Effects of high dose intravenous fish oil on human atrial electrophysiology: implications for possible anti- and pro-arrhythmic mechanisms in atrial fibrillation.
Intravenous omega-3 polyunsaturated fatty acids (ω-3 PUFAs) may prevent atrial fibrillation (AF) inducibility and perpetuation in animal models. We examined the effect of high dose IV ω-3 PUFAs on human atrial electrophysiology. We randomised 88 patients with no structural heart disease to receive saline (control group) or high dose IV ω-3 PUFA infusion prior to detailed atrial electrophysiologic evaluation. Biologically active components, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were measured in total lipids, free fatty acid and phospholipid (membrane incorporated) fraction pre and post infusion. Compared to pre-infusion values, EPA and DHA increased significantly in the total lipids and free fatty acid but were unchanged in the phospholipid fraction. IV ω-3 did not alter atrial refractory periods, however it slowed right, left and global atrial conduction (P<.05). Inducible AF was significantly less likely in ω-3 patients compared to controls (AF ≥ 5 min, 20% vs. 58%, P = .02) and was non-sustained (mean AF duration: 14s vs. 39 s, P<.001), however inducible and sustained atrial flutter was more common (≥ 5 min: 28% vs. 0%, P = .01). Organisation of AF into flutter was observed in a greater proportion of inductions in the ω-3 group (8.5% vs. 0.6%, P<.001). IV ω-3 PUFAs (as free fatty acids) cause acute atrial conduction slowing, suppress AF inducibility, organise AF into atrial flutter and enhance atrial flutter inducibility. These findings provide a novel insight into potential anti and pro-arrhythmic mechanisms of fish oils in human AF.


Probing multiple core-hole interactions in the nitrogen K-edge of DNA base pairs by multidimensional attosecond X-ray spectroscopy. A simulation study.
Two-dimensional X-ray correlation spectroscopy (2DXCS) signals of the isolated DNA bases and Watson-Crick base pairs which contain multiple absorbing nitrogen atoms are calculated. Core-hole excited states are calculated using density functional theory with the B3LYP functional and 6-311G** basis set. Sum over states calculations of the signals reveal changes in cross-peak intensities between hydrogen-bonded and stacked base pairs. Nucleobase analogues are proposed for investigating base-stacking and hydrogen-bonding interactions.


Isocyanate and total inhalable particulate air measurements in the European wood panel industry.
It is well known that the use of MDI (methylene diphenyldiisocyanate) as an alternative for formaldehyde-based resins is seen as a responsible option to reduce formaldehyde emissions for CWP (Composite Wood Products) in buildings. However, there are concerns raised regarding the exposure risk of workers. The purpose of this article is to provide the reader with factual information to demonstrate that the use of MDI compared to other agents used in CWP production processes does not pose increased inhalation exposure risks for workers. Personal and area air measurements were carried out at nine Composite Wood Panel plants throughout Europe to assess potential inhalation exposures to MDI and wood dust as Total Inhalable Particulates (TIP). In total, 446 pairs of samples were collected for MDI and TIP of which 283 pairs were personal samples and the remaining 163 pairs were area samples collected at key locations along the production line. This data together with published formaldehyde exposure data has been used to evaluate the exposure safety margin opposite what are considered relevant occupational exposure limits. The methods used for sampling and analysing MDI and TIP are based on internationally accepted methods, i.e. MDHS 25/3 (or ISO 16702) for MDI, and MDHS 14/3 for TIP. The job functions with an increased exposure profile for TIP were the cleaners, drying operators and quality control staff, and for MDI, the cleaners and quality control staff. The areas with an increased exposure profile for TIP are the conveyor area from OSB blender to former area and the OSB press infeed, and for MDI the OSB weigh belt and OSB former bin area. The exposure safety margin opposite the selected exposure limits can be ranked as MDI>TIP>formaldehyde (high margin of safety to low margin of safety), indicating that the use of MDI also reduces the exposure risks to workers during production of CWP compared to formaldehyde. By reducing the airborne TIP concentrations, a respiratory sensitiser, MDI workplace concentrations in general can be reduced further. This can be achieved by improving design and/or maintenance and testing programmes of existing control measures, which should be in place already to effectively control exposure to TIP and formaldehyde. The airborne concentration of MDI at workstations situated after pressing (curing) is regarded as extremely low and likely mainly constituted by workplace emissions from elsewhere in the plant.


NAD glycohydrolase activity in dog cardiac tissue.
1. Dog heart tissue suspension hydrolyzes NAD, NADP and NMN, and releases nicotinamide stoichiometrically. 2. Maximum activity was observed at 50 degrees C and the activation energy was 10 kcal/mol. 3. Optimum pH range was 6.2-7.6. 4. Compounds with adenine-ribose moiety increased the enzymatic activity. 5. Nicotinamide released during incubation produced reaction nonlinearity. 6. Km for NAD and NADP were about the same; Vmax was higher for NAD. Similar findings have been reported for rabbit heart. 7. Dog enzyme appears to be more sensitive than the rabbit enzyme to noncompetitive inhibitors. 8. Pyrophosphatase activity was not detected in dog heart in contrast to rabbit and rat heart preparations.


Changes of drebrin expression in the visual cortex of the cat during development.
The expression of and developmental changes in drebrin were studied in cat visual cortex using immunohistochemistry and immunoblot analysis. Drebrin is a developmentally regulated brain protein which in the chicken has characteristic changes in expression related to developmental stage. A monoclonal antibody (MAb M2F6) raised against drebrin, was found to label the neuropil of the kitten visual cortex in the early postnatal period. At 1-3 weeks of age, the staining was prominent in layer IV of the visual cortex. The immunoreactivity, however, was found to be dramatically decreased around the end of the sensitive period for ocular dominance plasticity (approximately 3 months of age). In the adult visual cortex, almost no immunostaining was observed. These developmental changes revealed by an immunohistochemical method were confirmed using immunoblot analysis. Upon immunoblot analysis after SDS-PAGE of protein from the kitten visual cortex, MAb M2F6 was found to recognize two protein bands with molecular weights of 130 kDa (drebrin E) and 140 kDa (drebrin A). The developmental profile of the intensity of the two bands of the drebin closely parallels in time the postnatal changes in cortical susceptibility to visual deprivation. These results indicate that the expression of drebrin in kitten visual cortex is restricted to the early postnatal period and suggest that it may play an important role in the experience-dependent modification of cortical circuitry during the sensitive period.


Workplace Wellness Program Interest and Barriers Among Workers With Work-Related Permanent Impairments.
Nearly half of U.S. workers have access to workplace wellness programs (WWPs), 58% of workers with access participate. The aim of this study was to assess interest in WWP participation and identify reasons for lack of interest among workers with work-related permanent impairments-a population at elevated risk of adverse health outcomes. Workers who returned to work after a work-related permanent impairment were interviewed 11 to 15 months after workers' compensation claim closure. Qualitative content analysis methods were used to code open-ended responses. Of 560 respondents, 51.4% expressed interest in WWP participation. Numerous adverse health and economic characteristics were associated with WWP interest, for example, interest was expressed by 63.3% of workers reporting fair/poor health status versus 47.1% reporting good/excellent; 56.9% of workers reporting moderate/severe pain versus 41.4% reporting mild/no pain; 64.7% of workers without health insurance versus 50.1% with health insurance; 69.0% of workers reporting depression versus 47.2% without depression; 70.4% of workers reporting obesity versus 48.0% without obesity; and 63.2% of workers often worried about expenses versus 46.9% reporting sometimes/never worried. Specific participation barriers were described by 34.2% of the 272 workers who were not interested. A majority of workers with work-related permanent impairments-particularly those with adverse health and economic characteristics-were interested in WWPs. Many workers who reported no interest cited participation barriers. Further research is needed to determine whether addressing such barriers would enhance equitable access. Those undertaking WWP planning, implementation, and outreach should ensure that WWPs are inclusive and serve workers with disabilities.


Abnormal CD4 + T helper (Th) 1 cells and activated memory B cells are associated with type III asymptomatic mixed cryoglobulinemia in HCV infection.
Mixed cryoglobulinemia (MC) in hepatitis C virus (HCV) infection is associated with abnormal immune responses mediated by T cells and B cells, while the relationships of different subsets of CD4 + T helper (Th) cells, B cells and associated cytokines with type III asymptomatic MC in HCV infection are poorly understood. Fifty-four chronic hepatitis C (CHC) patients and 23 healthy controls (HCs) were enrolled in the study. Serum cryoglobulins were detected by cryoprecipitation. The types of cryoglobulin were determined by western blot. The phenotypes and frequencies of Th cell and B cell subsets were detected by flow cytometric analysis. The cytokines IFN-γ, IL-4, IL-17, IL-21, IL-22, and TGF-β were measured by enzyme-linked immunosorbent assay. Twenty-six CHC patients were detected with type III asymptomatic MC. The frequencies of Th2, Th17, follicular helper T (Tfh cells), Th22, and tissue-like B cells were significantly higher in CHC patients compared to HCs, while these cell subsets were not significantly different between CHC patients and HCV-related MC patients. The frequencies of Th1 and activated memory B cells increased in HCV-related MC patients compared to HCs, although the difference between the two cell subsets in CHC patients and HCs was not significant. The frequency of regulatory T cells (Treg cells) was higher in CHC patients than in HCV-related MC patients and HCs. Higher expressions of serum IFN-γ, IL-17, IL-21, and IL-22 were observed in CHC patients than in HCs, but the differences were not significantly different in CHC patients and HCV-related MC patients. The frequency of Th1 cells was associated with activated memory B cells in HCV-related MC patients, and the frequency of Th1 cells and activated memory B cells was closely related to HCV RNA in HCV-related MC patients. The increased frequencies of Th17 cells, Tfh cells, Th22 cells, Treg cells, cytokines IL-17, IL-21, IL-22, and tissue-like B cells, were related to HCV infection but not type III asymptomatic MC. Higher frequencies of Th1 cells and activated memory B cells were associated with type III asymptomatic MC in HCV infection.


Neurotoxic properties of the Zika virus envelope protein.
Prenatal Zika virus (ZIKV) infection is a serious global concern as it can lead to brain injury and many serious birth defects, collectively known as congenital Zika syndrome. Brain injury likely results from viral mediated toxicity in neural progenitor cells. Additionally, postnatal ZIKV infections have been linked to neurological complications, yet the mechanisms driving these manifestations are not well understood. Existing data suggest that the ZIKV envelope protein can persist in the central nervous system for extended periods of time, but it is unknown if this protein can independently contribute to neuronal toxicity. Here we find that the ZIKV envelope protein is neurotoxic, leading to overexpression of poly adenosine diphosphate -ribose polymerase 1, which can induce parthanatos. Together, these data suggest that neuronal toxicity resulting from the envelope protein may contribute to the pathogenesis of post-natal ZIKV-related neurologic complications.


