Effects of 7-day continuous D-amphetamine, methylphenidate, and cocaine treatment on choice between methamphetamine and food in male rhesus monkeys.
Methamphetamine addiction is a significant public health problem for which no Food and Drug Administration-approved pharmacotherapies exist. Preclinical drug vs. food choice procedures have been predictive of clinical medication efficacy in the treatment of opioid and cocaine addiction. Whether preclinical choice procedures are predictive of candidate medication effects for other abused drugs, such as methamphetamine, remains unclear. The present study aim was to determine continuous 7-day treatment effects with the monoamine releaser d-amphetamine and the monoamine uptake inhibitor methylphenidate on methamphetamine vs. food choice. In addition, 7-day cocaine treatment effects were also examined. Behavior was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and methamphetamine injections (0-0.32mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=4). Methamphetamine choice dose-effect functions were determined daily before and during 7-day periods of continuous intravenous treatment with d-amphetamine (0.01-0.1mg/kg/h), methylphenidate (0.032-0.32mg/kg/h), or cocaine (0.1-0.32mg/kg/h). During saline treatment, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Continuous 7-day treatments with d-amphetamine, methylphenidate or cocaine did not significantly attenuate methamphetamine vs. food choice up to doses that decreased rates of operant responding. However, 0.1mg/kg/h d-amphetamine did eliminate methamphetamine choice in two monkeys. The present subchronic treatment results support the utility of preclinical methamphetamine choice to evaluate candidate medications for methamphetamine addiction. Furthermore, these results confirm and extend previous results demonstrating differential pharmacological mechanisms between cocaine choice and methamphetamine choice.


Ultrasound-guided erector spinae plane catheter versus video-assisted paravertebral catheter placement in minimally invasive thoracic surgery: comparing continuous infusion analgesic techniques on early quality of recovery, respiratory function and chronic persistent surgical pain: study protocol for a double-blinded randomised controlled trial.
Compared to conventional thoracotomy, minimally invasive thoracic surgery (MITS) can reduce postoperative pain, reduce tissue trauma and contribute to better recovery. However, it still causes significant acute postoperative pain. Truncal regional anaesthesia techniques such as paravertebral and erector spinae blocks have shown to contribute to postoperative analgesia after MITS. Satisfactory placement of an ultrasound-guided thoracic paravertebral catheter can be technically challenging compared to an ultrasound-guided erector spinae catheter. However, in MITS, an opportunity arises for directly visualised placement of a paravertebral catheter by the surgeon under thoracoscopic guidance. Alongside with thoracic epidural, a paravertebral block is considered the "gold standard" of thoracic regional analgesic techniques. To the best of our knowledge, there are no randomised controlled trials comparing surgeon-administered paravertebral catheter and anaesthesiologist-assisted erector spinae catheter for MITS in terms of patient-centred outcomes such as quality of recovery. This trial will be a prospective, double-blinded randomised controlled trial. A total of 80 eligible patients will be randomly assigned to receive either an anaesthesiologist-assisted ultrasound-guided erector spinae catheter or a surgeon-assisted video-assisted paravertebral catheter, in a 1:1 ratio following induction of general anaesthesia for minimally assisted thoracic surgery. Both groups will receive the same standardised analgesia protocol for both intra- and postoperative periods. The primary outcome is defined as Quality of Recovery (QoR-15) score between the two groups at 24 h postoperative. Secondary outcomes include assessment of chronic persistent surgical pain (CPSP) at 3 months postoperative using the Brief Pain Inventory (BPI) Short Form and Short Form McGill (SF-15) questionnaires, assessment of postoperative pulmonary function, area under the curve for Verbal Rating Score for pain at rest and on deep inspiration versus time over 48 h, total opioid consumption over 48 h, QoR-15 at 48 h, and postoperative complications and morbidity as measured by the Comprehensive Complication Index. Despite surgical advancements in thoracic surgery, severe acute postoperative pain following MITS is still prevailing. This study will provide recommendations about the efficacy of an anaesthesia-administered ultrasound-guided erector spinae catheter or surgeon-administered, video-assisted paravertebral catheter techniques for early quality of recovery following MITS. ClinicalTrials.gov NCT04729712 . Registered on 28 January 2021. All items from the World Health Organization Trial Registration Data Set have been included.


Extracellular vesicles transmit epithelial growth factor activity in the intestinal stem cell niche.
Extracellular vesicles (EV) are membrane-surrounded vesicles that represent a novel way of intercellular communication by carrying biologically important molecules in a concentrated and protected form. The intestinal epithelium is continuously renewed by a small proliferating intestinal stem cell (ISC) population, residing at the bottom of the intestinal crypts in a specific microenvironment, the stem cell niche. By using 3D mouse and human intestinal organoids, we show that intestinal fibroblast-derived EVs are involved in forming the ISC niche by transmitting Wnt and epidermal growth factor (EGF) activity. With a mouse model that expresses EGFP in the Lgr5+ ISCs, we prove that loss in ISC number in the absence of EGF is prevented by fibroblast-derived EVs. Furthermore, we demonstrate that intestinal fibroblast-derived EVs carry EGF family members, such as amphiregulin. Mechanistically, blocking EV-bound amphiregulin inhibited the EV-induced survival of organoids. In contrast, EVs have no role in transporting R-Spondin, a critical niche factor amplifying Wnt signaling. Collectively, we prove the important role of fibroblast-derived EVs as a novel transmission mechanism of factors in the normal ISC niche.


Determination of porcine fibrinogen in rat and dog plasma after intraperitoneal injection of a porcine-derived fibrin glue by fluorescein-labeled assay method: Comparison with isotope-labeled assay method.
A sensitive and specific fluorescein isothiocyanate (FITC) label coupled with size-exclusion high-performance liquid chromatography-fluorescence detection (SE-HPLC-FLD) method was developed and validated for the estimation of the pharmacokinetic profiles of porcine fibrinogen after intraperitoneal injection of a porcine-derived fibrin glue (FG) to SD rats and beagle dogs with three single doses. Porcine fibrinogen, the major composition of the FG, was labeled with FITC. The FG containing FITC-labeled porcine fibrinogen was intraperitoneally administered to SD rats at three single dosages (100, 200, 400mg/kg of porcine fibrinogen), and the collected plasma was then detected by SE-HPLC-FLD method. The present technique was compared to the previously introduced isotope-labeled assay method for the pharmacokinetic studies in SD rats. The pharmacokinetic studies in SD rats showed that the correlation coefficient between the FITC-labeled assay and (125)I-labeled assay methods was r(2)=0.989. Thus, this FITC-labeled assay method performed well and demonstrated high concordance with the previous (125)I-labeled assay method, suggesting that FITC-labeled assay could substitute the (125)I-labeled assay as a method of choice for quantification in beagle dogs. Then the plasma levels of porcine fibrinogen in beagle dogs were studied by the FITC-labeled assay method with three single doses (15, 30, 60mg/kg of porcine fibrinogen). The method validation showed that the FITC label coupled with SE-HPLC-FLD method was suitable for the quantification of porcine fibrinogen in plasma samples with satisfactory linear (r(2)>0.999), precision (<12%), accuracy (95.5-104.9%) and recovery (>88%). The results showed linear disposition of porcine fibrinogen at the examined dosage range in SD rats or beagle dogs.


