Evaluation of a bracketing calibration-based isotope dilution liquid chromatography-tandem mass spectrometry candidate reference measurement procedure for 17α-hydroxyprogesterone in human plasma.
A candidate reference measurement procedure (RMP) based on isotope dilution coupled with liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) was developed and validated for the quantification of 17α-hydroxyprogesterone (17-OHP) in human plasma. 17-OHP spiked with a deuterium-labeled internal standard was extracted from plasma by liquid-liquid extraction with 1 mL n-hexane/ethyl acetate (3:2, v/v). Reversed-phase chromatography and positive electrospray ionization were used in the ID-LC-MS/MS. Gradient elution coupled with use of a C18-packed ultrahigh-performance liquid chromatography column allowed complete baseline resolution of 17-OHP from its structural analogue desoxycorticosterone in 6 min. To determine the 17-OHP level in human plasma, a bracketing calibration method was used to give higher accuracy and precision. The limit of detection and the lower limit of the measuring interval for the candidate RMP were 2.1 pg/mL (6.4 pmol/L) and 4.6 pg/mL (13.9 pmol/L), respectively. Extraction recovery was determined to be (96.08 ± 3.03)% (n = 3). Imprecision (intra-assay and interassay) was 4.03% or less at 0.83, 15.19, 64.22, and 313.46 ng/mL (2.51, 45.97, 194.34, and 948.56 nmol/L, respectively). Recoveries ranged from 98.05% to 102.24%. When comparing our RMP results with those obtained with an established RMP via International Federation of Clinical Chemistry and Laboratory Medicine external quality assessment scheme for reference laboratories in laboratory medicine (RELA) samples, we found that the biases ranged from -1.99% to 3.08% against the targets. No interference was observed, and the linear response ranged from 0.47 to 958.63 ng/mL (1.42 to 2900.90 nmol/L). Moreover, the candidate RMP was used to measure the concentration of 17-OHP in human plasma and was compared with an immunoassay using 40 plasma samples. The performance of the method meets the needs of an RMP (total coefficient of variation of 5% or less and bias of 3.08% or less). This method can be used for reference material value assignment of 17-OHP in human plasma matrix. It could also serve as an accurate reference baseline for routine methods to increase the accuracy and precision of certain clinical laboratory measurements. Graphical abstract Selected ion chromatograms obtained by liquid chromatography-tandem mass spectrometry with a C18 column for 17α-hydroxyprogesterone (17-OHP) from a plasma sample.


Identification and function of the second eIF4E-binding region in N-terminal domain of eIF4G: comparison with eIF4E-binding protein.
The eukaryotic initiation factor 4E (eIF4E) serves as a master switch that controls mRNA translation through the promotive binding to eIF4G and the regulative binding with the endogenous inhibitor 4E-BP. Although the bindings of eIF4G and 4E-BP to eIF4E proceed through the common eIF4E recognition Y(X)(4)Lφ motif (X: variable, φ: hydrophobic) (first binding site), the relationship between their eIF4E binding mode and the functional difference is hardly known. Recently, we have clarified the existence and function of the second eIF4E binding site in 4E-BP. Surface plasmon resonance (SPR) analysis based on the sequential comparison between 4E-BP and eIF4GI clarified that eIF4G has the second binding site at the periphery of the (597)SDVVL(601) sequence and that it plays an auxiliary but indispensable function in stabilizing the binding of the first binding sequence (572)YDREFLL(578). The kinetic parameters of the interactions of the eIF4GI and 4E-BP2 fragment peptides with eIF4E showed that the association (ka) and dissociation (kd) rates of the former peptide are about three and two orders of magnitude lower than those of the latter peptide, respectively. This means that eIF4G has a potent resistive property for release from eIF4E, although its rate of binding to eIF4E is not as high as that of 4E-BP, that is, 4E-BP is apt to bind to and be released from eIF4E, as compared with eIF4G. Isothermal titration calorimetry (ITC) showed the opposite behavior between the second binding sites of eIF4GI and 4E-BP for the interaction with eIF4E. This clearly indicates the importance of the second binding region for the difference in function between eIF4G and 4E-BP for eIF4E translation.


Interference between pathway-specific transcription factors: glucocorticoids antagonize phorbol ester-induced AP-1 activity without altering AP-1 site occupation in vivo.
Phorbol esters stimulate and glucocorticoid hormones down-regulate a variety of promoters such as that of the collagenase gene through the transcription factor AP-1 (Fos/Jun). We now show by genomic footprinting of the collagenase promoter that phorbol ester treatment of cells results in the binding of AP-1 to its cognate DNA binding site in vivo. The DNA-protein contacts obtained in living cells are also found in vitro using cloned DNA and purified AP-1. Although in vitro synthesized glucocorticoid receptor can disturb the DNA binding of Jun homodimers, it does not interfere with the binding of Fos-Jun heterodimers or of purified AP-1 in vitro. Consistently, fully inhibitory doses of glucocorticoid hormone cause no change in apparent occupation of the AP-1 binding site in vivo. The hormone receptor acts without itself binding to DNA.


Adrenocorticotropin and cortisol responses to a naloxone challenge and risk of alcoholism.
Because abnormalities in opioid neurotransmission appear to underlie some of the inherited risk for alcoholism, we examined the effects of naloxone, an opioid antagonist, on corticotropin and cortisol responses in nonalcoholic subjects differentiated by paternal history of alcoholism. Placebo-controlled, balanced, within-subject design involving 2 test days over a period of 3 to 7 days. Thirty-six subjects (67% male; 53% paternal-history-positive; mean age = 25.0 years) were screened to exclude substance abuse or dependence. Subjects received intravenous naloxone 125 microg/kg or placebo, with sessions in random order. Plasma corticotropin and cortisol were measured for up to 120 min post infusion. Corticotropin responses at baseline and following naloxone did not differ by paternal history of alcoholism; however, paternal-history-positive subjects exhibited greater cortisol concentrations at baseline, and at 15 and 30 min after naloxone administration. Paternal-history-positive subjects also had an earlier and greater peak cortisol response to naloxone and a nonsignificant trend for a greater area under the cortisol time curve than paternal-history-negative subjects. These findings suggest that individuals with greater vulnerability to alcoholism may have altered Hypothalamic-pituitary axis (HPA) dynamics, a finding that is consistent with a growing body of data on the role of opioidergic neurotransmission in the inherited risk of alcoholism.


Cystic Fibrosis & disorders of the large intestine: DIOS, constipation, and colorectal cancer.
Since 1966 when the Cystic Fibrosis Foundation Patient Registry (CFFPR) was founded, clinicians have witnessed significant advances in both the quality and quantity of life for patients living with Cystic Fibrosis (CF). As patients with CF live longer and fuller lives, increasing encumbrances from gastrointestinal manifestations of CF will be observed. This article serves to discuss "below the diaphragm" concerns involving the large intestine (Distal Intestinal Obstruction Syndrome, Constipation, and Colorectal Cancer). Avenues for development and implementation of clinical care protocols, particularly regarding proactive management of known associated conditions and cancer screening, will continue to be refined in the coming years. It falls to the multidisciplinary CF care team to be actively engaged in addressing these concerns effectively as priority shifts from relative acuity (typically related to early nutrition and lung function) to the travails of longevity as the CF population continues to age.


Relative in vitro effectiveness of 17 alpha, 20 beta-dihydroxy-4-pregnen-3-one and other pregnene derivatives on germinal vesicle breakdown in oocytes of ayu (Plecoglossus altivelis), amago salmon (Oncorhynchus rhodurus), rainbow trout (Salmo gairdneri), and goldfish (Carassius auratus).
The relative effectiveness of several pregnene derivatives, which had previously been identified in the ovaries of ayu (Plecoglossus altivelis), on germinal vesicle breakdown (GVBD) was investigated in vitro using folliculated oocytes of four species of teleosts, ayu, amago salmon (Oncorhynchus rhodurus), rainbow trout (Salmo gairdneri), and goldfish (Carassius auratus). Although some species differences existed in the relative effectiveness of each steroid on GVBD, 17 alpha, 20 beta-dihydroxy-4-pregnen-3-one (17 alpha, 20 beta-diOHprog) was consistently the most potent inducer of final oocyte maturation. Both progesterone and 17 alpha-hydroxyprogesterone were effective at relatively high concentrations. Of the 5 beta-reduced metabolites, 17 alpha, 20 beta-dihydroxy-5 beta-pregnan-3-one was almost as effective as 17 alpha, 20 beta-diOHprog in oocytes of amago salmon and rainbow trout, while the other 5 beta-reduced compounds (3 alpha-hydroxy-5 beta-pregnan-20-one, 17 alpha-hydroxy-5 beta-pregnane-3,20-dione, 3 alpha, 17 alpha-dihydroxy-5 beta-pregnan-20-one, 5 beta-pregnane-3 alpha, 17 alpha, 20 beta-triol, and 5 beta-pregnane-3 beta, 17 alpha, 20 beta-triol) were almost or totally ineffective at the concentrations tested (1-0.001 micrograms/ml). These bioassay results, together with previous findings on the capacity of the ovary to produce 17 alpha, 20 beta-diOHprog, indicate that 17 alpha, 20 beta-diOHprog is the natural maturation-inducing steroid hormone common to three species of Salmoniformes, ayu, amago salmon, and rainbow trout. These results, however, only suggest that 17 alpha, 20 beta-diOHprog is involved in maturation of goldfish oocytes, since supportive physiological and biochemical data are lacking. Possible regulatory roles of 5 beta-reduced metabolites on steroid-induced oocyte maturation are discussed.


The quality of denominator data in surgical site infection surveillance versus administrative data in Norway 2005-2010.
High quality of surveillance systems for surgical site infections (SSIs) is the key to their usefulness. The Norwegian Surveillance System for Antibiotic Consumption and Healthcare-Associated Infections (NOIS) was introduced by regulation in 2005, and is based largely on automated extraction of data from underlying systems in the hospitals. This study investigates the quality of NOIS-SSI's denominator data by evaluating completeness, representativeness and accuracy compared with de-identified administrative data for 2005-2010. Comparisons were made by region, hospital type and size, age and sex for 4 surgical procedures. The completeness of NOIS improved from 29.2 % in 2005 to 79.8 % in 2010. NOIS-SSI became representative over time for most procedures by hospital size and type, but not by region. It was representative by age and sex for all years and procedures. Accuracy was good for all years and procedures by all explanatory variables. A flexible and incremental implementation strategy has encouraged the development of computer-based surveillance systems in the hospitals which gives good accuracy, but the same strategy has adversely affected the completeness and representativeness of the denominator data. For the purpose of evaluating risk factors and implementing prevention and precautionary measures in the individual hospitals, representativeness seems sufficient, but for benchmarking and/or public reporting it is not good enough.


