstring autograft harvest. Three databases (MEDLINE, PubMed and EMBASE) were searched from inception to April 27th, 2023 for studies investigating contralateral hamstring autografts in primary or revision ACLR. The authors adhered to the PRISMA and R-AMSTAR guidelines as well as the Cochrane Handbook for Systematic Reviews of Interventions. Data on demographics, strength measures, patient-reported outcome measures (PROMs), and rates of positive Lachman test, positive pivot-shift test and graft rupture were extracted. PROMs included Lysholm, International Knee Documentation Committee (IKDC) and Tegner scores. Nine studies comprising 371 patients were included in this review. In primary ACLR, there were no significant differences between contralateral and ipsilateral groups in isokinetic hamstring torque in the non-ACLR limb or isokinetic quadriceps torque in both limbs when tested at 60, 90, 120 or 180 degrees/second. Isokinetic hamstring torque in the non-ACLR limb was significantly weaker in the contralateral group at six months for primary ACLR; however, these deficits did not persist. There were no significant differences in postoperative median Tegner scores and Lysholm scores between contralateral and ipsilateral groups in primary ACLR. There were no significant differences in postoperative median Tegner, mean Lysholm and IKDC scores between groups in revision ACLR. There were no significant differences in positive Lachman, positive pivot-shift and rupture rates in primary ACLR between groups. Rates of positive Lachman and pivot-shift were slightly higher in the contralateral than ipsilateral group for revision ACLR. Contralateral hamstring autografts results in comparable muscle strength to ipsilateral hamstring autografts, with the exception of weaker hamstring strengths in the early postoperative period. Patient-reported outcome measures were similar between the two groups across both primary and revision ACLR, with rates of instability and failure being similar between groups for primary ACLR. Contralateral hamstring grafts do not provide additional benefit when compared to ipsilateral options for either primary or revision ACLR, and should be used only in select circumstances including insufficient ipsilateral hamstring grafts or situations where quadriceps or patella autografts are not optimal. Level IV.


Genetic heterogeneity of lymphangiogenesis in different mouse strains.
Lymphangiogenesis plays an important role in tumor metastasis, wound healing, and immune reactions, such as after organ transplantation. Furthermore, novel antilymphangiogenic drugs are moving into clinical medicine, but so far nothing is known about a potential genetic heterogeneity influencing lymphangiogenesis. Using the mouse cornea micropocket assay (VEGF-C) and the suture-induced corneal neovascularization model in different inbred and wild-derived mouse strains (Balb/cAnNCrl, C57BL/6NCrl, 129S1/SvImJ, SJL/JCrl, Cast/EiJ, FVB/NCrl), significant differences in the lymphangiogenic response were detected: the lymphvascularized area varied up to 1.9-fold in the micropocket assay and up to 1.7-fold in the suture-induced neovascularization model between the "low-responder" strain BALB/c and the "high-responder" strain FVB in response to the same stimulus. Furthermore, the number of physiological lymphatic vascular extensions into the marginal zone of the normally alymphatic cornea in untreated eyes again showed a difference of 1.6-fold between low- and high-responders. An anti-inflammatory (prednisolone acetate) and a specific anti(lymph)angiogenic therapy (blocking anti-VEGFR-3 antibody) had different effects on the lymphvascularized area in BALB/c mice and FVB mice, suggesting a different responsiveness to antilymphangiogenic treatments. These data for the first time demonstrate significant differences in the lymphangiogenic response of several mouse strains and suggest underlying genetic factors influencing the lymphangiogenic response. These considerations need to be taken into account when using different mouse strains to study lymphangiogenesis and may also explain different success of antilymphangiogenic treatments in tumor patients.


Electromechanical performance of piezoelectric scanning mirrors for medical endoscopy.
The electromechanical performance of piezoelectric scanning mirrors for endoscopy imaging is presented. The devices are supported by a single actuating cantilever to achieve a high fill factor, the ratio of mirror area to the combined mirror and actuator area. The largest fill factor devices (74%) achieved 10° mechanical scan range at +/-10V with a 300 μm long cantilever. The largest angular displacement of 30° mechanical scan range was obtained with a 500 μm long cantilever device with a 63% fill factor driven at 40 Vpp. A systematic investigation of device performance (displacement and speed) as a function of fabrication and operational parameters including the stress balance in the cantilever revealed unexpectedly large displacements with lack of inversion at the coercive field. An interpretation of the results is presented based on piezoelectric film domain orientation and clamping with supporting piezoelectric film characterization measurements.


[Diagnosis of hemorrhagic diseases (author's transl)].
Bleeding symptoms require in many instances immediate professional care. In order to avoid unnecessary treatment, an exact diagnosis is mandatory. In most cases a differentiation between primary humoral and thrombocytogenic bleeding disorders and a secondary bleeding diathesis due to consumption coagulopathy is possible by means of anamnestic, clinical and laboratory parameters. As a single test, the bleeding time gives the best information, followed by the heparin-tolerance-time, the PTT and the platelet count. Withe Quick-test alone, only 5% of children with severe bleeding diathesis are detected. For preoperative laboratory evaluation we recommend a combination of PTT, Quick-test, platelet count and bleeding-time. For the diagnosis of disseminated intravascular coagulation, anamnestic criteria (procoagulant triggers) and clinical evaluation [thrombohemorrhagic syndrome of organ(s)] are as important als laboratory parameters (platelet count, plasminogenproactivator, splits, PTT, Quick-test).


Effects of RNA degradation on gene expression analysis of human postmortem tissues.
The Affymetrix GeneChip platform was used to build a gene expression database of the normal human body. Postmortem human tissues represent a valuable source of biological materials for this type of study, but their use entails some delays before harvesting such tissues. We first evaluated the RNA quality obtained from tissues obtained 3-5 h postmortem and found variations that were both tissue and donor-dependent. RNAs extracted from brain regions were of higher quality than those obtained from the gut, while the cause of death was a significant factor in donor-dependent differences. To avoid these variables, we used rat duodenum to determine the effects of RNA degradation on the analysis of gene expression. Surprisingly, even samples exhibiting significant RNA degradation yielded robust gene expression results, comparable to those obtained using intact samples at a certain signal intensity cutoff. We extended these findings to our human expression database and obtained similar results, indicating that the Affymetrix platform, which is biased to the 3' end of transcripts for detection, can tolerate significant RNA degradation, while still yielding high quality expression data. Our resulting body index expression database is a valuable research tool. As examples of potential uses, we report novel expression sites for four potential therapeutic targets--CCL27, GPR22, GPR113 and GPR128--and as well as a set of thymus-specific genes, including three not previously associated with the thymus.


Rapid changes in gene expression direct rapid shifts in intestinal form and function in the Burmese python after feeding.
Snakes provide a unique and valuable model system for studying the extremes of physiological remodeling because of the ability of some species to rapidly upregulate organ form and function upon feeding. The predominant model species used to study such extreme responses has been the Burmese python because of the extreme nature of postfeeding response in this species. We analyzed the Burmese python intestine across a time series, before, during, and after feeding to understand the patterns and timing of changes in gene expression and their relationship to changes in intestinal form and function upon feeding. Our results indicate that >2,000 genes show significant changes in expression in the small intestine following feeding, including genes involved in intestinal morphology and function (e.g., hydrolases, microvillus proteins, trafficking and transport proteins), as well as genes involved in cell division and apoptosis. Extensive changes in gene expression occur surprisingly rapidly, within the first 6 h of feeding, coincide with changes in intestinal morphology, and effectively return to prefeeding levels within 10 days. Collectively, our results provide an unprecedented portrait of parallel changes in gene expression and intestinal morphology and physiology on a scale that is extreme both in the magnitude of changes, as well as in the incredibly short time frame of these changes, with up- and downregulation of expression and function occurring in the span of 10 days. Our results also identify conserved vertebrate signaling pathways that modulate these responses, which may suggest pathways for therapeutic modulation of intestinal function in humans.


Release of cytokines and hemodynamic instability during the reperfusion of a liver graft.
The objectives of this prospective, observational study were (1) to determine whether a transplanted liver graft releases proinflammatory cytokines into the systemic circulation upon reperfusion and (2) to determine whether they contribute to any subsequent hemodynamic instability observed after graft reperfusion (if this release occurs). Blood samples from 17 consecutive patients undergoing liver transplantation were analyzed for cytokines, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), IL-2, IL-6, and IL-8. Blood samples were obtained from the radial artery, portal vein, and flush blood (a sample taken from a catheter placed above the infrahepatic inferior vena cava clamp). The amount of catecholamines necessary to maintain a mean arterial pressure between 65 and 75 mm Hg during graft reperfusion was compared with the level of cytokines. A statistical analysis was performed with the least squares method, Kendall's tau-b test, and regression analysis. We demonstrated that flush blood from the liver grafts contained a significant amount and variety of cytokines. Most of these were removed by graft irrigation. The concentration of TNF-α in samples obtained from flush blood at the end of liver irrigation was significantly higher than the concentration in samples obtained from the radial artery (P = 0.0067) or portal vein (P = 0.0003) before reperfusion. This correlated directly with the amount of catecholamines used to treat hemodynamic instability. Although there were increased levels of IL-1β, IL-2, and IL-8 in the flush blood, there was no statistically significant correlation between the levels of these cytokines and the amount of catecholamines used.