Preparation of seaweed polysaccharide based hydrophobic composite membranes for the separation of oil/water emulsion and protein.
Agarose is a seaweed-based polysaccharide and is widely used for the separation of nucleic acids in molecular biology. Cross-linked agarose beads are also used as solid-phase matrices in size exclusion chromatography for the separation of proteins. To find the application of agarose for the separation of oil/water emulsion and protein, herein hydrophobic derivative of the seaweed biopolymer [MW (1.27 ± 0.17) × 10 5 g/mol; sulphate content (0.29 ± 0.09) %, gel strength (2242 ± 21) g/cm2] is prepared by reacting the biopolymer with stearic acid and was used to prepare a composite membrane on polyester fabric. The oil and BSA rejection performance of the composite membrane was greater than 98%. The rejection rate increased with the increase in polymer content in the respective membranes for both oil/water and protein separation. The composite membrane showed a stable oil/water emulsion and protein separation performance over a period of six hours. Due to the biodegradable nature of the major components of the membrane, it has the potential for industrial applications.


New insights for the risk of bisphenol A: inhibition of UDP-glucuronosyltransferases (UGTs).
Bisphenol A (BPA), the important endocrine-disrupting chemical (EDC), has been reported to be able to induce various toxicity. The present study aims to understand the toxicity behavior of bisphenol A through evaluating the inhibition profile of bisphenol A towards UDP-glucuronosyltransferase (UGT) isoforms. In vitro recombinant UGTs-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction was employed as probe reaction for all the tested UGT isoforms. The results showed that bisphenol A exerted stronger inhibition towards UGT2B isoforms than UGT1A isoforms. Furthermore, the inhibition kinetic type and parameters (K(i)) were determined for the inhibition of bisphenol A towards UGT2B4, 2B7, 2B15, and 2B17. Bisphenol A exhibited the competitive inhibition towards UGT2B4, and noncompetitive inhibition towards UGT2B7, 2B15 and 2B17. The inhibition kinetic parameters (K(i)) were calculated to be 1.1, 32.6, 5.6, and 19.9 μM for UGT2B4, 2B7, 2B15 and 2B17, respectively. In combination with the in vivo concentration of bisphenol A, the elevation of exposure dose was predicted to increase by 29.1%, 1%, 5.7%, and 1.6% for UGT2B4, 2B7, 2B15, and 2B17, indicating the high influence of bisphenol A towards the in vivo UGT2B isofroms-mediated metabolism of xenobiotics and endogenous substances. All these data provide the supporting information for deeper understanding of toxicology of bisphenol A.


Imaging for percutaneous renal access and management of renal calculi.
Percutaneous renal stone surgery requires detailed imaging to define stone burden and delineate the anatomy of the kidney and nearby organs. It is also essential to carry out safe percutaneous access and to assess postoperative outcomes. The emergence of CT as the imaging modality of choice for detecting renal calculi and the ability of CT urography with or without three-dimensional reconstruction to delineate the collecting system makes this the most versatile and sensitive imaging modality for pre- and postoperative evaluation. At present, intravenous urogram continues to play an important role in the evaluation of patients considered for percutaneous nephrostolithotomy. Fluoroscopy re-mains the mainstay of intraoperative imaging, although ultrasound is a useful alternative. Selection and application of appropriate imaging modalities for patients undergoing per-cutaneous nephrostolithotomy enhances the safety and success of the procedure.


Unexpected sex-ratios in families of language/learning-impaired children.
There is a well-documented propensity of males affected with developmental language/learning impairment. Results from this study demonstrate, unexpectedly, that this sex-ratio difference of males to females with developmental language/learning disorders was found to occur significantly only in families with a language/learning-impaired mother. In addition, a remarkably aberrant offspring sex-ratio was found in families of language/learning-impaired children who had an affected mother, but not father. Mothers who were developmentally language/learning-impaired had three times as many sons as daughters, and five times as many language/learning-impaired sons as daughters. Genetic and hormonal influences that might affect both sex-ratio and neuroanatomical development and disorders are discussed.


Left atrial wall motion velocity measured by the velocity profile method with tissue Doppler echocardiography in normal subjects: its relation to aging.
The aim of this study was to find a method for measuring left atrial wall velocity (LAWV) during atrial contraction using tissue Doppler echocardiography. The velocity profile method was used to measure left atrial wall velocity at several sites in 64 healthy individuals aged 25-84 years. We attempted to find maximum left atrial wall velocity (LAWVmax) by mapping on four-chamber, two-chamber, short-axis, and long-axis views and studied the relations between maximum left atrial wall velocity, age, and peak velocity during atrial contraction in mitral or pulmonary venous flow. Left atrial wall velocity was varied by changing the position of the sampling volume. The velocity profile pattern was similar to the left ventricular wall velocity pattern near the mitral valve annulus in the left atrium. Left atrial wall velocity had a positive peak during atrial contraction when the sample volume was located in the cranial and dorsal area. Maximum left atrial wall velocity was obtained in 74% of cases with the two-chamber view. Maximum left atrial wall velocity in healthy subjects was 3.1 ± 0.7 cm/s, and the duration of the atrial contraction was 112 ± 12 ms. Maximum left atrial wall velocity increased slightly with age but was not significantly correlated with peak velocity during atrial contraction in mitral or pulmonary venous flow. Left atrial wall velocity was measured by the velocity profile method in 64 healthy subjects aged 25-84 years. Maximum left atrial wall velocity increased slightly with age but was not significantly correlated with the peak velocity during atrial contraction in mitral or pulmonary venous flow.


Rationale, design and protocol of a cross-sectional study on pregnancy-related cardiovascular diseases in Tanzania (PRECARDT): burden, characterisation and prognostic significance at delivery.
The paucity of data describing cardiovascular disease (CVD) in pregnancy in many parts of Africa including Tanzania has given rise to challenges in proper management by the healthcare providers. This study is set out to (1) determine the prevalence of a range of CVDs during pregnancy in women attending antenatal clinics in Tanzania and (2) determine the impact of these CVDs on maternal and fetal outcomes at delivery. This is a cross-sectional study with a prospective component to be conducted in two referral hospitals in Tanzania. Pregnant women aged ≥18 years diagnosed with a CVD during the antenatal period are being identified and extensively characterised by performing clinical assessment, modified WHO staging, electrocardiography, echocardiography and laboratory tests. Patients identified with CVDs (exposed) and a subset without (unexposed) will be followed up to determine maternal and fetal outcomes at delivery. A minimum sample of 1560 will be sufficient to estimate the prevalence of CVDs with a 95% CI of 2.75% to 5.25%. The study is being conducted in accordance with the Helsinki declaration on studies involving human subjects. Ethical approvals have been obtained from Muhimbili University (reference number DA.282/298/01.C/) and Bugando Medical Centre (reference number CREC/330/2019) Ethics Committees. Informed consent is sought from all potential participants before any interview or investigations are performed. Study findings will be disseminated to the scientific community through different methods. Results will also be communicated to policymakers and to the public, as appropriate.