Synthesis and physicochemical properties of thiadiazolo[3,2-a]pyrimidinesulfonamides and thiadiazolo[3,2-a]triazinesulfonamides as candidates for topically effective carbonic anhydrase inhibitors.
A series of bicyclic 1,3,4-thiadiazolo[3,2-a]pyrimidine- and 1,3,4-thiadiazolo[3,2-a]triazine-7-sulfonamides were synthesized from 5-amino-1,3,4-thiadiazole-2-sulfonamide and evaluated for topical efficacy as ocular hypotensive agents. The compounds were tested for the physicochemical properties of sulfonamide pKa, free acid water solubility, CHCl3/buffer partition, and transcorneal penetration (kin), as well as for activity against carbonic anhydrase (I50). A number of these compounds exhibited lower sulfonamide pKa and higher water solubility than those of acetazolamide (1) and methazolamide (2), and one, 12, brought about a small reduction in IOP in the normal rabbit eye.


Perceived access to cannabis and ease of purchasing cannabis in retail stores in Canada immediately before and one year after legalization.
Background: Canada legalized non-medical cannabis in October 2018. Little research has examined the change in perceived access to cannabis after legalization in Canada, including the perceived ease of purchasing cannabis in a legal market.Objectives: To: 1) describe changes in perceived ease of access to cannabis before and one year after legalization; 2) examine associations between perceived ease of cannabis access and cannabis use; and 3) examine associations between perceived ease of purchasing from cannabis stores and cannabis use.Methods: Repeat cross-sectional data come from Canadian respondents aged 16-65 (50% male) in August-October 2018 (n = 10,057) and September-October 2019 (n = 15,256). Respondents were recruited through commercial online panels. Multivariable logistic regression models examined correlates of perceived proximity to retail stores, ease of access, and ease of purchasing from retail stores.Results: Canadians who do not consume cannabis were more likely to report "easy" access to cannabis in 2019 than in 2018 (55% vs. 42%; AOR = 1.80:1.66,1.96). All cannabis consumer groups were more likely to report living 15 minutes or less from a retail store in 2019 than 2018, but the association was strongest among non-consumers in 2019 vs 2018 (AOR = 2.01:183,2.21 vs. AOR = 1.33:1.03,1.73 for daily consumers). Non-daily and daily cannabis consumers were more likely to report it was easy to purchase from an illegal (AOR ranged 1.58-2.22) or legal (AOR ranged 1.31-1.39) store than non-consumers in 2019.Conclusion: Most cannabis consumers and non-consumers perceived access to cannabis as 'easy' before legalization and the percentage increased one year after legalization.


Squaraines bearing halogenated moieties as anticancer photosensitizers: Synthesis, characterization and biological evaluation.
We report the synthesis and characterization of a series of symmetrical indolenine-based squaraine dyes along with the evaluation of their singlet oxygen generation efficiency. The photodynamic activity of these new photosensitizers has been evaluated on a human tumor fibrosarcoma (HT-1080) cell line. The cytotoxicity increased over time and is induced by the photoactivation of bromo (Br-C4) and iodio (I-C4) long carbon chain squaraine dyes and the consequent increase in reactive oxygen species (ROS) production (p < 0.001), which leads to necrosis 6 h after treatment. Induction of cytochrome c release, DNA damage and up-regulation of GPX1, NQO1 and SOD2 mRNA gene expression after PDT were investigated.


Ventricular diverticula with localized dysgenesis of the temporal lobe in cloverleaf skull anomaly.
An early fetal case of cloverleaf skull anomaly associated with thanatophoric chondrodystrophy is described. Localized ventricular diverticula are a peculiar finding. In addition there are previously described malformations limited to the temporal lobes and comprising plump gyri with abnormal deep sulci, thick periventricular heterotopias, dysgenesis of the parahippocampal gyrus, agenesis of the Ammon's horn, and small micropolygyria. The skull deformity is not dependent on hydrocephalus, demonstrating inconsistencies in previous pathogenetic concepts.


Cost-effectiveness of paclitaxel-coated balloon angioplasty in patients with drug-eluting stent restenosis.
The economic impact of drug-eluting stent (DES) in-stent restenosis (ISR) is substantial, highlighting the need for cost-effective treatment strategies. Compared to plain old balloon angioplasty (POBA) or repeat DES implantation, drug-coated balloon (DCB) angioplasty is a cost-effective therapy for DES-ISR. A Markov state-transition model was used to compare DCB angioplasty with POBA and repeat DES implantation. Model input parameters were obtained from the literature, and the cost analysis was conducted from a German healthcare payer's perspective. Extensive sensitivity analyses were performed. Initial procedure costs amounted to €3488 for DCB angioplasty and to €2782 for POBA. Over a 6-month time horizon, the DCB strategy was less costly (€4028 vs €4169) and more effective in terms of life-years (LYs) gained (0.497 versus 0.489) than POBA. The DES strategy incurred initial costs of €3167 and resulted in 0.494 LYs gained, at total costs of €4101 after a 6-month follow-up. Thus, DCB angioplasty was the least costly and most effective strategy. Base-case results were influenced mostly by initial procedure costs, target lesion revascularization rates, and the costs of dual antiplatelet therapy. DCB angioplasty is a cost-effective treatment option for coronary DES-ISR. The higher initial costs of the DCB strategy compared to POBA or repeat DES implantation are offset by later cost savings.


Functional attachment of primary neurons and glia on radiopaque implantable biomaterials for nerve repair.
Repairing peripheral nerve injuries remains a challenge, even with use of auxiliary implantable biomaterial conduits. After implantation the location or function of polymeric devices cannot be assessed via clinical imaging modalities. Adding nanoparticle contrast agents into polymers can introduce radiopacity enabling imaging using computed tomography. Radiopacity must be balanced with changes in material properties impacting device function. In this study radiopaque composites were made from polycaprolactone and poly(lactide-co-glycolide) 50:50 and 85:15 with 0-40 wt% tantalum oxide (TaOx) nanoparticles. To achieve radiopacity, ≥5 wt% TaOx was required, with ≥20 wt% TaOx reducing mechanical properties and causing nanoscale surface roughness. Composite films facilitated nerve regeneration in an in vitro co-culture of adult glia and neurons, measured by markers for myelination. The ability of radiopaque films to support regeneration was driven by the properties of the polymer, with 5-20 wt% TaOx balancing imaging functionality with biological response and proving that in situ monitoring is feasible.


Velocity of change in vegetation productivity over northern high latitudes.
Warming is projected to increase the productivity of northern ecosystems. However, knowledge on whether the northward displacement of vegetation productivity isolines matches that of temperature isolines is still limited. Here we compared changes in the spatial patterns of vegetation productivity and temperature using the velocity of change concept, which expresses these two variables in the same unit of displacement per time. We show that across northern regions (>50° N), the average velocity of change in growing-season normalized difference vegetation index (NDVIGS, an indicator of vegetation productivity; 2.8 ± 1.1 km yr-1) is lower than that of growing-season mean temperature (T GS; 5.4 ± 1.0 km yr-1). In fact, the NDVIGS velocity was less than half of the T GS velocity in more than half of the study area, indicating that the northward movement of productivity isolines is much slower than that of temperature isolines across the majority of northern regions (about 80% of the area showed faster changes in temperature than productivity isolines). We tentatively attribute this mismatch between the velocities of productivity and temperature to the effects of limited resource availability and vegetation acclimation mechanisms. Analyses of ecosystem model simulations further suggested that limited nitrogen availability is a crucial obstacle for vegetation to track the warming trend.


Feasibility of using a walking workstation during CT image interpretation.
Two-thirds of the US population is overweight or obese. Sedentary lifestyles and occupations are one factor in the development of obesity. Methods to help reduce sedentary work environments may help reduce obesity. The purpose of this study was to determine the feasibility of using a walking workstation during computed tomographic image interpretation. Two radiologists reinterpreted 100 clinical computed tomographic examinations they had previously interpreted, each while walking at 1 mph on a treadmill using an electronic workstation. Ten cases were reviewed per session. The time period between the initial conventional interpretations and the reinterpretations was greater than one year, to reduce recall bias. Discrepant findings were ranked according to a classification system based on clinical importance on a scale ranging from 1 to 6. Discrepant findings classified as greater than or equal to 3 were considered significant. Detection rates for the initial interpretations and reinterpretations were determined for each reviewer and compared using a paired t-test. A total of 1,582 findings were reported (825 by reviewer 1 and 757 by reviewer 2). There were 459 findings with clinical importance of 3 or higher. For reviewer 1 (91 cases of at least one important finding), the mean detection rates were 99.0% for the walking technique and 88.9% for the conventional interpretations (P = .0003). For reviewer 2 (89 cases with at least one important finding) the mean detection rates were 99.1% for the walking technique and 81.3% for the conventional interpretations (P < .0001). The use of a walking workstation for the interpretation of cross-sectional images is feasible. Further studies are needed to assess the potential impact on diagnostic accuracy.


Disentangling Social-Genetic From Rearing-Environment Effects for Alcohol Use Disorder Using Swedish National Data.
Investigations of social-genetic effects, whereby a social partner's genotype affects another's outcomes, can be confounded by the influence of the social partner's rearing environment. We used marital information on more than 300,000 couples from Swedish national data to disentangle social-genetic from rearing-environment effects for alcohol use disorder (AUD). Using observational and extended-family designs, we found that (a) marriage to a spouse with a predisposition toward AUD (as indexed by a parental history of AUD) increased risk for developing AUD; (b) this increased risk was not explained by socioeconomic status, the spouse's AUD status, or contact with the spouse's parents; and (c) this increased risk reflected the psychological consequences of the spouse having grown up with an AUD-affected parent (i.e., a rearing-environment effect) rather than a social-genetic effect. Findings illustrate that a spouse's rearing-environment exposures may confer risk for AUD.


Structure of Vibrio Phage XM1, a Simple Contractile DNA Injection Machine.
Antibiotic resistance poses a growing risk to public health, requiring new tools to combat pathogenic bacteria. Contractile injection systems, including bacteriophage tails, pyocins, and bacterial type VI secretion systems, can efficiently penetrate cell envelopes and become potential antibacterial agents. Bacteriophage XM1 is a dsDNA virus belonging to the Myoviridae family and infecting Vibrio bacteria. The XM1 virion, made of 18 different proteins, consists of an icosahedral head and a contractile tail, terminated with a baseplate. Here, we report cryo-EM reconstructions of all components of the XM1 virion and describe the atomic structures of 14 XM1 proteins. The XM1 baseplate is composed of a central hub surrounded by six wedge modules to which twelve spikes are attached. The XM1 tail contains a fewer number of smaller proteins compared to other reported phage baseplates, depicting the minimum requirements for building an effective cell-envelope-penetrating machine. We describe the tail sheath structure in the pre-infection and post-infection states and its conformational changes during infection. In addition, we report, for the first time, the in situ structure of the phage neck region to near-atomic resolution. Based on these structures, we propose mechanisms of virus assembly and infection.