The Stapled Peptide PM2 Stabilizes p53 Levels and Radiosensitizes Wild-Type p53 Cancer Cells.
The tumor suppressor p53 is a key mediator of cellular stress and DNA damage response cascades and is activated after exposure to ionizing radiation. Amplifying wild-type p53 expression by targeting negative regulators such as MDM2 in combination with external beam radiotherapy (EBRT) may result in increased therapeutic effects. The novel stapled peptide PM2 prevents MDM2 from suppressing wild-type p53, and is thus a promising agent for therapeutic combination with EBRT. Effects of PM2 and potential PM2-induced radiosensitivity were assessed in a panel of cancer cell lines using 2D cell viability assays. Western Blot and flow cytometric analyses were used to investigate the mechanisms behind the observed effects in samples treated with PM2 and EBRT. Finally, PM2-treatment combined with EBRT was evaluated in an in vitro 3D spheroid model. PM2-therapy decreased cell viability in wild-type p53, HPV-negative cell lines. Western Blotting and flow cytometry confirmed upregulation of p53, as well as initiation of p53-mediated apoptosis measured by increased cleaved caspase-3 and Noxa activity. Furthermore, 3D in vitro tumor spheroid experiments confirmed the superior effects of the combination, as the only treatment regime resulting in growth inhibition and complete spheroid disintegration. We conclude that PM2 induces antitumorigenic effects in wt p53 HPV-negative cancer cells and potentiates the effects of EBRT, ultimately resulting in tumor eradication in a 3D spheroid model. This strategy shows great potential as a new wt p53 specific tumor-targeting compound, and the combination of PM2 and EBRT could be a promising strategy to increase therapeutic effects and decrease adverse effects from radiotherapy.


Nonenzymatic RNA replication in a mixture of 'spent' nucleotides.
Nonenzymatic template-directed replication would have been affected by co-solutes in a heterogeneous prebiotic soup due to lack of enzymatic machinery. Unlike in contemporary biology, these reactions use chemically activated nucleotides, which undergo rapid hydrolysis forming nucleoside monophosphates ('spent' monomers). These co-solutes cannot extend the primer but continue to base pair with the template, thereby interfering with replication. We, therefore, aimed to understand how a mixture of 'spent' ribonucleotides would affect nonenzymatic replication. We observed the inhibition of replication in the mixture, wherein the predominant contribution came from the cognate Watson-Crick monomer, showing potential sequence dependence. Our study highlights how nonenzymatic RNA replication would have been directly affected by co-solutes, with ramifications for the emergence of functional polymers in an RNA World.


Haemodynamic and anatomic progression of aortic stenosis.
Aortic valve stenosis (AS) is a progressive disease, but the impact of baseline AS haemodynamic or anatomic severity on AS progression remains unclear. In 149 patients (104 mild AS, 36 moderate AS and 9 severe AS) enrolled in 2 ongoing prospective cohorts (COFRASA/GENERAC), we evaluated AS haemodynamic severity at baseline and yearly, thereafter, using echocardiography (mean pressure gradient (MPG)) and AS anatomic severity using CT (degree of aortic valve calcification (AVC)). After a mean follow-up of 2.9±1.0 years, mean MGP increased from 22±11 to 30±16 mm Hg (+3±3 mm Hg/year), and mean AVC from 1108±891 to 1640±1251 AU (arbitrary units) (+188±176 AU/year). Progression of AS was strongly related to baseline haemodynamic severity (+2±3 mm Hg/year in mild AS, +4±3 mm Hg/year in moderate AS and +5±5 mm Hg/year in severe AS (p=0.01)), and baseline haemodynamic severity was an independent predictor of haemodynamic progression (p=0.0003). Annualised haemodynamic and anatomic progression rates were significantly correlated (r=0.55, p<0.0001), but AVC progression rate was also significantly associated with baseline haemodynamic severity (+141±133 AU/year in mild AS, +279±189 AU/year in moderate AS and +361±293 AU/year in severe AS, p<0.0001), and both baseline MPG and baseline AVC were independent determinants of AVC progression (p<0.0001). AS progressed faster with increasing haemodynamic or anatomic severity. Our results suggest that a medical strategy aimed at preventing AVC progression may be useful in all subsets of patients with AS including those with severe AS and support the recommended closer follow-up of patients with AS as AS severity increases. COFRASA (clinicalTrial.gov number NCT 00338676) and GENERAC (clinicalTrial.gov number NCT00647088).


Overview of research progress on the association of dietary potassium intake with serum potassium and survival in hemodialysis patients, does dietary potassium restriction really benefit hemodialysis patients?
For the general population, increasing potassium intake can reduce the incidence of cardiovascular and cerebrovascular diseases. However, since hyperkalemia is a common and life-threatening complication in maintenance hemodialysis patients, which can increase the risk of malignant arrhythmia and sudden death, the current mainstream of management for hemodialysis patients is dietary potassium restriction in order to prevent hyperkalemia. Hemodialysis patients are usually advised to reduce dietary potassium intake and limit potassium-rich fruits and vegetables, but there is limited evidence to support this approach can reduce mortality and improve quality of life. There is still no consistent conclusion on the association between dietary potassium intake and serum potassium and survival in hemodialysis patients. According to the current small observational studies, there was little or even no association between dietary potassium intake and serum potassium in hemodialysis patients when assurance of adequate dialysis and specific dietary patterns (such as the plant-based diet mentioned in the article) are being followed, and excessive dietary potassium restriction may not benefit the survival of hemodialysis patients. Additionally, when assessing the effect of diet on serum potassium, researchers should not only focus on the potassium content of foods, but also consider the type of food and the content of other nutrients. However, more large-scale, multi-center clinical trials are required to provide high-quality evidence support. Besides, further research is also needed to determine the optimal daily potassium intake and beneficial dietary patterns for hemodialysis patients.


Challenges in communication, prognostication and dialysis decision-making in the COVID-19 pandemic: implications for interdisciplinary care during crisis settings.
Using case vignettes, we highlight challenges in communication, prognostication, and medical decision-making that have been exacerbated by the coronavirus disease-19 (COVID-19) pandemic for patients with kidney disease. We include best practice recommendations to mitigate these issues and conclude with implications for interdisciplinary models of care in crisis settings. Certain biomarkers, demographics, and medical comorbidities predict an increased risk for mortality among patients with COVID-19 and kidney disease, but concerns related to physical exposure and conservation of personal protective equipment have exacerbated existing barriers to empathic communication and value clarification for these patients. Variability in patient characteristics and outcomes has made prognostication nuanced and challenging. The pandemic has also highlighted the complexities of dialysis decision-making for older adults at risk for poor outcomes related to COVID-19. The COVID-19 pandemic underscores the need for nephrologists to be competent in serious illness communication skills that include virtual and remote modalities, to be aware of prognostic tools, and to be willing to engage with interdisciplinary teams of palliative care subspecialists, intensivists, and ethicists to facilitate goal-concordant care during crisis settings.


Reduced dependence of Crested Ibis on winter-flooded rice fields: implications for their conservation.
The Crested Ibis Nipponia nippon was once thought to be extinct in the wild until seven birds were discovered in a remote mountain village in China in 1981. Studies suggested that winter-flooded rice fields play an essential role in nest site selection by the Crested Ibis and hence in their survival. Considerable efforts were therefore made to conserve the winter-flooded rice fields, but these have caused conflicts between the agricultural and conservation communities. The population and geographical range of the wild Crested Ibis has expanded greatly since 1981, but there is no spatial information on the winter-flooded rice fields, nor on the current association of nest sites and winter-flooded rice fields. We mapped winter-flooded rice fields across the entire current range of Crested Ibis using innovative remote sensing and geographical information systems (GIS) techniques. The spatial relationships between the nest site clusters and winter-flooded rice fields were quantified using Ward's hierarchical clustering method and Ripley's K-function. We show that both have significantly clumped distribution patterns and that they are positively associated. However, the dependence of Crested Ibis on the winter-flooded rice fields varied significantly among the nest site clusters and has decreased over the years, indicating the absence of winter-flooded rice fields is not constraining their recovery and population expansion. We therefore recommend that efforts should be made to protect the existing winter-flooded rice fields and to restore the functionality of natural and semi-natural wetlands, to encourage both in-situ conservation and the re-introduction of the Crested Ibis. In addition, we recommend that caution should be exercised when interpreting the habitat requirements of species with a narrow distribution, particularly when that interpretation is based only on their current habitat.