Signs of critical conditions and emergency responses (SOCCER): a model for predicting adverse events in the inpatient setting.
Emergency response systems (ERS) are based on a set of triggers used to identify patients "at risk". This study aimed to establish the association between recordings of disturbed physiological variables and adverse events. A cross-sectional survey of 3,046 non Do Not Attempt Resuscitation (non DNAR) adult admissions in five hospitals over 14 days. Medical records were reviewed for 26 early signs (ES) and 21 late signs (LS) of critical conditions and serious adverse events (SAE): death, cardiac arrest, severe respiratory problems, or transfer to a critical care area. The LS included published medical emergency team (MET) call criteria. There were 12,384 ES and 1,410 LS. The 'top five' ES and the odds (OR) for death were: base deficit -5 to -8 mmol/L=40.2 (95% C.I. 7.7-208.8), partial airway obstruction OR=38.7 (3.9-64.4), poor peripheral circulation OR=34.4 (6.8-174.0), >expected drain fluid loss OR=30.1 (6.1-148.9), pH <7.3 >7.2 OR=29.0 (3.1-268.3). For LS: urine output <200 mL in 24 h OR=188.6 (95% C.I. 30.1-1179.8), pH <7.2 OR=116.1 (7.1-1906.1), unresponsive to voice OR=34.8 (10.7-113.0), anuric OR=29.0 (3.1-268.3), base deficit <-8.0 mmol/L OR=29.0 (3.1-268.3). OR for the other SAE were similar. Pulse oximetry abnormalities were associated with all SAE. The risk for death for ES: SpO2 90-95% OR=8.1 (3.0-21.3) and LS: SpO2 <90% OR=9.0 (4.2-19.4). Both ES and LS were associated with adverse events. This study confirms the validity of current MET call criteria but points to the need to expand them. It provides a possible explanation for the failure to demonstrate efficacy of a MET in some trials because current call criteria maybe too late in the progress of the patient's critical condition. It allows the modelling of ERS and education programmes focused on signs of critical conditions. It potentially brings together ICU outreach and ward based responses. Broader use of clinical signs, monitoring such as pulse oximetry and objective data such as blood gas results may assist early intervention and help prevent loss of life.


Hepatitis C virus core protein: its coordinate roles with PA28gamma in metabolic abnormality and carcinogenicity in the liver.
Hepatitis C virus (HCV) is a major cause of chronic liver diseases, including steatosis, cirrhosis and hepatocellular carcinoma, and epidemiological studies indicate that HCV is also associated with insulin resistance and type 2 diabetes mellitus. The HCV core protein is not only a viral structural component but also a pathogenic factor, since its expression leads to the development of liver steatosis, insulin resistance and hepatocellular carcinoma in mice. The nuclear proteasome activator PA28gamma/REGgamma, which specifically binds to the core protein, is required for the virulence of the core protein. Elucidation of the mechanisms by which HCV core protein participates in the above conditions may provide clues toward the development of novel therapeutic measures for chronic hepatitis C.


Risk factors for secondary fractures to percutaneous vertebroplasty for osteoporotic vertebral compression fractures: a systematic review.
Osteoporotic vertebral compression fracture (OVCF) is one of the most common fragile fractures, and percutaneous vertebroplasty provides considerable long-term benefits. At the same time, there are many reports of postoperative complications, among which fracture after percutaneous vertebroplasty is one of the complications after vertebroplasty (PVP). Although there are many reports on the risk factors of secondary fracture after PVP at home and abroad, there is no systematic analysis on the related factors of secondary fracture after PVP. The databases, such as CNKI, Wan Fang Database and PubMed, were searched for documents on secondary fractures after percutaneous vertebroplasty published at home and abroad from January 2011 to March 2021. After strictly evaluating the quality of the included studies and extracting data, a meta-analysis was conducted by using Revman 5.3 software. A total of 9 articles were included, involving a total of 1882 patients, 340 of them diagnosed as secondary fractures after percutaneous vertebroplasty. The additional history of fracture, age, bone mineral density (BMD), bone cement leakage, intravertebral fracture clefts and Cobb Angle might be risk factors related to secondary fractures after percutaneous vertebroplasty for osteoporotic vertebral compression fractures. The height of vertebral anterior and body mass index (BMI) were not correlated.


Neoadjuvant immune checkpoint inhibitor therapy in resectable non-small cell lung cancer.
Only a minority of lung cancers are resectable at diagnosis, and many of these will eventually relapse. Adjuvant chemotherapy in this setting has a modest survival advantage, and there is significant need for new approaches to improve cure rates. Checkpoint inhibitor immunotherapy has transformed the prognosis for advanced lung cancer, and is increasingly being used in the neoadjuvant setting alone, or in combination with cytotoxic chemotherapy. While this has demonstrated convincing improvements in event-free survival and pathologic response, questions remain over optimal duration of therapy, predictive and prognostic biomarkers, response assessment and combination with other modalities. In addition, these results must be considered in the context of recent positive studies of adjuvant immunotherapy. Here, we summarise preclinical context and clinical trials in this space, discuss areas of controversy and pitfalls, and consider future challenges.


Self-association of lyophilized horse liver alcohol dehydrogenase.
The molecular weights of lyophilized and non-lyophilized horse liver alcohol dehydrogenase have been compared by quasi-elastic light scattering, and ultracentrifugation. Whereas the non-lyophilized enzyme has the expected molecular weight of 78 000, the lyophilized enz)me has an initial molecular weight of about 10(6) which increases with time by an endothermic process. This result shows that any physical measurement using lyophilized liver alcohol dehydrogenase to investigate the enzyme mechanism, which relies upon the molecular size, will be invalid.


NSF--fusion and beyond.
NSF (N-ethylmaleimide-sensitive fusion protein) was the first protein to be isolated as a crucial factor in intracellular membrane-fusion events, such as the fusion of synaptic vesicles with the presynaptic membrane during neurotransmission. Although the activation of membrane SNARE proteins for subsequent fusion is clearly a primary role of NSF, recent studies have provided surprising evidence that NSF also interacts with glutamate receptors at the postsynaptic membrane in a way that does not seem to involve SNAREs. These results suggest that NSF might act as a molecular chaperone not only on SNAREs but also of other proteins.