Intravesical bacillus Calmette-Guérin and second primary malignancies.
In an effort to answer the question, "Does intravesical bacillus Calmette-Guérin (BCG) therapy increase the incidence of second primary malignancies," the records of 153 patients treated with BCG for carcinoma in situ of the urinary bladder were reviewed. The weight of the available evidence suggests that intravesical BCG does not increase the incidence of second primary malignancies. While this question should be investigated, at the present time it appears that the advantage of intravesical BCG for high-risk patients with superficial bladder cancer outweighs the known disadvantages.


The Arterial Anastomosis Between Deep Inferior Epigastric Artery and Small Polar Renal Artery in Kidney Transplantation: A Case Report.
The presence of multiple renal arteries is the most common form of vascular anomalies found in donor kidneys. In rare cases, small renal polar arteries may be found. They can be anastomosed with deep inferior epigastric arteries, resulting in vascular augmentation of transplanted kidneys and contributing to better graft function. Renal perfusion may be increased via 2 types of vascular reconstruction known as "turbocharging" and "supercharging". Turbocharging uses vascular sources within the same organ area, whereas supercharging uses distant vascular sources. Using additional vessels can either complicate the surgery or, contradictorily, ease the way of procedure. This case study presents a kidney transplant during which arterial anastomosis between deep inferior epigastric artery and small polar renal artery was performed.


Fetal renal pelvic dilatation--poor predictor of familial vesicoureteral reflux.
The sensitivity and positive predictive value (PPV) of fetal renal pelvic dilatation for detecting vesicoureteral reflux (VUR) can only be determined by performing voiding cystourethrography (VCUG) on all newborns in a study population. We sought to determine this for infants with a family history of reflux. From June 1989 to September 1996, 157 children (80 males) under 2 years with a family history of primary VUR in a first-degree relative had VCUG. VCUG results were compared with the fetal renal pelvic diameter on obstetric sonogram performed after 16 weeks gestation. Of the 157 infants, 33 (11 boys) had primary VUR. In those with a parent as the index case, the prevalence of reflux was 5% in boys and 35% in girls ( P=0.03). The largest renal pelvic diameter after 16 weeks was not discriminatory for VUR, but after 30 weeks gestation a 4 mm renal pelvis had a sensitivity of 33% and a PPV of 32%. The sensitivity was higher for grades 4 and 5 (75%) than for grades 1-3 reflux (17%), ( P=0.04). In conclusion, fetal renal pelvic diameter has a low sensitivity and poor predictive value for detecting VUR, but this improves a little after 30 weeks gestation.


Sargachromanol G inhibits osteoclastogenesis by suppressing the activation NF-κB and MAPKs in RANKL-induced RAW 264.7 cells.
Inflammatory cytokines play a major role in osteoclastogenesis, leading to the bone resorption that is frequently associated with osteoporosis. Sargachromanol G (SG), isolated from the brown alga Sargassum siliquastrum, inhibits the production of inflammatory cytokines. In the present study, we determined the effect of SG on receptor activator of NF-κB ligand (RANKL)-induced osteoclast formation. SG inhibited RANKL-induced osteoclast differentiation from RAW264.7 cells without signs of cytotoxicity. Additionally, the expression of osteoclastic marker genes, such as tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), matrix metalloproteinase 9 (MMP9), and calcitonin receptor (CTR), was strongly inhibited. SG inhibited RANKL-induced activation of NF-κB by suppressing RANKL-mediated IκB-α degradation. Furthermore, SG inhibited RANKL-induced phosphorylation of mitogen activated protein kinases (p38, JNK, and ERK). This study identified SG as an inhibitor for osteoclast formation and provided evidence that natural compounds, such as SG, are an alternative medicines for preventing and treating osteolysis.


[Thermal epiglottitis in a 3-month-old infant following feeding of hot vegetables].
A thermal epiglottitis after feeding hot food is a rare event in infancy. A 3 month old infant developed typical symptoms of an acute epiglottitis after feeding him hot vegetables. The child was intubated and treated with steroids and antibiotics. A laryngo-tracheobronchoscopy was performed. After 48 h he was extubated.


Origin of simple glial epiretinal membranes in an animal model.
Severe vitreous hemorrhage was simulated by the injection of 0.2 ml fresh uncoagulated autologous blood into the vitreous cavity of eight rabbits. Four weeks later, hemoglobin released from lysis of the original intravitreal clot had formed a thick layer on the retina. At this stage, many macrophages were conspicuous on the retinal surface and, in addition, in seven of the eight eyes, small cellular membranes were found by scanning electron microscopy. Light and transmission electron microscopy showed these membranes to be derived from accessory glial cells and their progeny. The membranes resembled the simple epiretinal membranes that occur in human eyes.


Ionic liquid functionalized multi-walled carbon nanotubes/zeolitic imidazolate framework hybrid membranes for efficient H2/CO2 separation.
A ZIF-9 membrane covered by ionic liquid (ILs) functionalized carbon nanotubes (CNTs) was grown using heat treatment of the layer-by-layer deposition method. This hybrid membrane exhibits a high selectivity for H2/CO2 due to the cooperative effect of ZIFs, CNTs and ILs.


[Primary alveolar hypoventilation. Clinical aspects and diagnostic problems. Apropos of a case].
Primary alveolar hypoventilation is a rare syndrome of unknown origin, characterized by a dysfunction of the automatic respiratory pattern in spite of normal lungs and in the absence of mechanical ventilatory defects. A reduction of the ventilatory response to CO2 is regularly found, and cardiac failure is common. The differential diagnosis mainly concerns the sleep apnoea syndrome. The usual treatments have little effectiveness.


Switch time-point for rapid experience-dependent changes in zinc-containing circuits in the mouse barrel cortex.
It has been previously demonstrated that in the mouse barrel cortex, synaptic zinc is regulated by sensory experience. In adult mice, cutting selected vibrissae produced a rapid but transient elevation of synaptic zinc in the corresponding barrels several hours later, whereas in 8 day-old animals this procedure did not affect synaptic zinc. In the present study, we wished to determine the postnatal age at which zinc-containing terminals gain the ability to respond rapidly to a restriction of sensory input. We therefore examined the effects of 1-day sensory deprivation starting at different postnatal ages. For this purpose we unilaterally trimmed all rows of vibrissae, except for row C, and we then visualized synaptic zinc in the barrel cortex 24h later. Up to postnatal day 15 such procedure had no effect on the level of synaptic zinc. However, beginning at postnatal day 16, 1-day sensory deprivation produced an increase in synaptic zinc within hollows of deprived rows of barrels as compared to non-deprived rows. These results show that during development there is a specific time-point after which zinc-containing circuits may respond rapidly to altered sensory inputs. A comparison of these findings with previous results obtained after chronic sensory deprivation suggests that a specific time window exists in development for persistent alterations in zinc-containing circuits.


The Era of Onyx Embolization: A Systematic and Literature Review of Preoperative Embolization Before Stereotactic Radiosurgery for the Management of Cerebral Arteriovenous Malformations.
The current treatment paradigm for intracranial arteriovenous malformations (AVMs) focuses on reducing the risk of intracranial hemorrhage using various therapeutic means including embolization, stereotactic radiosurgery (SRS), and microsurgical resection. To improve AVM obliteration rates with SRS, pre-radiosurgical embolization has been trialed in a number of studies to reduce the volume of the AVM nidus prior to radiosurgery. This study aimed to review the efficacy of pre-radiosurgical embolization in the pre-Onyx era compared to the current Onyx era. A systematic review was performed using PubMed to identify studies with 20 or more AVM patients, embolization material, and obliteration rates for both embolization + stereotactic radiosurgery (E+SRS) and SRS-only groups. Seventeen articles consisting of 1133 eligible patients were included in this study. A total of 914 (80.7%) patients underwent embolization prior to SRS. Onyx was used as the embolysate in 340 (37.2%) patients in the E+SRS cohorts. Mean obliteration rate for the embolized cohort was 46.9% versus 46.5% in the SRS-only cohort. When comparing obliteration rates based on embolysate material, obliteration rate was 42.1% with Onyx+SRS and 50.0% in the non-Onyx embolysate + SRS cohort. Onyx (ethylene vinyl-alcohol copolymer dissolved in dimethyl sulfoxide and suspended in micronized tantalum powder) has been increasingly used for the embolization of intracranial AVMs with increased success regarding its ease of use from a technical standpoint and performs similarly to other embolysate materials.


[Enzymehistochemical and immunopathological findings in the guinea pig lung after repeated doses of Freund's adjuvant (author's transl)].
An interstitial cell reaction was produced in guinea pigs by repeated doses of complete Freund's adjuvant. The resulting changes were investigated with enzymehistochemical and immunopathological methods. Histologically there were diffuse or focal interstitial infiltrations of histiocytes, lymphocytes, plasma cells, polymorphonuclear leucocytes and some eosinophils. Enzymehistochemically a strong activity of acid phosphatase and beta-glucuronidase is found in an increased number of alveolar macrophages, in contrast to the poor enzyme content of the interstitial cell infiltrations. Only some granulomas with starting fibrosis, visible after 6 weeks, exhibit an activity of leucine aminopeptidase and alkaline phosphatase. Immunopathologically, with the aid of anti-guinea pig-globulin, no immunoglobulins could be detected in the lungs of all animals.


Trypanosoma cruzi-heart muscle cell interaction: the presence of two or more trypomastigotes within a single endocytic vacuole.
Ultrastructural studies of the interaction between T. cruzi clone Dm28c and heart muscle cells (HMC) showed that in the initial phase of the cell recognition process several parasites could be found attached to a focal point on the surface of the host cell. Immediately following this phase, two or more parasites could be detected inside the same endocytic vacuole by electron spectroscopic imaging (ESI).


PXR variants and artemisinin use in Vietnamese subjects: frequency distribution and impact on the interindividual variability of CYP3A induction by artemisinin.
Artemisinins induce drug metabolism through the activation of the pregnane X receptor (PXR) in vitro. Here, we report the resequencing and genotyping of PXR variants in 75 Vietnamese individuals previously characterized for CYP3A enzyme activity after artemisinin exposure. We identified a total of 31 PXR variants, including 5 novel single nucleotide polymorphisms (SNPs), and we identified significantly different allele frequencies relative to other ethnic groups. A trend of significance was observed between the level of CYP3A4 induction by artemisinin and two PXR variants, the 8118C→T (Y328Y) and 10719A→G variants.