Conotruncal Heart Defect Repair in Sub-Saharan Africa: Remarkable Outcomes Despite Poor Access to Treatment.
The outcome of children born with conotruncal heart defects may serve as an indication of the status of pediatric cardiac care in sub-Saharan Africa (SSA). This study was undertaken to determine the outcome of children born with conotruncal anomalies in SSA, regarding access to treatment and outcomes of surgical intervention. From our institution in Ghana, we retrospectively analyzed the outcomes of surgery, in the two-year period from June 2013 to May 2015. The birth prevalence of congenital heart defects (CHDs) in SSA countries was derived by extrapolation using an incidence of 8 per 1,000 live births for CHDs. The birth prevalence of CHDs for the 48 countries in SSA using 2013 country data was 258,875; 10% of these are presumed to be conotruncal anomalies. Six countries (Nigeria, Democratic Republic of the Congo, Ethiopia, Tanzania, Uganda, and Kenya) accounted for 53.5% of the birth prevalence. In Ghana, 20 patients (tetralogy of Fallot [TOF], 17; pulmonary atresia, 3) underwent palliation and 50 (TOF, 36; double-outlet right ventricle, 14) underwent repair. Hospital mortality was 0% for palliation and 4% for repair. Only 6 (0.5%) of the expected 1,234 cases of conotruncal defects underwent palliation or repair within two years of birth. Six countries in SSA account for more than 50% of the CHD burden. Access to treatment within two years of birth is probably <1%. The experience from Ghana demonstrates that remarkable surgical outcomes are achievable in low- to middle-income countries of SSA.


Hospitalizations Are Increasing in Distal Upper Extremity Fractures.
Introduction Distal upper extremity (DUE) fractures are common and include bony fractures of the wrist, hand, and finger. DUE fractures can require hospital admission for clinical observation or surgical fixation. The trend of hospitalization rate for these injuries may more accurately predict future staffing needs, required resources, and expected revenue for orthopedic surgery hand services. The purpose of this study is to determine the trend of hospitalization percentage from 2009 to 2018 for patients presenting to the United States (US) emergency departments (EDs) with DUE fractures. Methods The National Electronic Injury Surveillance System (NEISS) was utilized to collect data from 138,700 patients with wrist, hand, or finger fractures presenting to the US EDs between 2009 and 2018. A total of 752 patients were excluded for ages less than two years old or no sex entry. The unadjusted and adjusted (age, sex, race, and fracture location) hospitalization rates across years were evaluated using binary logistic regression. Results From 2009 to 2018, 137,948 DUE fractures were reported, of which 4749 (3.4%) were hospitalized. Wrist fractures accounted for the highest amount (2953) and the highest proportion of hospitalized patients (62.2%). Higher hospitalization rates were seen among patients 40 years and older (p < 0.05). Together, the DUE fracture hospitalization rate increased significantly (p < 0.05) in 2016 (OR = 1.215, 95% CI = 1.070-1.380), 2017 (OR = 1.154, 95% CI = 1.016-1.311), and 2018 (OR = 1.154, 95% CI = 1.279-1.638) from 2009. The adjusted results showed hospitalization rate statistically increased (p < 0.05) in 2016 (OR = 1.184, 95% CI = 1.040-1.346) and 2018 (OR = 1.389, 95% CI = 1.225-1.575) compared to 2009. An inconsistent increase in hospitalization rate was seen across locations of fracture: wrist (2012, 2013, 2018), hand (2018), and finger (2016, 2018). Conclusions The hospitalization rate of patients with DUE fractures increased in 2016 and 2018 from 2009. These data may predict a need to increase future staffing and resources for orthopedic surgery hand services as hospitals resume pre-pandemic practices.


Performance of referral strategies for spondyloarthritis: a population-based nationwide study.
To evaluate the performance of the referral strategy (RS) for SpA of a nationwide epidemiological study (EpiReumaPt), as compared with previously proposed RSs. EpiReumaPt was a three-stage national epidemiologic study. In phase one, 10 661 adult participants were randomly selected and screened for rheumatic and musculoskeletal diseases. In the second phase, positive screenings for ⩾1 rheumatic and musculoskeletal disease plus 20% negative screenings were assessed by a rheumatologist. Finally, three rheumatologists revised all the information and defined the final diagnosis. All participants from phase two were included. Thirteen RS were tested against the SpA diagnosis using several metrics, including sensitivity, specificity, the post-test probability of SpA given a positive RS (positive predictive value) and given a negative RS (1 - negative predictive value). From the total 3877 participants, 92 received a SpA diagnosis [weighted national prevalence: 1.6% (95% confidence interval: 1.2, 2.1)]. Modified versions of the Assessment of SpondyloArthritis international Society-RS and EpiReumaPt-RS were the most sensitive (85% and 72%, respectively) and yielded the lowest post-test probabilities of SpA if negative (0.6% and 0.7%, respectively). Considering the national prevalence (pre-test probability) of SpA (1.6%), a negative screening by these two RSs decreased the probability of SpA substantially (Assessment of SpondyloArthritis international Society: -63%; EpiReumaPt: -56%). Other RSs performed less well in reducing disease probability (range: -6.3%; -37.5%). Overall, the probability of SpA given a positive RS was small (positive predictive value range: 2.2%; 7.6%) and the EpiReumaPt RS yielded the best balance between sensitivity and positive predictive value. The proposed EpiReumaPt RS performed the best as a screening tool for SpA in patients from the general population when laboratory and imaging data were not available.


Feasibility and Complications of Spinal Anaesthesia in Percutaneous Nephrolithotomy: Our Experience.
Percutaneous Nephrolithotomy (PCNL) is the treatment modality used for the extraction of large renal stones, or multiple calculi or stones resistant to shock wave lithotripsy. The General Anaesthesia (GA) is the standard modality for PCNL. However, few studies conclude that Spinal Anaesthesia (SA) can be an alternative method of anaesthesia with similar incidence of complications. In our study we evaluated the feasibility of spinal anaesthesia in terms of intraoperative and postoperative results in patients undergoing PCNL. The total 1298 PCNL operations were done for kidney stone from January 2013 to December 2016, out of which 1160 patients underwent PCNL under SA while remaining 138 operations were carried out under GA in the prone position. We retrospectively collected data from the patient's documents. The intraoperative haemodynamic stability was primary objective, and average fall of haemoglobin, postoperative anaesthetic outcome like total tramadol used in first 24 hours, surgical outcome like total clearance of stone burden, patient satisfaction, surgeon satisfaction, need of blood transfusion, conversion to general anaesthesia and pleural puncture were the secondary objectives. The mean age of the patients was 38.0±17.1 years, and the mean operative time was 80.0±25.9 minutes. The mean calculus size was 30.2±11.8 mm. Return of sensory and motor activity in our study was 150.0±29.2 minutes and 111.0±18.8 minutes, respectively. In first 10 minutes of anaesthesia, 148 (12.75%) patients developed hypotension, which was managed by ephedrine 6 mg intravenously (IV). Total seventy two patients (6.2%) needed blood transfusion and 32 (2.75%) complained of headache, dizziness and low back pain for two to four days after the operation, which improved with analgesics and bed rest. Ninety percent of the patients had complete clearance of calculus or there were no significant residual calculi larger than 5 mm on follow up ultrasonography. It can be concluded from our study that spinal anaesthesia is the safe and effective method of anaesthesia for PCNL in adult patients.


Nanocurcumin Reduces High Glucose and Particulate Matter-Induced Endothelial Inflammation: Mitochondrial Function and Involvement of miR-221/222.
Particulate matter (PM) 2.5, harmful air pollutants, and diabetes are associated with high morbidity and mortality from cardiovascular disease (CVD). However, the molecular mechanisms underlying the combined effects of PM and diabetes on CVD remain unclear. Endothelial cells (ECs) treated with high glucose (HG) and PM mimic hyperglycemia and air pollutant exposure in CVD. Endothelial inflammation was evaluated by Western blot and immunofluorescence of ICAM-1 expression and monocyte adhesion. The mechanisms underlying endothelial inflammation were elucidated through MitoSOX Red analysis, JC-1 staining, MitoTracker analysis, and Western blot analysis of mitochondrial fission-related, autophagy-related, and mitophagy-related proteins. Furthermore. nanocurcumin (NCur) pretreatment was used to test if it has a protective effect. ECs under co-exposure to HG and PM increased ICAM-1 expression and monocyte adhesion, whereas NCur pretreatment attenuated these changes and improved endothelial inflammation. PM exposure increased mitochondrial ROS levels, worsened mitochondrial membrane potential, promoted mitochondrial fission, induced mitophagy, and aggravated inflammation in HG-treated ECs, while NCur reversed these changes. Also, HG and PM-induced endothelial inflammation is through the JNK signaling pathway and miR-221/222 specifically targeting ICAM-1 and BNIP3. PM exposure also aggravated mitochondrial ROS levels, mitochondrial fission, mitophagy, and endothelial inflammation in STZ-induced hyperglycemic mice, whereas NCur attenuated these changes. This study elucidated the mechanisms underlying HG and PM-induced endothelial inflammation in vitro and in vivo. HG and PM treatment increased mitochondrial ROS, mitochondrial fission, and mitophagy in ECs, whereas NCur reversed these conditions. In addition, miR-221/222 plays a role in the amelioration of endothelial inflammation through targeting Bnip3 and ICAM-1, and NCur pretreatment can modulate miR-221/222 levels. Therefore, NCur may be a promising approach to intervene in diabetes and air pollution-induced CVD.