Role of epigenetics in cancer health disparities.
Cancer disparities in incidence and death rates exist among various racial and ethnic groups. These disparities are thought to be due to socioeconomic status, culture, diet, stress, the environment, and biology. Biological functions, such as epigenetic processes, are affected by all these causal factors and extend throughout the life course. Epigenetic processes, in particular DNA methylation, may play a role in the induction of phenotypes with increased cancer risk due to exposure to these multiple factors. DNA methylation is known to cause changes in gene expression of key regulatory genes in cancer. There are limited studies in which epigenetic changes have been explored to address cancer disparities in various racial and ethnic populations. These few studies have reported significant epigenetic differences in various racial and ethnic groups that could account for the differences seen in tumor initiation, progression, aggressiveness, and outcome of these cancers. Genes differentially methylated among these racially and ethnically diverse populations were involved in important cellular functions, such as tumor growth, tumor suppression, hormone receptors, and genes involved in tumor metastasis. Epigenetic research with the advancement in technology has helped identify biomarkers, therapeutic targets, and understand cancer causation in the general population. Unfortunately, these advances in technology have not been applied to explore the basis for cancer health disparities. More research in epigenetics is needed that will enhance our understanding of the determinants of cancer across various diverse populations and ultimately reduce cancer health disparities.


Metacognitive beliefs and anxiety symptoms could serve as mediators between fear of missing out and gaming disorder in adolescents.
Given the vulnerability to and prevalence of emotional problems and Internet gaming disorder (IGD) in adolescents, this study aimed to test the effects of fear of missing out (FoMO) on IGD and the mediating roles of metacognitive beliefs and anxiety symptoms based on the self-regulatory executive function (S-REF) model. At a Chinese high school, 283 participants (Mage = 16.89 years old; girls = 42.0%) with past-year gaming experience voluntarily completed an anonymous paper-and-pencil questionnaire. FoMO showed significant, positive associations with IGD, anxiety symptoms, and metacognitive beliefs. Results of path analysis showed a significant direct effect of FoMO on IGD, whereas anxiety symptoms mediated the relationship between FoMO and IGD. The indirect effects of FoMO on IGD via serial mediations of three negative metacognitive beliefs (i.e., negative beliefs about worry, low cognitive confidence, and beliefs regarding need for control) and anxiety symptoms were also statistically significant. These findings demonstrated that maladaptive metacognitive beliefs and anxiety are risk-enhancing mediators in the relationship between FoMO and IGD. Therefore, metacognitive therapy, particularly for regulating those three specific significant metacognitive beliefs, is recommended for treating IGD and anxiety, especially for those with higher levels of FoMO.


fMRI brain response during sentence reading comprehension in children with benign epilepsy with centro-temporal spikes.
Children with benign epilepsy with centro-temporal spikes (BECTS) often have language problems. Abnormal epileptic activity is found in central and temporal brain regions, which are involved in reading and semantic and syntactic comprehension. Using functional magnetic resonance imaging (fMRI), we examined reading networks in BECTS children with a new sentence reading comprehension task involving semantic and syntactic processing. Fifteen children with BECTS (age=11y 1m ± 16 m; 12 boys) and 18 healthy controls (age=11 y 8m ± 20 m; 11 boys) performed an fMRI reading comprehension task in which they read a pair of syntactically complex sentences and decided whether the target sentence (the second sentence in the pair) was true or false with respect to the first sentence. All children also underwent an exhaustive neuropsychological assessment. We demonstrated weaknesses in several cognitive domains in BECTS children. During the sentence reading fMRI task, left inferior frontal regions and bilateral temporal areas were activated in BECTS children and healthy controls. However, additional brain regions such as the left hippocampus and precuneus were activated in BECTS children. Moreover, specific activation was found in the left caudate and putamen in BECTS children but not in healthy controls. Cognitive results and accuracy during the fMRI task were associated with specific brain activation patterns. BECTS children recruited a wider network to perform the fMRI sentence reading comprehension task, with specific activation in the left dorsal striatum. BECTS cognitive performance differently predicted functional activation in frontal and temporal regions compared to controls, suggesting differences in brain network organisation that contribute to reading comprehension.


Insulin receptor kinase in human skeletal muscle.
Receptor-associated protein kinase activity has been shown in all primary target tissues of insulin action in the rat and a function of insulin receptor phosphorylation in signal transmission was proposed. Insulin receptor phosphorylation so far has not been demonstrated in human target tissues of insulin. We describe here insulin receptor kinase activity in human skeletal muscle. Insulin (10(-8) mol/l) stimulates the phosphorylation of a 95-kDa protein from skeletal muscle 2-fold. The phosphoprotein is quantitatively immunoprecipitated with insulin receptor antibody identifying it as the beta-subunit of the insulin receptor. The insulin stimulation of phosphorylation is detectable also at physiological insulin concentrations (10(-9) mol/l) showing that receptor phosphorylation could be involved in insulin action in human skeletal muscle as well.


Essential features of Chiari II malformation in MR imaging: an interobserver reliability study--part 1.
Brain MR imaging is essential in the assessment of Chiari II malformation in clinical and research settings concerning spina bifida. However, the interpretation of morphological features of the malformation on MR images may not always be straightforward. In an attempt to select those features that unambiguously characterize the Chiari II malformation, we investigated the interobserver reliability of all its well-known MR features. Brain MR images of 79 children [26 presumed to have Chiari II malformation, 36 presumed to have no cerebral abnormalities, and 17 children in whom some Chiari II malformation features might be present; mean age 10.6 (SD 3.2; range, 6-16) years] were blindly and independently reviewed by three observers. They rated 33 morphological features of the Chiari II malformation as present, absent, or indefinable in three planes (sagittal, axial, and coronal). The interobserver reliability was assessed using κ statistics. Twenty-three of the features studied turned out to be unreliable, whereas the interobserver agreement was almost perfect (κ value > 0.8) for nine features (eight in the sagittal plane and one in the axial plane, but none in the coronal plane). This study presents essential features of the Chiari II malformation on MR images by ruling out the unreliable features. Using these features may improve the assessment of Chiari II malformation in clinical and research settings.


Cleavage of pyrene-stabilized RNA bulge loops by trans-(±)-cyclohexane-1,2-diamine.
Chemical agents that cleave HIV genome can be potentially used for anti-HIV therapy. In this report, the cleavage of the upper stem-loop region of HIV-1 TAR RNA was studied in a variety of buffers containing organic catalysts. trans-(±)-Cyclohexane-1,2-diamine was found to cleave the RNA with the highest activity (31%, 37°C, 18 h). Cleavage of the RNA in trans-(±)-cyclohexane-1,2-diamine buffer was also studied when the RNA was hybridized with complementary DNAs. A pyrene-modified C3 spacer was incorporated to the DNA strand to facilitate the formation of a RNA bulge loop in the RNA/DNA duplex. In contrast, unmodified DNAs cannot efficiently generate RNA bulge loops, regardless of the DNA sequences. The results showed that the pyrene-stablized RNA bulge loops were efficiently and site-specifically cleaved by trans-(±)-cyclohexane-1,2-diamine.


Chemokine signaling defines novel targets for therapeutic intervention.
Members of the human chemokine family are considered a suitable target for therapeutic intervention, as they have a fundamental role in several important human diseases. Here we outline potential new areas of intervention based on recent findings on chemokine receptor function.