Evaluation of intracranial pressure from transcranial Doppler studies in cerebral disease.
The extent to which estimations of intracranial pressure can be derived from intracranial flow patterns was studied. The blood flow velocity in the middle cerebral artery was recorded with the EME TC 2-64 transcranial Doppler (TCD) device in 26 patients suffering from various severe cerebral diseases. Simultaneously the mean intracranial pressure (ICP) was measured by means of an epidural device. Arterial carbon-dioxide tensions were monitored by blood gas analysis. In all patients it was observed that the middle cerebral artery flow patterns changed distinctly when the ICP increased; these changes were distinguished by a decrease of the mean flow velocity and an increase of the Pourcelot index. A good correlation between the ICP and the flow parameters (especially the product mean systemic arterial pressure x Pourcelot index/mean flow velocity) was found in a select group of 13 patients, in whom comparable initial conditions existed and in whom additional parameters influencing the TCD recordings could be kept constant (r = 0.873; P less than 0.001).


Incidence Morbidity and Mortality From Falls in Skilled Nursing Facilities: A Systematic Review and Meta-Analysis.
The primary objective of this study was to systematically review and meta-analyze the incidence and consequential morbidity and mortality from falls in skilled nursing facilities. Our secondary objective is to synthesize current evidence on risk factors for injurious falls. Systematic review and meta-analysis. Older adults residing in skilled nursing facilities or similar settings. We completed study screening, data extraction, and quality assessment in duplicate. Random effects models were used for meta-analysis of fall incidence rates and proportions of outcomes per fall. Sensitivity analysis and meta-regression were completed to assess differences based on study design, quality, and population characteristics. The Newcastle Ottawa Scale and Cochrane Risk of Bias tools were used to assess quality of observational and intervention-based studies, respectively. The GRADE tool was used to evaluate strength of evidence for fall risk factors. We identified 3103 unique references, of which 38 were included in systematic review and 37 in meta-analysis. Pooled incidence of falls was 121 per 100 person-years (95% CI 86-170). Outcomes of transfer to hospital, admission to hospital, overall injury, head injury, fracture, 30-day mortality, death in hospital, and disability were reported by included studies. Sensitivity analysis indicated no significant difference in fall rates between study designs. Meta-regression indicated no significant relationship between fall rate and age or sex; however, a weak positive correlation was identified with increasing prevalence of dementia. No fall risk factors were supported by high-quality evidence. Our study confirms that falls in skilled nursing facilities are common and cause significant morbidity, mortality and health system use. As populations in high-income countries age, falls will become increasingly prevalent. Future research should be directed at preventing injurious falls and determining when hospital care will benefit a faller.


Alteration of hepatic structure and oxidative stress induced by intravenous nanoceria.
Beyond the traditional use of ceria as an abrasive, the scope of nanoceria applications now extends into fuel cell manufacturing, diesel fuel additives, and for therapeutic intervention as a putative antioxidant. However, the biological effects of nanoceria exposure have yet to be fully defined, which gave us the impetus to examine its systemic biodistribution and biological responses. An extensively characterized nanoceria (5 nm) dispersion was vascularly infused into rats, which were terminated 1 h, 20 h or 30 days later. Light and electron microscopic tissue characterization was conducted and hepatic oxidative stress parameters determined. We observed acute ceria nanoparticle sequestration by Kupffer cells with subsequent bioretention in parenchymal cells as well. The internalized ceria nanoparticles appeared as spherical agglomerates of varying dimension without specific organelle penetration. In hepatocytes, the agglomerated nanoceria frequently localized to the plasma membrane facing bile canaliculi. Hepatic stellate cells also sequestered nanoceria. Within the sinusoids, sustained nanoceria bioretention was associated with granuloma formations comprised of Kupffer cells and intermingling CD3⁺ T cells. A statistically significant elevation of serum aspartate aminotransferase (AST) level was seen at 1 and 20 h, but subsided by 30 days after ceria administration. Further, elevated apoptosis was observed on day 30. These findings, together with increased hepatic protein carbonyl levels on day 30, indicate ceria-induced hepatic injury and oxidative stress, respectively. Such observations suggest a single vascular infusion of nanoceria can lead to persistent hepatic retention of particles with possible implications for occupational and therapeutic exposures.


Fast atom bombardment-collision activated dissociation-linked field scanning mass spectrometry of the neuropeptide substance P.
Amino acid sequence-determining information is obtained from nanomole amounts of the underivatized, biologically important peptide substance P by combining fast atom bombardment, collision activated dissociation, and linked field scanning mass spectrometry. Protonated molecular ions of substance P are produced by fast atom bombardment mass spectrometry, accelerated to high translational energy (8 kV), and transit a collision chamber. Collision activated dissociations occur in the first field-free region. Amino acid sequence-determining ions are collected by scanning the magnetic and electric fields, keeping their ratio constant. In this manner, the precursor-product relationship among ions produced during fragmentation of the protonated molecular ion is firmly established.


A Single Eu-Doped In₂O₃ Nanobelt Device for Selective H₂S Detection.
Eu-doped In₂O₃ nanobelts (Eu-In₂O₃ NBs) and pure In₂O₃ nanobelts (In₂O₃ NBs) are synthesized by the carbon thermal reduction method. Single nanobelt sensors are fabricated via an ion beam deposition system with a mesh-grid mask. The gas-sensing response properties of the Eu-In₂O₃ NB device and its undoped counterpart are investigated with several kinds of gases (including H₂S, CO, NO₂, HCHO, and C₂H₅OH) at different concentrations and different temperatures. It is found that the response of the Eu-In₂O₃ NB device to 100 ppm of H₂S is the best among these gases and the sensitivity reaches 5.74, which is five times that of pure In₂O₃ NB at 260 °C. We also found that the former has an excellent sensitive response and great selectivity to H₂S compared to the latter. Besides, there is a linear relationship between the response and H₂S concentration when its concentration changes from 5 to 100 ppm and from 100 to 1000 ppm. The response/recovery time is quite short and remains stable with an increase of H₂S concentration. These results mean that the doping of Eu can improve the gas-sensing performance of In₂O₃ NB effectually.


Neoadjuvant chemotherapy in breast cancer: which diagnostic procedures can be used?
To improve breast cancer treatment, the evaluation of predictive factors is in the focus of clinical research. Significant discrepancies between the clinical assessment of response to neoadjuvant chemotherapy (NACT) and the pathological assessment of response from post-therapy surgical specimens have been demonstrated. We focused on comparing the value of various diagnostic methods used in medical routine. A clinical evaluation of the primary tumour and regional lymph nodes before and after NACT was performed in 139 patients by physical examination, sonography and mammography. Mammography and physical examination correlated best with pathological findings in the measurement of the tumour, whereas sonography was the most accurate predictor of the status for axillary lymph nodes. Mammography and physical examination are the best non-invasive predictors of the real size of the primary breast cancer, whereas sonography correlates better with the proven status of axillary lymph nodes.


Levator hiatus dimensions and pelvic floor function in women with and without major defects of the pubovisceral muscle.
The aim of present study was to compare pelvic floor morphology and function in women with and without major defects of the pubovisceral muscle. One hundred fifty-seven women with pelvic organ prolapse participated in this cross-sectional study. Participants answered a symptom questionnaire and underwent clinical and three- and four-dimensional transperineal ultrasound examination. Pelvic floor muscle maximum voluntary contraction (MVC), endurance, and resting vaginal pressure were registered with a vaginal balloon catheter. Offline analyses were performed for the presence of major pubovisceral muscle defects (PVMD) and hiatal dimensions. The levator hiatus dimensions at rest and contraction were significantly larger in women with than without major PVMD. Mean differences in levator hiatus area between women with and without major PVMD were: rest 1.9 cm(2) 95% confidence intervals (CI) 0.21-3.7, P = 0.028 and contraction 2.75 cm(2) 95% CI 1.0-4.5, P =0.002; and Valsalva maneuver mean difference was 0.82 cm(2) 95% CI 2.18-3.83, P = 0.543. Women with major PVMD had lower MVC and endurance measurements as compared with women without major PVMD, but the differences were not statistically significant. Women with major pubovisceral muscle defects have larger hiatal dimensions at rest and at contraction than women without PVMD. We were unable to prove the corresponding relationship for hiatal dimensions on Valsalva.


Idiopathic Chronic Diarrhea in Rhesus Macaques Is Not Associated with Enteric Viral Infections.
While recent changes in treatment have reduced the lethality of idiopathic chronic diarrhea (ICD), this condition remains one of the most common causes of rhesus macaque deaths in non-human primate research centers. We compared the viromes in fecal swabs from 52 animals with late stage ICD and 41 healthy animals. Viral metagenomics targeting virus-like particles was used to identify viruses fecally shed by each animal. Five viruses belonging to the Picornaviridae, one to the Caliciviridae, one to the Parvoviridae, and one to the Adenoviridae families were identified. The fraction of reads matching each viral species was then used to estimate and compare viral loads in ICD cases versus healthy controls. None of the viruses detected in fecal swabs were strongly associated with ICD.


Changes in pulmonary mechanics after fiberoptic bronchoalveolar lavage in mechanically ventilated patients.
We prospectively assessed the impact of bronchoalveolar lavage (BAL) on respiratory mechanics in critically ill, mechanically ventilated patients. Mechanically ventilated patients underwent BAL of one lung segment using 5 x 20 ml of sterile, physiologic saline with a temperature of 25-28 degrees C. The fractional inspired oxygen was increased to 1.0, but ventilator settings were otherwise left unchanged. Static pulmonary compliance, pulmonary resistance, alveolar ventilation, and serial dead space were measured 60 min and 2 min before and 8, 60, and 180 min after BAL to assess the consequences of the procedure. In addition, blood gases [partial pressure of carbon dioxide in arterial blood (PaCO2) and arterial oxygen tension (PaO2)], hemodynamic variables (heart rate, systolic and diastolic blood pressure), and body temperature were recorded at the same time points. Intensive care unit of a university hospital. 18 consecutive critically ill, mechanically ventilated patients. Pulmonary compliance decreased by 23% (p < 0.05) and pulmonary resistance increased by 22% (p < 0.05) shortly after BAL. The changes in pulmonary compliance and resistance were more than 30% in one third of the patient population. One hour after the procedure, PaO2 was significantly lower and PaCO2 significantly higher than before the procedure. Three hours after the procedure, pulmonary resistance returned to pre-BAL values but compliance remained 10% below baseline values (p < 0.05). BAL in mechanically ventilated patients is associated with deterioration of pulmonary mechanics and function.


