Maternal aerobic running during mid or late gestation improves the quality of oogenesis and folliculogenesis in the ovary of neonatal rats: An experimental study.
Regular maternal exercise in pregnancy enhances the physiological, metabolic, and psychological health of mother and fetus. To determine the effect of maternal aerobic running during mid or late gestation on plasma levels of estrogen and progesterone and the histological alterations in the ovary of neonatal rats. Twenty-one female Wistar rats were randomly divided into experimental groups to exercises during the 2 nd or 3 rd wk of pregnancy (n = 14) and a control group (n = 7). After birth, the neonate's blood was obtained and the estrogen and progesterone levels were evaluated. The ovaries were then removed and used for histological investigations and apoptic assessment. Higher concentrations of estrogen and progesterone were found in the neonates of the experimental groups (p = 0.001) compared to the control group. The experimental groups had a large ovarian diameter (2 nd wk: p = 0.044; 3 rd wk: p = 0.005) and angiogenesis (2 nd wk: p = 0.003; 3 rd wk: p = 0.001). In addition, significant enhancements were seen in the the experimental groups in terms of the number (2 nd wk: p = 0.017; p = 0.035) and diameter (2 nd wk: p = 0.046; 3 rd wk: p = 0.004) of primordial follicles, as well as in the diameter of primary oocytes (2 nd wk: p = 0.073; 3 rd wk: p = 0.019) compared to the control group. Moreover, rats that exercised had a lower number of apoptotic primordial follicles than the control group (2 nd wk: p = 0.001; 3 rd wk: p = 0.001). It was shown that maternal aerobic running can lead to increased plasma levels of estrogen and progesterone, also improved histological characteristics of the ovary in neonatal rats.


Bioorthogonal click chemistries enable simultaneous spatial patterning of multiple proteins to probe synergistic protein effects on fibroblast function.
Three biorthogonal click reactions, a photoinitiated thiol-yne reaction, an azide-alkyne cycloaddition, and a methyltetrazine-transcyclooctene Diels Alder, were used to independently control the presentation of several bioactive proteins to valvular interstitial cells (VICs) in hydrogel scaffolds. Tethered fibroblast growth factor (FGF-2) was found to suppress myofibroblast activation (from 48 ± 7% to 17 ± 6%) and promote proliferation (from 10 ± 2% to 54 ± 3%) at a concentration of 10 ng/mL. In the presence of the pro-fibrotic cytokine transforming growth factor-beta (TGF-β1), FGF-2 could protect the VIC fibroblast phenotype, even at much higher concentrations of TGF-β1 than that of FGF-2. With respect to the fibrocalcific VIC phenotype, TGF-β1 and bone-morphogenic protein-2 (BMP-2) were found to synergistically promote calcific nodule formation (a five-fold increase in nodules compared to TGF-β1 or BMP-2 alone). Exploiting the orthogonal click reactions, FGF-2, TGF-β1 and BMP-2 combinations were patterned into distinct regions on a hydrogel to control VIC activation and nodule formation. Cellular crosstalk between separate regions of the same scaffold was affected by the size of each region as well as the interfacial area between different regions. Collectively, these results demonstrate the versatility and robustness of a photoinitiated thiol-yne reaction to template pendant functionalities that allow for the bioconjugation of multiple proteins. This approach maintains protein bioactivity, providing an in vitro platform capable of achieving a better understanding of the complex mechanisms involved in tissue fibrosis.


Children's perception of certain musical properties: scale and contour.
Children's perception of scale and contour in melodies was investigated in five studies. Experimental tasks included judging transposed renditions of melodies (Studies 1 and 3), discriminating between transposed renditions of a melody (Study 2), judging contour-preserving transformations of melodies (Study 4), and judging similarity to a familiar target melody of transformations preserving rhythm or rhythm and contour (Study 5). The first and second studies showed that young children detect key transposition changes even in familiar melodies and they perceive similarity over key transpositions even in unfamiliar melodies. Young children also are sensitive to melodic contour over transformations that preserve it (Study 5), yet they distinguish spontaneously between melodies with the same contour and different intervals (Study 4). The key distance effect reported in the literature did not occur in the tasks of this investigation (Studies 1 and 3), and it may be apparent only for melodies shorter or more impoverished than those used here.


Calcipotriol cream with or without concurrent topical corticosteroid in psoriasis: tolerability and efficacy.
The objectives of the study were to determine whether concurrent treatment with calcipotriol (50 microg/g) and either clobetasone 17-butyrate cream (0.5 mg/g) (moderate potency) or betamethasone 17-valerate cream (1 mg/g) (potent) or placebo (vehicle of calcipotriol) was more effective and/or caused less skin irritation than calcipotriol cream (50 microg/g) used twice daily. It was a multicentre, double-blind, parallel group study. Patients applied calcipotriol cream in the morning and either vehicle (n = 174), calcipotriol (n = 174), clobetasone (n = 175) or betamethasone creams (n = 176) in the evening for up to 8 weeks. Adverse events led to withdrawal in 20 patients (2.9%). The mean percentage change in PASI (psoriasis area and severity index) was -40.6 in the calcipotriol/vehicle group, -48.3 in the calcipotriol/calcipotriol group, -53.7 in the calcipotriol/clobetasone 17-butyrate group and -57.5 in the calcipotriol/betamethasone 17-valerate group. A statistically significant difference was seen between the four treatment groups (P = 0.006) with calcipotriol/vehicle being less effective than the other treatments. A statistically significant difference in favour of calcipotriol/betamethasone 17-valerate was seen between the calcipotriol/calcipotriol group and the calcipotriol/betamethasone 17-valerate group. The majority of adverse events were skin irritations, which were reported for 31.2% of patients treated with calcipotriol/vehicle, 34.3% of patients treated with calcipotriol twice daily and 23.8% vs. 17.1% of patients treated with calcipotriol/clobetasone 17-butyrate and calcipotriol/betamethasone 17-valerate, respectively. Skin irritation was seen statistically significantly less frequently in patients treated with calcipotriol/ clobetasone 17-butyrate or calcipotriol/betamethasone 17-valerate (P = 0.001), whereas no difference was seen between the other groups. In conclusion, calcipotriol applied twice daily was as effective as calcipotriol/clobetasone 17-butyrate, but slightly less effective than calcipotriol/betamethasone 17-valerate. The incidence of skin irritation was less for patients using concurrent corticosteroids, whereas treatment with calcipotriol/vehicle did not reduce the incidence of skin irritation when compared with calcipotriol twice daily.


Bridging theory and experiments of priority effects.
Priority effects play a key role in structuring natural communities, but considerable confusion remains about how they affect different ecological systems. Synthesizing previous studies, we show that this confusion arises because the mechanisms driving priority and the temporal scale at which they operate differ among studies, leading to divergent outcomes in species interactions and biodiversity patterns. We suggest grouping priority effects into two functional categories based on their mechanisms: frequency-dependent priority effects that arise from positive frequency dependence, and trait-dependent priority effects that arise from time-dependent changes in interacting traits. Through easy quantification of these categories from experiments, we can construct community models representing diverse biological mechanisms and interactions with priority effects, therefore better predicting their consequences across ecosystems.


Recent analysis of status and outcomes of peritoneal dialysis in the Tokai area of Japan: the second report of the Tokai peritoneal dialysis registry.
Early withdrawal within 3 years after starting peritoneal dialysis (PD) and PD-related peritonitis have been major obstacles preventing increases in the population of PD patients. To address these problems, we implemented education programs for medical staff. This study analyzed the recent status and outcomes of PD therapy, focusing on findings such as the incidence and prognosis of peritonitis as of 5 years after our last study. We investigated background, laboratory data and status of PD therapy, reasons for withdrawal from PD and incidental statements on peritonitis from 2010 to 2012 (R2), and compared findings with those from our last study of 2005-2007 (R1). Early PD therapy withdrawal in R2 clearly improved to 44.7 %, compared with 50.9 % in R1. Peritonitis incidence improved slightly from once per 42.8 months/patient in R1 to once per 47.3 months/patient in R2. Notably, PD-related peritonitis as a cause of mortality improved markedly in R2, but outcomes of PD-related peritonitis did not change significantly between R1 and R2. In contrast, social problems increased as a reason for withdrawal from PD therapy. Our efforts at education might have been useful for improving early withdrawal from PD and deaths attributable to PD-related peritonitis. However, since improvements to incidence of PD-related peritonitis were limited by education, further improvement in PD-related peritonitis incidence requires development of new sterilized connecting systems during PD-bag exchanges to decrease PD-related peritonitis opportunities. Construction of medical support systems to address social problems is required to maintain long-term PD therapy.


K562 cells induced to differentiate by phorbol ester tumor promotors resist NK lysis.
The effect of various phorbols and phorbol diesters on the NK sensitivity of the human leukemic K562 cells was studied. A marked decrease in K562 cell susceptibility was achieved by culture in the presence of either 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or beta-phorbol-dibutyrate. The maximum protection against NK lysis was achieved when K562 cells were cultured in the presence of 160 nM TPA for 48 hr (mean percentage inhibition: 61% of specific lysis). As for untreated targets, the residual killing of K562 cells after TPA treatment was mediated through large granular lymphocytes (LGL). The experimental procedures required to achieve maximal NK protection with TPA resulted simultaneously in marked phenotypical changes in K562 cells: erythroid and early myeloid markers decreased, whereas the expression of megakaryocytic markers was increased as shown by staining with antiplatelet monoclonal antibodies and assessment of platelet peroxidase activity. Chemical phorbol analogs which were unable to induce K562 cell differentiation did not affect K562 cell sensitivity to NK lysis. De novo protein synthesis is involved in the TPA-induced NK resistance, since this effect was abolished by pretreatment of K562 cells with actinomycin D or cycloheximide. TPA has been previously demonstrated to reduce NK effector activity. In our data however, the observed TPA effects were not due to release of TPA acting on effector cells during the NK assay since TPA-treated K562 cell supernatants were unable to inhibit NK activity in control assays. Thus, TPA appears to decrease NK killing of malignant cells, both by depressing NK effector cells functions and by reducing the susceptibility to NK lysis of the target cells. In single-cell agarose assays, TPA-treated K562 cells demonstrated reduced NK-binding capacity and reduced sensitivity to lysis after binding. These defects could not be reversed by activation of the NK effector cells with interferon. The results here reported extend the previously suggested relations between the expression of NK-target structures and the differentiation stage of malignant cells.