Vasopressin in dehydrated and rehydrated ponies.
Six pony mares deprived of water for 24 hours showed significant increases in plasma vasopressin (2.8 pg/ml) and osmolality (9 mosmol/kg). When water was made available the ponies drank rapidly (5 of 6 drank to satiety within 90 seconds) and corrected their fluid deficits precisely. Vasopressin did not return to predehydration levels until osmolality did after 15 minutes of access to water. The horse differs from rodents and humans, but is similar to pigs in that vasopressin levels do not fall before osmolality returns to normal. Oropharyngeal factors, therefore, may not be as important in vasopressin release in horses as in other species.


The role of HLA-B27 polymorphism and molecular mimicry in spondylarthropathy.
Ankylosing spondylitis (AS), reactive arthritis (ReA) and other related spondyloarthropathies (SpAs) are characterized by a strong association with the major histocompatibility complex allele HLA-B27. Experimental evidence from humans and transgenic rodents suggests that HLA-B27 is itself involved in the pathogenesis of SpA. Population and peptide-specificity analysis of HLA-B27 suggest it has a pathogenic function related to antigen presentation. Putative roles for infectious agents have been proposed in ReA and suggested in AS. However, the mechanism by which HLA-B27 and bacteria interact to induce arthritis is not clear. Molecular mimicry between bacterial epitopes that cross-react with self-B27 peptides is the most persuasive explanation for the pathogenesis of SpA. The experimental studies reviewed here have greatly increased our knowledge of the structure, function and disease association of HLA-B27.


Improving readability of an evaluation tool for low-income clients using visual information processing theories.
Literacy is an issue for many low-income audiences. Using visual information processing theories, the goal was improving readability of a food behavior checklist and ultimately improving its ability to accurately capture existing changes in dietary behaviors. Using group interviews, low-income clients (n = 18) evaluated 4 visual styles. The text plus color photographs style was preferred over the other 3 visual styles: text only, text plus black and white line drawings, and text plus gray-scale photographs. Employing cognitive interviewing in an iterative process, clients (n = 25) recommended simplifying text for 10 items, modifying content for 15 of 16 visuals, and replacing text with visual content for 7 of 16 items. Professional staff (n = 7) and educators (n = 10) verified that visuals and revised text accurately reflected the content of each item. Clients reported that the revised checklist captured their attention, added pleasure to the evaluation process, improved their understanding of the behaviors in question, and facilitated comprehension of text. Readability scores improved by more than 2 grades. This process can be duplicated by others interested in enhancing the quality of existing evaluation tools.


A facile permethylation of cord factor.
Small quantities of cord factor (trehalose-6,6'-dimycolates) can be readily and almost quantitatively permethylated in anhydrous diethyl ether/dimethylformamide mixtures with CH3I and NaH-oil dispersion in the presence of molecular sieve. Hydrolysis of the permethylated products from cord factor "Peurois" and 'P3-Aoyama-b' prove these to be 6,6'-dimycolates. Experiments with a 4-palmitoyl glucose suggest that acyl migration in this system may not occur.


Refeeding syndrome in a young woman with argininosuccinate lyase deficiency.
A severely chronically protein and calorie restricted young woman with argininosuccinate lyase deficiency developed transient refeeding syndrome (RFS) and hyperammonemia after modest diet liberalization following initiation of glycerol phenylbutyrate (GPB). The patient required IV supportive care and supplementation with potassium, magnesium and calcium. She is now doing well on GPB and an appropriate maintenance diet. Susceptibility to RFS should be considered in chronically nutritionally restricted patients with metabolic disorders after liberalization of diet.


Impact of intermediate mammography assessment on the likelihood of false-positive results in breast cancer screening programmes.
Breast cancer screening is offered to 100% of the target population in Spain and intermediate mammograms (IMs) are sometimes indicated. This study was aimed at analysing the frequency of IMs, the factors determining their recommendation, and their impact on the risk of false-positive results and the detection rate. Data from 3,471,307 mammograms from Spanish breast cancer screening programmes were included. 3.36% of the mammograms were IMs. The factors associated with the use of IMs were age, initial screening, previous invasive tests, a familial history of breast cancer and use of hormone replacement therapy. In screening episodes with an IM, the probability of a false-positive result was 13.74% (95% CI: 13.43-14.05), almost double that in episodes without IMs (6.02%, 95% CI 5.99-6.05). In young women with previous invasive procedures, a familial history of breast cancer or hormone replacement therapy use who were undergoing their initial screen, this probability was lower when IMs were performed. IMs always increased the detection rate. The factors prompting IMs should be characterised so that radiologists can systematise their recommendations according to the presence of the factors maximising the benefits and minimising the adverse effects of this procedure. Intermediate mammograms in breast screening offer potential benefits but also disadvantages. Intermediate mammograms increase the false-positive rate except in specific groups. Intermediate mammograms reduce the false-positive rate in younger women and initial screens. Intermediate mammograms also reduce false-positive results in women with personal risk factors. Intermediate mammograms increase cancer detection mainly in women without risk factors.


Study of aldehyde oxidase by micellar electrokinetic chromatography separation of O6 -benzylguanine and 8-oxo-O6 -benzylguanine.
A separation method for O6 -benzylguanine (O6 -BG) and 8-oxo-O6 -benzylguanine (8-oxo-O6 -BG) is developed by using MEKC. This study includes the optimization of separation and incubation parameters for both off-line and on-line procedures. The BGE consisted of 25 mM sodium phosphate buffer-methanol (70:30, v/v), apparent pH 7.4, in which SDS and methyl-β-cyclodextrin were dissolved yielding final concentrations of 50 and 15 mM, respectively. Separations were performed at 15 kV using an untreated fused-silica capillary (40 cm length, effective length is 30 cm) with the detection wavelength at 195 nm. The capillary was kept at 15°C. Good performances were demonstrated for the repeatability and linearity. The LOQ was determined to be 14 μM for 8-oxo-O6 -BG (S/N = 10). The accuracy values showed a bias of +7.9% for 50 μM and -7.0% for 100 μM. Premix and transverse diffusion of laminar flow profiles (TDLFP) methods were used for on-line mixing and reaction of the substrate O6 -BG with aldehyde oxidase. Both procedures were successful in mixing as well as subsequent separation of the substrate and the metabolite, while the repeatability of TDLFP (14.7% (n = 3)) was much better than the premix technique.


Laparoscopic gastrectomy for gastric cancer: experience with more than 600 cases.
Among the less invasive operations noted in recent years, laparoscopic gastrectomy for gastric cancer has become popular because of advances in surgical techniques. The authors performed laparoscopic gastrectomy with regional lymph node dissection for 612 cases of gastric malignancies between March 1998 and August 2006. The technique and results of laparoscopic gastrectomy for gastric cancer are presented. Of the 612 gastric malignancy cases, distal gastrectomy was performed in 485 cases, proximal gastrectomy in 42 cases, and total gastrectomy in 85 cases. In all the cases, D1 or D2 lymph node dissection was performed according to the general rule of the Japanese Gastric Cancer Association. Quicker recovery was observed in the laparoscopic gastrectomy cases than in the open cases. The postoperative complications with this technique were within a permissible range. No statistical difference was seen in the survival curve after surgery between the laparoscopic group of advanced cases preoperatively diagnosed as surgical T2N1 or lower and the open group. The laparoscopic technique is not only less invasive, but also similarly safe and curative compared with open gastrectomy.