Are dietary intake and nutritional status of specific polyunsaturated fatty acids correlated with sarcopenia outcomes in community-dwelling older adults with sarcopenia? - Exploratory results from ENHANce.
To explore the relationship between dietary polyunsaturated fatty acids (PUFAs) intake, nutritional PUFAs status and sarcopenia outcomes in sarcopenic older adults. The Exercise and Nutrition for Healthy AgeiNg (ENHANce) is an ongoing 5-armed triple blinded randomized controlled trial, in sarcopenic older adults (> 65y) aiming to assess the effect of combined anabolic interventions (protein, omega-3 supplement and exercise) on physical performance in these adults, compared to single/placebo interventions. Baseline data were used for a secondary, exploratory, cross-sectional analysis. Dietary PUFAs intake was assessed with 4-day food records, status with RBC membrane fatty acids profiles. Spearman's rho(ρ) correlation coefficients were calculated to explore associations of PUFAs intake and status with sarcopenia-defining parameters (muscle strength, mass and physical performance), physical activity (step count) and quality of life (SF-36, SarQoL). In total, 29 subjects (9♂/20♀, mean age 76.3 ± 5.4y) were included. Total omega-3 intake of participants (1.99 ± 0.99 g/d) was below the recommended intake (♂:2.8-5.6 g/d; ♀:2.2-4.4 g/d). Intake and status of PUFAs were not correlated. Regarding correlations with outcomes, α-linolenic acid status was inversely associated with appendicular lean mass (aLM) (ρ:-0.439; p = 0.017), whereas docosahexaenoic acid status was positively associated with aLM (ρ:0.388; p = 0.038). Some omega-3 PUFAs intake and status markers were positively associated with step count, SF-36 and SarQoL scores, whereas gamma-linolenic acid status was inversely associated with SF-36 physical component summary score (ρ = -0.426; p = 0.024). Although intake of omega-3 and omega-6 was low, the present exploratory study generated new hypotheses for potential correlations of PUFAs intake and status with sarcopenia outcomes in older adults with sarcopenia.


Role of CYP2C9 genetic variants for salt sensitivity and the regulation of the renin-angiotensin-aldosterone system in normotensive men.
Cytochrome P450 (CYP) 2C9 gene polymorphisms have been implicated in regulation of the renin-angiotensin-aldosterone system (RAAS) and salt sensitivity in hypertensive patients. We tested the relevance of CYP2C9 genotypes for regulation of plasma renin activity (PRA), plasma aldosterone concentrations and blood pressure (BP) in response to changes in salt intake in normotensive individuals. Three hundred and ten normotensive men (mean age 24.9 ± 0.1) were studied after a standardized low = 20 mmol/day or high = 220 mmol/day sodium intake for 7 days. Individuals were classified as salt sensitive when the mean arterial BP was more than 3 mmHg higher after high compared with low-salt exposure. CYP2C9*2 and CYP2C9*3 alleles were not associated with salt-sensitivity status or BP phenotypes; CYP2C9*2 had no effect on PRA or plasma aldosterone. CYP2C9*3 carriers showed a significantly lower PRA compared with CYP2C9*1/*1 individuals in the overall study cohort (high salt: 0.39 ± 0.05 vs. 0.62 ± 0.04 ng/ml per h, P = 0.009; low salt: 2.19 ± 0.27 vs. 2.87 ± 0.13 ng/ml per h, P = 0.013). Salt-sensitive CYP2C9*3 carriers exhibited the lowest PRA values and significantly lower 24 h sodium excretion rates during high-salt intake (P = 0.005 vs. CYP2C9*1/*1). Lower plasma aldosterone concentrations were only observed in salt-resistant CYP2C9*3 carriers under low salt (P = 0.039). The present study confirms an association between CYP2C9 polymorphism and activity of the RAAS. Specifically, we detected an overall effect of CYP2C9*3 on lower PRA, but not on salt-sensitive BP regulation in normotensive men. Further studies are needed to analyze the long-term effects of CYP2C9*3 for salt sensitivity and hypertensive diseases.


Medico-legal indicators and cut-offs in different age classes through quantitative analysis of epiphyseal fusion segments on knee CT scans.
Scientists are interested in determining age in subadults for several forensic purposes. High- resolution instrumental techniques are being increasingly used for age estimation, driven by the need to minimize errors; in this context, several studies have focused on the knee joint, recognized as a potential site for age examination in late adolescence. We analyzed 200 CT scans performed on Russian subjects (106 males and 94 females) between 13 and 20 years, without growth diseases, endocrine disorders, or osteodystrophy. Each subject underwent two scans, one for each leg. Two indicators were measured for each bone (femur, tibia and fibula): the entire length of the epiphyseal scar and the length of the part/s that is/are fused with metaphysis. Intra class Correlation Coefficient (ICC) was performed to evaluate the intra-operator reproducibility. The ratio between the two lengths was calculated for each bone (FemurR, TibiaR and FibulaR). The first aim was to evaluate a correlation between the ratios of the three bones and the three bones treated as a single parameter (given by the sum of the ratios) versus age. The results showed good correlations in both cases (τ a = 0.74, 0.64, 0.57 and 0.67). The second aim was to estimate the cut-offs derived from the sum of the three ratios respect to four age classes (14-15 years: cut-off ≤ 0.63, 15-16 years: cut-off ≤ 1.19, 16-17 years: cut-off ≥ 0.68 and 17-18 years: cut-off ≥ 1.49. The results from this research encourage further studies of the knee joint as an indicator of legal adult age.


Direct evidence for concomitant release of noradrenaline, adenosine 5'-triphosphate and neuropeptide Y from sympathetic nerve supplying the guinea-pig vas deferens.
Concomitant release of noradrenaline (NA) (using tritium labelling), adenosine 5'-triphosphate (ATP) (using the luciferin-luciferase firefly technique) and neuropeptide Y (using the enzyme-linked immunosorbant assay) during electrical stimulation of the guinea-pig vas deferens has been demonstrated. In addition it has been shown: (1) that release of NA and ATP is unaffected following selective desensitization of the P2 (ATP)-purinoceptor by alpha, beta-methylene ATP and (2) that total block of contractile responses of the vas deferens to nerve stimulation by a combination of prazosin and alpha, beta-methylene ATP does not reduce the release of NA and ATP. These results are consistent with the hypothesis that NA, ATP and neuropeptide Y are released as co-transmitters or modulators in sympathetic nerves supplying the vas deferens.


First experience with a thermal-sprayed silver oxide-containing hydroxyapatite coating implant in two-stage total hip arthroplasty for the treatment of septic arthritis with hip osteoarthritis: A case report.
Septic arthritis of the hip joint in adults is a rare and potentially devasting disease. To the best of our knowledge, there have been no reports of two-stage total hip arthroplasty (THA) for the treatment of septic arthritis of the hip joint with a cementless hip implant that has antibacterial properties. We present a case of two-stage THA with a thermal-sprayed silver oxide-containing hydroxyapatite coating (Ag-HA) implant to treat septic arthritis of the hip joint with hip osteoarthritis in an 80-year-old woman. There was no complication or recurrence at 28 months follow-up after 2nd-stage operation. Ag-HA implants were found to have antibacterial activity within the subcutaneous tissues and bone, osteoconductive properties, and no adverse reactions in vivo. Moreover, no adverse events due to silver were reported in a clinical or radiographic study. To further reduce infection after two-staged THA for septic arthritis of the hip joint, antibacterial implants, such as an Ag-HA implant, may be used.


Blockade of glutamatergic transmission as treatment for dyskinesias and motor fluctuations in Parkinson's disease.
In animal models of Parkinson's disease (PD), glutamate antagonists diminish levodopa (LD)-associated motor fluctuations and dyskinesias. We sought to investigate if these preclinical observations can be extended to the human disease, by evaluating the effects of three non-competitive NMDA antagonists (dextrorphan, dextromethorphan and amantadine) on the motor response to LD in patients with advanced PD. In four separate trials, adjuvant therapy with these drugs reduced LD-induced dyskinesias and motor fluctuations. These findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptor can ameliorate LD associated motor response complications.


Immunohistochemical study of fibronectin in human glioma and meningioma.
The presence of fibronectin (FN) and glial fibrillary acidic protein (GFAP) in two astrocytomas, 17 glioblastomas, and five meningiomas was studied by indirect immunoperoxidase staining of formalin-fixed and paraffin-embedded surgical specimens. Angiogenesis in tumor was scored by the microscopic angiogenesis grading system (MAGS), and plasma FN levels were measured by single radial immunodiffusion. In astrocytomas and glioblastomas, GFAP-positive tumor cells had no FN expression and FN was confined to proliferating vessel walls and the leptomeninges, showing a mutually exclusive FN and GFAP expression. GFAP-positive tumor cells were occasionally surrounded by a network of FN-positive matrix produced by cells derived from the leptomeninges or blood vessels. In meningiomas, FN expression was found in vessel walls and meningioma cells including whorl formations and psammoma bodies. In general, deep immunoperoxidase staining for FN was shown in the endothelial cells and the psammoma bodies. Plasma FN levels were correlated significantly not to the degree of leptomeningeal proliferation but to the MAGS scores in gliomas.


Determination of Plant Volatile Apocarotenoids.
Volatile compounds derived from carotenoid cleavage are biologically relevant molecules in plants, as they are involved in different processes of plant communication and also have a significant effect on our perception of food flavor.Here we describe two methods for the determination of volatile apocarotenoids in fruit based on extraction by means of headspace solid-phase microextraction (HS-SPME) and separation and detection by means of gas chromatography coupled to mass spectrometry (GC-MS). The first method is optimised for the detection of the complete volatile profile in Citrus fruit, including those compounds derived from carotenoids. The second is a shorter method focused to the detection of volatile apocarotenoids in the tomato fruit.


Endothelin-converting enzyme-1 inhibition and renoprotection in end-stage renal disease.
Endothelin is one of the most potent peptide vasoconstrictors thus far characterised. It is produced by the cleavage of its precursor big endothelin-1 by endothelin-converting enzyme-1 (ECE-1). The endothelin system which includes endothelin-1 (ET-1), ET receptors and ECE-1 is well characterised in the kidney and is known to play a key role in the pathogenesis of end-stage renal disease (ESRD). Therefore, inhibition of ECE-1 and antagonism of ET receptors represent potential therapeutic approaches for the treatment of ESRD. Here, we review the current literature on the localisation of ECE-1 in the normal kidney and how ECE-1 expression is altered in pathological conditions leading to ESRD. We also discuss the roles of neutral endopeptidase (NEP) and chymase in mediating the production of ET-1 in the kidney in ESRD. As such, we also discuss that complete inhibition of ET-1 production in the kidney requires the inhibition of ECE-1, NEP and chymase.