Functional morphology of accommodation in the raccoon.
The raccoon (Procyon lotor) is a small carnivore which eats in the upright position, using hand- and finger-like front paws and digits to wash, hold and examine its food at close range. These anatomic and behavioral characteristics prompted structural and functional studies of the accommodative capability of this species. By light and electron microscopy, we observed a prominent ciliary smooth muscle and zonular apparatus. When stimulated by carbachol or pilocarpine, the muscle and zonular apparatus exhibited a shift from longitudinal to reticular or circular orientation of some ciliary muscle bundles, anterior movement of the muscle as a whole, and more oblique crossing of the zonular fiber bundles in the zonular plexus. Maximum carbachol-induced accommodative amplitude measured by coincidence refractometry ranged from 3 to 19 diopters in these 1 to 9 yr old animals, with no definite age-accommodation relationship. A-scan ultrasonographic biometry showed that during accommodation the lens thickened very little, if at all, but moved anteriorly, while the apparent cornea to retina distance increased slightly. The raccoon thus exhibits the greatest accommodative capability of any non-primate terrestrial mammal so far studied.


An anatomic study of the divisions of the lateral pterygoid muscle based on the findings of the origins and insertions.
The lateral pterygoid muscle has been generally described as a muscle composed of two separate heads, however, the border between these heads has not clearly identified. In the present study, we investigated the positional relationships between the muscle and the surrounding nerves, and examined the muscle bundle arrangements to determine the detailed information of the origins and insertions. We used 94 specimens of 52 Japanese cadavers (29 males and 25 females) for the investigations of the nerve courses, and randomly chose and used 10 specimens of 5 (2 males and 3 females) cadavers from above-mentioned 52 cadavers for the detailed examinations of the muscle fiber constructions. In some specimens, the buccal nerve passed through the gap in the muscle, however, in many cases the nerve pierced the muscle. The muscle inserted into the medial half of the anterior surface and the medial surface of the condylar process. Only a thin superficial layer of the muscle fibers was attached to the inferior surface of the articular disc. According to the positions of the origins and insertions of the muscle and the positional relationships to the nerves, the muscle was not clearly divided into heads. The detailed findings of the origins and insertions of the present study suggest that the muscle is a single muscle with no clear border, containing fibers of various directions. A two-head muscle pattern would be indicated by the differences of the convergences of the muscle fibers.


Use of a spin-labeled cerebrospinal fluid magnetic resonance imaging technique to demonstrate successful endoscopic fenestration of an enlarging symptomatic cavum septi pellucidi.
The aim of this study was to noninvasively visualize whether cerebrospinal fluid (CSF) compartments are in communication. An enlarging cavum septi pellucidi (CSP) produced progressive hydrocephalus following subarachnoid hemorrhage. We questioned what were the dynamics of CSF flow that led to enlargement of the CSP. With this case report, we show the usefulness of a newly described magnetic resonance imaging time-spatial labeling inversion pulse technique to establish that an enlarging CSP was the cause of progressive hydrocephalus and that the hydrocephalus was successfully endoscopically treated when the CSP was fenestrated into the ventricular system, establishing communication between the two CSF compartments.


The reduction of chronic, nonspecific low back pain through the control of early morning lumbar flexion: 3-year follow-up.
Three years ago, an 18-month randomized controlled trial of chronic, nonspecific low back pain investigated the effectiveness of instructing subjects to restrict bending activities in the early morning, when the fluid content in the disc is increased. Pain days (as recorded by daily diaries) were reduced 23% in the treatment group, compared to a 2% reduction in the control (sham treatment) group. The purpose of the current follow-up study was to determine whether the results of that trial were maintained during the 3 years following completion of the trial. A questionnaire was mailed to the 60 subjects who completed the original trial. Fifty subjects completed the questionnaire for a response rate of 83%. Thirty-one subjects (62%) continued to restrict bending activities in the early morning, and experienced a further reduction of 10.1 pain days per month (51%) since the completion of the experiment. However, some of the subjects who did not continue to comply also improved. Several possible explanations for the improvement of noncompliant subjects are offered.


Pigment dispersing hormone modulates spontaneous electrical activity of the cerebroid ganglion and synchronizes electroretinogram circadian rhythm in crayfish Procambarus clarkii.
In crayfish, one very well-studied circadian rhythm is that of electroretinogram (ERG) amplitude. The cerebroid ganglion has been considered a plausible site for the circadian pacemaker of this rhythm and for the retinular photoreceptors, as the corresponding effectors. The pigment dispersing hormone (PDH) appears to synchronize ERG rhythm, but its characterization as a synchronizer cue remains incomplete. The main purposes of this work were a) to determine whether PDH acts on the cerebroid ganglion, and b) to complete its characterization as a non-photic synchronizer. Here we show that PDH increases the number of the spontaneous potentials of the cerebroid ganglion, reaching 149.92±6.42% of the activity recorded in the controls, and that daily application of PDH for 15 consecutive days adjusts the ERG circadian rhythm period to 24.0±0.2h and the end of the activity period of the rhythm coincides with the injection of the hormone. In this work, we hypothesized that in crayfish, PDH transmits the "day" signal to the ERG circadian system and acts upon both the presumptive circadian pacemaker and the corresponding effectors to reinforce the synchronization of the system.


Anterior pelvic plane estimation for total hip arthroplasty using a joint ultrasound and statistical shape model based approach.
Orienting properly the prosthetic cup in total hip arthroplasty is key to ensure the postoperative stability. Several navigation solutions have been developed to assist surgeons in orienting the cup regarding the anterior pelvic plane (APP), defined by both anterior superior iliac spines (ASIS) and the pubic symphysis. However acquiring the APP when the patient is ready for surgery, i.e., mainly in lateral decubitus, is difficult due to the contralateral ASIS being against the operating table. We propose a method to determine the APP from both (1) alternative anatomical landmarks which are easy to acquire with a navigated ultrasound probe and (2) a Statistical Shape Model (SSM) of the pelvis. After creating a pelvic SSM from 40 data, a SSM-based morphometric analysis has been carried out to identify the best anatomical landmarks allowing the easy determination of the APP. The proposed method has then been assessed with both in silico and in vivo experiments on respectively forty synthetic data, and five healthy volunteers. The in silico experiment shows the feasibility to determine the APP with an average error of 4.7∘ by only acquiring the iliac crest, the anterior superior iliac spine, the anterior inferior iliac spine, and the pubic symphysis. The average in vivo error using the ultrasound modality was 7.3∘ with an estimated impact on both the cup anteversion and inclination of 4.0∘ and 1.7∘ respectively. The proposed method shows promising results that could allow the determination of the APP in lateral decubitus with a clinically acceptable impact on the computation of the cup orientation.


Computed tomography of a double inferior vena cava: the "double cava" sign.
Right-sided retroperitoneal adenopathy or right adrenal masses demonstrated by CT in cross sectional display may mimic the CT appearance of the inferior- vena cava. This finding has been recently described as the "double cava" sign. The authors report this sign in a patient who actually has a double IVC. "CT angiography" with the technique described herein, will determine that the retroperitoneal structures demonstrated by CT are indeed vessels rather than enlarged nodes or adrenal masses.


The prevalence of lisping in gay men.
This study evaluated the stereotype that gay men lisp. Two clinicians who were unaware of the specific purpose of the study and the populations involved judged randomized audio-recordings of 175 gay males, 100 heterosexual males and 100 heterosexual females for the presence of lisping during reading of a standardized text. In the gay males a significantly higher prevalence of lisping was found than in the heterosexual males and females. Breakdown of the results of the gay participants in two different age groups showed a higher prevalence of lisping in the younger age group than in the older age group. No relation was found between lisping and age of coming-out or lisping and the probability of being gay as assessed by a questionnaire about sexual orientation. The origin of the high prevalence of lisping in gay men needs further investigation. The readers of this article will able (1) to discuss articulatory behaviour as a possible marker that may distinguish gay from heterosexual men (2) to discuss the prevalence of lisping in gay men.


Comparison of HPLC with electrochemical detection and LC-MS/MS for the separation and validation of artesunate and dihydroartemisinin in animal and human plasma.
High-performance liquid chromatography with reductive electrochemical detection (HPLC-ECD) method has been used for assaying artemisinins since 1985. Although the methods have been remarkably improved, tandem mass spectrometry (LC-MS/MS) systems with significant advantages have gradually replaced HPLC-ECD to analyze artesunate and dihydroartemisinin in plasma. In the present study, the two methods were evaluated for linearity, quantitation limits, selectivity, precision, and accuracy. The HPLC-ECD performed well in terms of various validation parameters, and showed a good agreement with the LC-MS/MS when calibrated in plasma. However, the major benefit of LC-MS/MS is that it requires only one-tenth the plasma volume needed by HPLC-ECD assay.


Targeted Therapy for EWS-FLI1 in Ewing Sarcoma.
Ewing sarcoma (EwS) is a rare and predominantly pediatric malignancy of bone and soft tissue in children and adolescents. Although international collaborations have greatly improved the prognosis of most EwS, the occurrence of macrometastases or relapse remains challenging. The prototypic oncogene EWS-FLI1 acts as an aberrant transcription factor that drives the cellular transformation of EwS. In addition to its involvement in RNA splicing and the DNA damage response, this chimeric protein directly binds to GGAA repeats, thereby modifying the transcriptional profile of EwS. Direct pharmacological targeting of EWS-FLI1 is difficult because of its intrinsically disordered structure. However, targeting the EWS-FLI1 protein complex or downstream pathways provides additional therapeutic options. This review describes the EWS-FLI1 protein partners and downstream pathways, as well as the related target therapies for the treatment of EwS.


The differential effects of three forms of interferon alfa on hepatic regeneration after partial hepatectomy in the rat.
The purpose of this study was to determine whether all commercially available forms of interferon alfa (INF alpha) have the same inhibitory effect on hepatic regeneration and whether this inhibitory effect can be prevented by putrescine, a hepatic growth promotor. Adult male Sprague-Dawley rats (n = 92) received either IFN alpha-2a, 2b, n1, or saline, 0 and 18 hours after partial hepatectomy (PHx) or 16 hours before PHx. A subgroup of 29 rats being treated with IFn alpha-2a or saline also received putrescine (5, 50, or 500 mg/kg) 16 hours before PHx. Hepatic regeneration was documented by determining [3H]-thymidine incorporation into hepatic DNA (DNA synthesis), hepatic putrescine levels, and, in selected cases, ornithine decarboxylase (ODC) activity at 24 hours after PHx. The results of the study showed that hepatic regeneration was unaffected when IFN alpha was administered 0 and 18 hours after PHx. When administered at -16 hours, only IFN alpha-2a significantly inhibited DNA synthesis and was associated with decreased hepatic putrescine levels. Inhibition was dose-dependent in that a 10-fold increase in IFN alpha-2a caused a further decrease in both DNA synthesis and hepatic putrescine levels. At the higher dose, IFN alpha-2b and n1 also inhibited DNA synthesis and lowered hepatic putrescine levels and ODC activity. Exogenous putrescine (5 and 50 mg/kg) restored hepatic regenerative activity to normal but was toxic at high concentrations (500 mg/kg). These data indicate that not all commercially available forms of IFN alpha inhibit hepatic regeneration in the rat to the same extent.