Insights into response mechanism of anaerobic digestion of waste activated sludge to particle sizes of zeolite.
Anaerobic digestion has been proved as one promising strategy to simultaneously achieve resource recovery and environmental pollution control for biosolid treatment, and adding exogenous materials is a potential alternative to promote the above process. This study investigated response mechanisms of anaerobic digestion of waste activated sludge (WAS) to particle sizes of zeolite. Results showed that the methane production reached 186.75 ± 7.62 mL/g volatile suspended solids (VSS) with zeolite of the particle size of 0.2-0.5 mm and the additive dosage of 0.1 g/g VSS, which increased by 22.08% compared to that in control. Mechanism study revealed that zeolite could improve hydrolysis, acidification, and methanogenesis stages. Rapid consumption rates of soluble polysaccharides and proteins were observed, correspondingly, the accumulations of short-chain fatty acids (SCFAs) were enhanced, and the compositions of SCFAs were optimized. Moreover, the activities of F420 increased by 28% with zeolite, and the syntrophic metabolism between bacteria and methanogens were promoted.


Safety of paranasal sinus surgery in patients with cystic fibrosis.
Document the safety of paranasal sinus surgery in cystic fibrosis patients and review the changing trends in paranasal sinus surgery in the cystic fibrosis population. Retrospective review. Chart review of cystic fibrosis patients who underwent paranasal sinus surgery from 1955 to 1997. Indications for surgery included chronic sinusitis, nasal obstruction, purulent rhinorrhea, head pain, and pyocele. Average duration of anesthesia was 2.1 hours. The complication rate from general anesthesia was zero. Excessive bleeding and significant hypoxia did not occur. Paranasal sinus surgery and general anesthesia can be safely performed in cystic fibrosis patients. The indications for paranasal sinus surgery are changing from symptomatic nasal obstruction to pre-lung transplantation care. Today, treatment has evolved to include placement of sinus catheters for direct topical instillation of antibiotics and consideration of maxillary and frontal sinus obliteration.


Intramucosal-lymphatic invasion has a slight impact on lymph node metastasis in patients with early gastric cancer.
Lymphatic invasion (LI) is associated with lymph node metastasis (LNM) and a poor prognosis in patients with early gastric cancer (EGC). Although the impact of the LI volume on LNM has been described, no reports have assessed the impact of its depth on LNM. A total of 360 EGC patients with pathologically proven LI who underwent radical gastrectomy with lymphadenectomy between January 2005 and June 2018 at our institution were extracted from our database. Patients were divided into 2 groups: the mLI group, in which LI was limited to the muscularis mucosae (n = 34); and the smLI group, in which LI reached the submucosal region (n = 326). Clinicopathological features, including the LNM incidence, were compared between the groups. LNM was recognized in 3 patients (9%) in the mLI group and 101 (31%) in the smLI group (P = 0.005). In the mLI group, LNM was not recorded in any patients who met the curative criteria of ESD other than mLI. LI limited to the mucosal region does not seem to be a strong indicator for LNM. When pathological findings of an endoscopic submucosal dissection specimen show only mLI as a non-curative criterion, the probability of LNM may be very low.


Mapping evidence of Iran diabetes research: protocol for a scoping review.
A considerable amount of research funding goes to diabetes management strategies to improve therapeutic goals and reduce the burden of diabetes. A vast amount of the budget is wasted due to unnecessary studies. A scoping review is a pivotal study to overview the available evidence and avoid research waste. In this review, we will try to find out the scope of available studies on diabetes management interventions, identify associated research gaps, and prioritize future studies. We will carry out a study using Arksey and O'Malley's scoping review framework. We will search the Scopus and PubMed databases from 01/01/2015 till 01/01/2020. Only original articles related to pharmacological and non-pharmacological management interventions will be included. These interventional studies should be conducted on the Iranian population. After data extraction, a descriptive data analysis will be used to present information in different charts or tables. We will evaluate related published articles based on their document type, level of evidence, type of diabetes, subject area, interventions types, main findings and outcomes. This study represents the first attempt to sum up available studies related to diabetes management interventions performed in Iran. The results of this study will be useful for all the stakeholders and policy-makers involved in diabetes research. It can help clinicians to be informed about studies on management interventions and can guide scientists eager to diabetes research to choose their future research plans based on diabetes research requirements and gaps.


Altered amount and activity of superoxide dismutase in sickle cell anemia.
The amount and activity of superoxide dismutase (SOD) (EC 188.8.131.52) were measured in red cells collected from 50 white controls, 101 black controls, 50 patients with sickle hemoglobin (SS Hb), 12 with sickle trait, and 11 with other sickling hemoglobinopathies. Red cells from normal black subjects had more SOD amount and activity than normal whites (1.77 U/mg Hb and 2.96 micrograms/mg Hb vs. 1.47 U/mg Hb and 2.64 micrograms/mg Hb, respectively) or blacks with SS Hb or other sickling hemoglobinopathies. Patients with more severe manifestations of SS Hb had lower levels of SOD activity than those with milder symptoms but had the same amount of enzyme protein. Individuals with sickle trait had amounts and activities of SOD comparable to black controls. An alteration in defense to free radical oxygen may play a role in the severity of symptoms experienced by patients with homozygous sickle cell disease.


BCR-JAK2 fusion as a result of a translocation (9;22)(p24;q11.2) in a patient with CML-like myeloproliferative disease.
Translocation (9;22)(q34;q11.2) resulting in BCR/ABL1 fusion at the molecular level is the hallmark of chronic myelogenous leukemia (CML). Variants of the Philadelphia translocation and complex translocations involving BCR have been reported in myeloproliferative disorders (MPD). A rare translocation, t(9;22)(p24;q11.2), resulting in a novel BCR-JAK2 fusion has been reported in a handful of cases of CML and acute myelogenous leukemia (AML). We present clinical-pathological and cytogenetic evaluation of a patient with Philadelphia-chromosome negative CML/MPD harboring a t(9;22)(p24;q11.2) resulting in BCR-JAK2 fusion. Fluorescence in situ hybridization and molecular characterization of the translocation confirmed a BCR-JAK2 fusion and helped delineate the breakpoints upstream of exon 1 of minor cluster region of BCR gene and likely intron 18 of the JAK2 gene, resulting in an in-frame transcript This case provides convincing support, along with two previous case-reports, for a role for activation of the Janus kinase 2 in evolution of myeloproliferative disease. The recurrent, albeit rare, nature of the breakpoints within BCR and JAK2 suggests a potential new diagnostic target that should be interrogated in Ph-negative CML/MPD patients.