Past Year Quit Attempts and Use of Cessation Resources Among Cigarette-Only Smokers and Cigarette Smokers Who Use Other Tobacco Products.
It is unclear how use of other tobacco products impacts cigarette-smoking cessation. We assessed differences in past year cigarette smoking quit attempts and use of counseling and medication among current cigarette-only users, cigarette and cigar users, and cigarette and smokeless tobacco (SLT) users. Data came from 24 448 current cigarette-only, 1064 cigarette and cigar only, and 508 cigarette and SLT only users who responded to the 2010-2011 Tobacco Use Supplement to the Current Population Survey. Demographic, smoking, and cessation characteristics were computed by group. Bivariate and multivariable logistic regression models assessed the relationship of tobacco use group to making a past year quit attempt, and use of counseling or medication during the last quit attempt. Dual users of cigarettes and cigars or SLT had similar interest in quitting and prevalence of reported past year quit attempts compared to cigarette-only users. In unadjusted analyses, cigarette and SLT users had higher odds of trying to quit in the past year compared to cigarette-only users (odds ratio [OR] = 1.31, 95% confidence interval [CI] = 1.05, 1.64); no differences were found for cigarette and cigar users. However, adjusting for demographic and cigarette smoking variables, both groups of dual users had similar odds as cigarette-only users for having made a past year cigarette smoking quit attempt, and to have used counseling or medication during the last quit attempt. Dual tobacco use was not associated with decreased attempts to quit smoking cigarettes; however, use of evidence-based treatment was sub-optimal among cigarette-only and dual users, and should be increased.


Multidisciplinary Cancer Care Model: A Positive Association Between Oncology Nurse Navigation and Improved Outcomes for Patients With Cancer.
Patients with cancer often experience prominent deficiencies in cancer care in the immediate period following initial cancer diagnosis. This article aims to determine whether the inclusion of a gastrointestinal (GI) oncology nurse navigator (ONN) on the multidisciplinary cancer care team is associated with improved quality of care for patients. This retrospective study compared randomly selected patients with GI cancer with and without an ONN. Two endpoints, the time from diagnosis to treatment and the average number of missed appointments, were evaluated through a review of healthcare records using the Epic electronic health records system. Patients with an ONN had a shorter time lapse between diagnosis and treatment commencement (p < 0.001). In this group, the average time spent between initial diagnosis and the start of treatment was 15.15 days, compared to 42.93 days for patients who were not part of the multidisciplinary cancer care model.


Pediatric Crohn's disease from onset to adulthood: granulomas are associated with an early need for immunomodulation.
Childhood onset Crohn's disease (CD) is considered more aggressive than adult onset disease. Epithelioid cell granulomas in intestinal biopsies are one, non-obligate, criterion of CD. We investigated granulomas as markers of CD severity in children followed to adulthood. Forty-five individuals with childhood onset CD were studied from diagnosis until attainment of final height, with data on disease location, medical and surgical management and with detailed growth data analyses. A blinded review of diagnostic biopsies was also performed. We found granulomas in 22/45 (49%) children at diagnosis, altogether in 28/45 (62%) patients during the disease course (median overall follow-up - 12.3 years, range 9.3-18). Granulomas were found in 9/11 (82%) with upper gastrointestinal involvement (cumulatively 17/20, 85%) (p = 0.017 and p = 0.006, respectively). The time from diagnosis to initiating immune modulating treatment (median 4.5 months, range 0-75) was shorter in the granuloma-positive group (16/22) compared to the granuloma-negative group (18/23) (median 33 months, range 2-105; p = 0.01). The median standard deviation score height at diagnosis and final adult height (both adjusted for target height) did not correlate to findings of granulomas. Epithelioid cell granulomas were associated with a shorter time to initiating immune modulating drugs, as a possible sign of more severe disease, but growth was not affected.


Survey of canine babesiosis in South Africa.
A questionnaire, designed to obtain qualitative information on a number of variables concerning canine babesiosis (biliary fever) in South Africa, was sent to 510 veterinary practices in late 1993. Of the 157 practices that responded, all were presented with cases of babesiosis and most were situated in Gauteng, the Western Cape and KwaZulu-Natal. Apart from the Western Cape, a winter-rainfall region, the prevalence of babesiosis cases in dogs was highest in summer. Most of the respondent practices treated between 1,000 and 5,000 sick dogs that included 100 to 500 babesiosis cases each year. Respondents identified cerebral babesiosis, enterorrhagia, 'red' or haemoconcentrated babesiosis, acute renal failure and pulmonary babesiosis or 'shock lung', amongst others, as the most prevalent forms of complicated ('atypical') babesiosis. Diminazene, imidocarb and trypan blue were the most popular antibabesials. Trypan blue was most often used in shocked patients, whereas diminazene and imidocarb were preferred when there was a high parasitaemia in the absence of shock. At least 19 antibabesial treatment regimens were used in practices. These comprised the use of single doses of antibabesial drugs; split doses with repeat injections, and combined drug variations, some of which are undesirable due to possible sterilisation of Babesia infection or potential toxicity. Side-effects were most commonly associated with imidocarb use. Ninety-six percent of respondents used supportive treatment (e.g. corticosteroids, vitamins and 'liver support') in all cases of babesiosis. The use of blood transfusion as supportive treatment varied according to practice and severity of the case. Most practices never cross-matched blood to be transfused, and transfusion reactions were rare. Diminazene was most frequently incriminated in cases where drug 'resistance' or relapses occurred. Cerebral and 'red' cases resulted in high mortality. Treatment of babesiosis costs the dog-owning public in South Africa more than R20 million each year. Information on the distribution and possible complicating role of Ehrlichia canis was obtained. Development of a vaccine was the first research priority identified.


[Isolated bacteria from nasal cultures. Are they important in patients with acute leukemia?].
The nasal colonization by Staphylococcal (epidermidis or aureus) is frequent and it has importance when it is associated to bacteremia in immunocompromised patients. The objective was to determine the frequency of strains that colonize the nasal mucosa in patients with leukemia and its relationship with peripheral blood cultures. A retrospective, observational, transversal, retrolective study was done. We analyzed the weekly results of nasal cultures and peripheral blood cultures in patients with leukemia undergoing chemotherapy. The chi-squared test and odds ratio value were estimated in the statistical analysis. We included 67 patients, 55 of them with acute lymphocytic leukemia (ALL); 28.5 % of the cultures (n = 47) corresponded to a positive nasal culture. Staphylococcus epidermidis and Staphylococcus aureus were the most isolated bacteria. During the first week of treatment, the positive cultures were the most frequently. All the samples isolated were sensitive to vancomycin or linezolid. It was established only the association between negative nasal cultures and negative peripheral blood cultures (p = 0.0005). Odds ratio for positive nasal cultures and the risk of bacteremia was 0.0269. The frequency of the positive bacteria culture was low, with an adequate sensitivity measure. The presence of bacteria in nasal culture was not identified as a risk factor for the occurrence of bacteremia.