An electrophysiological study of the sequential water swallowing.
Sequential water swallowing (SWS) was mostly investigated by the videofluoroscopic and endoscopic methods. However some physiological features of SWS was rarely evaluated by neurophysiological techniques. Our aim was to investigate some neural and muscular changes on sequences of SWS using electromyography (EMG) methods. Fifty-eight normal adults were investigated. SWS was initiated voluntarily with 50ml and 100ml water volumes from a cup. Submental EMG, respiratory signals, heart rate, and sympathetic skin responses (SSR) were measured during SWS. All parameters were increased significantly during the 100ml SWS. During swallowing apnea period, compensatory respiration cycles occurred in 24% and 48% of participants in the 50ml and 100ml SWS, respectively. Heart rate increased during swallowing apnea. SSR were evoked just before and just after the SWS in more than halves of participants. A foreburst EMG in SM muscles at the initiation of SWS was recorded in 86% of normal participants. Older age was associated with a prolonged duration of the apnea period. All parameters of the SWS could be recorded numerically and objectively using electrphysiological methods. These are similar to those obtained by videofluoroscopic and similar methods. The foreburst activity of the initiation of SWS may represents preparatory activity from the activation of the fast cortical descending motor pathway. Increasing heart rate and the prolonged apnea urged that older people and patients could be carefully tested for respiratory and cardiac rhythm disorders.


Congenital heart malformations associated with dilated cardiomyopathy.
From June 1977 to February 1986 we studied 31 children with dilated cardiomyopathy. Seven patients (22%) aged 8 months to 3 years had associated congenital cardiac lesions--tetralogy of Fallot (3), coarctation of the aorta (2), ventricular septal defect (1) and Ebstein's malformation (1). The diagnosis was confirmed by hemodynamic and angiographic studies in 5 patients and by autopsy in 2. Although different congenital lesions were present, all 7 patients had congestive heart failure, flattening of T-waves or ST-segment depression on the electrocardiogram and significant decrease in the left ventricular shortening fraction as judged by echo. We conclude that the incidence of dilated cardiomyopathy associated with congenital heart malformations is high in our pediatric population. The clinical status of patients appears to be more dependent on the improvement of dilated cardiomyopathy and less dependent upon the underlying congenital heart malformations.


Smoking and health: the association between smoking behaviour, total mortality, and cardiorespiratory disease in west central Scotland.
The relationship of smoking to total mortality and to the prevalence of cardiorespiratory symptoms has been studied in three prospective surveys in west central Scotland in which 18 786 people attended a multiphasic screening examination. The prevalence of respiratory symptoms, and to a lesser extent cardiovascular symptoms, increased with the number of cigarettes smoked, with inhalation, and with a younger age of starting to smoke. A lower prevalence of respiratory symptoms in both sexes was observed in smokers of filter cigarettes than in smokers of plain cigarettes, and in those who smoked cigarettes with lower tar levels, irrespective of whether these were filtered or plain. In general, the relationships found between smoking and mortality were similar to those reported by other workers. Current cigarette smokers had a death rate from all causes which was twice that of those who had never smoked. No difference was found between the mortality rates of smokers of plain and filter cigarettes.


A case report of pediatric systemic lupus erythematosus with diffuse alveolar hemorrhage following COVID-19 infection: Causation, association, or chance?
Diffuse alveolar hemorrhage (DAH) is a rare manifestation of childhood systemic lupus erythematosus (SLE) that can be life-threatening. Several reports have linked previous or concurrent coronavirus disease (COVID-19) infections with a high prevalence of autoimmune and autoinflammatory disorders. We report a case of a 13-year-old female who presented with DAH due to SLE 2 months after a laboratory-confirmed severe COVID-19 infection. The patient was diagnosed with DAH due to SLE 2 months after a laboratory-confirmed severe COVID-19 infection. The patient was treated with intravenous methylprednisolone pulse, broad-spectrum antibiotics, and supportive measures. In addition, she received 6 sessions of plasma exchange and maintenance methylprednisolone therapy (2 mg/kg/day). The patient then improved and was discharged on prednisolone, hydroxychloroquine, and azathioprine. We suggest plasmapheresis be considered a treatment for SLE-associated DAH in the context of active disease when conventional treatment has failed to induce a rapid response. In addition, further studies are needed to assess the role of COVID-19 as an autoimmune disease trigger, particularly for SLE.


Hydrolysis of Chlorella biomass for fermentable sugars in the presence of HCl and MgCl2.
When Chlorella biomass was hydrolyzed in the presence of 2% HCl and 2.5% MgCl(2), a sugar concentration of nearly 12%, and a sugar recovery of about 83% was obtained. Fermentation experiments demonstrated that glucose in the Chlorella biomass hydrolysates was converted into ethanol by Saccharomyces cerevisiae with a yield of 0.47 g g(-1), which is 91% of the theoretical yield. This chemical hydrolysis approach is thus a novel route for the hydrolysis of biomass to generate fermentable sugars.


Meta-analysis of the influence of TM6SF2 E167K variant on Plasma Concentration of Aminotransferases across different Populations and Diverse Liver Phenotypes.
A nonsynonymous E167K (rs58542926 C/T) variant in TM6SF2 gene was recently associated with nonalcoholic fatty liver disease (NAFLD). We explored the association between E167K and plasma concentrations of alanine (ALT) and aspartate (AST) aminotransferases through a meta-analysis. We also estimated the strength of the effect across diverse liver phenotypes, including NAFLD and chronic viral hepatitis; fourteen studies were included. We found that ALT (p = 3.2 × 10(-6), n = 94,414) and AST (p = 0007, n = 93,809) levels were significantly associated with rs58542926 in NAFLD. By contrast, rs58542926 was not associated with either ALT (p = 0.24, n = 4187) or AST (p = 0.17, n = 2678) levels in four studies on chronic hepatitis. In conclusion, the results of the pooled estimates in patients with NAFLD showed that carriers of the T allele (EK + KK), when compared with homozygous subjects for the C allele (EE genotype) have increased levels of aminotransferases; however, this increase represents -2.5 (9.8%) and 1.2 (5%) IU/L of ALT and AST respectively, which is fairly small compared with the large effect of PNPLA3- rs738409-G allele that is associated with a -28% increase in serum ALT.


Elevated blood favipiravir levels are inversely associated with ferritin levels and induce the elevation of uric acid levels in COVID-19 treatment: A retrospective single-center study.
Measurement of blood Favipiravir (FPV) levels and accumulation of data in COVID-19 patients are critical for assessing FPV efficacy and safety. We performed a retrospective study based on measurements of blood levels of FPV and related factors in COVID-19 patients admitted to our hospital. Furthermore, we also investigated the association between blood FPV levels and uric acid level alterations before and after FPV administration. We enrolled 27 COVID-19 patients who had received FPV treatment at Hokushin General Hospital from April 1 to December 31, 2020. Age, gender, COVID-19 severity, presence of comorbidities, and laboratory data for each subject were investigated to identify factors that correlate with blood FPV levels. Uric acid levels were measured before and after FPV administration and a difference between the levels (i.e., a change of uric acid level) was evaluated. When a significant univariate variable was input by the stepwise method and a combination of variables that maintained statistical superiority was searched, serum ferritin was the only factor that independently affected blood FPV level. Furthermore, in the high-FPV group (20 μg/mL or more), a significant increase in uric acid levels was observed after FPV administration. The increment value was significantly larger than that in the low-FPV group (less than 20 μg/mL). Ferritin level was an important independent factor inversely affecting blood FPV level. Furthermore, a high blood FPV level induced the elevation of uric acid levels in COVID-19 treatment.


Strain and Complexity, Passerini and Ugi Reactions of Four-Membered Heterocycles and Further Elaboration of TOSMIC Product.
Straightforward and general Passerini and Ugi procedures have been developed to incorporate four-membered heterocycles into highly functionalized scaffolds. Additionally, toslymethyl isocyanide (TosMIC)-derived Ugi adducts have been prepared, showcasing the prospect of the multicomponent reaction.


Regional distribution of blood volume within the preterm infant thorax during synchronised mechanical ventilation.
Perfusion in healthy adults is gravity-dependent. Little is known about lung perfusion in the preterm infant. The aim of this study was to describe the regional distribution of blood volume within the thorax in preterm infants receiving synchronised volume-targeted mechanical ventilation (SIPPV + TTV) and to compare this to regional distribution of tidal ventilation using electrical impedance tomography (EIT). Stable supine ventilated preterm infants (<32-week gestation) were studied. Three sets of artefact-free 30-s EIT recordings of the right hemithorax were filtered in the cardiac and respiratory frequency domains to differentiate impedance change due to blood (ΔZ (c)) and gas volume (ΔZ (v)). The distribution of ΔZ (c) and ΔZ (v) in the anterior-to-posterior regions of the right chest were compared. Infants were subdivided by age (≤ 7, >7 days) and oxygen requirement. A total of 5,471 beats were analysed from 26 infants (78 recordings); mean (standard deviation (SD)) gestational age was 26 (2) weeks and mean (SD) postnatal age was 9 (10) days. The median (interquartile range) ΔZ (c) in the anterior half of the hemithorax was 1.41-fold (0.88-2.11) greater than that in the posterior half. The geometric centre of ΔZ (c) was located at 46.7% of the anterior-posterior thoracic distance, compared to a more centrally located ΔZ (v) (49.6%; p < 0.0001). The ΔZ (v)/ΔZ (c) ratio was 1.7 in the anterior third of the chest and 2.2 in the posterior (p < 0.0001). The area under the curve (AUC) analysis showed that ΔZ (c) was more evenly distributed in infants >7 days of age and not influenced by oxygen requirement. There are gravity dependent differences in the distribution of blood volume and ventilation in the ventilated preterm chest.


Design of experiment and data analysis by JMP (SAS institute) in analytical method validation.
Validation of an analytical method through a series of experiments demonstrates that the method is suitable for its intended purpose. Due to multi-parameters to be examined and a large number of experiments involved in validation, it is important to design the experiments scientifically so that appropriate validation parameters can be examined simultaneously to provide a sound, overall knowledge of the capabilities of the analytical method. A statistical method through design of experiment (DOE) was applied to the validation of a HPLC analytical method for the quantitation of a small molecule in drug product in terms of intermediate precision and robustness study. The data were analyzed in JMP (SAS institute) software using analyses of variance method. Confidence intervals for outcomes and control limits for individual parameters were determined. It was demonstrated that the experimental design and statistical analysis used in this study provided an efficient and systematic approach to evaluating intermediate precision and robustness for a HPLC analytical method for small molecule quantitation.