Poststroke Depression: An Update.
The presence of neuropsychiatric disorders after stroke has been recognized for more than 100 years, but controlled systematic studies did not begin until the 1970s. The most clinically important advances, however, have been in the treatment and prevention of poststroke depression (PSD). Recent meta-analyses of randomized controlled trials (RCTs) for the treatment of PSD have demonstrated the efficacy of antidepressants. Similarly, RCTs for the prevention of PSD have shown that antidepressants significantly decrease the incidence of PSD compared with placebo. Early treatment of PSD with antidepressants also appears to enhance both physical and cognitive recovery from stroke and may increase survival up to 10 years. Genetic and epigenetic variations, white matter disease, cerebrovascular deregulation, altered neuroplasticity, and changes in glutamate neurotransmission may be relevant etiological factors.


Optimizing Li-ion Solvation in Gel Polymer Electrolytes to Stabilize Li-Metal Anode.
Gel polymer electrolytes (GPEs) have potential as substitutes for liquid electrolytes in lithium-metal batteries (LMBs). Their semi-solid state also makes GPEs suitable for various applications, including wearables and flexible electronics. Here, we report the initiation of ring-opening polymerization of 1,3-dioxolane (DOL) by Lewis acid and the introduction of diluent 1,1,2,2-tetrafluoroethyl 2,2,3,3-tetrafluoropropyl ether (TTE) to regulate electrolyte structure for a more stable interface. This diluent-blended GPE exhibits enhanced electrochemical stability and ion transport properties compared to a blank version without it. FTIR and NMR proved the effectiveness of monomer polymerization and further determined the molecular weight distribution of polymerization by gel permeation chromatography (GPC). Experimental and simulation results show that the addition of TTE enhances ion association and tends to distribute on the anode surface to construct a robust and low-impedance SEI. Thus, the polymer battery achieves 5 C charge-discharge at room temperature and 200 cycles at low temperature -20 °C. The study presents an effective approach for regulating solvation structures in GPEs, promoting advancements in the future design of GPE-based LMBs.


Cross-Cultural Validation of the Definition of Multimorbidity in the Bulgarian Language.
Multimorbidity is a health issue with growing importance. During the last few decades the populations of most countries in the world have been ageing rapidly. Bulgaria is affected by the issue because of the high prevalence of ageing population in the country with multiple chronic conditions. The AIM of the present study was to validate the translated definition of multimorbidity from English into the Bulgarian language. The present study is part of an international project involving 8 national groups. We performed a forward and backward translation of the original English definition of multimorbidity using a Delphi consensus procedure. The physicians involved accepted the definition with a high percentage of agreement in the first round. The backward translation was accepted by the scientific committee using the Nominal group technique. Some of the GPs provided comments on the linguistic expressions which arose in order to improve understanding in Bulgarian. The remarks were not relevant to the content. The conclusion of the discussion, using a meta-ethnographic approach, was that the differences were acceptable and no further changes were required. A native version of the published English multimorbidity definition has been finalized. This definition is a prerequisite for better management of multimorbidity by clinicians, researchers and policy makers.


Localized alopecia with itching on the scalp.
We describe the use of trichoscopy to arrive at a diagnosis, and discuss the possible differential diagnoses in a patient presenting with localized itching and alopecia of the scalp.


Molecular and epidemiological characterization of Plasmodium vivax recurrent infections in southern Mexico.
In southern Mexico, malaria transmission is low, seasonal, and persistent. Because many patients are affected by two or more malaria episodes caused by Plasmodium vivax, we carried out a study to determine the timing, frequency, and genetic identity of recurrent malaria episodes in the region between 1998 and 2008. Symptomatic patients with more than one P. vivax infection were followed up, and blood samples were collected from primary and recurrent infections. DNA extracted from infected blood samples was analyzed for restriction fragment length polymorphism (RFLP) in genes encoding csp and msp3α, as well as size variation in seven microsatellites. One hundred and forty six parasite samples were collected from 70 patients; of these, 65 patients had one recurrent infection, four had two, and one had three recurrent infections. The majority of recurrent infections occurred within one year of the primary infection, some of which were genetically homologous to the primary infection. As the genetic diversity in the background population was high, the probability of homologous re-infection was low and the homologous recurrences likely reflected relapses. These homologous recurrent infections generally had short (< 6 months) or long (6-12 months) intervals between the primary (PI) and recurrent (RI) infections; whereas infections containing heterologous genotypes had relatively longer intervals. The epidemiological data indicate that heterologous recurrences could be either relapse or re-infections. Genetic and temporal analysis of P. vivax recurrence patterns in southern Mexico indicated that relapses play an important role in initiating malaria transmission each season. The manifestation of these infections during the active transmission season allowed the propagation of diverse hypnozoite genotypes. Both short- and long-interval relapses have contributed to parasite persistence and must be considered as targets of treatment for malaria elimination programs in the region to be successful.


Gene content evolution on the X chromosome.
Compared with autosomes, the X chromosome shows different patterns of evolution as a result of its hemizygosity in males. Additionally, inactivation of the X during spermatogenesis can make the X chromosome an unfavorable location for male-specific genes. These factors can help to explain why in many species gene content of the X chromosome differs from that of autosomes. Indeed, the X chromosome in mouse is enriched for male-specific genes while they are depleted on the X in Drosophila but show neither of these trends in mosquito. Here, we will discuss recent findings on the ancestral and neo-X chromosomes in Drosophila that support sexual antagonism as a force shaping gene content evolution of sex chromosomes and suggest that selection could be driving male-biased genes off the X.


Corrigendum: Psymberin, a marine-derived natural product, induces cancer cell growth arrest and protein translation inhibition.
[This corrects the article DOI: 10.3389/fmed.2022.999004.].


Pro and con arguments in using alternative dialysis regimens in the frail and elderly patients.
In the last decade, an increasing number of patients over 75 years of age are starting renal replacement therapy. Frailty is highly prevalent in elderly patients with end-stage renal disease (ESRD) in the context of the increased prevalence of some ESRD-associated conditions: protein-energy wasting, inflammation, anaemia, acidosis or hormonal disturbances. There are currently no hard data to support guidance on the optimal duration of dialysis for frail/elderly ESRD patients. The current debate is not about starting dialysis or managing conservatory frail ESRD patients, but whether a more intensive regimen once dialysis is initiated (for whatever reasons and circumstances) would improve patients' outcome. The most important issue is that all studies performed with extended/alternative dialysis regimens do not specifically address this particular type of patients and therefore all the inferences are derived from the general ESRD population. Care planning should be responsive to end-of-life needs whatever the treatment modality. Care in this setting should focus on symptom control and quality of life rather than life extension. We conclude that, similar to the general dialysed population, extensive application of more intensive dialysis schedules is not based on solid evidence. However, after a thorough clinical evaluation, a limited period of a trial of intensive dialysis could be prescribed in more problematic patients.


Acute pancreatitis in obstructive jaundice following combined internal and external percutaneous transhepatic bile duct drainage (PTBD).
Percutaneous transhepatic biliary drainage (PTBD) was performed on 85 patients with obstructive jaundice. Four patients developed an acute pancreatitis after internal drainage of which one died. To our knowledge this serious complication has not yet been described in detail. These four cases are, therefore, reported and the possible causes are discussed.


Variation within the PPARG gene is associated with residual beta-cell function and glycemic control in children and adolescents during the first year of clinical type 1 diabetes.
Conflicting evidence exists as to whether the Pro12Ala single nucleotide polymorphism of the type 2 diabetes susceptibility gene peroxisome proliferator-activated receptor gamma (PPARG) also confers risk for type 1 diabetes (T1D). The objective of this study was to investigate the PPARG gene in relation to residual beta-cell function and glycemic control in newly diagnosed T1D. Prospective, non-interventional, 12-month follow-up study, conducted in 18 centers in 15 countries. Two hundred and fifty-seven children and adolescents (aged <16 yr) with newly diagnosed T1D. Beta-cell function was determined as 90-min meal-stimulated C-peptide (Boost test) 1, 6, and 12 months after diagnosis. Hemoglobin A1c (HbA1c) and daily insulin dose (IU/kg/d) were recorded at 1, 3, 6, 9, and 12 months after diagnosis. Haplotypes within PPARG were estimated by SNPHap program. Statistical analyses were performed in a repeated measurements model. Five haplotypes within PPARG were generated (h1, 68.4%; h2, 16.3%; h3, 8.3%; h4, 3.5%; and hx, 3.5%). Compared with the most frequent h1 haplotype, the haplotypes h3 and h4 of the PPARG associated with residual beta-cell function during the first year of clinical disease: h3 with a 27% lower C-peptide (p = 0.02) and h4 with a 39% lower C-peptide (p = 0.01). Haplotype h4 also associated with a 0.86% (absolute) higher HbA1c, after adjustment for the insulin dose (p = 0.02). Variation in the PPARG locus may influence disease progression during the first year after the presentation of T1D.


Rapid recovery following fulminant meningococcemia complicated by myocarditis in a 15-year-old Nepalese girl: a case report.
Fulminant meningococcemia is a relatively rare life-threatening disease caused by Neisseria meningitidis. The clinical presentation is varied, but, when associated with myocarditis, it carries a particularly poor prognosis. We report a case of a patient with fulminant meningococcemia who subsequently developed severe myocardial dysfunction and successfully recovered within a period of 14 days of hospitalization. A 15-year-old girl presented with headache, fever, body ache, and diarrhea for 1 day, and ecchymotic rash over her body for 4 hours. Blood cultures confirmed infection with N. meningitidis. After 6 days in the hospital, the patient developed anasarca, elevated jugular venous pressure, and shock. The patient was managed with intravenous ceftriaxone and captopril. Over the next 3 days the patient rapidly improved and started walking. Meningococcemia complicated by myocarditis has an extremely poor prognosis with high mortality. Our case suggests that recovery from a severe myocardial dysfunction can occur rapidly within a few days. Prompt recognition and management in this case might have contributed to the patient's rapid recovery from myocarditis.


Further studies on the mitogenic response of cultured Schwann cells to rat CNS axolemma-enriched fractions.
Axolemma-enriched fractions isolated from rat CNS stimulated cultured Schwann cells to divide without changing their morphology. Fluorescent activated cell sorter analysis of the axolemma-stimulated cells demonstrated an approximate 3-fold increase in the number of Schwann cells in the S-phase of the cell cycle. This increase correlated well with increases in the number of [3H]thymidine-labeled nuclei observed by light level radioautography. The membrane-bound mitogen was relatively heat-stable, but trypsin-sensitive, and was inactivated both by lipid extraction and sonication. Liver plasma membranes did not increase the mitotic index over that of untreated cells, indicating the axolemma-induced mitosis was not a general response to exogenous membranes. Increasing serum concentrations in the presence of a constant level of axolemma did not change the mitotic index, suggesting that the axolemma did not cause mitosis by removal of an inhibitory factor in serum. Potential mitogens such as gangliosides, myelin basic protein, heparin, an axolemmal lipid extract, and cGMP had no effect on the cultured Schwann cells. The characteristics of the axolemma-related mitogenic factor are discussed relative to other known mitogens for cultured Schwann cells.