Enhancement of homomeric glycine receptor function by long-chain alcohols and anaesthetics.
1. The effects of n-alcohols (ethanol to dodecanol) and anaesthetics on strychnine-sensitive glycine receptors were studied in Xenopus oocytes expressing homomeric alpha 1 or alpha 2 glycine receptor subunits, with the two electrode voltage-clamp recording technique. 2. The glycine-induced chloride conductance of homomeric alpha glycine receptors was potentiated by all the alcohols tested when an EC2 concentration of glycine was used. Homomeric alpha 1 and alpha 2 receptors were potentiated similarly by the n-alcohols, except that low concentrations of ethanol produced greater potentiation with alpha 1, as previously reported. 3. Increasing the n-alcohol carbon number has been shown to increase the potency of the alcohols up to decanol at concentrations corresponding to EC50s for producing loss of righting reflex in tadpoles. However, dodecanol was no more potent than decanol, and only modest potentiation (30-60%) was obtained with dodecanol, in contrast to marked (150-200%) potentiation with the other alcohols. Thus, a "cut-off' occurred at about dodecanol. 4. Propofol, alphaxalone, pentobarbitone, halothane and enflurane, reversibly potentiated the function of homomeric alpha 1 glycine receptors at concentrations which represent approximately twice the EC50 for production of anaesthesia in mammals, but ketamine and etomidate were ineffective. 5. Two novel cyclobutane compounds were tested; the anaesthetic compound (1-chloro-1,2,2-trifluorocyclobutane) from 0.5 to 5 mM potentiated the action of glycine in a concentration-dependent manner; however, the non-anaesthetic analogue (1,2-dichloro-hexfluorocyclobutane) had no effect on glycine receptor function at concentrations (25 to 80 microM) predicted to be anaesthetic, based on the lipid solubility of this compound. 6. These results suggest that the alpha subunits of strychnine-sensitive glycine receptors contain sites of action for n-alcohols, propofol, alphaxalone, pentobarbitone and volatile anaesthetics, but not for ketamine and etomidate. Potentiation of glycine receptor function may contribute to the anaesthetic action of n-alcohols and volatile agents.


[Fetal and neonatal outcome prolonged ruptured membranes in a gestational age of less than 24 weeks].
The view appears to be generally held that the survival chances of fetuses in cases of very early rupture of the membranes are low. We report a retrospective study of 12 pregnancies with prolonged rupture of the membranes less than or equal to 24 weeks menstrual age. There was no significant maternal morbidity. After birth special attention was given to respiratory problems, deformities and infections. Four children were born at menstrual age less than 26 weeks. In all cases an intrauterine infection was found (chorioamnionitis). The eight children born greater than or equal to 26 weeks had good chances of survival despite oligohydramnios (all) and deformities (four). Severe intrauterine infections were not present in this group. An expectant obstetric management in cases of very early prolonged rupture of the membranes seems justified.


Regulatory mechanism of macrophage polarization based on Hippo pathway.
Macrophages are found to infiltrate and migrate in a large number of Tumor-associated macrophages (TMEs) and other macrophages in the microenvironment of tumors and related diseases, and undergo phenotypic changes in response to a variety of cytokines, mainly including the primary phenotype M2 and the anti-tumor phenotype M1. The Hippo signaling pathway affects the development of cancer and other diseases through various biological processes, such as inhibition of cell growth. In this review, we focus on immune cells within the microenvironment of tumors and other diseases, and the role of the Hippo pathway in tumors on macrophage polarization in the tumor microenvironment (TME) and other diseases.


In vitro ligation of oligodeoxynucleotides containing C8-oxidized purine lesions using bacteriophage T4 DNA ligase.
Ligases conduct the final stage of repair of DNA damage by sealing a single-stranded nick after excision of damaged nucleotides and reinsertion of correct nucleotides. Depending upon the circumstances and the success of the repair process, lesions may remain at the ligation site, either in the template or at the oligomer termini to be joined. Ligation experiments using bacteriophage T4 DNA ligase were carried out with purine lesions in four positions surrounding the nick site in a total of 96 different duplexes. The oxidized lesion 8-oxo-7,8-dihydroguanosine (OG) showed, as expected, that the enzyme is most sensitive to lesions on the 3' end of the nick compared to the 5' end and to lesions located in the intact template strand. In general, substrates containing the OG.A mismatch were more readily ligated than those with the OG.C mismatch. Ligations of duplexes containing the OA.T base pair (OA = 8-oxo-7,8-dihydroadenosine) that could adopt an anti-anti conformation proceeded with high efficiencies. An OI.A mismatch-containing duplex (OI = 8-oxo-7,8-dihydroinosine) behaved like OG.A. Due to its low reduction potential, OG is readily oxidized to secondary oxidation products, such as the guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp) nucleosides; these lesions also contain an oxo group at the original C8 position of the purine. Ligation of oligomers containing Gh and Sp occurred when opposite A and G, although the overall ligation efficiencies were much lower than those of most OG base pairs. Steady-state kinetic studies were carried out for representative examples of lesions in the template. Km increased by 90-100-fold for OG.C-, OI.C-, OI.A-, and OA.T-containing duplexes compared to that of a G.C-containing duplex. Substrates containing Gh.A, Gh.G, Sp.A, and Sp.G base pairs exhibited Km values 20-70-fold higher than that of the substrate containing a G.C base pair, while the Km value for OG.A was 5 times lower than that for G.C.


Human RPA activates BLM's bidirectional DNA unwinding from a nick.
BLM is a multifunctional helicase that plays critical roles in maintaining genome stability. It processes distinct DNA substrates, but not nicked DNA, during many steps in DNA replication and repair. However, how BLM prepares itself for diverse functions remains elusive. Here, using a combined single-molecule approach, we find that a high abundance of BLMs can indeed unidirectionally unwind dsDNA from a nick when an external destabilizing force is applied. Strikingly, human replication protein A (hRPA) not only ensures that limited quantities of BLMs processively unwind nicked dsDNA under a reduced force but also permits the translocation of BLMs on both intact and nicked ssDNAs, resulting in a bidirectional unwinding mode. This activation necessitates BLM targeting on the nick and the presence of free hRPAs in solution whereas direct interactions between them are dispensable. Our findings present novel DNA unwinding activities of BLM that potentially facilitate its function switching in DNA repair.


Pro: cardiovascular calcifications are clinically relevant.
It is increasingly acknowledged that mineral and bone disorders (MBDs) contribute to the excessively high cardiovascular (CV) disease morbidity and mortality observed in patients with chronic kidney disease (CKD). There is ongoing debate as to whether screening for CV calcification, one of the hallmarks of CKD-MBD, should be implemented in clinical practice in patients with CKD. Issues to be considered in this controversy relate to prevalence, severity, relevance, and last but not least, modifiability and reversibility of vascular and valvular calcifications in the setting of CKD. The recent expansion of the armamentarium to treat CKD-MBD (calcium-free phosphate binders and calcimimetics) creates new opportunities. Mounting experimental and clinical evidence indicates that progression of CV calcification may indeed be attenuated. Whether this will translate into better outcomes remains to be proven. We acknowledge that hard outcome data so far are limited and, overall, yielded inconclusive results. Nevertheless, in an era in which personalized medicine has gained much popularity, we consider it reasonable, awaiting the results of additional studies, to screen for CV calcification in selected individuals. This policy may help to stratify CV risk and to guide therapy. We speculate that such an approach will ultimately improve outcomes and reduce health costs.


Disclosure of Personalized Rheumatoid Arthritis Risk Using Genetics, Biomarkers, and Lifestyle Factors to Motivate Health Behavior Improvements: A Randomized Controlled Trial.
To determine the effect of disclosure of rheumatoid arthritis (RA) risk personalized with genetics, biomarkers, and lifestyle factors on health behavior intentions. We performed a randomized controlled trial among first-degree relatives without RA. Subjects assigned to the Personalized Risk Estimator for Rheumatoid Arthritis (PRE-RA) group received the web-based PRE-RA tool for RA risk factor education and disclosure of personalized RA risk estimates, including genotype/autoantibody results and behaviors (n = 158). Subjects assigned to the comparison arm received standard RA education (n = 80). The primary outcome was readiness for change based on the trans-theoretical model, using validated contemplation ladder scales. Increased motivation to improve RA risk-related behaviors (smoking, diet, exercise, or dental hygiene) was defined as an increase in any ladder score compared to baseline, assessed immediately, 6 weeks, and 6 months post-intervention. Subjects reported behavior change at each visit. We performed intent-to-treat analyses using generalized estimating equations for the binary outcome. Subjects randomized to PRE-RA were more likely to increase ladder scores over post-intervention assessments (relative risk 1.23, 95% confidence interval [95% CI] 1.01, 1.51) than those randomized to nonpersonalized education. At 6 months, 63.9% of PRE-RA subjects and 50.0% of comparison subjects increased motivation to improve behaviors (age-adjusted difference 15.8%; 95% CI 2.8%, 28.8%). Compared to nonpersonalized education, more PRE-RA subjects increased fish intake (45.0% versus 22.1%; P = 0.005), brushed more frequently (40.7% versus 22.9%; P = 0.01), flossed more frequently (55.7% versus 34.8%; P = 0.004), and quit smoking (62.5% versus 0.0% among 11 smokers; P = 0.18). Disclosure of RA risk personalized with genotype/biomarker results and behaviors increased motivation to improve RA risk-related behaviors. Personalized medicine approaches may motivate health behavior improvements for those at risk for RA and provide rationale for larger studies evaluating effects of behavior changes on clinical outcomes, such as RA-related autoantibody production or RA development.