Debilitating interaction of adrenalectomy and intrahypothalamic implants of prostaglandin E2 upon open-field activity levels and sexual receptivity in estrogen-primed ovariectomized rats.
A group of estrogen-primed, ovariectomized rats was adrenalectomized and tested for sexual receptivity following hypothalamic implantations of PGE2. The combination of PGE2 and adrenalectomy led to severe debilitation as manifested by greatly reduced open-field activity scores and inhibition of estrogen and progesterone induced sexual receptivity. Neither exogenous progesterone nor corticosterone was able to restore these behaviors to normal levels. A mechanism involving PGE2 and adrenalectomy-induced transient ischemia was discussed as a possible cause of the debilitation.


Measurement of corneal tangent modulus using ultrasound indentation.
Biomechanical properties are potential information for the diagnosis of corneal pathologies. An ultrasound indentation probe consisting of a load cell and a miniature ultrasound transducer as indenter was developed to detect the force-indentation relationship of the cornea. The key idea was to utilize the ultrasound transducer to compress the cornea and to ultrasonically measure the corneal deformation with the eyeball overall displacement compensated. Twelve corneal silicone phantoms were fabricated with different stiffness for the validation of measurement with reference to an extension test. In addition, fifteen fresh porcine eyes were measured by the developed system in vitro. The tangent moduli of the corneal phantoms calculated using the ultrasound indentation data agreed well with the results from the tensile test of the corresponding phantom strips (R(2)=0.96). The mean tangent moduli of the porcine corneas measured by the proposed method were 0.089±0.026MPa at intraocular pressure (IOP) of 15mmHg and 0.220±0.053MPa at IOP of 30mmHg, respectively. The coefficient of variation (CV) and intraclass correlation coefficient (ICC) of tangent modulus were 14.4% and 0.765 at 15mmHg, and 8.6% and 0.870 at 30mmHg, respectively. The preliminary study showed that ultrasound indentation could be applied to the measurement of corneal tangent modulus with good repeatability and improved measurement accuracy compared to conventional surface displacement-based measurement method. The ultrasound indentation can be a potential tool for the corneal biomechanical properties measurement in vivo.


Direct admission versus transfer of AMI patients for primary PCI.
Guidelines for the treatment of patients with ST-elevation myocardial infarction (STEMI) recommend primary PCI as first choice therapy. This recommendation has been linked to defined time limits achievable in a logistic network for the treatment of ACS. In the present study we analyzed the difference in 6 months outcome between STEMI patients who were admitted directly to a PCI center and those requiring transfer for primary PCI. 2,034 consecutive patients were included in the Bad Nauheim ACS registry. Admission diagnosis was STEMI in 1,057 (52%) patients (71% male, aged 63 ± 13). 637 (60%) patients were directly admitted for primary PCI with a time delay from first medical contact until admission in the PCI center of 64 min (IQR 45-90) at median and door-to-balloon time (DTB) at median 29 min (IQR 20-41). 420 (40%) patients were transferred from peripheral hospitals. In this subgroup time delay was 135 min (IQR 69-285) and DTB at median 31 min (IQR 22-49). 178 (16.8%) patients were at high risk (CPR or cardiogenic shock). Patients, who were admitted directly had a better outcome as transferral patients (log rank 6.1; p = 0.013 for 6 months mortality). However, Kaplan-Meier survival analysis (log rank 4.25; p = 0.039) and Cox regression analysis (95% CI 1.08-3.17; p = 0.026) revealed that this difference in outcome was restricted to high-risk patients. A network for the treatment of STEMI provides the logistic basis for the initiation of primary PCI according to current guidelines. However, transferral patients do not meet the defined time limits. Mortality rates for high-risk transferral patients appear to be higher as those of patients taken directly to the center by the EMS.


Accumulation and removal of Hg203 in different regions of the rat brain.
We have studied the brain regional distribution of methyl mercury following intravenous administration of CH3 203HgCl in rat. Early peak levels were obtained in cerebellum, medulla oblongata and midbrain. The efficacy of removal of 203Hg by different chelators is also region dependent. The most efficient chelator for brain mercury proved to be mesodimercaptosuccinic acid.


Liver neoplasms and the oral contraceptives.
For sixteen years (1954 to 1970) oral steroids had been used for contraception by millions of women. We were unable in this time span to find any cases of liver neoplasms in women using oral contraceptives. However, since 1970, there have been 138 cases reported in the English literature. We will add nine cases to this number, including an unusual case report. Evidence for the oral contraceptive as an etiologic agent in causing liver neoplasms is circumstantial but but nevertheless substantial. The literature is reviewed, and our case is presented. At present, the etiology of liver neoplasms is an enigma. Close clinical surveillance with an awareness of this potentially fatal pathologic entity is essential in women who have ingested oral contraceptives.


Misoprostol vs vasopressin as a single hemostatic agent in laparoscopic myomectomy: Comparable, or just better than nothing?
Laparoscopic myomectomy may be associated with considerable blood loss, especially in patients in whom no specific hemostatic measures are used. We conducted this retrospective comparative study to investigate whether misoprosol is an effective and safe alternative to vasopressin when used as single hemostatic agent in laparoscopic myomectomy. Two hundred cases undergoing laparoscopic myomectomy (-ies), were included. Of these, 50 pre-treated with vaginal misoprostol 400mcg 1 h before surgery (group 1), were compared with two historic consecutive groups: 100 patients treated with intraoperative intra-myometrial injection of dilute vasopressin (20 IU/100 mL normal saline) (group 2), and 50 treated without use of any hemostatic agent (group3). Mean procedure length did not differ significantly between the three groups (127.9 vs 100.6 vs 130.8 min). Mean estimated blood loss (EBL) was 179.7 ± 200.0 mL in group 1, compared with 147.8 ± 171.8 mL in group 2 (P = 0.793) and 321.8 ± 246.0 mL in group 3, respectively (P < 0.001). EBL was lower in group 2 in most of the study's subgroups of patients stratified according to size and number of fibroids compared with group 1, with the exception of patients with ≥4 fibroids, and ≥7 cm in size. In these subgroups, misoprostol appeared more effective. Neither agent was associated with serious adverse events. Vaginal misoprostol can be effective in reducing blood loss during laparoscopic myomectomy. Although rates of EBL are, in general, higher compared with those obtained with vasopressin, they are significantly reduced compared with those observed when no hemostatic agent is used. In extended procedures, vaginal misoprostol, due to its prolonged uterotonic action, may be associated with reduced blood loss compared with vasopressin.


[Exposed superior bulb of the internal jugular vein. Differential hearing loss diagnosis with pulse synchronous tinnitus].
A case report is presented of a 54-year-old woman with tinnitus synchronous with her pulse and an ipsilateral conductive hearing loss. Otoscopy showed a pulsatile structure behind the right eardrum. Imaging with high-resolution computed tomography of the temporal bone showed an enlarged jugular vein bulb. Magnetic resonance imaging could not be performed because of an implanted pacemaker. Since a glomus jugulare tumor could not be excluded right diagnostic tympanoscopy was performed and revealed a high jugular bulb that filled nearly a third of the tympanum.


Wood waste valorization: Ethanol based organosolv as a promising recycling process.
Wood waste is a valuable material that could constitute an abundant and inexpensive source for the production of new materials the recovery of energy. In Europe, about 46% of wood waste is recycled to particleboard and fiberboard, while the other fraction is incinerated. However, a considerable quantity of wood waste shows potential for its transformation into value-added products due to its compositional quality. In this work, wood waste collected at a mechanical treatment plant underwent organosolv treatment to produce a cellulose pulp suitable for manufacturing containerboard. Three variables (temperature, acid concentration, and ethanol concentration) were investigated to find an optimal solution to produce wood pulp by means of Design of Experiment. Wood waste was microwave-heated at 160 °C for 15 min using an acidified ethanol-water solution (2% w/w H2SO4 and 0.8 w/w ethanol concentration), producing pulp with an average cellulose content of 76% where 93% of initial cellulose was retained. Thanks to a one-pot approach, ethanol was totally recovered, 62% of initial lignin was precipitated, and 20 g/l of hemicellulose-derived sugars solution was obtained. Finally, three wood waste samples collected in different periods of the year yielded comparable outcomes, suggesting a good reproducibility of the organosolv process. ANOVA test with a significance level of 0.01 showed a p-value of 0.029 and 0.235 for cellulose content and cellulose recovery, respectively. This study paves the way for an industrial symbiosis between recycling centers and paper mills located in the same territory.


High mortality without ESCAPE: the registry of heart failure patients receiving pulmonary artery catheters without randomization.
In the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE), there was no difference in days alive and out of the hospital for patients with decompensated heart failure randomly assigned to therapy guided by pulmonary artery catheter (PAC) plus clinical assessment versus clinical assessment alone. The external validity of these findings is debated. ESCAPE sites enrolled 439 patients receiving PAC without randomization in a prospective registry. Baseline characteristics, pertinent trial exclusion criteria, reasons for PAC use, hemodynamics, and complications were collected. Survival was determined from the National Death Index and the Alberta Registry. On average, registry patients had lower blood pressure, worse renal function, less neurohormonal antagonist therapy, and higher use of intravenous inotropes compared with trial patients. Although clinical assessment anticipated less volume overload and greater hypoperfusion among the registry population, measured filling pressures were similarly elevated in the registry and trial patients, whereas measured perfusion was slightly higher among registry patients. Registry patients had longer hospitalization (13 vs 6 days, P < .001) and higher 6-month mortality (34% vs 20%, P < .001) than trial patients. The decision to use PAC without randomization identified a population with higher disease severity and risk of mortality. This prospective registry highlights the complex context of patient selection for randomized trials.


Multiple regimes of robust patterns between network structure and biodiversity.
Ecological networks such as plant-pollinator and host-parasite networks have structured interactions that define who interacts with whom. The structure of interactions also shapes ecological and evolutionary dynamics. Yet, there is significant ongoing debate as to whether certain structures, e.g., nestedness, contribute positively, negatively or not at all to biodiversity. We contend that examining variation in life history traits is key to disentangling the potential relationship between network structure and biodiversity. Here, we do so by analyzing a dynamic model of virus-bacteria interactions across a spectrum of network structures. Consistent with prior studies, we find plausible parameter domains exhibiting strong, positive relationships between nestedness and biodiversity. Yet, the same model can exhibit negative relationships between nestedness and biodiversity when examined in a distinct, plausible region of parameter space. We discuss steps towards identifying when network structure could, on its own, drive the resilience, sustainability, and even conservation of ecological communities.