Correction to: Palliative long-term abdominal drains versus repeated drainage in individuals with untreatable ascites due to advanced cirrhosis: study protocol for a feasibility randomised controlled trial.
Following publication of the original article [1], the authors reported that the figure legend for Figure 3 was absent. In addition, they have requested additional funding information to be added. In this Correction the initial and updated funding information are shown. The original publication of this article has been corrected.


Enzymatic synthesis of adenosine 5'-O-(3-[35S]-thiotriphosphate).
A method for the enzymatic synthesis of adenosine 5'-O-(3-[35S]thiotriphosphate) is described. The method involves the thiophosphate exchange of adenosine 5'-O-(3-thiotriphosphate) with [35S]thiophosphate with the aid of glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate kinase in the presence of 3-phosphoglycerate. The method is also applicable for the synthesis of guanosine 5'-O-(3-[35S]thiotriphosphate).


Erratum: Prevalence and characterization of urolithiasis in the Western region of Saudi Arabia.
[This corrects the article on p. 347 in vol. 11, PMID: 31649451.].


Bleeding and embolic risk in patients with atrial fibrillation and cancer.
The impact of cancer on clinical outcomes in patients with atrial fibrillation (AF) is unclear. The aim of this study was to assess how cancer influences the prediction and risk of embolic and hemorrhagic events in patients with AF. The study population comprised 16 056 patients from a Spanish health area diagnosed with AF between 2014 and 2018. Of these, 1137 (7.1%) had a history of cancer. During a median follow-up of 4.9 years, we assessed the relationship between cancer and bleeding and embolic events by competing risk analysis, considering death as a competing risk. No association was detected between an increased risk of embolic events and cancer overall (sHR, 0.73; 95%CI, 0.41-1.26), active cancer, or any subgroup of cancer. However, cancer was associated with an increased risk of bleeding, although only in patients with active cancer (sHR, 1.42; 95%CI, 1.20-1.67) or prior radiotherapy (sHR, 1.40; 95%CI, 1.19-1.65). Both the CHA2DS2-VASc and HAS-BLED scores showed suboptimal performance to predict embolic and bleeding risk (c-statistic <0.50), respectively, in nonanticoagulated patients with active cancer. The ratio between the increase in bleeding and the decrease in embolisms with anticoagulation was similar in patients with and without cancer (5.6 vs 7.8; P <.001). Cancer was not associated with an increased risk of embolic events in AF patients, only with an increased risk of bleeding. However, active cancer worsened the ability of the CHA2DS2-VASc and HAS-BLED scores to predict embolic and bleeding events, respectively, in nonanticoagulated patients.


Recombinant human erythropoietin in nephrology.
rEPO therapy provides a unique opportunity to correct anemia in end-stage renal failure patients. Complete correction of the anemia, although possible, has some obvious disadvantages over a partial correction with a target hemoglobin of 10-13 g/dl or a hematocrit of 30-35%, respectively. Unresponsiveness to rEPO seems to be rare; in most cases the predicted hemoglobin increase could be seen as soon as an underlying iron deficiency was treated adequately. Blood loss and aluminum toxicity are the next most frequent reasons for an inadequate response to rEPO. Hypertension (and its complications) as well as fistula clotting are the most important side-effects which require close attention when patients at risk for these complications are treated with rEPO.


The link between abnormal calcium handling and electrical instability in acquired long QT syndrome--Does calcium precipitate arrhythmic storms?
Release of Ca(2+) ions from sarcoplasmic reticulum (SR) into myocyte cytoplasm and their binding to troponin C is the final signal form myocardial contraction. Synchronous contraction of ventricular myocytes is necessary for efficient cardiac pumping function. This requires both shuttling of Ca(2+) between SR and cytoplasm in individual myocytes, and organ-level synchronization of this process by means of electrical coupling among ventricular myocytes. Abnormal Ca(2+) release from SR causes arrhythmias in the setting of CPVT (catecholaminergic polymorphic ventricular tachycardia) and digoxin toxicity. Recent optical mapping data indicate that abnormal Ca(2+) handling causes arrhythmias in models of both repolarization impairment and profound bradycardia. The mechanisms involve dynamic spatial heterogeneity of myocardial Ca(2+) handling preceding arrhythmia onset, cell-synchronous systolic secondary Ca(2+) elevation (SSCE), as well as more complex abnormalities of intracellular Ca(2+) handling detected by subcellular optical mapping in Langendorff-perfused hearts. The regional heterogeneities in Ca(2+) handling cause action potential (AP) heterogeneities through sodium-calcium exchange (NCX) activation and eventually overwhelm electrical coupling of the tissue. Divergent Ca(2+) dynamics among different myocardial regions leads to temporal instability of AP duration and - on the patient level - in T wave lability. Although T-wave alternans has been linked to cardiac arrhythmias, non-alternans lability is observed in pre-clinical models of the long QT syndrome (LQTS) and CPVT, and in LQTS patients. Analysis of T wave lability may provide a real-time window on the abnormal Ca(2+) dynamics causing specific arrhythmias such as Torsade de Pointes (TdP).


[Morten Parelius. A polyhistorian and an occasional poet, but above all a physician].
Parelius worked as local medical officer in the western parts of Norway. He wrote poems and medical articles, most of which were published in journals. This article is a biography.


Pentobarbital coma for management of intracranial hypertension following traumatic brain injury: Lack of early response to treatment portends poor outcomes.
Traumatic brain injury (TBI) results in the death of over 50,000 and the permanent disability of 80,000 individuals annually in the United States. Much of the permanent disability is the result of secondary brain injury from intracranial hypertension (ICH). Pentobarbital coma is often instituted following the failure of osmotic interventions and sedation to control intracranial pressure (ICP). The goal of this study was to evaluate the efficacy of pentobarbital coma with respect to ICP management and long-term functional outcome. Traumatic brain injury patients who underwent pentobarbital coma at a level 1 trauma center between 2014 and 2021 were identified. Patient demographics, injury characteristics, Glasgow Coma Scale (GCS) scores, intracranial pressures (ICPs), and outcomes were obtained from the trauma registry as well as inpatient and outpatient medical records. The proportion of ICPs below 20 for each hospitalized patient-day was calculated. The primary outcome measured was GCS score at the last follow-up visit. 25 patients were identified, and the majority were male (n = 23, 92%) with an average age of 30.0 years ± 12.9 and median injury severity score of 30 (21.5-33.5). ICPs were monitored for all patients with a median of 464 (326-1034) measurements. The average hospital stay was 16.9 days ± 11.5 and intensive care stay was 16.9 ± 10.8 days. 9 (36.0%) patients survived to hospital discharge. Mean follow-up time in months was 36.9 ± 28.0 (min-max 3-80). 7 of the 9 surviving patients presented as GCS 15 on follow-up and the remaining were both GCS 9. Patients presenting at last follow-up with GCS 15 had a significantly higher proportion of controlled ICPs throughout their hospitalization compared to patients who expired or with follow-up GCS <15 (GCS 15: 88% ± 10% vs. GCS <15 or dead: 68% ± 22%, P = 0.006). A comparison of the daily proportion of controlled ICPs by group revealed negligible differences prior to pentobarbital initiation. Groups diverged nearly immediately upon pentobarbital coma initiation with a higher proportion of controlled ICPs for patients with follow-up GCS of 15. Patients that do not have an immediate response to pentobarbital coma therapy for ICH universally had poor outcomes. Alternative therapy or earlier palliation should be considered for such patients. In contrast, patients whose ICPs responded quickly to pentobarbital had excellent long-term outcomes.


The influence of fish predation on the abundance cycles of an algal turf invertebrate fauna.
A fauna of small invertebrates in a perennial algal turf habitat showed marked seasonal fluctuations in abundance. These were characterised by a summer (December) peak in the abundance of gammarid amphipods and an autumn (April) peak in polychaete densities. Invertebrate abundance was lowest during the period February-March which coincided with an influx of very high densities of juveniles (0+ year class) of the sparid fish Chrysophrys auratus. Both juvenile C. auratus and also the mullid Upeneichthys porosus achieved their highest densities over coralline turf areas and fed on the associated invertebrates. Gammarid amphipods constituted the main food items of each species. All these observations suggested a key role of fish predators in determining the observed seasonal patterns of invertebrate abundance.This hypothesis was investigated by the use of replicated fish exclusion shields and cages which excluded both species from the algal turf and also permitted an assessment of Upeneichthys porosus feeding in the absence of Chrysophrys auratus. The experiment ran from November until June and covered the period of invertebrate and fish abundance changes. Little evidence of a fish predation effect on either the densities of or the timing of abundance peaks of the invertebrate fauna was detected. Sediment analysis of the cage and control experimental sites revealed no evidence of a cage effect on the microhabitat. It is suggested that seasonal changes in the abundance of invertebrates occurs independently of the high densities of predatory fish recorded in this habitat.


[Pleural effusion in hereditary haemorrhagic telangiectasia: hemothorax or empyema?].
In hereditary hemorrhagic telangiectasia the pulmonary arteriovenous malformations frequently lead to complications. In a case of pleural effusion in a patient with known pulmonary arterio-venous malformations, the first diagnosis to consider is a hemothorax even though alternatives such as empyema are possible. We report the case of a 35-year-old woman with a known diagnosis of hereditary hemorrhagic telangiectasia with bilateral arteriovenous malformations, who was admitted to the emergency department with subacute dyspnoea and left thoracic pain. The clinical examination suggested a hemothorax. Pulmonary angiography was performed and showed an arteriovenous malformation in the left lower lobe. Embolisation was undertaken and at the same time a chest tube was inserted. Pus was evacuated leading to the final diagnosis of pleural empyema. Progress was good despite an episode acute respiratory distress due to a pulmonary embolism. Pleural empyema is rarely described in the context of hereditary hemorrhagic telangiectasia with pulmonary arteriovenous malformations. In the case of pleural effusion this diagnosis should be considered even though hemothorax is more common.