Occurrence and reduction of biogenic amines in traditional Asian fermented soybean foods: A review.
Biogenic amines are harmful substances generated during the fermentation process. Regulations on biogenic amine content in fermented foods are currently insufficient in comparison to the popularity of fermented food consumption in Asian countries. The current review evaluated the biogenic amine content of fermented soybean-based Asian foods to determine whether the food products are safe for consumption. Though the reported ranges of biogenic amine content in fermented soybean foods varied widely, most products contained biogenic amine concentrations at potentially hazardous levels. To ensure the safety of fermented soybean food products, further efforts are required in the improvement of the food manufacturing process, as well as the establishment of regulations on managing biogenic amine content.


The effects of circuit resistance training on plasma progranulin level, insulin resistance and body composition in obese men.
Background Progranulin (PGRN) is implicated in obesity and insulin resistance (IR). The aim of this study was to evaluate the effects of 8 weeks of circuit resistance training (CRT) on plasma PGRN, IR and body composition in obese men. Materials and methods Twenty-eight healthy obese men [age: 36 ± 7.7 years, body weight (BW): 96.4 ± 15.6 kg, body mass index (BMI): 32.4 ± 4.5 kg/m2] completed the study. Subjects were randomly assigned to two groups of control and training. Subjects in the training group underwent training for 8 weeks, 3 times a week. Blood samples and anthropometric characteristics were taken before the commencement of the exercise protocol and 72 h after the last training session. The homeostatic model assessment of insulin resistance (HOMA-IR) was used to measure IR. Results BW, BF%, BMI, waist-hip ratio (WHR), HOMA-IR and plasma PGRN levels except lean body mass (LBM) were significantly reduced in the training group (p < 0.05). Additionally, except for LBM, subjects in the training group had significantly decreased BW, BF%, BMI, WHR, HOMA-IR and plasma PGRN levels compared to changes in those in the control group (p < 0.05). Significant correlations were found between the changes in plasma PGRN and the changes in insulin, HOMA-IR and BMI (p < 0.05). Conclusions The findings showed that 8 weeks of CRT improved body composition and IR which were accompanied by reduced plasma PGRN levels. This study suggests that CRT has the potential for obese individuals to counteract obesity-associated health impairments.


Site-specific identification of SUMO-2 targets in cells reveals an inverted SUMOylation motif and a hydrophobic cluster SUMOylation motif.
Reversible protein modification by small ubiquitin-like modifiers (SUMOs) is critical for eukaryotic life. Mass spectrometry-based proteomics has proven effective at identifying hundreds of potential SUMO target proteins. However, direct identification of SUMO acceptor lysines in complex samples by mass spectrometry is still very challenging. We have developed a generic method for the identification of SUMO acceptor lysines in target proteins. We have identified 103 SUMO-2 acceptor lysines in endogenous target proteins. Of these acceptor lysines, 76 are situated in the SUMOylation consensus site [VILMFPC]KxE. Interestingly, eight sites fit the inverted SUMOylation consensus motif [ED]xK[VILFP]. In addition, we found direct mass spectrometric evidence for crosstalk between SUMOylation and phosphorylation with a preferred spacer between the SUMOylated lysine and the phosphorylated serine of four residues. In 16 proteins we identified a hydrophobic cluster SUMOylation motif (HCSM). SUMO conjugation of RanGAP1 and ZBTB1 via HCSMs is remarkably efficient.


Attenuation of gentamicin-induced nephrotoxicity in rats by fleroxacin.
The effect of fleroxacin on gentamicin-induced nephrotoxicity was evaluated with female Sprague-Dawley rats. Animals were injected during 4 or 10 days with saline (NaCl; 0.9%), gentamicin alone at doses of 10 and 40 mg/kg of body weight/12 h (subcutaneously), fleroxacin alone at a dose of 25 mg/kg/12 h (intraperitoneally), or the combination gentamicin-fleroxacin in the same regimen. Gentamicin induced a dose- and time-dependent renal toxicity as evaluated by gentamicin cortical levels, sphingomyelinase activity in the renal cortex, histopathologic and morphometric analysis, blood urea nitrogen and serum creatinine levels, and cellular regeneration ([3H]thymidine incorporation into DNA of cortical cells). The extent of these changes was significantly reduced when gentamicin was given in combination with fleroxacin. Although the mechanisms by which fleroxacin reduces the nephrotoxic potential of gentamicin are unknown, we propose that the fleroxacin-gentamicin combination enhances exocytosis activity in proximal tubular cells, as suggested by the higher excretion of urinary enzymes and lower cortical levels of gentamicin observed in animals treated with the combination fleroxacin-gentamicin compared with those treated with gentamicin alone. The protective effect of fleroxacin on gentamicin nephrotoxicity should be investigated further.


Balance and coordination training for patients with genetic degenerative ataxia: a systematic review.
The group of genetic degenerative ataxias shares the same feature of gradual deterioration in balance and coordination. However, no cure is yet available for this group of disorders, while rehabilitation remains a cornerstone in the current therapy. This review aims to present a summary of the current knowledge of balance and coordination training in patients with inherited degenerative ataxia and to discuss the training effectiveness accordingly. A comprehensive search was performed in 5 electronic databases (i.e., Cochrane Library, PEDro, EMbase, PubMed and MEDLINE) to identify the related publications from January, 1999 to January, 2020. Methodological quality was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) grading system and the PEDro scale. A total of 33 out of 515 studies met the eligibility criteria, and were categorized and discussed by their training methods including: (1) conventional physical/occupational therapy, (2) virtual reality/videogame-based training, and (3) adapted physical activity. Despite the substantial variation among included studies, most patients achieved significant improvement in the aspect of balance and coordination following individually-tailored rehabilitation programs. The effects of training showed a relative consistency regardless of the functional dependency level on admission. Balance and coordination training, especially the conventional physical/occupational therapy, is able to improve the balance and coordinative function of patients with genetic degenerative ataxia, but more high-quality studies are needed to formulate recommendations for clinical practice.


The crystal structure of the tryptophan synthase beta subunit from the hyperthermophile Pyrococcus furiosus. Investigation of stabilization factors.
The structure of the tryptophan synthase beta2 subunit (Pfbeta2) from the hyperthermophile, Pyrococcus furiosus, was determined by X-ray crystallographic analysis at 2.2 A resolution, and its stability was examined by DSC. This is the first report of the X-ray structure of the tryptophan synthase beta2 subunit alone, although the structure of the tryptophan synthase alpha2beta2 complex from Salmonella typhimurium has already been reported. The structure of Pfbeta2 was essentially similar to that of the beta2 subunit (Stbeta2) in the alpha2beta2 complex from S. typhimurium. The sequence alignment with secondary structures of Pfbeta and Stbeta in monomeric form showed that six residues in the N-terminal region and three residues in the C-terminal region were deleted in Pfbeta, and one residue at Pro366 of Stbeta and at Ile63 of Pfbeta was inserted. The denaturation temperature of Pfbeta2 was higher by 35 degrees C than the reported values from mesophiles at approximately pH 8. On the basis of structural information on both proteins, the analyses of the contributions of each stabilization factor indicate that: (a) the higher stability of Pfbeta2 is not caused by either a hydrophobic interaction or an increase in ion pairs; (b) the number of hydrogen bonds involved in the main chains of Pfbeta is greater by about 10% than that of Stbeta, indicating that the secondary structures of Pfbeta are more stabilized than those of Stbeta and (c) the sequence of Pfbeta seems to be better fitted to an ideally stable structure than that of Stbeta, as assessed from X-ray structure data.


[Influence of heavy water (D20) on the conformation and UV-sensitivity of proteins].
The heavy water (D2O) has been shown to induce the conformational transitions in trypsin, chymotrypsin and pepsin. The transfer of proteins from H2O into D2O results a change in their sensitivity to UV-light. An increase in sensitivity to the irradiation at 248 nm and a decrease in sensitivity to the irradiation at 280 nm were observed. The quantum yield of chromophore photolysis (for cystyne and tryptophan) is correspondingly changed. However, although the quantum yield of sensitized reduction of cystine by solvated electrons photochemically ejected from the aromatic acid residues during irradiation at 280 nm increases instead of a rise a drop in the quantum yield of protein inactivation is registered. The data obtained are discussed in terms of importance of solvated shell for conformational stability of proteins. The solvated electrons are suggested to be transfered mainly to nonessential disulfide bridges within trypsin molecule. Rupture of these bonds does not result in trypsin inactivation.


[Possible functional role of the DD-domain of RNA-dependent polymerases].
An attempt to study the functional role of one of the most conservative domains found in all RNA-dependent RNA and DNA polymerases of plant and animal viruses (the so called "DD-domain") was made. A structure similar to the "DD-domain" was found in a minor T7 phage tail protein--gpII. Antibodies against this phage protein have been raised and used to probe "DD-domain" in molecules of avian myeloblastose virus reverse transcriptase and E. coli RNA-dependent RNA polymerase. The antibodies are shown to inhibit the activity of these enzymes under certain conditions. At the same time inhibition of the reverse transcriptase reaction causes the decrease in length of the most high molecular cDNA-products as well. The experimental data obtained are discussed in view of the suggested hypothesis on the probable functional role of the "DD-domain" of RNA-dependent polymerases.