Resolving the contributions of fatigue-induced migration and scapular reorientation on the subacromial space: an orthopaedic geometric simulation analysis.
Subacromial impingement occurs when tissues interposed between the humeral head and the acromion become compressed between the bones. Two fatigue-related mechanisms are suggested to contribute to this impingement: superior humeral head migration and scapular reorientation, specifically downward rotation, anterior tilt and protraction. Although both mechanisms have received attention, controversy exists regarding their relative contributions to reducing subacromial space width. This simulation study presents a three-dimensional orthopedic model for assessing the spatial relationship between the humerus and the scapula. Through incorporating empirically generated fatigue data as inputs, changes in the subacromial space associated with each mechanism acting independently and in combination were quantified. These changes were examined for three scenarios (average, impingement sparing, impingement causing) and at three humeral elevation angles (0°, 45° and 90°) in a total of 36 unique simulations. Humeral head migration generally decreased the subacromial space and scapular reorientation generally increased the space across scenarios. This strongly implies that superior humeral migration is the dominant fatigue-related mechanism associated with increasing the likelihood of impingement. The results suggest that future research should target efforts to reduce migration in industry, primarily through avoidance or modification of situations known to induce rotator cuff fatigue, such as overhead work.


Carbon-rich molecules: synthesis and isolation of aryl/heteroaryl terminal bis(butadiynes) (HC[triple bond]C-C[triple bond]C-Ar-C[triple bond]C-C[triple bond]CH) and their applications in the synthesis of oligo(arylenebutadiynylene) molecular wires.
The synthesis, isolation and characterisation are reported for a series of terminal aryl/heteroaryl bis(butadiynes) (HC[triple bond]C-C[triple bond]C-Ar-C[triple bond]C-C[triple bond]CH) 4a-e including the X-ray molecular structure of the 2,5-pyridylene derivative 4d; compound 4a and the mono-protected analogue [HC[triple bond]C-C[triple bond]C-Ar-C[triple bond]C-C[triple bond]C-C(OH)Me2] 5a serve as convenient precursors for the synthesis of highly-conjugated oligo(arylenebutadiynylene)s.


Development of analytical methods to study the effect of malting on levels of free and modified forms of Alternaria mycotoxins in barley.
A liquid chromatography tandem mass spectrometry (LC-MS/MS) multi-mycotoxin method was developed for the analysis of the Alternaria toxins alternariol (AOH), alternariol monomethyl ether (AME), tentoxin (TEN), altertoxin I (ATX I), altertoxin II (ATX II), alterperylenol (ALTP), and altenuene (ALT), as well as the modified toxins AOH-3-glucoside (AOH-3-G), AOH-9-glucoside (AOH-9-G), AME-3-glucoside (AME-3-G), AOH-3-sulfate (AOH-3-S), and AME-3-sulfate (AME-3-S) in barley and malt. The toxin tenuazonic acid (TeA) was analyzed separately as it could not be included into the multi-mycotoxin method. Quantitation was conducted by using a combination of stable isotope dilution analysis (SIDA) for AOH, AME, and TeA, and matrix-matched calibration for all other toxins. Limits of detection were between 0.05 µg/kg (AME) and 2.45 µg/kg (ALT), whereas limits of quantitation ranged from 0.16 µg/kg (AME) to 8.75 µg/kg (ALT). Recoveries between 96 and 107% were obtained for the analytes when SIDA was applied, while recoveries between 84 and 112% were found for analytes quantified by matrix-matched calibration. The method was applied for the analysis of 50 barley samples and their respective malts from the harvest years 2016-2020 for their mycotoxin content, showing the overall potential of toxin formation during the malting process. The toxins ALTP and ATX I were mainly found in the malt samples, but not in barley.


Perceived norms moderate the association between mental health symptoms and drinking outcomes among at-risk adolescents.
There has been limited research examining the association between mental health symptoms, perceived peer alcohol norms, and alcohol use and consequences among samples of adolescents. The current study used a sample of 193 at-risk youths with a first-time alcohol and/or other drug offense in the California Teen Court system to explore the moderating role of perceived peer alcohol norms on the association between mental health symptoms and drinking outcomes. Measures of drinking, consequences, mental health symptoms, and perceived peer alcohol norms were taken at baseline, with measures of drinking and consequences assessed again 6 months later. Regression analyses examined the association of perceived norms and mental health symptoms with concurrent and future drinking and consequences. We found that higher perceived drinking peer norms were associated with heavy drinking behavior at baseline and with negative alcohol consequences both at baseline and 6 months later. Also, perceived drinking norms moderated the association between mental health symptoms and alcohol-related consequences such that better mental health was related to increased risk for alcohol-related consequences both concurrently and 6 months later among those with higher baseline perceptions of peer drinking norms. Findings demonstrate the value of norms-based interventions, especially among adolescents with few mental health problems who are at risk for heavy drinking.


Order scheduling optimization in manufacturing enterprises based on MDP and dynamic programming.
In the era of Industry 4.0, order scheduling is a crucial link in the production of manufacturing enterprises. In view of order scheduling in manufacturing enterprises, a finite horizon Markov decision process model is proposed in this work based on two sets of equipment and three types of orders with different production lead times to maximize the revenue in manufacturing production systems. Then, the dynamic programming model is incorporated into the optimal order scheduling strategy. Python is employed to simulate the order scheduling in manufacturing enterprises. Based on survey data, the superiority of the proposed model compared to traditional first come, first served order scheduling is verified by experimental cases. Finally, sensitivity analysis is conducted on the longest service hours of the devices and the order completion rate to explore the applicability of the proposed order scheduling strategy.


Detection of ovarian cancer by the humoral leukocyte adherence inhibition test using a purified tumor-associated antigen.
The defined, purified ovarian cancer-associated antigen, NB/70K, was used as tumor antigen in the humoral leukocyte adherence inhibition (H-LAI) assay. Bell-shaped dose-response relationships were obtained with increasing concentrations of NB/70K and constant serum concentration from ovarian cancer patients. The concentrations of NB/70K used in this study were 100-250 times less than what had been used in previous H-LAI studies with crude antigen extracts. The response rate of ovarian cancer patients was greatly influenced by the stage of the disease. Thus 75% (6/8) of the patients with disease restricted to the pelvis (stages I and II) reacted while only 20% (5/24) of the patients with more advanced stages (stages III and IV) gave response. Of patients with other gynecological cancers, 17% (1/6) were positive and only 8% (1/13) of patients with other malignant diseases reacted. One of the 11 controls (9%) was found to give positive response. The importance of the present investigation was the finding that a defined, purified, cancer-associated antigen elicited reactivity in the H-LAI assay and that a high sensitivity for detection of early stages of ovarian cancer was obtained with this antigen. The results suggest that TAAs involved in immune recognition of cancer can be identified by the H-LAI assay.


Registries supporting new drug applications.
Knowledge of the benefits and risks of new drugs is incomplete at the time of marketing approval. Registries offer the possibility for additional, post-approval, data collection. For all new drugs, which were approved in the European Union between 2007 and 2010, we reviewed the frequency, the type, and the reason for requiring a registry. The European Public Assessment Reports, published on the website of the European Medicine Agency, were reviewed for drugs approved by the Committee for Medicinal Products for Human Use. We searched for key characteristics of these drugs, including therapeutic area (ATC1 level), level of innovation (the score is an algorithm based on availability of treatment and therapeutic effect), and procedural characteristics. In addition, we identified if these registries were defined by disease (disease registry) or exposure to a single drug (drug registry). Out of 116 new drugs approved in the predefined period, for 43 (37%), 1 to 6 registry studies were identified, with a total of 73 registries. Of these 46 were disease registries and 27 (single) drug registries. For 9 drugs, the registry was a specific obligation imposed by the regulators. The level of innovation and the orphan status of the drugs were determinants positively predicting post-approval registries (OR 10.3 [95% CI 1.0-103.9] and OR 2.8 [95% CI 1.0-7.5], respectively). The majority of registries required by regulators are existing disease registries. Registries are an important and frequently used tool for post-approval data collection for orphan and innovative drugs.


MPO-ANCA-associated pseudovasculitis in cardiac myxoma.
We describe a case of cardiac myxoma whose clinical presentation mimicked that of polyarteritis nodosa. The serum levels of MPO-ANCA and IL-6 were elevated on laboratory investigation and normalized after the removal of the tumor. We suggest that a 'true' vasculitic mechanism contributes to the pathogenesis of pseudovasculitis in cardiac myxoma.


Mechanism of recovery from acute virus infection. II. Effect of treatment of mice with cyclosporin A on their ability to eliminate the lymphocytic choriomeningitis virus.
Illness and death of mice infected by intracerebral inoculation with lymphocytic choriomeningitis virus are pathologic immune phenomena, and mice thus infected were protected when immunosuppressed with cyclosporin A (CSA), although the virus multiplied extensively in all major organs. Concentrations remained high as long as the drug was administered but declined when the treatment was discontinued; also, cytotoxic T lymphocytes appeared. Virus elimination was slower and cytotoxic T cell activity lower than in mice not previously treated with CSA.


Hidradenitis suppurativa in pediatric patients.
Interest in and research on hidradenitis suppurativa (HS) have increased during the past decade, resulting in expanded knowledge about associated comorbidities and treatment efficacy. Knowledge about pediatric-onset HS is still limited, based on case studies, small case series, and extrapolation from adult studies. With increasing prevalence of childhood obesity, decreasing pubertal age, and increasing awareness of HS, physicians may start encountering younger HS patients. This review presents an updated discussion on the epidemiology, pathophysiology, and associated comorbidities in HS, with a focus on pediatric and adolescent patients. It also suggests recommendations for investigation and treatment based on current evidence.


CT artifacts of the proximal aortic neck: an important problem in endograft planning.
To describe the imaging error introduced by noncircular abdominal aortic aneurysm (AAA) necks in axial and reformatted computed tomographic (CT) images and discuss the potential implications for aortic endografting. The records of 120 endograft patients with preoperative CT axial scans and subsequent 3-dimensional (3D) computerized reconstructions were reviewed. Maximum and minimum infrarenal aortic neck diameters were measured from axial CT scans and 3D reformatted slices at the same point on the vessel. Diameter measurements were made at the largest point within the 10-mm segment of vessel below the lowest renal artery. Excluded were aneurysms with proximal neck minimum diameters >30 mm, neck lengths < 15 mm, or angulation > 75 degrees measured on the axial CT slice. Measuring from reformatted CT slices, 86 (71.6%) cases had < or = 2-mm differences between maximal and minimal neck diameters, comprising the "round neck" group A. In 34 (28.4%) cases, the neck was not round: 26 (21.7%) had diameter differences between 2 and 4 mm (group B) and 8 (6.7%) had a > 4-mm difference (group C; range 4.1-8.1 mm). Although AAA diameter, neck length, and neck angle progressively increased as the difference between neck maximum and minimum diameters grew, i.e., greater eccentricity, these trends did not reach statistical significance. Mean infrarenal neck maximum diameter was significantly larger in group C (30.2 +/- 3.4 mm) compared to groups A (23.0 +/- 2.9 mm, p = 0.0002) and B (23.8 +/- 3.6 mm, p = 0.0003). Hence, 28.4% of AAAs had a noncircular aortic neck of varying degree, and 6.7% had an eccentricity factor that may have clinical significance. This study confirms the importance of selecting an endoprosthesis sized 15% to 20% larger than the infrarenal aortic neck diameter. Three-dimensional reconstruction using reformatted CT slices perpendicular to the flow lumen is an important tool that offers enhanced accuracy of infrarenal aortic neck evaluation.