Mental strain and changes in psychological health hub among intern-nursing students at pediatric and medical-surgical units amid ambience of COVID-19 pandemic: A comprehensive survey.
COVID-19 pandemic brings with it a new reality and changes in the context of traditional nursing clinical training. Intern-nursing students face challenges in providing care for suspected and confirmed patients with COVID-19. This cross-sectional descriptive study aimed to explore the mental strain and changes in the psychological health hub among the intern-nursing students during COVID-19 pandemic. A sample of 150 intern-nursing students from 13 pediatric and medical-surgical units at Alexandria University Hospitals completed the Middle East Respiratory Syndrome COVID-19 Staff Questionnaire and rated their psychological distress on the General Health Questionnaire. Study results revealed that the most stressful factors were related to possibility of getting COVID-19 infection (2.89 ± 0.39) and transmitting it to their families (2.72 ± 0.62). Moreover, the availability of cure or vaccine for the disease was the most important motivational factor to participate in future outbreaks (2.64 ± 0.77). Regarding intern-nursing students' psychological health hub, 77.3% of them felt under strain, worthless and depressed (64.7%, 62.7%) since the influx of COVID-19 pandemic. Binary logistic regression indicated that students' age (23-24), clinical experience (8 months) and clinical placement in adults' units served as risk factor for developing psychological distress while, male gender and training in pediatric units were protective factors. Designating an emergency psychiatric unit for ongoing monitoring and providing psychological first aids to the vulnerable health care providers is recommended.


Cancer stem cells and field cancerization of oral squamous cell carcinoma.
Oral squamous cell carcinoma (OSCC) has a high propensity for local failure, which is attributed to recurrence at the primary site or the development of second primary tumors (SPT). Field cancerization that refers to the existence of transformed cells in areas adjacent to the primary tumor, has been attributed to be one of the probable reasons underlying disease relapse. The carcinogenic process necessitates multiple molecular events for the transformation of a normal cell into a cancer cell. This implies that only the long-time residents of the epithelium, such as the stem cells, might be the candidates capable of accumulating these genetic hits. These transformed stem cells- the 'Cancer stem cells' (CSCs), are further known to be equipped with the properties of tumor initiation and migration, both of which are essential for orchestrating field cancerization. The concept that the CSCs might be responsible for field cancerization in OSCC has not been explored extensively. If the role of CSCs as the primary units of field cancerization process is established, their presence in the mucosa adjacent to the tumor may be an indicator for local recurrence and/or development of second primary tumors. In this review, we examine the available evidence in literature exploring the possibilities of CSCs driving the process of field cancerization and thereby being the underlying mechanism for disease recurrence and development of SPT.


Postoperative interictal epileptiform discharge within 1 month is associated with seizure recurrence after anterior temporal lobectomy.
To investigate the relationship of interictal epileptiform discharges (IEDs) within 1 month of anterior temporal lobectomy (ATL) to seizure outcome, we reviewed data for 202 (107 left ATL, 95 right ATL) patients who had undergone ATL for mesial temporal epilepsy. Postoperative EEGs within 30 days and other preoperative variables were analyzed to examine the significant factors that determine freedom from disabling seizures. IEDs were noted in 29 (22.3%) of the 130 patients without seizures for 2 years after ATL compared with 31 (43.1%) of the 72 patients with recurrent seizures (P = 0.002). Postoperative IEDs remained an independent predictive factor for seizure outcome by logistic regression (adjusted OR = 2.38, 95% CI = 1.18-4.81, P = 0.016, 2 years postoperatively; adjusted OR = 2.22, 95% CI = 1.03-4.82, P = 0.043, 5 years postoperatively) and Cox hazard regression analysis (adjusted HR = 1.76, 95% CI = 1.18-2.62, P = 0.006) after controlling for other predicting factors (unilateral hippocampal atrophy, history of febrile seizures, and IQ scores). In this study, IEDs on the EEG obtained soon after surgery were associated with postoperative seizure recurrence. These results can be used in the assessment of risk of seizure recurrence after ATL.


Staged surgical treatment for symptomatic vertebrobasilar artery stenosis: combined treatment with endovascular angioplasty and bypass surgery.
Because the early risk of stroke recurrence in patients with posterior circulation infarctions is high, patients with vertebrobasilar events require active preventive treatment. Previous reports have described the use of balloon angioplasty and stenting or surgical revascularization to the vertebrobasilar artery area. To compensate for the disadvantages of these techniques, we combined endovascular and surgical treatments in a patient with symptomatic vertebrobasilar artery stenosis. After endovascular surgery, we continued medical therapy to stabilize the blood flow in the posterior circulation. Superficial temporal artery-superior cerebellar artery bypass was planned for the chronic stage (∼1-2 months). Three cases (2 vertebral artery stenosis, 1 basilar artery stenosis) presented with recurrent transient ischemic attacks or deteriorating symptoms under intensive medical treatment. We conducted staged therapy using balloon angioplasty followed by superficial temporal artery-superior cerebellar artery bypass. All patients were symptom-free after treatment with the combined therapy. Our staged therapy may be an effective treatment for symptomatic vertebrobasilar artery stenosis.


Reparative reactions of the skeletal muscles in early aging OXYS rats with toxic metabolic injuries caused by bupivacaine.
Comparative analysis of reparative reactions in the anterior tibialis muscles of OXYS and Wistar rats after intramuscular injections of bupivacaine was carried out for eva, luating the regeneratory potential of skeletal muscles under conditions of chronic disorders of oxidative metabolism. Lumpy degradation of lesion foci and mononuclear cell infiltration predominated on day 1; after 3 days myoblast proliferation and fusion processes were maximally pronounced; after 7 days maturing myotubules created groups of fibers with central nuclei. At the ultrastructural level, regeneration of the muscle fibers was associated with signs of activation of their nuclei and of satellite cell nuclei. Lesser (in comparison with the control) mean cross-section areas of the muscle fibers on day 14 after the start of the experiment indicated that the regeneration processes were not completed by this term. The proliferative potential of myogenic precursor cells was retained in hereditary dysfunction of mitochondria in OXYS rats.


Sensitivity, specificity and clinical relevance of different cross-matching assays in deceased-donor renal transplantation.
To assess the significance of antibodies detected by complement-dependent cytotoxicity (CDC), solid phase (SPA) and flow cytometry (FC) assays we compared their predictive value in 354 consecutive cases of deceased-donor kidney transplantation. Pre-transplantation screening of anti-HLA class I and class II antibodies was performed by CDC and SPA. The direct crossmatch between recipients' sera and donors' T and B cells was performed by CDC followed by FC and SPA ("virtual cross-match"). The past history of antibodies displayed by the recipient was not considered a contraindication for transplantation even when it showed DSA. A side-by-side comparison of the correlation between graft loss, history of DSA and cross-match results indicated that sensitivity was 5%, 16% and 17% while specificity was 99%, 93% and 86% in CDC, SPA, FC crossmatches respectively. There was no significant difference between the 3 year survival of primary and secondary kidney allografts. We conclude that screening and cross-matching the sera by CDC provides reliable results and optimizes the patient's chances to receive a transplant. SPA and FC, however, are of great importance for identifying patients which require close monitoring by biopsy and serology for early diagnosis and treatment of acute antibody mediated rejection (AAMR).


Association of healthy beverage index with circadian rhythm and quality of sleep among overweight and obese women: a cross-sectional study.
Circadian rhythm is a behavioral, physiological, and molecular change with a cycle length of approximately 24 h. Changes to the circadian rhythm can result in sleep difficulty. The healthy beverage index (HBI) is a holistic concept for evaluating the quality of overall beverage intake and its association with health-related outcomes in nutritional epidemiological studies. This study aimed to assess the relationship of HBI with circadian rhythm and sleep quality among overweight/obese women. The current study was conducted among 208 overweight and obese women between 18-48 years in Tehran, Iran. We evaluated potential HBI with a valid food frequency questionnaire. Following standard procedures, trained personnel assessed anthropometric measures, blood samples, and other baseline characteristics. The Pittsburgh Sleep Quality Index and the morning-eveningness questionnaire were applied to evaluate sleep quality and circadian rhythm respectively. The mean (SD) BMI for this study was 30.8 (4.2) kg/m2. We observed that subjects in the least tertile had significantly high levels of triglyceride (p = 0.04) and low-density lipoprotein (p = 0.009). High-density lipoprotein was significantly different across the tertiles (p = 0.003). After adjusting for potential covariates, subjects in the second tertile of HBI had 5.07 odds of having the worst quality of sleep as compared to those in the third tertile, p < 0.05. We also observed a significant inverse association between the HBI and the "moderately evening type" participants (OR 0.86; 95% CI 0.68-0.99; p: 0.02) after adjusting for potential confounders. Healthy beverage consumption may have the potential of improving sleep quality among overweight and obese subjects. Level IV, evidence obtained from a descriptive study.


Process improvement to prevent the formation of biogenic amines during soy sauce brewing.
Biogenic amines (BAs) are a class of bioactive organics produced during the fermentation of soy sauce. A high concentration of BAs may bring about serious physiological and toxicological effects on the human body. In this study, we reported an optimized process to produce soy sauce with lower BA concentration and found the contents of putrescine, cadaverine and histamine increased with the increase of fermentation temperature but decreased with the increase of NaCl concentration. The final content of total BAs with improved fermentation was 105.56 ± 0.13 mg/L, which was reduced by 89.11% compared to traditional brewing. Besides, the pilot production test was performed to verify the optimized conditions and physicochemical indexes were measured to better understand the change principle of the chemical compounds. Taken together, we present an effective process to inhibit the formation of BAs while ensuring that characteristic nutrients are not lost.


The potential for the use of cell proliferation studies in carcinogen risk assessment.
The use of observations on cellular proliferation in assessing the mechanism of action of certain factors in the genesis of tumors of the urinary bladder, forestomach, and intestine, or on the effects of dietary restriction, is illustrated. It is suggested that, particularly with nongenotoxic carcinogens, such studies may be of great use in risk assessment especially for those cases in which animals are exposed at very much higher levels of the test agent in the carcinogenesis bioassay than are humans as the result of the environmental or other use of the agent.