Pup contact induces the expression of long form prolactin receptor mRNA in the brain of female rats: effects of ovariectomy and hypophysectomy on receptor gene expression.
Prolactin receptor (PRL-R) mRNA expression levels in the female rat brain (cerebrum) during pup contact stimulation were determined by the reverse transcription-PCR method. The high expression levels of long form PRL-R mRNA found in the brain of lactating rats were markedly reduced by removal of pups, and long form PRL-R mRNA levels were recovered by resumption of pup contact. Interestingly, pup contact stimuli of nulliparous virgin rats also markedly induced long form but not short form PRL-R mRNA expression in the brain in 1.3 days, together with the expression of maternal behaviour. In ovariectomized (OVX) or hypophysectomized (HYPOX) virgin rats, or in OVX plus HYPOX virgin rats, however, brain long form PRL-R mRNA was not significantly induced by pup contact stimuli for as long as 7 days, while maternal behaviour was fully expressed in these rats after 7 days of pup contact. The in situ hybridization experiments revealed that the long form PRL-R mRNA induced in virgin rats in contact with pups or in lactating rats was localized in the epithelial cells of the choroid plexus. No significant increase in mRNA was detected in other regions of the brain, such as the hypothalamus or cortex, in these maternal female rats. These results suggest that pup contact induces the expression of long form PRL-R mRNA in the choroid plexus of the brain in the presence of female sex steroid and pituitary hormones for the rapid expression of maternal behaviour. Our studies also suggested that maternal behaviour can be expressed in OVX or HYPOX rats after exposure to pups for 7 days without any significant increase in brain PRL-R mRNA expression.


Exploring RAD18-dependent replication of damaged DNA and discontinuities: a collection of advanced tools.
DNA damage tolerance (DDT) pathways mitigate the effects of DNA damage during replication by rescuing the replication fork stalled at a DNA lesion or other barriers and also repair discontinuities left in the newly replicated DNA. From yeast to mammalian cells, RAD18-regulated translesion synthesis (TLS) and template switching (TS) represent the dominant pathways of DDT. Monoubiquitylation of the polymerase sliding clamp PCNA by HRAD6A-B/RAD18, an E2/E3 protein pair, enables the recruitment of specialized TLS polymerases that can insert nucleotides opposite damaged template bases. Alternatively, the subsequent polyubiquitylation of monoubiquitin-PCNA by Ubc13-Mms2 (E2) and HLTF or SHPRH (E3) can lead to the switching of the synthesis from the damaged template to the undamaged newly synthesized sister strand to facilitate synthesis past the lesion. When immediate TLS or TS cannot occur, gaps may remain in the newly synthesized strand, partly due to the repriming activity of the PRIMPOL primase, which can be filled during the later phases of the cell cycle. The first part of this review will summarize the current knowledge about RAD18-dependent DDT pathways, while the second part will offer a molecular toolkit for the identification and characterization of the cellular functions of a DDT protein. In particular, we will focus on advanced techniques that can reveal single-stranded and double-stranded DNA gaps and their repair at the single-cell level as well as monitor the progression of single replication forks, such as the specific versions of the DNA fiber and comet assays. This collection of methods may serve as a powerful molecular toolkit to monitor the metabolism of gaps, detect the contribution of relevant pathways and molecular players, as well as characterize the effectiveness of potential inhibitors.


Adherence to screening and management guidelines of maternal Group B Streptococcus colonization in pregnancy.
To investigate Group B Streptococcus (GBS) colonization in pregnancy; adherence to antenatal GBS screening and adherence to the intrapartum antibiotics protocol within two models of care (midwifery and non-midwifery led). This retrospective quantitative study has employed a descriptive design using administrative health data. Data from five maternity hospitals in metropolitan and regional Western Australia that included 22,417 pregnant women who gave birth between 2015 and 2019 were examined, applying descriptive statistics using secondary data analysis. The study revealed an overall GBS colonization rate of 21.7% with similar rates in the different cohorts. A lower adherence to screening was found in the midwifery led model of care (MMC, 68.76%, n = 7232) when compared with the non-midwifery led model of care (NMMC, 90.49%, n = 10,767). Over the 5 years, screening rates trended down in the MMC with stable numbers in the counterpart. Adherence in relation to intrapartum antibiotic prophylaxis revealed discrepant findings between the study groups. Adherence to screening and management guidelines of maternal GBS colonization in pregnancy is lower within the MMC when compared with the NMMC. This is the first cohort study to describe the adherence to the recommended Western Australian GBS screening guidelines in the two different models of care. Findings may assist in the guidance and improvement of clinical protocols as well as the planning of clinical care in relation to GBS screening to reduce the risk of neonatal GBS infection.


Detecting Specular Reflections and Cast Shadows to Estimate Reflectance and Illumination of Dynamic Indoor Scenes.
The goal of Mixed Reality (MR) is to achieve a seamless and realistic blending between real and virtual worlds. This requires the estimation of reflectance properties and lighting characteristics of the real scene. One of the main challenges within this task consists in recovering such properties using a single RGB-D camera. In this article, we introduce a novel framework to recover both the position and color of multiple light sources as well as the specular reflectance of real scene surfaces. This is achieved by detecting and incorporating information from both specular reflections and cast shadows. Our approach is capable of handling any textured surface and considers both static and dynamic light sources. Its effectiveness is demonstrated through a range of applications including visually-consistent mixed reality scenarios (e.g., correct real specularity removal, coherent shadows in terms of shape and intensity) and retexturing where the texture of the scene is altered whereas the incident lighting is preserved.


The utility of the monocular trial: data from the ocular hypertension treatment study.
To determine whether adjusting the intraocular pressure (IOP) change of the trial eye for the IOP change of the fellow eye (i.e., monocular trial) is a better assessment of medication response than testing each eye independently. Analysis of data from a prospective, randomized, clinical trial. Two hundred six participants with ocular hypertension randomized to the observation group and later started on a topical prostaglandin analog (PGA). Participants were started on a topical PGA in 1 eye and returned in approximately 1 month to determine medication response. The IOP response of the trial eye was determined by the IOP change between baseline and 1 month in the trial eye alone (unadjusted method) and by adjusting for the IOP change in the fellow eye between the same visits (adjusted method). Our "gold standard" for medication response was the IOP change in the trial eye between up to 3 pre- and 3 posttreatment visits on the same medication. Pearson correlation was used to compare the gold standard with the unadjusted and adjusted methods. In addition, symmetry of IOP response between trial and fellow eyes to the same medication was determined by correlating the trial eye IOP change between up to 3 pre- and 3 posttreatment visits to the fellow eye IOP change between the same visits. Correlations of IOP change of the trial eye using the gold standard to the IOP change of the trial eye using the unadjusted and adjusted methods. The correlations of IOP change using the gold standard to the IOP change using the unadjusted and adjusted methods were r = 0.40 and r = 0.41, respectively. The correlation of IOP change of both eyes between the same pre- and posttreatment visits was r = 0.81. The monocular trial (i.e., adjusted method) appears equivalent to testing each eye independently (i.e., unadjusted method); however, neither method is adequate to determine medication response to topical PGAs. Both eyes have a similar IOP response to the same PGA. Further studies to understand IOP fluctuation are necessary to improve current methods of assessing medication response. Proprietary or commercial disclosure may be found after the references.


Ethically designing research to inform multidimensional, rapidly evolving policy decisions: Lessons learned from the PROMISE HIV Perinatal Prevention Trial.
Research in rapidly evolving policy contexts can lead to the following ethical challenges for sponsors and researchers: the study's standard of care can become different than what patients outside the study receive, there may be political or other pressure to move ahead with unproven interventions, and new findings or revised policies may decrease the relevance of ongoing studies. These ethical challenges are considerable, but not unprecedented. In this article, we review the case of a multinational, randomized, controlled perinatal HIV prevention trial, the "PROMISE" (Promoting Maternal Infant Survival Everywhere) study. PROMISE compared the relative efficacy and safety of interventions to prevent mother to child transmission of HIV. The sponsor engaged an independent international ethics panel to address controversy about the study's standard of care and relevance as national and international guidelines changed. This ethics panel concluded that continuing the PROMISE trial as designed was ethically permissible because: (1) participants in all arms received interventions that were effective, and there was insufficient evidence about whether one intervention was more effective or safer than the other, and (2) data from PROMISE could be useful for a diverse range of stakeholders. In general, trials designed to inform rapidly evolving policy issues should develop mechanisms to revisit social value while recognizing that the value of research varies for diverse stakeholders with legitimate reasons to weigh evidence differently. We conclude by providing four reasons that trials may depart from the standard of care after a change in policy, while remaining ethically justifiable, and by suggesting how to improve existing trial oversight mechanisms to address evolving social value.