CIGB-247: a VEGF-based therapeutic vaccine that reduces experimental and spontaneous lung metastasis of C57Bl/6 and BALB/c mouse tumors.
CIGB-247 is a novel cancer therapeutic vaccine that uses a mutated form of human VEGF as antigen. Being metastatic disease the most dramatic factor of tumor biology affecting patient survival and cure, preclinical evaluation of the impact of CIGB-247 vaccination on experimental metastasis mouse models is highly relevant, and constitutes the focus of this work. CIGB-247 was administered in a weekly schedule known to effectively reduce primary tumor growth. The vaccine was tested in experimental and spontaneous metastasis models of colon (CT26), lung (3LL-D122) and breast (F3II) carcinomas growing in C57Bl/6 or BALB/c mice. Primary tumor growth parameters, metastatic counts, and/or animal survival were recorded. Histology and specific humoral and cellular responses to the vaccine were evaluated. As compared to control groups, CIGB-247 vaccination significantly reduced the number and size of metastatic tumor foci in lungs after intravenous inoculation of CT26 and 3LL-D122 tumor cells. Spontaneous lung dissemination from 3LL-D122 and F3II breast tumor cells implanted in the footpad, or subcutaneously, was also reduced by immunization with CIGB-247. The vaccine elicited in both mouse strains antibodies specific for human and murine VEGF that effectively blocked the interaction of VEGF with VEGF receptor 2. Differing from other experimental reports that describe the use of VEGF for active tumor immunotherapy, CIGB-247 elicited a specific cellular response, measured both by a DTH increment and the induction of spleen cells cytotoxic to syngeneic tumor cells producing murine VEGF. In summary our results reinforce the potential of CIGB-247 vaccination to reduce both tumor growth and the number and size of tumor metastasis in lungs, the latter both after direct inoculations of cells in the blood stream, or as part of primary tumor progression in immunocompetent mice.


Propensity-Matched Comparison of Endovascular versus Open Reconstruction for TASC-II C/D AortoIliac Occlusive Disease. A Ten-Year Single-Center Experience with Self-Expanding Covered Stents.
To compare endovascular therapy (EVT) using kissing self-expanding covered stents, with open repair (OR) with aortobifemoral bypass (ABF), for reconstruction of the aortic bifurcation in Trans-Atlantic Inter-Society Consensus II (TASC-II) C/D aortoiliac occlusive disease (AIOD). A single-center retrospective analysis of patients treated by EVT or ABF for TASC-II C/D AIOD (2009-2018) was carried out. The perioperative risk was quantified by the Society for Vascular Surgery (SVS) and American Society of Anesthesiologists (ASA) scores. Outcomes of interest were early (30 days) mortality and complication rates, length of hospitalization, and midterm patency that were compared between EVT and OR after propensity score matching. Follow-up results were analyzed with Kaplan-Meier curves. Cox proportional hazards were used to identify predictors of patency. Sixty-three EVT and 55 OR patients were treated; the EVT group had higher perioperative risk (ASA score, P = 0.012. SVS score, P = 0.012) and less advanced disease (TASC D lesions, 52.3% vs. 72.7%; P = 0.036. Iliac occlusion, 46.8% vs. 87.2%; P = 0.024). After propensity score matching, 148 limbs were selected (74 EVT and 74 OR), resulting in well-balanced groups regarding risk (ASA score, P = 0.514. SVS score, P = 0.373) and anatomical complexity (TASC D lesions, 60.4% vs. 63.0%; P = 0.516. Iliac occlusion, 47.3% vs. 59.5%; P = 0.187). Mortality was 0%. The EVT group showed significantly shorter hospital (4.5 ± 7.6 days vs. 9.9 ± 6.8 days; P < 0.001) and intensive care unit stay (0 ± 0.1 days vs. 1.7 ± 1.5 days; P = 0.046) and less surgical complications (4% vs. 14.8%; P = 0.046). Five-year primary patency was similar between EVT and OR (84.1% vs. 88.3%; P = 0.454); multivariate analysis showed that Rutherford category was the only predictor of primary patency (HR 4.1, P = 0.023). The endovascular kissing self-expanding covered stent technique for TASC-II C/D AIOD presented a primary patency equal to ABF at 5 years, with the advantage of less surgical complications and shorter hospitalization. Therefore, it may be considered as a valid option for complex atherosclerotic lesions involving the aortic bifurcation.


A theoretical study on the quenching mechanisms of triplet state riboflavin by tryptophan and tyrosine.
The reactions of tryptophan (Trp) and tyrosine (Tyr) with endogenous photosensitizer riboflavin (RF) have gained much interest for their crucial roles in various photobiological processes. In this paper, the quenching mechanisms of triplet state RF by Trp and Tyr have been explored employing density functional theory calculations. It is revealed that the H-atom transfer reaction from Trp and Tyr to triplet state RF is more favorable on thermodynamic grounds compared with direct energy transfer or direct electron transfer pathways. During the photosensitization, RF can photogenerate various reactive oxygen species (ROS) as intermediates, while the present study provides some deeper insights into the photosensitizing behaviors of triplet state RF by reacting directly with Trp and Tyr.


Autolytic phenotype of Lactococcus lactis strains isolated from traditional Tunisian dairy products.
To evaluate the autolytic properties of Lactococcus lactis strains isolated from artisan Tunisian dairy products, their peptidoglycan hydrolase content and their activity spectrum. The autolytic phenotype of Lactococcus strains was evaluated under starvation conditions in potassium phosphate buffer. The results obtained highlighted a high degree of diversity among the strains analysed, allowing the identification of high and low autolytic Lactococcus lactis strains. Peptidoglycan hydrolase content was evaluated by renaturing SDS-PAGE using cells of Micrococcus lysodeikticus as a target for the enzymatic activity. A major activity band migrating at about 45 kDa was observed. The lytic activity, evaluated in the presence of different chemicals, was retained in 8% NaCl, 15 mmol l(-1) CaCl2, and in a pH range between 5 and 9.5. The substrate specificity of peptidoglycan hydrolase from Lactococcus strains was evaluated in renaturing SDS-PAGE incorporating cells of different bacterial species. The major autolysin of Lactococcus lactis was active against cells of Lactococcus lactis subsp. lactis, Streptococcus thermophilus, Lactobacillus delbrueckii subsp. bulgaricus, Lactobacillus helveticus and Listeria monocytogenes. Autolytic activity is widely distributed in Lactococcus lactis and the rate of autolysis is strain-dependent. The major peptidoglycan hydrolase showed a wide spectrum of activity against several lactic acid bacteria and bacterial species involved in food-related infection. The autolytic phenotype of Lactococcus lactis strains isolated from Tunisian artisan dairy products has been determined, and the data obtained should allow the selection of strains of technological interest in the cheese-ripening process.


Fine mapping of HIV-1 Nef-epitopes by monoclonal antibodies.
A panel of newly isolated murine monoclonal antibodies is described which are specific for the Nef protein of the human immunodeficiency virus type 1 (HIV-1). Epitope mapping using recombinant Nef-related proteins, synthetic peptides and lipopeptides showed 3 independent antigenic determinants located within the regions of amino acids 83-93, 175-190 and 86-166 of the Nef protein. None of the monoclonal antibodies reacted with recombinant Nef proteins of HIV-2.


The prevalence of retinopathy and associated medical risk factors in type I (insulin-dependent) diabetes mellitus.
The prevalence of diabetic retinopathy and the associated medical risk factors, such as age at onset and duration of diabetes, metabolic control, blood pressure, albumin clearance and serum creatinine, were studied in 501 patients with type I diabetes mellitus. The prevalence of retinopathy, characterized as simplex, maculopathy, preproliferative, and proliferative, was 60.5%. Patients with retinopathy were younger at the onset of diabetes, and had a longer duration of disease. In patients with more than 10 years of diabetes, proliferative retinopathy was more frequent if onset was before they were 15 years old, despite the fact that the duration of diabetes did not differ. Patients with severe retinopathy had worse metabolic control, and were more frequently treated for hypertension. In addition, the systolic blood pressure was elevated in all groups of patients with any type of retinopathy, whereas the diastolic blood pressure was elevated only in patients with more severe forms. Patients with severe retinopathy also had higher levels of albumin clearance.


Do microemboli reach the brain penetrating arteries?
As they are "end arteries," microembolic obstruction of brain penetrating arteries would be expected to create ischemia. Yet the mammalian brain appears to have an impressive tolerance to experimental microembolization with ischemia occurring only after the injection of large numbers of particulates. Potential explanations could be that the majority of these particulates marginate along the pial vasculature or escape the cerebral circulation via arteriovenous (AV) fistulae. To test these theories, we first established the level of injury created by the injection of 20, 45, and 90 μm fluorescent microspheres in Sprague-Dawley rats. Brains were examined by immunohistochemistry for injury and for infarction. We then injected 1000 size 20 μm, 500 size 45 μm, and 150 size 90 μm and harvested the brains and lungs for assays of fluorescence. The location of microemboli within the brain was established by determining the percent of 20 and 45 μm fluorescent microspheres entering the superficial versus deeper layers of the brain. The location of larger microemboli was established by 2T-MRI after injection of 60-100 μm microthrombi labeled with supraparamagnetic iron oxide (SPIO) particles. With 20 μm microspheres there were no areas of injury or infarction after injection of 500 and rare areas of injury and no infarctions after injection of 1000 microspheres. With either 250 or 500 size 45 μm microspheres there were a few (≤ 6) small areas of injury per animal with ≤ 2 areas of infarction. After injection, 93%-96% of injected microspheres remained in the brain. Approximately 40% of either fluorescent or SPIO labeled microthrombi were found on the brain surface. As in humans, the rat brain has an impressive tolerance to microemboli, although this clearly varies with emboli size and number. Wash out of particulates through AV connections is not a major factor in brain tolerance in this model. Approximately 40% of microemboli remain in the larger pial vasculature where the more extensive collateralization may limit their effects on distal perfusion. However, the remaining 60% enter penetrating arteries but few create ischemia.