Chromosome findings and prognosis in 15 patients with neuroblastoma found by VMA mass screening.
We performed chromosome analysis of 15 neuroblastomas found by mass screening using a vanillymandelic acid spot test. We found near triploid chromosome abnormalities, ranging from 60 to 77 chromosomes, in the tumor cells from 14 patients, and hyperdiploidy with the mode of 50 in cells from one. A structural abnormality was observed in only one patient. We did not find a marker chromosome 1, homogeneously staining region, or double minutes, which have been previously reported in advanced neuroblastomas or in cell lines. All of our patients were completely free of disease 4 to 32 months after diagnosis. We consider that patients with hyperdiploidy or near triploidy are different from those with marker chromosome 1, homogeneously staining region, or double minutes and may constitute a subgroup with a good prognosis in childhood neuroblastoma.


A novel extracellular subtilisin-like protease from the hyperthermophile Aeropyrum pernix K1: biochemical properties, cloning, and expression.
A novel extracellular serine protease designated Pernisine was purified to homogeneity and characterized from the archaeon Aeropyrum pernix K1. The molecular mass, estimated by SDS-PAGE analysis and by gel filtration chromatography, was about 34 kDa suggesting that the enzyme is monomeric. Pernisine was active in a broad range of pH (5.0-12.0) and temperature (60-120 degrees C) with maximal activity at 90 degrees C and between pH 8.0 and 9.0. In the presence of 1 mM CaCl(2) the activity, as a function of the temperature, reached a maximum at 90 degrees C but at 120 degrees C the enzyme retained almost 80% of its maximal activity. Activity inhibition studies suggest that the enzyme is a serine metalloprotease and biochemical data indicate that Pernisine is a subtilisin-like enzyme. The protease gene, identified from the sequenced genome of A. pernix, was amplified from total genomic DNA by PCR technique to construct the expression plasmid pGEX-Pernisine. The Pernisine, lacking the leader sequence, was expressed in Escherichia coli BL21 strain as a fusion protein with glutathione- S-transferase. The biochemical properties of the recombinant enzyme were found to be similar to those of the native enzyme.


Epileptic seizures associated with cisplatin administration.
Eighty-one patients with germ cell tumors or ovarian carcinoma were treated over a 4-year period with cisplatin-containing combination chemotherapy. Eight patients (9.8%) experienced epileptic seizures during or within 3 months of this chemotherapy. While a definite causal relationship between the seizures and cisplatin could not be established, we have rarely seen such episodes in relationship to other cytotoxic drugs. A number of possible contributing factors were apparent, including hyponatremia and pretreatment impairment of renal function.


Experimental research on heavy metal wastewater treatment with dipropyl dithiophosphate.
In view of the existing technical problems about treatment of heavy metal pollution, a new organic heavy metal chelator-dipropyl dithiophosphate has been developed. This paper focuses on the mechanism about the laboratory synthesis of dipropyl dithiophosphate and chelate heavy metal, discusses the effects of pH value, added quantity of chelator, reactive time and coexistence of several heavy metal ions on the treatment effectiveness, and compares the stability of chelate complex with conventional neutral precipitation method. The results of the experiment show that, within the scope of pH 3-6, for the wastewater with the concentration of lead, cadmium, copper and mercury being 200 mg/L, dipropyl dithiophosphate enjoys a removal rate about these elements up to over 99.9%, and the concentrations of the lead, cadmium, copper and mercury in the wastewater after treatment are less than 1, 0.1, 0.5 and 0.05 mg/L, respectively, which meet the limit value of concentration stipulated in the Integrated Wastewater Discharge Standard (GB8978-1996). And the treatment effectiveness are not affected by pH value and coexistent heavy metal ions, which makes up the deficiency that neutral precipitation must be used under the condition of high alkalinity. The optimum quantity of dipropyl dithiophosphate chelator added is 1.2 times as much as stoichiometric amount and the optimum reactive time is 20 min for lead, cadmium and copper, and 30 min for mercury. Within the scope of pH 3-9, each heavy metal ion release of chelate complex will decrease along with increased pH value. But under any pH conditions, the release of heavy metal ions in hydroxide is far higher than that in chelate complex, therefore reducing the risk of polluting the environment again.


Increasing disparities in the embedded carbon emissions of provincial urban households in China.
In the context of carbon neutrality and the National Economic Circle Strategy, understanding regional disparities in carbon emissions from household consumption is conducive to regional coordination as well as high-quality and low-carbon development in China. In this study, a multiregional input-output (MRIO) model and structural decomposition analysis (SDA) are adopted to investigate the regional disparity change trends of embedded carbon emissions (ECEs) from urban households and the underlying drivers during the rapid economic development period from 2002 to 2012 in China. The results indicate that the eastern regions tended to have larger increments in total urban household ECEs, while the western regions tended to have faster growth rates. An increasing disparity and evident outsourcing pattern can be observed during the study period. The consumption level had a strong positive effect on urban household ECEs in all of the provinces, while the carbon efficiency, consumption pattern, production structure, and population size had differentiated offsetting effects on urban household ECEs in various provinces. The results obtained in this study are conducive to promoting joint efforts for carbon emission reduction and narrowing regional disparities.


Health-related quality of life of children with first onset steroid-sensitive nephrotic syndrome.
This study assessed HRQoL and emotional and behavioral difficulties (EBD) and associated variables in children with first onset SSNS. While relapsing steroid-sensitive nephrotic syndrome (SSNS) in children is associated with lower health-related quality of life (HRQoL), little is known about first onset. Four weeks after onset, children (2-16 years) and/or their parents who participated in a randomized placebo-controlled trial, completed the Pediatric Quality of Life Inventory 4.0 (PedsQL) and Strengths and Difficulties Questionnaire (SDQ) to measure HRQoL and EBD, respectively. Total and subscale scores and the proportion of children with impaired HRQoL (> 1 SD below the mean of the reference group) or SDQ clinical scores (< 10th and > 90th percentile) were compared to the Dutch general population (reference group). Regression analyses were used to identify associated variables. Compared to the reference group, children 8-18 years reported significantly lower total HRQoL, and physical and emotional functioning. A large proportion (> 45%) of these children had impaired HRQoL. There were no differences in HRQoL between children 2-7 years and the reference group, except for higher scores on social functioning (5-7 years). Similar proportions of SSNS and reference children scored within the clinical range of SDQ subscales. Age, sex, and steroid side-effects were negatively associated with HRQol and/or EBD. Conclusion: This study showed that HRQoL and EBD are affected in children of different ages with first onset SSNS. This calls for more awareness from healthcare providers and routinely monitoring of HRQoL and EBD in daily clinical care to prevent worsening of symptoms. Clinical trial registry: Netherlands Trial Register ( https://trialsearch.who.int/ ; NTR7013), date of registration: 02 June 2018. What is Known: • Health-related quality of life (HRQoL) is lower and emotional and behavioral difficulties (EBD) is more affected in children with frequently-relapsing and steroid-dependent nephrotic syndrome. What is New: • HRQoL and EBD are affected in children with first onset steroid-sensitive nephrotic syndrome compared to a reference group of the Dutch general population. • To what extent HRQoL and EBD are affected depends on the age of the patient.


Effects of Curcuminoid Pyrazoles on Cancer Cells and on the Expression of Telomerase Related Genes.
A group of 13 curcuminoid pyrazoles was investigated for their cytotoxicity on three tumoral cell lines (HT-29, MCF-7, and HeLa) and one non-tumoral human cell line (HEK-293). The values obtained were compared with those of curcumin. A subset of selected derivatives was also studied for their ability to downregulate expression of the hTERT and c-Myc genes, which are both involved in telomerase activity.


TBX6, LHX1 and copy number variations in the complex genetics of Müllerian aplasia.
Müllerian aplasia (MA) is a congenital disorder of the female reproductive tract with absence of uterus and vagina with paramount impact on a woman's life. Despite intense research, no major genes have been found to explain the complex genetic etiology. We have used several genetic methods to study 112 patients with MA. aCGH identified CNVs in 8/50 patients (16%), including 16p11.2 and 17q12 deletions previously associated with MA. Subsequently, another four patients were shown to carry the ~0.53 Mb deletion in 16p11.2. More importantly, sequencing of TBX6, residing within 16p11.2, revealed two patients carrying a splice site mutation. Two previously reported TBX6 variants in exon 4 and 6 were shown to have a significantly higher frequency in patients (8% and 5%, respectively) than in controls (2% each). We also sequenced LHX1 and found three apparently pathogenic missense variants in 5/112 patients. Altogether, we identified either CNVs or variations in TBX6 or LHX1 in 30/112 (26.8%) MA patients. CNVs were found in 12/112 (10.7%), patients, novel variants in TBX6 or LHX1 in 7/112 (6.3%), and rare variants in TBX6 in 15/112 (13.4%) patients. Furthermore, four of our patients (4/112, 3.6%) were shown to carry variants in both TBX6 and LHX1 or a CNV in combination with TBX6 variants lending support to the complex genetic etiology of MA. We have identified TBX6 as a new gene associated with MA. Our results also support the relevance of LHX1 and CNVs in the development of this congenital malformation.


Thermococcus sp. KS-1 PPIase as a fusion partner improving soluble production of aromatic amino acid decarboxylase.
Peptidyl-prolyl cis-trans isomerase (PPIase, EC 220.127.116.11) catalyzes the racemization reaction of proline residues on a polypeptide chain. This enzyme is also known to function as a molecular chaperon to stabilize protein conformation during the folding process. In this study, we noted FK506 binding protein (FKBP)-type PPIase from a hyperthemophilic archaeon Thermococcus sp. strain KS-1 (PPIase KS-1) to improve the solubility of Pseudomonas putida aromatic amino acid decarboxylase (AADC) that is an indispensable enzyme for fermentative production of plant isoquinoline alkaloids. AADC fused N-terminally with the PPIase KS-1 (PPIase KS-1-AADC), which was synthesized utilizing Escherichia coli host, showed improved solubility and, consequently, the cell-free extract from the recombinant strain exhibited 2.6- to 3.4-fold elevated AADC activity than that from the control strain that expressed the AADC gene without PPIase KS-1. On the other hand, its thermostability was slightly decreased by fusing PPIase KS-1. The recombinant E. coli cells expressing the PPIase KS-1-AADC gene produced dopamine and phenylethylamine from L-dopa and phenylalanine by two- and threefold faster, respectively, as compared with the control strain. We further demonstrated that the efficacy of PPIase KS-1-AADC in solubility and activity enhancement was a little but obviously higher than that of AADC fused N-terminally with NusA protein, which has been assumed to be the most effective protein solubilizer. These results suggest that PPIase KS-1 can be used as one of the best choices for producing heterologous proteins as active forms in E. coli.