Is screening for fetal anomalies reliable in HIV-infected pregnant women? A multicentre study.
To assess the impact of HIV infection on the reliability of the first-trimester screening for Down syndrome, using free beta-human chorionic gonadotrophin, pregnancy-associated plasma protein-A and fetal nuchal translucency, and of the second-trimester screening for neural tube defects, using alpha-fetoprotein. Multicentre study comparing the multiples of the median of markers for Down syndrome and neural tube defect screening among 214 HIV-infected pregnant women and 856 HIV-negative controls undergoing a first-trimester Down syndrome screening test, and 209 HIV-positive women and 836 HIV-negative controls with a risk evaluation for neural tube defect. The influence of treatment, chronic hepatitis and HIV disease characteristics were also evaluated. Multiples of the median medians for pregnancy-associated plasma protein-A and beta-human chorionic gonadotrophin were lower in HIV-positive women than controls (0.88 vs. 1.05 and 0.84 vs. 1.09, respectively; P < 0.005), but these differences had no impact on risk estimation; no differences were observed for the other markers. No association was found between HIV disease characteristics, antiretroviral treatment use at the time of screening or chronic hepatitis and marker levels. Screening for Down syndrome during the first trimester and for neural tube defect during the second trimester is accurate for HIV-infected women and should be offered, similar to HIV-negative women.


Adolescent suicide: endpoint of long-term difficulties.
Characteristics of adolescent suicide victims (N = 53) were investigated in a nationwide study of suicides in Finland. The data were collected through interviews with the victims' parents and attending health care personnel and from official records. Four victims in 10 had shown antisocial behavior. One-third of the adolescents had previous suicide attempts, and 6 in 10 were known to have verbalized their suicidal thoughts. One-third of the victims had been in contact with a psychiatric care system. The results suggest that most adolescent suicides are an endpoint of long-term difficulties, and all suicidal tendencies among adolescents should be taken seriously.


A comparative study of access topologies for chip-level address-event communication channels.
We examine channel access algorithms and circuits for intra and inter chip communication channels. Classical access techniques such as arbitration, scanning, ALOHA, and priority encoding are compared by assessing throughput, latency, and power consumption. Our results provide guidance in the design of bio-inspired networks of processors, for efficient transmission of information with limited power consumption and reduced latency.


Refractory Angioedema in a Patient with Systemic Lupus Erythematosus.
Angioedema secondary to C1 inhibitor deficiency has been rarely reported to be associated with systemic lupus erythematosus. A genetic defect of C1 inhibitor produces hereditary angioedema, which is usually presented with cutaneous painless edema, but edema of the genital area, gastrointestinal and laryngeal tracts have also been reported. In lupus patients, angioedema may be the result of an acquired type of C1 inhibitor deficiency, most probably due to antibody formation directed against the C1 inhibitor molecule. Herein we report a new case of lupus nephritis that developed angioedema and a rapid course of disease progression with acute renal failure and alveolar hemorrhage without response to high dose steroid and plasmapheresis.


Metabolic Perturbations Associated with an Exposure Mixture of Per- and Polyfluoroalkyl Substances in the Atlanta African American Maternal-Child Cohort.
Prenatal exposure to single chemicals belonging to the per- and polyfluoroalkyl substances (PFAS) family is associated with biological perturbations in the mother, fetus, and placenta, plus adverse health outcomes. Despite our knowledge that humans are exposed to multiple PFAS, the potential joint effects of PFAS on the metabolome remain largely unknown. Here, we leveraged high-resolution metabolomics to identify metabolites and metabolic pathways perturbed by exposure to a PFAS mixture during pregnancy. Targeted assessment of perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS), along with untargeted metabolomics profiling, were conducted on nonfasting serum samples collected from pregnant African Americans at 6-17 weeks gestation. We estimated the overall mixture effect and partial effects using quantile g-computation and single-chemical effects using linear regression. All models were adjusted for maternal age, education, parity, early pregnancy body mass index, substance use, and gestational weeks at sample collection. Our analytic sample included 268 participants and was socioeconomically diverse, with the majority receiving public health insurance (78%). We observed 13.3% of the detected metabolic features were associated with the PFAS mixture (n = 1705, p < 0.05), which was more than any of the single PFAS chemicals. There was a consistent association with metabolic pathways indicative of systemic inflammation and oxidative stress (e.g., glutathione, histidine, leukotriene, linoleic acid, prostaglandins, and vitamins A, C, D, and E metabolism) across all metabolome-wide association studies. Twenty-six metabolites were validated against authenticated compounds and associated with the PFAS mixture (p < 0.05). Based on quantile g-computation weights, PFNA contributed the most to the overall mixture effect for γ-aminobutyric acid (GABA), tyrosine, and uracil. In one of the first studies of its kind, we demonstrate the feasibility and utility of using methods designed for exposure mixtures in conjunction with metabolomics to assess the potential joint effects of multiple PFAS chemicals on the human metabolome. We identified more pronounced metabolic perturbations associated with the PFAS mixture than for single PFAS chemicals. Taken together, our findings illustrate the potential for integrating environmental mixture analyses and high-throughput metabolomics to elucidate the molecular mechanisms underlying human health.


Effect of the calcium buffer EGTA on the "hump" component of charge movement in skeletal muscle.
Three manifestations of excitation-contraction (E-C) coupling were measured in cut skeletal muscle fibers of the frog, voltage clamped in a double Vaseline gap: intramembrane charge movements, myoplasmic Ca2+ transients, and changes in optical transparency. Pulsing patterns in the presence of high [EGTA] intracellularly, shown by García et al. (1989. J. Gen. Physiol. 94:973-986) to deplete Ca2+ in the sarcoplasmic reticulum, were found to change the above manifestations. With an intracellular solution containing 15 mM EGTA and 0 Ca, 10-15 pulses (100 ms) to -20 mV at a frequency of 2 min-1 reduced the "hump" component of charge movement current. This effect was reversible by 5 min of rest. The same effect was obtained in 62.5 mM EGTA and 0 Ca by pulsing at 0.2 min-1. This effect was reversible by adding calcium to the EGTA solution, for a nominal [Ca2+]i of 200 nM, and was prevented by adding calcium to the EGTA solution before pulsing. The suppression of the hump was accompanied by elimination of the optical manifestations of E-C coupling. The current suppressed was found by subtraction and had the following properties: delayed onset, a peak at a variable interval (10-20 ms) into the pulse, a negative phase (inward current) after the peak, and a variable OFF transient that could be multi-phasic and carried less charge than the ON transient. In the previous paper (Csernoch et al., 1991. J. Gen. Physiol. 97:845-884) it was shown that several interventions suppress a similar component of charge movement current, identified with the "hump" or Q gamma current (I gamma). Based on the similarity to that component, the charge movement suppressed by the depletion protocols can also be identified with I gamma. The fact that I gamma is suppressed by Ca2+ depletion and the kinetic properties of the charge suppressed is inconsistent with the existence of separate sets of voltage sensors underlying the two components of charge movement, Q beta and Q gamma. This is explicable if Q gamma is a consequence of calcium release from the sarcoplasmic reticulum.


Peroxynitrite-induced neuronal apoptosis is mediated by intracellular zinc release and 12-lipoxygenase activation.
Peroxynitrite toxicity is a major cause of neuronal injury in stroke and neurodegenerative disorders. The mechanisms underlying the neurotoxicity induced by peroxynitrite are still unclear. In this study, we observed that TPEN [N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine], a zinc chelator, protected against neurotoxicity induced by exogenous as well as endogenous (coadministration of NMDA and a nitric oxide donor, diethylenetriamine NONOate) peroxynitrite. Two different approaches to detecting intracellular zinc release demonstrated the liberation of zinc from intracellular stores by peroxynitrite. In addition, we found that peroxynitrite toxicity was blocked by inhibitors of 12-lipoxygenase (12-LOX), p38 mitogen-activated protein kinase (MAPK), and caspase-3 and was associated with mitochondrial membrane depolarization. Inhibition of 12-LOX blocked the activation of p38 MAPK and caspase-3. Zinc itself induced the activation of 12-LOX, generation of reactive oxygen species (ROS), and activation of p38 MAPK and caspase-3. These data suggest a cell death pathway triggered by peroxynitrite in which intracellular zinc release leads to activation of 12-LOX, ROS accumulation, p38 activation, and caspase-3 activation. Therefore, therapies aimed at maintaining intracellular zinc homeostasis or blocking activation of 12-LOX may provide a novel avenue for the treatment of inflammation, stroke, and neurodegenerative diseases in which the formation of peroxynitrite is thought to be one of the important causes of cell death.