Specific Factors Affecting Operating Room Efficiency: An Analysis of Case Time Estimates.
Operating room (OR) efficiency has an impact on surgeon productivity and patient experience. Accuracy of case duration estimation is important to optimize OR efficiency. The purpose of this study was to identify factors associated with inaccurate case time estimates in outpatient hand surgery. A better understanding of these findings may help to improve OR efficiency and scheduling. All outpatient hand surgical cases from 2018 to 2019 were reviewed. Poorly-estimated cases (i.e., poor scheduling accuracy) were defined as those cases where the actual operative time differed from the predicted time by >50% (either quicker by >50% or slower by >50% than the predicted time). The percentages of poorly-estimated cases were analyzed, categorized, and compared by surgeon, procedure type, and scheduled case length. A total of 6,620 cases were identified. Of 1,107 (16.7%) cases with poorly estimated case durations, 75.2% were underestimated. There was no difference in the likelihood of poor estimation related to start time. Well-estimated cases tended to have longer scheduled case duration, but shorter realized case duration and surgical time. Our systems analysis identified specific surgeons and procedures as predictable outliers. Cases scheduled for 15-30 minutes frequently were inaccurate, whereas cases scheduled for 30-45 and 106-120 minutes had accurate estimates. The accuracy of case time estimations in a standard outpatient hand surgery practice is highly variable. Nearly one-fifth of outpatient hand surgery case durations are poorly estimated, and inaccurate case time estimation can be predicted based on surgeon, procedure type, and case time. Maximizing OR efficiency should be a priority for surgeons and hospital systems. With multiple surgeries done per day, the efficiency of the OR has an impact on surgeon productivity and patient experience.


Orofacial movement disorders.
This article reviews three poorly recognized yet relatively common presentations of hyperactive orofacial movement disorders: oromandibular dystonia, orofacial dyskinesia, and drug-induced extrapyramidal syndrome reactions. Orofacial movement disorders are often misdiagnosed as temporomandibular disorders, hence understanding these conditions is pertinent for the practitioner treating orofacial pain. Aspects of epidemiology, etiology, pathophysiology, clinical presentation, and diagnosis are discussed along with treatment considerations for these orofacial movement disorders.


Review: Discogenic Back Pain: Update on Treatment.
Lower back pain (LBP) has a lifetime prevalence of 80% in the United States population. Discogenic back pain (DBP), a subcategory of LBP, occurs as a result of the interverbal disc degeneration without disc herniation. Diagnosis relies on history, physical exam, and imaging such as MRI, provocative discography, or CT discography. Treatment of DBP involves a multifaceted approach with an emphasis on conservative measures including behavioral modification, pharmacologic management, and other non-pharmacologic interventions with invasive therapy reserved for select patients. Due to the paucity of data on the treatment of DBP, treatment also relies on data derived from treatment of chronic LBP (CLBP). Despite the scarcity of data for the treatment of DBP, treatments do exist with varying efficacy for DBP. Novel techniques such as the use of biologics may provide another avenue for treatment though further studies are needed to better evaluate the most efficacious regimen for both novel and existing treatments.


Thromboelastometric detection of clotting Factor XIII deficiency in cardiac surgery patients.
In this article, we aimed to investigate plasma Factor XIII levels after extracorporeal circulation in cardiac surgery by thromboelastometric detection, as extracorporeal circulation causes various coagulation disorders due to the exposure of blood to artificial surfaces, inflammatory induction and mechanical destruction of platelets and coagulation factors, which may particularly affect factors with long half-lives, such as Factor XIII. Since transfusion algorithms are often empirical and laboratory analysis of Factor XIII plasma levels may not be available 24 h a day, bed-side testing using rotational thromboelastometry (ROTEM) could offer a splendid option to define the cause of excessive peri-operative bleeding disorders in general and Factor XIII levels in particular in a timely manner and thus facilitating exact substitution therapy. In this trial, we investigated 25 cardiac surgery patients with extracorporeal bypass times over 100 min. Standard laboratory and ROTEM analyses were performed post-operatively at the time of intensive care unit admission and 6 h later. We implemented EXTEM with additional Factor XIII (teenTEM) as additional test by adding 0·625 IU Factor XIII to standard EXTEM reagents. In this observational study, we could not demonstrate a correlation between Factor XIII and MCFEXTEM , CFTEXTEM or MLEXTEM . Neither Factor XIII plasma levels nor MCFEXTEM could predict blood loss. In accordance with previous findings, we were able to demonstrate increased maximum clot firmness (MCF), decreased clot formation time and decreased maximum lysis by adding Factor XIII in vitro (teenTEM vs EXTEM) indicating an improvement in the coagulation process. As shown before, we also found a strong correlation between MCF and platelet and fibrinogen plasma levels. In summary, 'teenTEM' test does not seem to detect Factor XIII deficient patients in cardiac surgery. Furthermore, post-operative blood loss could not be predicted neither by ROTEM nor by laboratory analysis of Factor XIII. In vitro administration of Factor XIII appears to improve laboratory measures of haemostasis.


The role of mu opioid receptors in psychomotor stimulation and conditioned place preference induced by morphine-6-glucuronide.
Previous studies have shown that morphine-6-glucuronide (M6G), a metabolite of morphine, induces reward and psychomotor stimulation but the role of the mu opioid receptor in these actions of the drug is not fully characterized. Thus, using mice lacking exon-2 of the mu opioid receptor and their wild-type littermates/controls, we determined the role of this receptor in psychomotor stimulation, sensitization, and conditioned place preference (CPP) induced by M6G. For comparison, we also assessed the role of the mu opioid receptor in the rewarding action of morphine. For the measurement of locomotor activity and sensitization, mice were habituated to motor activity chambers for 1h, then injected with M6G (10mg/kg) and locomotor activity was recorded for an additional 1h. The same treatment was given for five days and mice were tested for sensitization a week later. For the CPP experiments, mice were tested for baseline place preference on day 1, then received single or repeated alternate-day saline/drug or drug/saline conditioning and tested for CPP the following day. Mice were also tested for CPP under a drugged state. M6G induced psychomotor stimulation, a response that was enhanced upon repeated administration of the drug, showing that locomotor sensitization developed to the motor stimulatory action of M6G. However, M6G induced a weaker CPP response compared to morphine. None of these actions of M6G was detected in mice lacking the mu opioid receptor. Together, the current results suggest that M6G induces psychomotor stimulation and a weaker rewarding action via the mu opioid receptor.


Drugs in development for relapsing multiple sclerosis.
Drug development for multiple sclerosis (MS), as with any other neurological disease, faces numerous challenges, with many drugs failing at various stages of development. The disease-modifying therapies (DMTs) first introduced for MS are only moderately effective, but given the lack of competition, they have been widely accepted in clinical practice. Although safety and efficacy continue to be the two main metrics by which drugs will be judged, the newer agents in the market also face challenges of a more comparative nature-are they more efficacious than the currently available drugs on the market? Are they safer or better tolerated? Do they offer any practical advantages over current treatments? Fingolimod represented a milestone following its approval as an oral drug for MS in 2010, offering patients a far more convenient administration route. However, association with cardiovascular complications has led to a more cautious approach in its initial prescribing, now requiring cardiac monitoring for the first 6 h as well as subsequent monitoring of blood pressure and for macular oedema. Natalizumab, amongst licensed drugs, represents the current benchmark for efficacy. The risk of progressive multifocal leukoencephalopathy during natalizumab treatment is now more quantifiable. Other monoclonal antibodies are in various phases of development. Marketing authorisation for alemtuzumab has been filed, and whilst trial data suggest that its efficacy outperforms both licensed drugs and others in development, there is a significant risk of secondary autoimmunity. Its once-yearly administration, however, seems particularly advantageous. Rituximab is unlikely to be developed further as its license will expire, but ocrelizumab, another monoclonal antibody directly targeting B cells, is currently in phase 2 development and looks promising. Daclizumab is also moderately efficacious but may struggle to establish itself given its monthly subcutaneous dosing. There are new oral drugs in development, and it is likely that BG-12 will be licensed this year. This has been licensed for psoriasis so there are good safety data in humans that may also hold true in MS; however, its three times daily dosage will probably impact on patient compliance. Laquinimod has lower efficacy than BG-12 but appears safe and could find a place as a first-line agent. Teriflunomide has just been licensed by the US FDA and may challenge the current injectable first-line therapies as it has a similar efficacy but the advantage of being taken orally. However, risk of teratogenicity may caution against its use in some women of child-bearing potential. This review will examine drugs that have been recently approved as well as those that are in late phase 2 or 3 development as treatment for relapsing MS, highlighting their mechanism of action as well as the clinical trial and safety data before discussing their potential for success in an increasingly florid and complex DMT armamentarium.


Signalling mechanisms mediating Zn2+-induced TRPM2 channel activation and cell death in microglial cells.
Excessive Zn2+ causes brain damage via promoting ROS generation. Here we investigated the role of ROS-sensitive TRPM2 channel in H2O2/Zn2+-induced Ca2+ signalling and cell death in microglial cells. H2O2/Zn2+ induced concentration-dependent increases in cytosolic Ca2+ concentration ([Ca2+]c), which was inhibited by PJ34, a PARP inhibitor, and abolished by TRPM2 knockout (TRPM2-KO). Pathological concentrations of H2O2/Zn2+ induced substantial cell death that was inhibited by PJ34 and DPQ, PARP inhibitors, 2-APB, a TRPM2 channel inhibitor, and prevented by TRPM2-KO. Further analysis indicate that Zn2+ induced ROS production, PARP-1 stimulation, increase in the [Ca2+]c and cell death, all of which were suppressed by chelerythrine, a protein kinase C inhibitor, DPI, a NADPH-dependent oxidase (NOX) inhibitor, GKT137831, a NOX1/4 inhibitor, and Phox-I2, a NOX2 inhibitor. Furthermore, Zn2+-induced PARP-1 stimulation, increase in the [Ca2+]c and cell death were inhibited by PF431396, a Ca2+-sensitive PYK2 inhibitor, and U0126, a MEK/ERK inhibitor. Taken together, our study shows PKC/NOX-mediated ROS generation and PARP-1 activation as an important mechanism in Zn2+-induced TRPM2 channel activation and, TRPM2-mediated increase in the [Ca2+]c to trigger the PYK2/MEK/ERK signalling pathway as a positive feedback mechanism that amplifies the TRPM2 channel activation. Activation of these TRPM2-depenent signalling mechanisms ultimately drives Zn2+-induced Ca2+ overloading and cell death.