Innate immunity in tuberculosis: how the sensing of mycobacteria and tissue damage modulates macrophage death.
The success of Mycobacterium tuberculosis as a human pathogen has been attributed to the ability of the bacillus to proliferate inside macrophages and to induce cell death. This review describes how the sensors of the innate immune system modulate the cell death pathways in infected macrophages and, consequently, the pathogenesis of tuberculosis.


Mutations in the GABRA1 and EFHC1 genes are rare in familial juvenile myoclonic epilepsy.
Juvenile myoclonic epilepsy (JME), accounting for approximately 25% of idiopathic generalized epilepsies, is genetically heterogeneous. Mutations in the alpha-1 subunit of the GABAA receptor (GABRA1) and EFHC1 genes have been reported in a few families with autosomal dominant (AD) JME. We have investigated the contribution of these two genes to familial JME in our cohort of 54 JME Caucasian families. Syndromic classification of JME was based on previously published criteria. We considered kindreds with at least one affected first-degree relative and the evidence of a vertical transmission as definite AD JME, and families with at least one affected second-degree relative as probable AD JME. We included 33 families meeting criteria for definitive AD JME and 21 that were classified as probable AD JME. None of these families were considered informative enough to analyze candidate loci for JME using linkage analysis. We have systematically screened coding exons of these two genes using temperature gradient capillary electrophoresis. Every heteroduplex with an abnormal mobility was sequenced. No disease-causing mutations in the GABRA1 gene were identified. Analysis of EFHC1 gene found one putative disease-causing mutation R221H that was previously reported as a tandem mutation. Several synonymous and non-synonymous coding polymorphisms were identified but the allelic frequency did not differ between controls and affected individuals. Our data suggests that the majority of familial AD JME is not caused by mutations in the GABRA1 and EFHC1 genes.


Effects of a magnesium-free dialysate on magnesium metabolism during continuous ambulatory peritoneal dialysis.
While the use of magnesium-containing compounds is usually contraindicated in dialysis patients, the risk of toxicity from hypermagnesemia can be reduced by lowering the magnesium concentration in dialysate. We examined the effects of a magnesium-free dialysate on both serum magnesium level and the peritoneal removal rate of magnesium over 12 weeks in 25 stable patients undergoing continuous ambulatory peritoneal dialysis (CAPD). After 2 weeks, the serum magnesium level decreased from 2.2 to 1.9 mg/dL (0.9 to 0.8 mmol/L) (P less than .02) and the peritoneal removal rate increased from 66 to 83 mg/d (2.8 to 3.5 mmol/d) (P less than .05), with both values remaining stable thereafter. There was a strong association between these parameters (r = -0.62, P less than .05), suggesting that the serum magnesium level decreased as a result of the initial increased peritoneal removal rate. For an additional 4-week period, a subgroup of nine patients received magnesium-containing, phosphate binding agents instead of those containing only aluminum. During this phase, serum inorganic phosphorus was well controlled. The serum magnesium level increased only from 1.8 to 2.5 mg/dL (0.7 to 1.0 mmol/L) (P less than .05), due in great part to the concomitant 41% rise in peritoneal magnesium removal from 91 to 128 mg/d (3.8 to 5.3 mmol/d) (P less than .05). No toxicity was noted during the entire 16-week study period, nor did serum calcium change. Thus, serum magnesium levels remained within an acceptable range as magnesium-containing phosphate binders were given through the use of magnesium-free peritoneal dialysate.(ABSTRACT TRUNCATED AT 250 WORDS)


Changes in lectin binding pattern of gonads of developing mice.
Changes in lectin binding of developing fetal mouse testes and ovaries were examined by light and electron microscopy, with much attention paid particularly to those in carbohydrates of germ cells. Characteristic binding patterns were observed with three lectins (BPA, GS-I, and GS-II) in the germ cells and the somatic cells during the process of testicular and ovarian development. GS-I and BPA, which showed similar binding patterns, preferentially bound to the plasma membrane and small dense bodies (SDB) of germ cells in both testes and ovaries during the 12th to 14th day post coitum (p.c.). In the fetal testes on day 16 p.c., the reaction with both GS-I and BPA completely disappeared. While, in the ovaries, a weak reaction with these lectins was retained as it was in germ cells until the 16th day p.c. The reaction with GS-II was restricted to Sertoli cells in the fetal testes during the 12th to 14th day p.c., and thereafter disappeared on day 16 p.c. The distribution of GS-II binding sites was in agreement with that of the glycogen granules. No positive staining with GS-II was seen in the ovaries throughout their development. These results indicate that certain glycoconjugates containing D-galactose and N-acetyl-D-galactosamine residues are expressed on the cell surface and in the SDB of germ cells during the period of the 12th to 14th day p.c., and that striking changes in function as well as in structure may take place in both germ cells and somatic cells during the 14th to 16th day p.c. in association with testicular and ovarian development.


Antidepressant use in late gestation and risk of postpartum haemorrhage: a retrospective cohort study.
To investigate the association between antidepressant use in late gestation and postpartum haemorrhage (PPH). Retrospective cohort study. Tertiary teaching hospital in Adelaide, Australia. A total of 30 198 women delivering between 2002 and 2008. Relative risks adjusted for maternal sociodemographics and comorbidities (aRRs) were calculated for PPH, comparing women with late-gestation exposure to antidepressants (n = 558), women with a psychiatric illness but no antidepressant use (n = 1292), and women with neither antenatal exposures (n = 28 348). Additional sensitivity analyses were undertaken, examining associations with severe PPH and postpartum anaemia. The primary outcome was PPH, defined as a recorded blood loss of ≥500 mL for vaginal deliveries and ≥1000 mL for caesarean sections. Secondary outcomes included severe PPH (≥1000 mL blood loss, irrespective of method of delivery), and the presence of postpartum anaemia (identified from hospital medical records). Compared with unexposed controls, women exposed to antidepressants had an increased risk of PPH (aRR 1.53; 95% confidence interval, 95% CI 1.25-1.86), whereas no increased risk was observed for women with a psychiatric illness but no antidepressant use (aRR 1.04; 95% CI 0.89-1.23). In sensitivity analyses, late gestation antidepressant exposure was associated with an increased risk of severe PPH (aRR 1.84; 95% CI 1.39-2.44), as well as postpartum anaemia (aRR 1.80; 95% CI 1.46-2.22). Exposure to antidepressants in late gestation was associated with a significantly increased risk of PPH. Although potential confounding by unmeasured factors cannot be ruled out, these findings suggest a direct effect of antidepressant exposure on PPH. Late gestation antidepressant exposure is associated with a significantly increased risk of postpartum haemorrhage.


The rapidly evolving field of plant centromeres.
Meiotic and mitotic chromosome segregation are highly conserved in eukaryotic organisms, yet centromeres--the chromosomal sites that mediate segregation--evolve extremely rapidly. Plant centromeres have DNA elements that are shared across species, yet they diverge rapidly through large- and small-scale changes. Over evolutionary time-scales, centromeres migrate to non-centromeric regions and, in plants, heterochromatic knobs can acquire centromere activity. Discerning the functional significance of these changes will require comparative analyses of closely related species. Combined with functional assays, continued efforts in plant genomics will uncover key DNA elements that allow centromeres to retain their role in chromosome segregation while allowing rapid evolution.


A Multifunctional Cascade Bioreactor Based on Hollow-Structured Cu2 MoS4 for Synergetic Cancer Chemo-Dynamic Therapy/Starvation Therapy/Phototherapy/Immunotherapy with Remarkably Enhanced Efficacy.
The unique tumor microenvironment (TME) facilitates cancer proliferation and metastasis, and it is hard to cure cancer completely via monotherapy. Herein, a multifunctional cascade bioreactor based on hollow mesoporous Cu2 MoS4 (CMS) loaded with glucose oxidase (GOx) is constructed for synergetic cancer therapy by chemo-dynamic therapy (CDT)/starvation therapy/phototherapy/immunotherapy. The CMS harboring multivalent elements (Cu1+/2+ , Mo4+/6+ ) exhibit Fenton-like, glutathione (GSH) peroxidase-like and catalase-like activity. Once internalized into the tumor, CMS could generate ·OH for CDT via Fenton-like reaction and deplete overexpressed GSH in TME to alleviate antioxidant capability of the tumors. Moreover, under hypoxia TME, the catalase-like CMS could react with endogenous H2 O2 to generate O2 for activating the catalyzed oxidation of glucose by GOx for starvation therapy accompanied with the regeneration of H2 O2 . The regenerated H2 O2 can devote to Fenton-like reaction for realizing GOx-catalysis-enhanced CDT. Meanwhile, the CMS under 1064 nm laser irradiation shows remarkable tumor-killing ability by phototherapy due to its excellent photothermal conversion efficiency (η = 63.3%) and cytotoxic superoxide anion (·O2 - ) generation performance. More importantly, the PEGylated CMS@GOx-based synergistic therapy combined with checkpoint blockade therapy could elicit robust immune responses for both effectively ablating primary tumors and inhibiting cancer metastasis.


Uptake and inactivation of thrombin on the subendothelium: comparisons with endothelium.
One aspect of the non-thrombogenicity of endothelium is the property to bind and inhibit thrombin. Loss of the endothelial layer gives rise to a thrombogenic surface. The present study concerns uptake and inactivation of thrombin on endothelium as well as subendothelium. Both the immediate subendothelial layer and the media were investigated. Binding and inhibition of thrombin was assayed using both a synthetic chromogenic substrate and fibrinogen. In the latter case thrombin enzymatic activity was assessed by measuring liberation of fibrinopeptide A. There was a linear relationship between thrombin in the solution and thrombin enzymatic activity recovered on the surface on both endothelium and media. 30-50 per cent of the surface bound thrombin measured with the chromogenic substrate was also active towards fibrinogen. Preincubation of endothelium with plasma gave rise to an increased loss of thrombin from the solution at the same time as less thrombin was recovered on the surface. This indicates increased inactivation. Increased inactivation could also be obtained by pretreatment with antithrombin (AT) but not with AT-depleted plasma. The same general pattern was seen on the subendothelium but not on the media. It is concluded that inhibition of thrombin occurs on the endothelium and can be augmented by prior binding of AT to the surface. This effect although less pronounced can also be obtained on the subendothelium. The deeply injured vessel is much less capable of inhibiting thrombin.