Lipid distribution in Acholeplasma laidlawii membrane. A study using the lactoperoxidase-mediated iodination.
The lactoperoxidase-mediated radioiodination has been applied to study the transbilayer distribution of phospho- and glycolipids in Acholeplasma laidlawii membranes. After radioiodination, about 5% of the 125I-iodine was found in membrane lipids. A comparison of the labeling intensities of the various lipid species between iodinated intact cells and isolated membranes revealed that the glycolipids monoglucosyldiglyceride and diglucosyldiglyceride are located almost exclusively in the outer half of the bilayer, whereas the phospholipids phosphatidylglycerol and diphosphatidylglycerol as well as the phosphoglycolipids glycerophosphoryl-diglucosyldiglyceride and glycerophosphoryl-monoglucosyldiglyceride are almost equally distributed in the outer and inner halves of A. laidlawii membranes.


A ferroptosis-related gene in Helicobacter pylori infection, SOCS1, serves as a potential prognostic biomarker and corresponds with tumor immune infiltration in stomach adenocarcinoma: In silico approach.
Helicobacter pylori (H. pylori) is a major risk factor for the stomach adenocarcinoma (STAD). This study aimed to investigate the potential role of a H. pylori infection-related gene, SOCS1, in STAD. Online available databases were analyzed to determine the expression, correlations with clinicopathologic parameters, patients' survival, and immunological characteristics of SOCS1 in TCGA-STAD or GEO datasets. Univariate and multivariate Cox regression analyses were used to determine independent risk factors, which were further integrated to establish a nomogram. A comparison of drug sensitivity was conducted for the chemotherapy responses between individuals with low- and high-SOCS1. Prediction of tumor response to checkpoint inhibitors was based on the tumor immunodeficiency and exclusion (TIDE) score. SOCS1 expression was significantly increased in both H. pylori-infected and STAD patients. Higher SOCS1 expression indicated an undesirable prognosis in STAD patients. SOCS1 upregulation was related to enhanced immune cell infiltrations and the upregulation of immune checkpoints in STAD patients. N stage, age and SOCS1 were identified as independent risk factors for higher mortality of STAD patients and confirmed using the nomogram. Drug sensitivity analyses demonstrated that high expression of SOCS1 in STAD patients could improve the sensitivity to chemotherapy. TIDE score showed that STAD patients with high SOCS1 expression would have superior response to immunotherapy. SOCS1 may act as a potential biomarker for uncovering the underlying mechanisms of gastric cancer. Increasing the activity of immunotherapy through ferroptosis-immunomodulation may be a viable strategy in STAD therapy.


N-pyrene dodecanoyl sulfatide as membrane probe: a study of glycolipid dynamic behavior in model membranes.
An N-linked pyrene-dodecanoyl sulfatide was employed to measure the ratio of excimer fluorescence to monomer fluorescence intensities (E/M). The E/M values provided information about both the dynamic behavior and the structural distribution of the labelled glycolipid in note dispersion of micellar sulfatides and multilamellar vesicles of different phospholipids. Most of the labelled sulfatide seems to be located in domains sequestered from the surrounding phospholipids still above the phase transition temperature of the vesicles. The glycolipids sequestered in these domain environments are less sensitive to the structural changes that the addition of cholesterol or Ca2+ can induce in the phospholipid regions during the phase transition.


Osteomyelitis and Septic Arthritis of the Foot and Ankle: Imaging Update.
Radiography is considered the first-line screening exam for clinically suspected osteomyelitis. However, additional evaluation is generally needed. MRI is the definitive diagnostic exam with high sensitivity and specificity combined with excellent anatomic definition. Gadolinium contrast can be useful to detect areas of devitalization before surgery. Bone marrow edema on fluid-sensitive images and low signal intensity on T1-weighted images in the presence of secondary MRI findings, including ulcer, sinus tract, and cellulitis with or without abscess are typical findings of osteomyelitis. If MRI is contraindicated, three phase bone scan can be used. Early diagnosis and treatment is essential.


Functional and Biomechanical Performance of Stentless Extracellular Matrix Tricuspid Tube Graft: An Acute Experimental Porcine Evaluation.
Stentless porcine extracellular matrix tricuspid tubular valves have been developed for tricuspid valve reconstruction. The purpose of this study was to compare biomechanical and functional performance of native and tube graft valves in an acute porcine model. Twenty-two 65-kg pigs were randomized to tube graft or control with native valve preservation. Anterior papillary muscle force was measured with a dedicated force transducer. Microtip pressure catheters were placed in the right atrium and ventricle. Leaflet motion and three-dimensional valve geometry were evaluated using 13 sonomicrometry crystals: six in the tricuspid annulus, one on each leaflet free edge, one on each papillary muscle tip, and one in the right ventricular apex. No regurgitation and no significant differences in intracavitary pressures, annular motion, or leaflet excursion angles were observed after tube graft implantation (p > 0.05). Compared with the native valve, the tricuspid annulus, leaflet orifice area, annular diameters, and the septal segment of the annulus were significantly smaller in the tube graft group (p < 0.05). Maximum anterior papillary muscle force was significantly lower in the tube graft group (p < 0.005). The implantation technique led to an annular circumferential downsizing of 20% ± 17%. An extracellular matrix tube graft implanted in the tricuspid position produces a competent valve with physiologic performance that, despite downsizing, makes the tube graft an attractive alternative to valve replacement. The downsizing of the implantation should be considered when planning tube graft size and may be potentially beneficial by relieving tension on the repaired tissue, thereby increasing durability.


Transition to adult care in cystic fibrosis: The challenges and the structure.
In developed countries, it is projected that there will be a 70% increase in the number of adults living with Cystic Fibrosis (CF) between 2010 and 2025. This shift in demographics highlights the importance of high-quality transition programmes with developmentally appropriate integrated health care services as the individual moves through adolescence to adulthood. Adolescents living with CF face additional and unique challenges that may have long-term impacts on their health, quality of life and life-expectancy. CF specific issues around socially challenging symptoms, body image, reproductive health and treatment burden differentiate people with CF from their peers and require clinicians to identify and address these issues during the transition process. This review provides an overview of the health, developmental and psychosocial challenges faced by individuals with CF, their guardians and health care teams considering the fundamental components and tools that are required to build a transition programme that can be tailored to suit individual CF clinics.


Aortic dissection detected by transoesophageal echocardiography.
The diagnostic value of transoesophageal echocardiography was evaluated in 24 patients with aortic dissection and compared to transthoracic two-dimensional echocardiography, computer tomography, aortography, surgery and autopsy. Using transoesophageal echocardiography we found in 5 patients a type I dissection, in 5 patients a type II and in 14 patients a type III dissection. Transthoracic two-dimensional echocardiography was positive in 3/5 type I, 2/5 in type II and 2/14 in type III dissections. Computer tomography was unable to demonstrate an intimal flap in 1/2 patients with type I, 2/3 type II and 1/11 type III dissections. Aortography was negative in 1/4 type I, 3/5 type II and 3/12 patients with type III dissection. Additional information concerning thrombus formation, localisation of the entry tear, differentiation between true and false lumen, flow dynamics within the true and false lumen as well as accompanying aortic regurgitation may be obtained by transoesophageal echocardiography.


Masticatory performance with one missing molar.
This study aimed to evaluate masticatory performance in cases where one molar was missing. Participants were 156 adults with one molar missing from their natural teeth, who were divided into group A (without prosthetic treatment) and group B (with prosthetic treatment). The non-missing side was designated as A1 or B1, and the missing side was designated as A2 or B2. The amount of glucose eluted (AG) when the participants chewed a gummy jelly was measured and used as a parameter for masticatory performance. AG was compared between the non-missing side (A1, B1) and missing side (A2, B2), and between the first molar missing group and second molar missing group. AG was significantly greater on the dentate side (P < 0.001) and was significantly less in the A2 group when the first molar was missing (P = 0.002). The rate of decrease of AG was 11.1%, 14.3%, and 8.4% in groups A+B, A, and B, respectively. Masticatory performance appears to decrease even with only one missing molar. Although improvement is achieved by prosthetic treatment, performance remains inferior to that on the dentate side.


Retracted: Activating Transcription Factor 3 Based Early Alarm Model of Acute Kidney Injury after Cardiopulmonary Bypass in Adults.
[This retracts the article DOI: 10.1155/2022/8076718.].


Metal-Free Aminocarbonylation of p-Quinone Methides with Isocyanides: Synthesis of Sterically Hindered α-Arylated Acetamides.
The synthesis of sterically hindered α-arylated acetamides generally requires a multistep reaction sequence and is also difficult to access due to steric constraints. This protocol allows the synthesis of sterically hindered α-arylated acetamides in moderate to high yields via 1,6-addition of isocyanides to p-quinone methides in the presence of BF3 .OEt2 . The present transformation features transition metal-free conditions, avoiding the use of toxic carbon monoxide, broad substrate scope, mild reaction conditions, and operational simplicity.


Injecting 5-HT into the PVN does not prevent feeding induced by injecting 8-OH-DPAT into the raphe.
The selective 5-hydroxytryptamine1A (5-HT1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) activates raphe somatodendritic autoreceptors, leading to an inhibition of 5-HT neuronal activity and reduced synthesis and release of 5-HT in forebrain terminal areas. One behavioural consequence of this is increased feeding in satiated rats. Because injections of 5-HT agonists into the medial hypothalamus suppress feeding, it has been proposed that 8-OH-DPAT-induced feeding may involve a reduction of 5-HT release within this area. This hypothesis was tested by examining the ability of 5-HT injected into the medial hypothalamus to reverse the feeding-stimulant action of 8-OH-DPAT following injection into the dorsal raphe or median raphe. Two groups of rats, maintained with free access to food at all times, were used. Each was prepared with two cannulae, one aimed at the paraventricular nucleus (PVN) of the medial hypothalamus and the other at either the dorsal raphe nucleus or median raphe nucleus. Food intake over the next hour was increased following dorsal raphe or median raphe injections of 8-OH-DPAT (1 and 0.5 microgram, respectively). These effects were not blocked by injections of 7.5 or 15 micrograms 5-HT into the PVN. However, 15 micrograms 5-HT did attenuate the feeding-stimulant action of 10 micrograms norepinephrine injected into the PVN. These results do not support the hypothesis that a reduction in 5-HT release within the medial hypothalamus is responsible for the feeding-stimulant action of 8-OH-DPAT.