Potential of circulating receptor-interacting protein kinase 3 levels as a marker of acute liver injury.
The pathogenesis of acute liver failure (ALF) involves cell death. Necroptosis is a newly suggested programmed cell death, and receptor-interacting protein kinase 3 (RIPK3) has been reported as a marker for necroptosis. However, there are few reports on necroptosis in ALF. Therefore, we evaluated the role of cell death markers such as cytokeratin (CK) 18, cleaved CK (cCK) 18, and RIPK3 in ALF, as well as cytokines and hepatocyte growth factor (HGF). Seventy-one hospitalized patients with acute liver injury (38 nonsevere hepatitis [non-SH]/22 severe hepatitis [SH]/11 ALF) were studied. No significant difference was found for cytokines, but a substantial increase in HGF levels was found following the severity of hepatitis. The non-SH group had lower levels of CK18 and cCK18 than the SH/ALF group. RIPK3 was significantly lower in the non-SH/SH group than in the ALF group. HGF, RIPK3, and albumin levels were found to be important predictive variables. The present study suggests that cCK18, CK18, and RIPK3 are associated with the severity of hepatitis. RIPK3 and other markers related cell death may be useful for understanding the pathogenesis of ALF and as a prognostic marker of acute liver injury.


Echophonocardiographic study of the initial low frequency component of the first heart sound.
To investigate the genesis of the initial low frequency component of the first heart sound that precedes the high frequency vibrations associated with closure of the atrioventricular valves, echophonocardiograms of 36 persons were recorded. These included 10 normal subjects and 26 patients with various types of heart disease including mitral valve replacement. Electrocardiograms demonstrated normal sinus rhythm in 23 subjects, atrial fibrillation in 9, complete atrioventricular block in 2 and atrial flutter in 2. In the phonocardiogram, the low frequency component of the first heart sound followed the onset of the QRS complex and preceded the first high frequency component of this sound. The low frequency component occurred simultaneously with the beginning of the final fast closing movement of the mitral valve on the echocardiogram and was found both in normal rhythm and in arrhythmias. However, in arrhythmias its intensity varied on a beat to beat basis, being loudest after a short RR interval or when atrial systole occurred very close to the expected time of ventricular systole. In patients in whom apexcardiograms were recorded, the low frequency component was coincident with or very close to the onset of ventricular systole. It is concluded that the low frequency component of the first heart sound represents vibrations caused by contraction of the left ventricle and deceleration of antegrade blood flow across the mitral valve. Neither atrial contraction nor mitral valve tension is necessary for the production of this soft initial component.


Mechanical ventilation strategy following Glenn and Fontan surgeries: On going challenge!
The Glenn and Fontan operations put the pulmonary and systemic circulations in series. It has been shown that positive pressure ventilation (PPV) decreases pulmonary blood flow (PBF) and cardiac output (CO), and negative pressure ventilation (NPV) significantly improves PBF and CO. If early extubation is not achievable, the postoperative ventilator management strategy should aim at promoting PBF and CO by lowering pulmonary vascular resistance (PVR) and intrathoracic pressure. Multiple ventilator strategies have been evaluated to optimize this physiology, including high frequency ventilation, hyperventilation post Glenn, hypoventilation post Glenn with buffered pH, and the use of inhaled nitric oxide as an adjunct therapy for mechanical ventilation. In this review, the results of these studies will be reviewed and discussed.


Therapeutic trial of intracisternal human tetanus immunoglobulin in clinical tetanus.
A trial has been conducted of the efficacy of human tetanus immunoglobulin (250 I U) administered intrathecally (intracisternally) in addition to standard treatment (equine antitoxin intravenously, penicillin, anticonvulsants). The trial was analysed sequentially and was stopped for 120 patients when there was no longer any chance of achieving a statistically significant difference in favour of intrathecal administration. The sequential plan was modified during the trial. A prognostic correlation was found between onset of the first symptom and admission to hospital.


Hierridin B and 2,4-dimethoxy-6-heptadecyl-phenol, secondary metabolites from the cyanobacterium Phormidium ectocarpi with antiplasmodial activity.
Bioassay guided fractionation of the lipophilic extract of the marine cyanobacterium Phormidium ectocarpi yielded a new natural product hierridin B and the previously described compound 2,4-dimethoxy-6-heptadecyl-phenol. Both structures were secured by extensive spectroscopic analysis (1D and 2D NMR, MS, GC-MS, IR). The isolate (mixture) showed antiplasmodial activity towards Plasmodium falciparum.


Photosensitive epilepsy and image safety.
Photosensitive epilepsy came to prominence in the 1950s with the advent of television. Photosensitive epilepsy occurs in 1 in 4000 of the population. The incidence is 1.1 per 100,000 per annum, however amongst 7-19 year-olds the incidence is more than five times as common. Photosensitive epilepsy is twice as common in females as in males. The onset is around puberty, but less than 25 per cent of patients lose their photosensitivity in their twenties. Patients are investigated in the EEG laboratory using intermittent photic stimulation. Peak sensitivity is between 16 and 20 flashes/s but 49 per cent of patients are sensitive to 50 flashes/s, explaining the sensitivity to PAL television systems. From 1993 the development of broadcast guidelines was developed restricting both flash rates and the areas of screen involved, as well as the use of long-wavelength red. Automatic analysis systems can now test material for compliance with guidelines in real time.


The Impact of Metabolic Syndrome on Microvascular Head and Neck Reconstruction: An ACS-NSQIP data analysis.
Metabolic syndrome (MetS) can predispose patients to poorer surgical outcomes. In this study, we sought to evaluate the impact of MetS on the postoperative outcomes of head and neck microvascular reconstruction. Review of the 2015-2019 NSQIP database identified 5,323 cases of microvascular reconstruction, of which 3,809 were head and neck cases. Of the included patients, 184 had MetS and 3625 did not. The groups were compared in terms of demographics and comorbidities. Postoperative outcomes assessed included mortality, average operative time and length of hospital stay, surgical and medical complications, and nonhome discharge. The MetS group had higher rates of medical complications (p<0.0001), sepsis (p=0.02), septic shock (p=0.01), and skilled care-discharge (p=0.0004). Analysis by flap type revealed that MetS patients receiving free skin flaps experienced higher rates of organ space infection (p=0.02), sepsis (p<0.0001), and lower home-discharge (p=0.01). In the free muscle group, superficial incisional infection (p=0.04), UTI (p=0.02), and septic shock (p=0.01) were higher in MetS patients. Stratification by surgical site showed that the occurrence of sepsis was significantly higher in the patients receiving microvascular flap reconstruction of the larynx (p=0.04) or tongue(p=0.03). Stratification of the MetS patients according to treatment for diabetes showed that patients receiving insulin experienced a higher rate of superficial incisional infection (p=0.04). A multivariate analysis verified significantly higher rates of medical complications (p<0.0001), sepsis (p=0.03) and septic shock (p=0.01) in the MetS group. Patients with MetS undergoing head and neck microvascular reconstruction are at increased risk of postoperative medical complications, including sepsis and septic shock, and are more likely to be discharged to a skilled care facility. Surgical outcomes were found to depend on the type of flap and site of surgery.


Late results of isolated mitral annuloplasty for "functional" ischemic mitral insufficiency.
Repair of functional ischemic mitral regurgitation (MR) due to annular deformity and leaflet restriction remains a challenge for the surgeon and lacks well-documented outcomes. We investigated outcomes in the treatment of functional ischemic MR corrected by annuloplasty techniques alone. From May 1980 to July 1999, 174 patients underwent repair for functional ischemic mitral insufficiency with annuloplasty alone (128 ring annuloplasty; 46 suture annuloplasty). Acute insufficiency was present in 25 (14.4%). Concomitant procedures included CABG (n = 152; 87.4%). Patients were studied longitudinally with annual follow-up and echocardiograms. Overall hospital mortality was 17.8% and was increased by NYHA Class 4 (23.8% vs. 8.7%; p = 0.011), diabetes (25.0% vs. 13.6%; p = 0.059), and chronic mitral insufficiency (16.4% vs. 8.0%; p = 0.070). Multivariate analysis revealed age (beta = 0.099; p = 0.049) and ejection fraction < 30% (beta = 1.260; p = 0.097) as significant predictors of hospital death. Mean postoperative mitral insufficiency was 0.84 +/- 0.86 (scale of 0-4). NYHA Class 4 (beta = 2.33; p = 0.034) and simple suture annuloplasty (beta = 2.08; p = 0.07) were associated with increased risk of late cardiac death. Cumulative incidence of mitral reoperation was 7.7% at 5 years. At follow-up, 89.7% of patients were in NYHA Class 1 or 2 with 83.4% having none or only mild mitral insufficiency. Ring annuloplasty is associated with a survival benefit when compared to simple suture repair in ischemic patients who require annuloplasty alone to correct the MR. Mitral reconstruction with a ring annuloplasty offers durable results in this homogeneous subset of functional ischemic MR patients. Ischemic mitral insufficiency is associated with significant late mortality.


Replacement of ureter by ileum.
The challenge of bridging long defects of ureter has been reviewed with particular emphasis on the utilization of ileum. The application of the Yang-Monti principle can provide an ileal tube of adequate length and suitable cross-sectional diameter. An antireflux ileovesical anastomosis is also feasible. Although long-term results are still lacking, an ileal tube constructed on the basis of the Yang-Monti principle seems ideal for ureteric substitution.


Comparative energetics of glucose and xylose metabolism in ethanologenic recombinant Escherichia coli B.
This study compared the anaerobic catabolism of glucose and xylose by a patented, recombinant ethanologenic Escherichia coli B 11303:pLOI297 in terms of overall yields of cell mass (growth), energy (ATP), and end product (ethanol). Batch cultivations were conducted with pH-controlled stirred-tank bioreactors using both a nutritionally rich, complex medium (Luria broth) and a defined salts minimal medium and growth-limiting concentrations of glucose or xylose. The value of gamma ATP was determined to be 9.28 and 8.19 g dry wt cells/mol ATP in complex and minimal media, respectively. Assuming that the nongrowth-associated energy demand is similar for glucose and xylose, the mass-based growth yield (Yx/s, g dry wt cells/g sugar) should be proportional to the net energy yield from sugar metabolism. The value of Yx/s was reduced, on average, by about 50% (from 0.096 g/g glu to 0.51 g/g xyl) when xylose replaced glucose as the growth-limiting carbon and energy source. It was concluded that this observation is consistent with the theoretical difference in net energy (ATP) yield associated with anaerobic catabolism of glucose and xylose when differences in the mechanisms of energy-coupled transport of each sugar are taken into account. In a defined salts medium, the net ATP yield was determined to be 2.0 and 0.92 for glucose and xylose, respectively.