Recent Advances in Burkholderia mallei and B. pseudomallei Research.
Burkholderia mallei and Burkholderia pseudomallei are Gram-negative organisms, which are etiological agents of glanders and melioidosis, respectively. Although only B. pseudomallei is responsible for a significant number of human cases, both organisms are classified as Tier 1 Select Agents and their diseases lack effective diagnosis and treatment. Despite a recent resurgence in research pertaining to these organisms, there are still a number of knowledge gaps. This article summarizes the latest research progress in the fields of B. mallei and B. pseudomallei pathogenesis, vaccines, and diagnostics.


Effects of the COVID-19 Pandemic on SMA Screening and Care: Physician and Community Insights.
As part of efforts to reduce diagnostic delays and enhance clinical trials, Cure SMA evaluated the effects of COVID-19 on SMA care and clinical trial conduct. Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive, potentially debilitating muscle weakness and atrophy. Uninterrupted access to early diagnosis, disease-modifying treatment, and care for SMA is vital to avoiding irreversible motor neuron death and achieving optimal patient outcomes. Two surveys were conducted: a provider survey and a community survey. The Provider Impact Survey, distributed from November 24, 2020, through March 8, 2021, assessed COVID-19's effects on referrals for evaluation of suspected SMA, cancellations and delays of SMA-related care, and clinical trials. The Community Impact Survey was fielded in three waves between April 7, 2020 and July 19, 2021, in tandem with Cure SMA COVID-19 support programs. A total of 48 completed provider surveys (22 from care sites, 26 from care-and-trial sites) reflected decreases in referrals for suspected SMA, increases in appointment cancellations and delays, and patient reluctance to attend in-person visits due to COVID-19. One-third of care-and-trial sites reported trial recruitment delays, and one-quarter reported pausing trial enrollment. Results of the Community Impact Survey, completed by 2047 individuals, showed similar disruptions, with 55% reporting changes or limitations in accessing essential SMA-related services. This research evaluates the pandemic's interruption of SMA care and research. These insights can help mitigate and increase preparedness for future disruptive events. Expanded use of virtual tools including telehealth and remote monitoring may enhance continuity and access. However, additional research is required to evaluate their effectiveness. While this research was specific to SMA, its findings may have relevance for other patient communities.


Novoglan device for treatment of adult phimosis: Novoglan-01 open-label clinical trial on safety, efficacy and tolerability.
At present, the only definitive treatment for adult phimosis is circumcision, which is a surgical removal of the prepuce. Novoglan is a novel device that could offer patients with phimosis an alternative to surgery. It is based on application of custom-moulded balloons for gradual skin remodelling and prepuce dilatation. This open-label clinical trial aimed to investigate the safety, efficacy and tolerability of the Novoglan treatment. A prospective trial was conducted on 20 patients with adult phimosis recruited at Macquarie University Hospital and Princess Alexandra Hospital. After eligibility screening and enrolment, patients were provided with the Novoglan product and training. The treatment involved twice daily 10-minute applications for a duration of 4-8 weeks with patient's degree of phimosis assessed before and at 6-8 weeks after the initiation of the treatment. Participants were also asked to complete questionnaires aimed to assess the safety and tolerability of the Novoglan treatment. The treatment was successful with improved foreskin retraction in 90% of patients and all patients achieving full foreskin retraction after the treatment. Ninety-five percent of patients reported reduced level of anxiety, and over 60% of patients reported reduced pain/discomfort during sexual activity or in general. Similarly, 95% of patients were moderately-to-very satisfied with the treatment and would recommend Novoglan to others. No adverse events were observed and only 15% of participants reported minor side effects. The Novoglan-01 trial demonstrated high safety, efficacy and tolerability of the Novoglan treatment for adult phimosis and its high potential as a conservative alternative to circumcision or steroid cream treatment. The Novoglan-01 study has been registered with the Australia and New Zealand Clinical Trial Registry under the reference ACTRN 1262 10009 24853, dated 15 July 2021.


Personalized medicine in severe influenza.
Existing therapies against infectious diseases may only be effective in limited subpopulations during specific phases of diseases, incorporating theranostics, and there is a clear need to individualize different therapeutic approaches depending on the host. Influenza A virus infection evolves into a severe respiratory failure in some young adult patients, related to an exaggerated inflammatory response. Mortality rates remain high despite antiviral treatment and aggressive respiratory support. The influenza A virus (IAV) infection will induce a proinflammatory innate immune response through recognition of viral RNA by Toll-like receptor (TLR) 7 and retinoic acid-inducible gene 1 (RIG-I) molecules by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB route). Anti-inflammatory therapies focused on modulating this inflammatory response to "all patients" have not been satisfactory. Steroids should be avoided because they do not improve survival and promote superinfections. Since clinical judgment has often been proven inadequate, interest in the use of biomarkers to monitor host response and to assess severity and complications is growing. It is well known that, if used appropriately, these can be helpful tools to predict not only severity but also mortality. We need more biomarkers that predict host response: it is time to change lactate measurement to proteomics and transcriptomics. Theranostics describes an approach covering both diagnosis and coupled therapy. Death is usually a fatal complication of a dysregulated immune response more than the acute virulence of the infectious agent. Future research demonstrating the usefulness of adjunctive therapy in a subset of critically ill patients with IAV pneumonia is an unmet clinical need.


Anterior shoulder anatomy and subcoracoid impingement: An anatomical study.
The aim of our study was to describe the anatomy of the anterior shoulder, specifically structures potentially involved in subscapularis tears pathophysiology and also to identify structures at risk during surgical approaches of this area. We designed an observational, experimental study based on cadaveric models. Dissection was performed and several structures of the anterior shoulder were characterized including the subscapularis, coracoid morphology, the coracoacromial ligament, coraco-humeral distance, and the axillary and musculocutaneous nerves. Our sample included 16 shoulders. The coracoacromial ligament presented two bands in 37.5%, and these variants were significantly wider and thinner, and were associated with inferior coraco-humeral distance in internal rotation. The subscapularis footprint was longer and the coracoid process was bigger in male specimens, and the median coracoid angle was 122°, corresponding to a Leite-Torres type I. The Subscapularis showed a median thickness of 0.7cm, while the coraco-humeral distance in our sample ranged from 0.30cm in internal rotation to 0.85cm in external rotation. Neurologic relevant structures were at least more than 2.55cm from the coracoid tip. This is the first paper to explore the eventual relationship between the presence of a double band coracoacromial ligament variant and subcoracoid impingement. Also, to our knowledge, this is the first cadaveric model study to postulate a possible anatomic base for subcoracoid impingement, as the SS myotendinous junction thickness was found to be greater than the coraco-humeral distance in neutral position and in IR.