The first complete genome of the simian malaria parasite Plasmodium brasilianum.
Naturally occurring human infections by zoonotic Plasmodium species have been documented for P. knowlesi, P. cynomolgi, P. simium, P. simiovale, P. inui, P. inui-like, P. coatneyi, and P. brasilianum. Accurate detection of each species is complicated by their morphological similarities with other Plasmodium species. PCR-based assays offer a solution but require prior knowledge of adequate genomic targets that can distinguish the species. While whole genomes have been published for P. knowlesi, P. cynomolgi, P. simium, and P. inui, no complete genome for P. brasilianum has been available. Previously, we reported a draft genome for P. brasilianum, and here we report the completed genome for P. brasilianum. The genome is 31.4 Mb in size and comprises 14 chromosomes, the mitochondrial genome, the apicoplast genome, and 29 unplaced contigs. The chromosomes consist of 98.4% nucleotide sites that are identical to the P. malariae genome, the closest evolutionarily related species hypothesized to be the same species as P. brasilianum, with 41,125 non-synonymous SNPs (0.0722% of genome) identified between the two genomes. Furthermore, P. brasilianum had 4864 (82.1%) genes that share 80% or higher sequence similarity with 4970 (75.5%) P. malariae genes. This was demonstrated by the nearly identical genomic organization and multiple sequence alignments for the merozoite surface proteins msp3 and msp7. We observed a distinction in the repeat lengths of the circumsporozoite protein (CSP) gene sequences between P. brasilianum and P. malariae. Our results demonstrate a 97.3% pairwise identity between the P. brasilianum and the P. malariae genomes. These findings highlight the phylogenetic proximity of these two species, suggesting that P. malariae and P. brasilianum are strains of the same species, but this could not be fully evaluated with only a single genomic sequence for each species.


Head injury patients admitted to general hospitals in Merseyside.
During 1975 and 1976, 11837 patients with head injury were admitted to 16 general hospitals serving 2.1 million people. Eight hundred and seventy-five had fractures of the skull, 178 died and 103 were transferred to the regional department of neurosciences. A fall was the cause of injury in 49 per cent, a traffic accident in 24 per cent and assault in 17 per cent. Seventeen per cent of adult patients had taken alcohol and 16 per cent had major extracranial injuries (including fractures of the bones of the face). Sixty-seven per cent stayed in hospital for 0-48 hours and 8 per cent for 8 days or more. The mortality rate and the number of deaths associated with avoidable factors both increased with the patient's ages. After standardization for age and sex, neither of these measures of the effectiveness of the management of head injury in hospital was found to differ significantly amongst the sixteen hospitals; nor were they related to differences in the way in which head injury patients were managed (for example, duration of stay in hospital) or to admission policy, work load (number of patients admitted with head injury per year) or the distance by road to the regional neurosciences department.


Quantitative magnetic resonance studies of manganese uptake by mitochondria.
The uptake of the paramagnetic ion manganese by rat liver mitochondria is studied by electron paramagnetic resonance (EPR) spectroscopy. Emphasis is placed on: (a) obtaining accurate EPR quantitation of intramitochondrial manganese fractions previously described (Gunter, T. E., and J. S.Puskin, 1972, Biophys. J. 12:625) (b) establishing competition for intramitochondrial binding between one of these fractions and calcium, (c) demonstrating the effects of substrate and ATP concentrations on each fraction observed through EPR, and (d) demonstrating the effect of inorganic phosphate (Pi) concentration and pH on each fraction.


Enhanced diagnostic power of exercise testing for myocardial ischemia by addition of postexercise left ventricular ejection time.
To improve both the sensitivity and specificity of the multistage treadmill test, postexercise systolic time intervals were prospectively studied in 73 patients with angina-like chest pain and normal resting ST-T segments. The decision to perform coronary angiography was made independent of the exercise test. Twenty-three patients had normal coronary arteries and 50 had more than 50 percent reduction of luminal diameter of one or more major coronary arteries. The systolic time intervals were measured before and 2,4,6,8 and 10 minutes after exercise. Of all the systolic time intervals, the 4 minute postexercise left ventricular ejection time proved most discriminating between normal subjects and those with coronary artery disease. The deviations of this interval from the normal regression with heart rate both before and after exercise were used to calculate the net delta left ventricular ejection time after exercise. A net increase of more than 31 msec represented 2 standard deviations above normal. Twenty-three (46 percent) of the patients with coronary artery disease had an abnormal net delta ejection time after exercise. Twenty-five (50 percent) had a positive electrocardiographic response with a 9 percent false positive rate. Thirteen (26 percent) had only a positive postexercise net delta ejection time so that a total of 76 percent of patients with coronary artery disease were identified. Thus, measurement of the postexercise net delta ejection time a simple and useful adjunct to multistage treadmill testing.


NGF and BDNF are differentially modulated by visual experience in the developing geniculocortical pathway.
Neuronal activity and trophic factors have been implicated in shaping the connectivity of functional synaptic circuits. We studied the development and regulation by sensory input of the neurotrophins NGF, BDNF and NT-3 in the developing rat visual system. In the occipital cortex, NT-3 mRNA was transiently expressed in the neonate. In contrast, BDNF and NGF mRNA's increased during postnatal development, and reached mature levels around 3 weeks of age. BDNF mRNA was ten times more abundant than NGF mRNA. In the lateral geniculate nucleus (LGN), NT-3 mRNA was also transiently expressed, whereas NGF and BDNF mRNA's did not vary significantly during development. The high-affinity neurotrophin receptors trkB and trkC were expressed both in the developing LGN and occipital cortex. These receptors for BDNF and NT-3, respectively, were expressed at birth, with little change during development. In contrast, trkA mRNA, which encodes the high-affinity NGF receptor, was undetectable in either region. Visual experience differentially modulated expression of NGF and BDNF mRNA's. NGF mRNA was slightly increased after 3 weeks of light-deprivation. In contrast, BDNF mRNA expression in visual cortex was significantly lower than normal in rats dark-reared from birth. Decreased BDNF expression after sensory deprivation was reversible by exposure to light. Thus, all three neurotrophins were detected in visual cortex and LGN. Differences in abundance developmental profiles, and regulation imply distinct functions for each factor in the visual system.


Recent progress in mass spectrometry for single-cell metabolomics.
Metabolites are the end products of cellular vital activities and can reflect the state of cellular to a certain extent. Rapid change of metabolites and the low abundance of signature metabolites cause difficulties in single-cell detection, which is a great challenge in single-cell metabolomics analysis. Mass spectrometry (MS) is a powerful tool that uniquely suited to detect intracellular small-molecule metabolites and has shown good application in single-cell metabolite analysis. In this mini-review, we describe three types of emerging technologies for MS-based single-cell metabolic analysis in recent years, including nano-ESI-MS based single-cell metabolomics analysis, high-throughput analysis via flow cytometry, and cellular metabolic imaging analysis. These techniques provide a large amount of single-cell metabolic data, allowing the potential of MS in single-cell metabolic analysis is gradually being explored and is of great importance in disease and life science research.


PNPLA3 I148M variant and hepatocellular carcinoma: a common genetic variant for a rare disease.
Hepatocellular carcinoma (HCC) is highly associated with chronic liver disease. The rs738409 genetic variant in the patatin-like phospholipase domain-containing 3 (PNPLA3, adiponutrin) gene has been implicated as a genetic determinant of the entire spectrum of liver diseases, ranging from steatosis, chronic hepatitis, cirrhosis and ultimately to HCC. In this review, first we will examine the current genetic theories of disease susceptibility. Next, we will analyze the evidences for the association between PNPLA3 I148M variant and HCC. Moreover, we will exploit this association to propose a new paradigm in human genetics: a common genetic variant contributing to a rare disease. Finally, we will examine the molecular genetics of PNPLA3 and, specifically, the theories that have been proposed to explain the function of PNPLA3 in health and disease.


Assessment of quality of life in patients having Poly-Cystic Ovarian Syndrome: A cross-sectional facility-based study.
Polycystic ovarian syndrome (PCOS) is a complex and heterogeneous disorder affecting various body organs. Menstrual irregularity, anovulation, and many cosmetic issues faced by PCOS patients endanger the essence of being a woman and may have a deleterious impact on their health-related quality of life (HRQOL). This study aimed to assess HRQOL in patients with PCOS and to identify the clinical and socio-demographic factors that might predict poor HRQOL. This cross-sectional study was carried out in the tertiary care hospital in India. A total of 275 women visiting the same setting and diagnosed with PCOS were included. The participants' quality of life was studied using a disease-specific HRQOL questionnaire. Information regarding clinical and socio-demographics was collected using the interviewer schedule. For evaluating the predictors of HRQOL in PCOS subjects, analysis of variance and independent t-test was applied. For subgroup analysis, the post hoc (Gabriel) test was applied. The average total score of HRQOL of the study participants was 125.41 ± 29.1. The lowest weighted mean score was for menstrual problems. Among the socio-demographic variables, age and educational level influenced the HRQOL scores. Highly educated women reported the poorest HRQOL. The analysis of variance also indicated a significant variation in HRQOL scores among body mass index categories [F (4,270) = 5.09, P = <.001] and hirsutism status [F (2,272) = 14.222, P =<.001]. Menstrual irregularity, hirsutism, increased body mass index, educational status, and age are critical in altering HRQOL in PCOS cases. Clinicians should inquire about the HRQOL of patients with severe clinical manifestations and appropriate support must be provided during patient care.


Changes in Clostridium (Clostridioides) difficile PCR-Ribotype Distribution and Antimicrobial Resistance in a German Tertiary Care Hospital Over the Last 10 Years.
Clostridium (Clostridioides) difficile ribotype 027 (RT027) was detected in Germany for the first time in 2007 during an outbreak in the region of Trier, Rhineland-Palatinate and is today the most prevalent ribotype (RT) in Europe. We aimed to determine the changes in RT distribution and corresponding antimicrobial resistance in clinical C. difficile isolates between two time points (2007 and 2017) in one tertiary care hospital in Germany. C. difficile isolates recovered in 2007 and in 2017 (80 isolates per year, respectively) from patients at a Tertiary Care University Hospital in North-Rhine Westphalia were analyzed. Isolates were characterized by ribotyping and susceptibility testing using gradient tests (metronidazole, vancomycin) and the disk diffusion method (moxifloxacin). Between 2007 and 2017, a clear switch from RT001 [18.75% (n = 15) in 2007 versus 3.75% (n = 3) in 2017 P = 0.003] to RT027 [0% in 2007 versus 21.25% (n = 17) in 2017] was evident. While minimal inhibitory concentrations (MICs) of vancomycin were stable, a significant metronidazole MIC creep was determined (MIC50 = 0.047 in 2007 versus MIC50 = 0.094 in 2017, P < 0.0001 using the Man-Whitney test). We detected one metronidazole-resistant isolate (0.6%). Interestingly, in total we encountered more isolates resistant to moxifloxacin in 2007 (42 (52.25%) than in 2017 [(30 (37.5%), P = 0.06)]). We could demonstrate that RT027 replaced RT001 in the last 10 years in our hospital. Furthermore, our data show a metronidazole MIC creep in C. difficile isolates over the last 10 years and an unexpected decrease of isolates resistant to moxifloxacin.