Neuropeptide Y increases the inhibitory effects of clonidine on potassium evoked 3H-noradrenaline but not 3H-5-hydroxytryptamine release from synaptosomes of the hypothalamus and the frontoparietal cortex of the male Sprague-Dawley rat.
The release of 3H-noradrenaline (3H-NA) and of 3H-5-hydroxytryptamine (3H-5-HT) evoked by high-K+ (15 mM) was studied in synaptosomes isolated from the hypothalamus and the frontoparietal cortex of the male Sprague-Dawley rat using a superfusion apparatus. Based on concentration-response curves obtained by analyzing the full-time course of the inhibitory effects of clonidine on 3H-NA and on 3H-5-HT release neuropeptide Y (NPY) (1 nM) was shown to significantly increase the ability of clonidine to inhibit 3H-NA release in synaptosomes isolated from the hypothalamus and from the frontoparietal cortex. NPY (1 nM) alone had no effect on K+-evoked 3H-NA release from these regions. In contrast, NPY (1 nM) did not modulate the inhibitory effects of clonidine on 3H-5-HT release in the above mentioned regions. These results indicate that NPY can increase the sensitivity of the alpha 2-autoreceptors belonging to hypothalamic NA and/or to adrenaline nerve terminals and to cortical NA nerve terminals, while the alpha 2-heteroreceptors inhibiting 3H-HT release in the same brain regions appear not to be regulated by high affinity NPY receptors. Thus, alpha 2-autoreceptors and alpha 2-heteroreceptors appear to be differentially controlled by high affinity NPY receptors at least with regard to regulation of 3H-NA and 3H-5-HT release, respectively.


Endogenous nitric oxide in the rat pons promotes sleep.
Pontine cholinergic structures are known to play a key role in the regulation of vigilance states associated with desynchronised EEG, i. e., wakefulness and paradoxical sleep. As the cholinergic cells of these nuclei, the pedunculopontine tegmentum (PPT) and the laterodorsal tegmentum, are enriched with nitric oxide synthase (NOS), we tested the hypothesis that nitric oxide (NO) in the pons is implicated in wake and sleep regulation. For this reason, a NOS inhibitor, a NO precursor and a NO donor were injected in the PPT of rats. Vigilance states were recorded for 6 h following the injections. Quantification of vigilance states after drug injections were compared to those obtained in control conditions. It appeared that the NO donor had a slight effect on vigilance states, but the NOS inhibitor decreased sleep and inversely the NO precursor increased sleep. These results show for the first time in the rat that a NOS inhibitor, injected directly into the PPT, is able to reduce sleep and that a NO precursor had the opposite effect. They suggest that endogenous NO production in the PPT has a somnogenic effect. The participation of endogenous NO in vigilance regulation is discussed in light of the role attributed to pontine cholinergic system in wakefulness and sleep.


Early heat shock proteins in primary thymocytes. Evidence for transcriptional and translational regulation.
Primary isolates of thymic lymphocytes maintained in vitro provide a physiologically well-characterized system in which to study induction of proteins by heat shock; this response is agent-specific and separable from inductions by glucocorticoids or heavy metals (Maytin, E. V., and Young, D. A. J. Biol. Chem. 258, 12718-12722). Here we identify 68 heat shock protein inductions among more than 2,500 individual proteins separated on giant two-dimensional gels and further describe their time course of appearance, sensitivity to cordycepin (3'-deoxyadenosine), and reversibility during recovery. Thirty-one changes are detectable within 1 h. Among these early increases, 20 are inhibitable by cordycepin. However, 11 early changes are not affected by cordycepin; all represent proteins found in relatively low abundance. Five of these inductions are rapidly reversible during recovery from heat shock, in contrast to most other heat shock proteins whose synthesis is maintained or enhanced. One protein identified here appears to be increased by recovery per se. Overall, these results provide evidence for two separate classes of heat shock inductions in normal mammalian cells, i.e. a transcriptionally regulated group, not readily reversible during recovery, and a translationally regulated group in which several inductions rapidly revert to normal during recovery.


Comparative assessment of matrix metalloproteinase (MMP)-2 and MMP-9, and their inhibitors, tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in preeclampsia and gestational hypertension.
To compare the circulating levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitors of metalloproteinase (TIMP)-1, TIMP-2, and the MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios in preeclampsia and gestational hypertension with those found in normotensive pregnancies. We studied 83 pregnant women (30 healthy pregnant women with uncomplicated pregnancies, 26 with gestational hypertension, and 27 with preeclampsia) and 30 healthy nonpregnant women in a cross-sectional study. MMP and TIMP concentrations were measured in plasma samples by gelatin zymography and ELISA, respectively. We found higher plasma pro-MMP-9 levels, and higher pro-MMP-9/TIMP-1 ratios in women with gestational hypertension (95%-CI: 1.031 to 2.357, and 0.012 to 0.031, respectively), but not with preeclampsia, compared with those found in normotensive pregnant women (95%-CI: 0.810 to 1.350, and 0.006 to 0.013, respectively; both P<0.05). We found no significant differences in pro-MMP-2 levels (P>0.05). The higher net MMP-9 (but not MMP-2) activity in gestational hypertension compared with normotensive pregnancy suggests that MMP-9 plays a role in the pathophysiology of gestational hypertension. Conversely, the lack of such alterations in preeclampsia is consistent with the notion that different pathophysiological mechanisms are involved in these hypertensive disorders.


Obesity and total joint arthroplasty: Does weight loss in the preoperative period improve perioperative outcomes?
The obese population is more likely to develop degenerative joint disease requiring total joint arthroplasty (TJA) and also experience increased rates of adverse post-surgical outcomes. This study assessed whether a quantifiable weight loss prior to TJA had any impact on perioperative and 30-day outcomes in obese patients. Using the American College of Surgeons-National Surgical Quality Improvement Program database, obese patients who underwent total hip or total knee arthroplasty and lost at least 10% of their total body weight prior to surgery were identified and matched to other obese individuals undergoing the same procedures without weight loss. Perioperative outcomes, including operative time, length of stay, discharge destination, or 30-day adverse events, including complications, re-admissions, re-operations, and mortality, were then compared using conditional Logistic regression analysis. Analysis showed no difference between the two groups in terms of operative time, length of stay, discharge destination, or 30-day adverse events, including complications, re-admissions, re-operations, and mortality. The results of this study suggest that weight loss alone in the preoperative period may not be sufficient to mitigate the effects of obesity on immediate post-TJA outcomes.


Perinatal Mortality Despite Prenatal Diagnosis of Vasa Previa: A Systematic Review.
To determine the causes and potential preventability of perinatal deaths in prenatally identified cases of vasa previa. Reports of prenatally identified cases of vasa previa published in the English language literature since 2000 were identified in Medline and ClinicalTrials.gov with the search terms "vasa previa," "abnormal cord insertion," "velamentous cord," "marginal cord," "bilobed placenta," and "succenturiate lobe." All cases from the above search with an antenatally diagnosed vasa previa present at delivery in singleton or twin gestations with perinatal mortality information were included. Cases meeting inclusion criteria were manually abstracted, and multiple antenatal, intrapartum, and outcome variables were recorded. Deaths and cases requiring neonatal transfusion were analyzed in relation to plurality, routine hospitalization, and cervical length monitoring. A total of 1,109 prenatally diagnosed cases (1,000 singletons, 109 twins) were identified with a perinatal mortality rate attributable to vasa previa of 1.1% (95% CI 0.6-1.9%). All perinatal deaths occurred with unscheduled deliveries. The perinatal mortality rate in twin pregnancies was markedly higher than that in singleton pregnancies (9.2% vs 0.2%, P <.001), accounting for 80% of overall mortality despite encompassing only 9.8% of births. Compared with individuals with singleton pregnancies, those with twin pregnancies are more likely to undergo unscheduled delivery (56.4% vs 35.1%, P =.01) despite delivering 2 weeks earlier (33.2 weeks vs 35.1 weeks, P =.006). An institutional policy of routine hospitalization is associated with a reduced need for neonatal transfusion (0.9% vs 6.0%, P <.001) and a reduction in the perinatal mortality rate in twin pregnancies (0% vs 25%, P =.002) but not in singleton pregnancies (0% vs 0.5%, P =.31). Routine hospitalization and earlier delivery of twins may result in a reduction in the perinatal mortality rate. A smaller benefit from routine admission of individuals with singleton pregnancies cannot be excluded. There is currently insufficient evidence to recommend the routine use of cervical length measurements to guide clinical management.


Implementation of flash glucose monitoring in four pediatric diabetes clinics: controlled before and after study to produce real-world evidence of patient benefit.
To assess the real-world evidence for flash glucose monitoring (Abbott FreeStyle Libre) for children with type 1 diabetes in terms of glucose control, secondary healthcare resources and costs. We conducted a controlled before and after study (approximately 12 months before and after) using routinely collected health record data on children who start using flash monitors and a control population of children with self-monitoring of blood glucose (SMBG). Our population-based sample of eligible individuals using flash monitoring (n=114) and controls (n=80) aged between 4 and 18 years was drawn from four paediatric diabetes clinics (secondary care) in the South West England. Outcome measures included: glycated hemoglobin (HbA1c), frequency of BG tests; frequency of sensor scans; time in recommended glucose range; short-term complications (hypoglycemia, diabetic ketoacidosis and related illness resulting in investigation) and secondary care costs. After adjustment for age, time since diagnosis, deprivation and the test modality (point of care or laboratory), the mean HbA1c reading for controls was 61.2 (mmol/mol) for the period before and 63.9 after. For individuals using flash monitoring, the adjusted mean HbA1c reading was 64.6 for the period before implementation and 63.8 after. Rates of short-term complications were low across all groups in the study. Whereas the 'after' flash monitoring group had substantially higher incremental costs (+£703 vs the flash monitoring 'before' comparison and +£841 vs contemporaneous SMBG controls), these cost differences were driven by primary care prescribing (sensor costs). There was some indication that flash monitoring might help young people improve the control of their diabetes but for our sample, the difference between finger-prick testing and flash monitoring was not clinically significant (HbA1c improvement <5 mmol/mol). Given the pace of technological change within diabetes, research efforts should now facilitate the real-time analysis of long-term routine data on flash and continuous glucose monitors.


Pulmonary Artery Hypoplasia in Neonates With Tetralogy of Fallot.
Neonates with symptomatic tetralogy of Fallot (sTOF) with hypoplastic pulmonary arteries (hPA) are considered high risk. Data are needed to inform the impact of hPA on outcomes, and the ideal management strategy. The objectives of this study were to quantify the impact of hPA on outcomes in neonates with sTOF and measure the impact of strategy on pulmonary artery (PA) growth in this population. Neonates with sTOF from 2005 to 2017 were reviewed from the Congenital Cardiac Research Collaborative. Criteria for hPA included a unilateral PA z score <-2.0 and contralateral PA z score <0. Primary outcome was mortality. Secondary outcomes included reintervention and PA growth. We included 542 neonates with sTOF, including 188 (35%) with hPA and 354 (65%) with normal PA, with median follow-up of 4.1 years. Median right and left hPA z scores were -2.19 (25th-75th percentile: -2.55 to -1.94) and -2.23 (25th-75th percentile: -2.64 to -1.91), respectively. Staged repair (vs primary TOF repair) was less common in the hPA cohort (36 vs 44%; P = 0.07). Survival was similar between groups (unadjusted P = 0.16; adjusted P = 0.25). Reintervention was more common in the hPA group (HR: 1.28; 95% CI: 1.01-1.63; P = 0.044); there was no difference after definitive repair (HR: 1.21; 95% CI: 0.93-1.58; P = 0.16). PA growth at 1 year was greater in the hPA cohort, particularly for the right PA (P < 0.001). Despite perception, the presence of hPA in neonates with sTOF conferred no increase in overall hazard of mortality or reintervention after definitive repair. PA growth was superior in the hPA cohort. These findings suggest that the presence of hPA does not adversely impact outcomes in sTOF.


Congenital vulvar lymphangioma circumscriptum.
Lymphangioma circumscriptum (LC) is a defect of lymphatic channels in the deep dermis and subcutaneous layers, characterized by grouped vesicles. This disorder rarely occurs in vulvar sites. We present a rare case of LC in a 72-year-old patient who presented with a vulvar mass and ipsilateral leg edema.


[Production of histological preparations from implanted vascular protheses (author's transl)].
The above mentioned method is suitable for the production of intact histological preparations of implanted vascular protheses. An even mounting of the sections is as possible as the application of the usual staining procedures except those containing methanol or any other agent dissolving collodion.


A silent response to the obesity epidemic: decline in US physician weight counseling.
Guidelines recommend that physicians screen all adults for obesity and offer an intensive counseling and behavioral interventions for weight loss for obese adults. Current trends of weight-related counseling are unknown in the setting of the US obesity epidemic. To describe primary care physician (PCP) weight-related counseling, comparing counseling rates in 1995-1996 and 2007-2008. Data analysis of outpatient PCP visits in 1995-1996 and 2007-2008, as reported in the National Ambulatory Medical Care Survey. A total of 32,519 adult primary care visits with PCPs. Rates of counseling for weight, diet, exercise, and a composite variable, weight-related counseling (defined as counseling for weight, diet, or exercise) between survey years. Adjusted analyses controlled for patient and visit characteristics. Weight counseling declined from 7.8% of visits in 1995-1996 to 6.2% of visits in 2007-2008 [adjusted odds ratios, 0.64; 95% confidence intervals, 0.53, 0.79]. Rates of receipt of diet, exercise, and weight-related counseling similarly declined. Greater declines in odds of weight-counseling receipt were observed among those with hypertension (47%), diabetes (59%), and obesity (41%), patients who stand the most to gain from losing weight. Rates of weight counseling in primary care have significantly declined despite increased rates of overweight and obesity in the United States. Further, these declines are even more marked in patients with obesity and weight-related comorbidities, despite expectations to provide such care by both patients and policymakers. These findings have implications for determining deliverable, novel ways to engage PCPs in addressing the obesity epidemic.


Plasma levels of 15(S)15-methyl PGF2alpha following administration via various routes for induction of abortion.
Plasma levels of 15(S)15-methyl PGF2alpha were measured by gas chromatography - mass spectrometry following intravenous, intramuscular and subcutaneous administration. During intravenous infusion of 1.0 and 2.5 microgram/min of the drug for six hours the plasma levels were relatively constant around 600 and 1200 picog/ml, respectively. At an infusion rate of 5 microgram/min the plasma level continuously increased during the administration. Intramuscular injections of 100-400 microgram of 15(S)15-methyl PGF2alpha gave maximum levels in plasma (700-1700 picog/ml) after 15-20 minutes followed by a gradual decrease during more than three hours. This rapid resorption of drug into plasma could be delayed by addition of 5 microgram epinephrine to the injected solution. Analyses during a series of intramuscular injections demonstrated that a therapeutical plasma level could be maintained by injections at two to three hour intervals.


The prosome: an ubiquitous morphologically distinct RNP particle associated with repressed mRNPs and containing specific ScRNA and a characteristic set of proteins.
A novel ribonucleoprotein (RNP) particle showing a highly compact and characteristic structure in the electron microscope was found associated with globin and other repressed mRNA in the cytoplasm of duck, mouse and HeLa cells. This 19S complex is of extraordinary stability: dissociated by 0.5 M KCl or EDTA from the (still repressed) core globin mRNP, it can be purified on gradients containing 1% Sarkosyl, and resists (unfixed) caesium sulphate-dimethylsulphoxide density centrifugation. Its density of 1.31 g/cm3 indicates an RNP complex with a 15% RNA component. In mouse and duck it contains approximately 10 proteins in the 20 000-30 000 mol. wt. range, a few components of 50 000-70 000 mol. wt., and two specific small cytoplasmic RNAs (ScRNA) of 70-90 nucleotides. Both of these RNAs have identical 3'-terminal oligonucleotides. We propose the name 'prosome' for this ScRNP particle which somehow participates in negative control of mRNA translation, and we believe will prove to be ubiquitous to animal species.


Genetic Counseling in Kidney Disease: A Perspective.
As genetic testing is increasingly integrated into nephrology practice there is a growing need for partnership with genetic experts. Genetic counselors are ideally suited to fill this role. The value of genetic counseling is born out of the clinical value of genetic test results against the backdrop of the complexity of genetic testing. Genetic counselors who specialize in nephrology are trained to understand and explain the potential effects of genes on kidney disease, which can enable patients to make informed decisions about proceeding with genetic testing, navigating variants of uncertain significance, educating on extrarenal features of hereditary kidney disease, facilitating cascade testing, providing post-test education about testing results, and assisting with family planning. Genetic counselors can partner with the nephrologist and provide the knowledge needed to maximize the use of genetic testing for patients for nephrology consultation. Genetic counseling is more than an element or extension of genetic testing; it is a dynamic, shared conversation between the patient and the genetic counselor where concerns, sentiments, information, and education are exchanged, and value-based decision making is facilitated.


Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.
The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population. To compare treatment with sacubitril/valsartan treatment with valsartan in patients with advanced heart failure and a reduced ejection fraction and recent New York Heart Association class IV symptoms. A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk. Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy. The area under the curve (AUC) for the ratio of N-terminal pro-brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy. Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08; P = .45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non-life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%]; P = .04), there were no observed safety concerns. The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels. ClinicalTrials.gov Identifier: NCT02816736.


Frequent expression of the novel cancer testis antigen MAGE-C2/CT-10 in hepatocellular carcinoma.
Cancer testis (CT) antigens are attractive targets for immunotherapy in cancer patients. Immunohistochemistry was used to study the expression of the CT antigens MAGE-C2/CT-10, MAGE-C1/CT-7, GAGE, MAGE-A4 and NY-ESO-1 in 146 hepatocellular carcinomas, 13 intrahepatic cholangiocarcinomas, 37 extrahepatic cholangiocarcinomas and 32 gallbladder carcinomas. Immunopositivity was correlated with clinicopathological parameters, MHC Class 1 expression, intratumoral CD4+, CD8+ and FOXP3+ T cells and CD163+ antigen-presenting cells. Of the 146 hepatocellular carcinomas, 34% were positive for MAGE-C2/CT-10, 12% for MAGE-C1/CT-7, 11% for GAGE and 2% for NY-ESO-1, respectively. MHC Class 1 coexpression was identified in almost all CT antigen-positive tumors. The number of intratumoral FOXP3+ regulatory T cells was increased in CT antigen-positive hepatocellular carcinomas (p<0.004), suggesting inhibition of immune response in such tumors. Furthermore, MAGE-C1/CT-7 and GAGE positivity was correlated with reduced overall survival in patients with hepatocellular carcinoma (p=0.03 and 0.01, respectively). Four (13%) gallbladder carcinomas stained positive for MAGE-C2/CT-10, of which 1 tumor (3%) was also positive for NY-ESO-1 and GAGE. CT antigens were not expressed in intra- and extrahepatic cholangiocarcinomas. Our results suggest that MAGE-C2/CT-10 may be a good candidate for peptide vaccination in patients with hepatocellular carcinoma.


Redundant role of TLR9 for anti-Candida host defense.
The role of Toll-like receptor-9 (TLR9) in the recognition of Candida albicans and anti-Candida host defense was investigated in a murine model of disseminated candidiasis and in human peripheral blood mononuclear cells (PBMC). Blocking TLR9 by a specific inhibitor of human TLR9 or stimulation of cells isolated from TLR9-deficient (TLR9-/-) mice resulted in a 20-30% reduction in cytokine production induced by C. albicans. However, this defect was not accompanied by differences in mortality and organ fungal growth between TLR9-/- and TLR9+/+ mice. In conclusion, TLR9 is a pathogen-recognition receptor for C. albicans, and TLR9 is involved in the induction of cytokines in response to C. albicans. However, the cytokine defect in TLR9-/- mice is compensated by alternative pathways, and the TLR9-dependent pathway seems to be redundant in the disseminated candidiasis model in mice.


The mortality risk of being overweight in the twentieth century: Evidence from two cohorts of New Zealand men.
How have health and social mortality risks changed over time? Evidence from pre-1945 cohorts is sparse, mostly from the United States, and evidence is mixed on long-term changes in the risk of being overweight. We develop a dataset of men entering the NZ army in the two world wars, with objectively measured height and weight, and socioeconomic status in early adulthood. Our sample includes significant numbers of indigenous Māori, providing estimates of weight and mortality risk in an indigenous population. We follow men from war's end until death, with data on more than 12,000 men from each war. Overweight and obesity were important risk factors for mortality, and associated with shorter life expectancy. However, the reduction in life expectancy associated with being overweight declined from 5 to 3 years between the two cohorts, consistent with the hypothesis that being overweight became less risky during the twentieth century.


Cytosolic phospholipase A2 and F2 isoprostanes are involved in semen quality and human infertility-A study on leucocytospermia, varicocele and idiopathic infertility.
Phospholipase A2 (PLA2 ) is involved in eicosanoid release, and F2 -isoprostanes (F2 -IsoPs), as free radical-generated eicosanoids released by PLA2 , are indicators of oxidative stress in different human conditions. This study investigated the interplay between cytosolic PLA2 (cPLA2 ), F2 -IsoPs and sperm features in male infertility, when the involvement of oxidative stress has been reported. Semen evaluation was performed following WHO guidelines, sperm ultrastructure was detected by transmission electron microscopy indicating a fertility index, and the percentages of sperm immaturity, apoptosis and necrosis. In sperm cells and seminal plasma, cPLA2 levels were determined by immunological method, whereas F2 -IsoPs by mass spectrometry. Sperm concentration, morphology, vitality and fertility index values were significantly lower in infertile groups compared with fertile men. An increase in sperm apoptosis and necrosis (p < .01), apoptosis (p < .01) and immaturity (p < .001) was detected in leucocytospermia, idiopathic infertility and varicocele, respectively. Seminal cPLA2 showed the highest value in varicocele group (p < .05), whereas seminal F2 -IsoPs increased in varicocele (p < .001) and leucocytospermia (p < .05) groups. In the whole population, F2 -IsoP and cPLA2 levels were positively correlated (p < .05). On the contrary, F2 -IsoPs and cPLA2 were not significantly different when investigated in sperm cells. Our data indicate that fatty acid oxidation/metabolism plays a role in different male reproductive pathological conditions.


[Primitive malignant melanoma arising in a spinal nerve root. A case report].
We report the fourth case of primitive malignant melanoma arising in a spinal nerve root. A 39-year-old woman complained of one-year low back pain radiating to the right thigh and knee, and loss of 7 kg. Clinical examination found moderate quadricipital amyotrophy and hypoesthesia of anterior side of the thigh. MRI study demonstrated an enlargement of right L3 root with scalloping of the L3/L4 foramen. The T1-weighted MRI images showed a tumor hyperintensity, the T2-weighted images showed tumor isointensity and mild contrast enhancement. Due to the scalloping of L3/L4 foramen with root enlargement and slow evolution (more than one year between the first symptom and surgery without clinical worsening), the initial preoperative diagnosis was L3 schwannoma. After laminoarthrectomy and dural opening, a firm black lesion, well encapsulated and involved in a dorsal spinal root, was totally removed. The tumor was composed of irregular melanocytoid cells with high proliferation index (20%). Immunohistochemistry showed melanin, HMB-45 and S100 positivity, but reticulin was negative (that eliminates malignant melanocytic schwannoma). An extensive clinical and paraclinical research of other melanotic localisation was negative. So, the final diagnosis was intradural primitive malignant melanoma. Radiotherapy was performed on the site of the tumor. Fatal pulmonary metastasis occurred 18 months after surgery. The most common tumor with root enlargement and bony scalloping is the benign schwannoma. Despite the above described radiological features, MRI characteristics (hyperintensity when images are T1-weighted) suggest a melanocytic tumor, a tumor with a high adipose component or an intratumoral bleeding. Specific MRI sequences can eliminate adipose tissue tumor, but diagnosis between melanin and methemoglobin is still difficult. According to the index of proliferation, a primitive central melanocytic lesion can be a meningeal melanocytoma (considered as benign) or a primitive malignant melanoma. These tumors show identical protein expressions in immunohistochemistry, and their prognosis is very variable (some long-term remissions are reported for malignant melanomas and fast disseminations are described for meningeal melanocytomas treated by sub-total surgery). The L3/L4 foramen scalloping is unusual for a malignant lesion with theoretic high-speed development. The other 3 patients (reported in the literature) survive more than 3 years. The histological features of malignant lesion with benign clinical features lead to interrogation upon the actual pathologic classification.


Clinical significance of serum lipids in idiopathic pulmonary alveolar proteinosis.
It is well known that pulmonary alveolar proteinosis(PAP) is characterised by accumulation of surfactant lipids and proteins within airspaces. However, few previous data describe the serum lipid levels associated with PAP. We retrospectively reviewed 25 patients with idiopathic PAP(iPAP). The serum lipid levels of patients with idiopathic PAP were compared with those of the healthy volunteers. In patients and healthy subjects, the LDL-C/HDL-C ratios were 2.94 ± 1.21 and 1.60 ± 0.70, respectively (p < 0.001), HDL-C were 1.11 ± 0.27 and 1.71 ± 0.71 respectively (p < 0.001). The values of LDL-C correlated significantly with those of PaO2 and PA-aO2 (r = -0.685, p = 0.003, and r = 0.688, p = 0.003, respectively). The values of LDL-C/HDL-C ratios also correlated with PaO2 levels and PA-aO2 levels (r = -0.698, p = 0.003, and r = 0.653, p = 0.006, respectively). 11 and 13 patients experienced respectively a decline in TC and LDL-C levels following whole lung lavage(WLL), the median decline was 0.71 mmol/L(p < 0.009) and 0.47 mmol/L(p < 0.003), respectively. the serum lipid levels, especially the levels of LDL-C and LDL-C/HDL-C, may reflect the severity of the disease in PAP patients, and predict the therapeutic effect of WLL.


Basic science through engineering? Synthetic modeling and the idea of biology-inspired engineering.
Synthetic biology is often understood in terms of the pursuit for well-characterized biological parts to create synthetic wholes. Accordingly, it has typically been conceived of as an engineering dominated and application oriented field. We argue that the relationship of synthetic biology to engineering is far more nuanced than that and involves a sophisticated epistemic dimension, as shown by the recent practice of synthetic modeling. Synthetic models are engineered genetic networks that are implanted in a natural cell environment. Their construction is typically combined with experiments on model organisms as well as mathematical modeling and simulation. What is especially interesting about this combinational modeling practice is that, apart from greater integration between these different epistemic activities, it has also led to the questioning of some central assumptions and notions on which synthetic biology is based. As a result synthetic biology is in the process of becoming more "biology inspired."


Circadian clocks and tumor biology: what is to learn from human skin biopsies?
Some of the components of the circadian molecular clock have been shown to link directly to tumor suppression. Most studies on human tumorous biopsies with consistently down-regulated clock gene expression suggested a protective role for these genes against cancer formation. To highlight some limitations of this hypothesis we review these data in light of recent evidences from animal research, epidemiologic studies, and clinical data on skin tumors. We emphasize the role of circadian rhythmic orchestration in cellular metabolism with a potential in cancer development.


Adiponectin is expressed in the brown adipose tissue and surrounding immature tissues in mouse embryos.
Adiponectin is one of the adipocytokines, which are adipose-specific secretory factors. We examined its expression during embryogenesis. Transcripts of adiponectin were detected at a late stage of embryogenesis on embryonic (E) day E16.5. In situ hybridization showed that adiponectin transcripts were localized in brown adipose tissues (BATs) and surrounding immature tissues in mouse embryos. Immunohistochemistry using a specific anti-adiponectin antibody showed that the distribution of adiponectin closely parallels that of its mRNA. Adiponectin was also detected in serum at day E16.5, and its concentration peaked at birth. By contrast, transcripts of both the adiponectin receptors 1 and 2 were already expressed by day E12.5 in many tissues. Thus, their expression profile differed from that of adiponectin itself. Furthermore, experiments using primary cultures of brown adipocytes showed that adiponectin is regulated in brown adipocytes by various modulators, similar to its regulation in white adipose tissues (WATs). These data indicate that adiponectin has important roles in glucose and lipid metabolism during the perinatal period.


Development of carpal tunnel syndrome in association with checkpoint inhibitors.
The incidence of neuropathy with checkpoint inhibitors is 0.3-1%, typically occurring 2-12 weeks after treatment initiation. Common neuropathy phenotypes include inflammatory myopathies, myasthenia gravis, acute and chronic demyelinating polyradiculopathies, vasculitic neuropathies, isolated cranial neuropathies, aseptic meningitis, autoimmune encephalitis, multiple sclerosis and hypophysitis. Carpal tunnel syndrome is the most common entrapment neuropathy in the general population; however, the association of carpal tunnel syndrome with checkpoint inhibitors is exceedingly rare. We report two cases of patients with no prior history of carpal tunnel syndrome treated with checkpoint inhibitors that developed de novo bilateral carpal tunnel syndrome.Management & Outcome: For both patients, the neurologic symptoms improved with cessation of the checkpoint inhibitor and initiation of corticosteroids. Given the prevalence of carpal tunnel syndrome in the general population, a high index of suspicion for carpal tunnel in patients receiving checkpoint inhibitors and prompt treatment with corticosteroids is essential.


Relationship between left-axis deviation and onset of cardiac adverse events in right ventricular pacing.
The electrical axis shows alterations during right ventricular pacing (RVP), including a normal axis and left axis deviation; however, it remains unknown if differences in the electrical axis affect the occurrence of cardiac adverse events. The purpose of this study was to determine whether a left axis deviation increases the incidence of adverse cardiac events compared with a normal axis. This study analysed 156 patients with RVP. The patients were divided into two groups: those with left axis deviation after RVP (LAD group) and those with a normal axis (NA group). The primary composite outcome was the new-onset of atrial fibrillation (AF) and worsening heart failure (HF). The QRS axis of the LAD (n = 77) and NA (n = 79) groups were - 64.5 ± 14.3° and 29.8 ± 36.5°, respectively (P < 0.001). The median follow-up was 1100 days and, regarding primary composite outcomes (hazard ratio, 1.03; 95% confidence interval, 0.64 to 1.65; P = 0.89), 29/77 (37.6%) and 28/79 (35.4%) patients in the LAD and NA groups, respectively, developed AF (hazard ratio, 1.07; 95% confidence interval, 0.64 to 1.81; P = 0.77). Furthermore, 8/77 (10.3%) and 12/79 (15.1%) patients in the LAD and NA groups, respectively, experienced worsening HF (hazard ratio, 0.65; 95% confidence interval, 0.26 to 1.60; P = 0.35). The risk of cardiac adverse events in patients with RVP (new-onset AF or worsening HF, cardiovascular death, myocardial infarction, and stroke) and overall mortality with LAD is not higher than that with NA.


Application of HbA2 levels and red cell indices-based new model in the differentiation of thalassemia traits from iron deficiency in hypochromic microcytic anemia Cases.
Thalassemia traits and iron deficiency anemia are the most common types of hypochromic microcytic anemia with similar clinical and laboratory features. It is vital to establish a new screening model based on HbA2 levels and red cell indices for the differentiation of TT from IDA in hypochromic microcytic anemia cases. The data comprised of the red blood cell indices and HbA2 prenatal diagnostic test results of 810 individuals who were identified to conform to the following criteria: MCV < 80 fl or MCH < 26 pg. We launched a new model consisting mainly of significative red cell indices and HbA2 levels, as well as proposing cutoff values by using decision trees and logistic regression analyses. Next, we evaluated our new method by comparing the sensitivity, specificity, positive, and negative predictive values with those of the previous formulas. We put forward a new model and compared it with 5 efficient formulas. The new model exhibited the highest accuracy (0.918), with its sensitivity and specificity calculated as 0.917 and 0.921, respectively. Our new model's Youden index was 0.838, which is higher than the other formulas' Youden indices. The new screening model, based on HbA2 levels and red cell indices, is suitable for the screening of thalassemia patients in the hypochromic microcytic anemia group and has the best efficiency in distinguishing TT and IDA.