Dose-dependency of Tl+ kinetics as studied in rabbits.
The dose-dependency of Tl+ kinetics was studied in rabbits by intravenous injection first of a 201Tl+ tracer dose and 2 weeks later of a 5.5 mumol/kg dose. For either dose level, an open three compartment model was appropriate to describe the course of the plasma concentration curve. With the dosage increase a slight to moderate decrease in the distribution volumes (11.2 l/kg versus 9.7 l/kg) and in the plasma clearance (13 ml/min versus 9 ml/min) was found. Two days after injection of both the high and the low dose considerable amounts of Tl+ were found in the intestinal contents and only small amounts were found in the bile.


Mononuclear phagocytes and the human immunodeficiency virus.
Macrophages are an important in vivo reservoir for HIV. Conclusive evidence that CNS, pulmonary, lymph node and blood-derived mononuclear phagocytes harbor and support HIV replication is supported by numerous independent studies. HIV variants which preferentially replicate in macrophages have been recovered from infected individuals, suggesting that these cells and variant viruses are involved in the establishment and progression of HIV-related disease.


Chemotherapy in the management of advanced cutaneous malignant melanoma.
The recent past has witnessed unprecedented clinical progress in the treatment of advanced malignant melanoma through targeting of mutant BRAF in approximately 50% of patients and immune check point blockade in all patients. As has been well documented, responses to targeted therapy are of limited duration, and rates of clinical benefit to immunotherapy are modest. Given these factors, palliation of patients with chemotherapy remains an essential aspect of melanoma oncology. Many chemotherapeutics (and combinations with other agents, such as immunotherapy) have been evaluated in melanoma, although no chemotherapy regimen has been documented to provide an overall survival benefit in a prospective, randomized, well-controlled phase III study. We provide an overview of the development of the most common chemotherapy regimens for melanoma, discuss the clinical trial evidence supporting and contrasting them, and highlight appropriate clinical situations in which they might be used. We also discuss the future of chemotherapy for melanoma, noting the potential for combinations of chemotherapy with either targeted or immunotherapeutic agents.


Biological Activity of Agaricinic Acid Nanoparticles against Human Hepatoma HepG2 Cells.
A stable preparation of agaricinic acid nanoparticles was obtained. The mean hydrodynamic size of nanoparticles according to photon correlation spectroscopy was 200 nm and zeta potential was -57 mV. Cytotoxic activity of agaricinic acid nanoparticles against human HepG2 hepatoma cells was evaluated. Nanoparticles with a low concentration of agaricinic acid stimulated and with high concentration - suppressed metabolic activity and viability of hepatoma cells. The EC50 for the stimulating effect was 32.8 μg/ml, and the IC50=602.1 mg/ml. The preparation of agaricinic acid nanoparticles can be used in medicine as a potential antitumor agent.


Step-size effect on calculated photon and electron beam Cherenkov-to-dose conversion factors.
Previous work presented and validated in-water Cherenkov emission (CE)-based radiotherapy dosimetry. Condensed history Monte Carlo (MC)-calculated electron beam CE-to-dose conversion with <4π CE detection, however, could exhibit step-size dependence. This work presents a physics update and numerical study of this step-size dependence in photon and electron beams, elucidates the CE generation physics, and guides further research. The CE-to-dose conversion, kCθ±δθ, is calculated for photons (6X, 15X) and electrons (6E, 20E) on-axis in-water with: θ±δθ∈{90°±90°(4π),90°±5°,45°±45°,90°±45°}, 10 cm equivalent square, 100 cm SSD, 1cm voxel radius and beam-dependent length. Relative deviation from single-scattering (SS) simulation is evaluated on maximum fractional electron step energy loss ESTEPE∈0.01-0.25. Standard uncertainties (k=1, 108histories) are reported. A simplified method considering only the straight step direction is also implemented. No significant step-size effect (>0.1%) was observed for dose and all kCθ±δθ, except for surface dosimetry at 90°±5° (-1.6%±0.5%, 20E), which is not recommended. Electron SS deviation uncertainties (k=1), otherwise, varied from <0.2% overall to <0.1% with large apertures. Photon uncertainties varied from <1.1% overall to <0.2% non-superficially with large apertures. The simplified straight-step method exhibited overall greater deviation from SS, most notably -2.8%±0.1% (6E) and -2.5%±0.4% (20E) superficially with 90°±45°, and -1.4%±0.3% (6X) and -0.6%±0.2% (15X) non-superficially with 90°±5° for ESTEPE∈[0.10,0.25]. We demonstrate step-size independence of newly-implemented correction in EGSnrc directional Cherenkov calculations. This advances clinical CE-based dosimetry and is useful for the general Monte Carlo community.


CYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients.
High inter-individual variability in tacrolimus clearance is attributed to genetic polymorphisms of CYP3A enzymes. However, due to CYP3A phenoconversion induced by non-genetic factors, continuous changes in tacrolimus-metabolizing capacity entail frequent dose-refinement for optimal immunosuppression. In heart transplant recipients, the contribution of patients' CYP3A-status (CYP3A5 genotype and CYP3A4 expression) to tacrolimus blood concentration and dose-requirement was evaluated in the early and late post-operative period. In low CYP3A4 expressers carrying CYP3A5*3/*3, the dose-corrected tacrolimus level was significantly higher than in normal CYP3A4 expressers or in those with CYP3A5*1. Modification of the initial tacrolimus dose was required for all patients: dose reduction by 20% for low CYP3A4 expressers, a 40% increase for normal expressers and a 2.4-fold increase for CYP3A5*1 carriers. The perioperative high-dose corticosteroid therapy was assumed to ameliorate the low initial tacrolimus-metabolizing capacity during the first month. The fluctuation of CYP3A4 expression and tacrolimus blood concentration (C0/D) was found to be associated with tapering and cessation of corticosteroid in CYP3A5 non-expressers, but not in those carrying CYP3A5*1. Although monitoring of tacrolimus blood concentration cannot be omitted, assaying recipients' CYP3A-status can guide optimization of the initial tacrolimus dose, and can facilitate personalized tacrolimus therapy during steroid withdrawal in the late post-operative period.


A mixed hamartoma of the liver: light and electron microscopy.
The gross, microscopic, and ultrastructural features of a mixed liver hamartoma occurring in a three month old infant are reported. The differentiation from two solid liver masses, focal nodular hyperplasia and liver cell adenoma is emphasized. Mesenchymal hamartomas, though usually cystic rather than solid masses, share the histologic feature of fibroductular tissue with mixed liver hamartomas and focal nodular hyperplasia. Only the mixed liver hamartoma has extremely broad fields of ductules and an embryonic type of hepatocyte at the ultrastructural level. These and other hepatic lesions show morphologic evidence of transformation of liver cells into biliary epithelial cells in association with vascular connective tissue.


Discovery of False Identification Using Similarity Difference in GC-MS based Metabolomics.
Compound identification is a critical process in metabolomics. The widely used approach for compound identification in gas chromatography-mass spectrometry (GC-MS) based metabolomics is the spectrum matching, in which the mass spectral similarity between an experimental mass spectrum and each mass spectrum in a reference library is calculated. While various similarity measures have been developed to improve the overall accuracy of compound identification, little attention has been paid to reducing the false discovery rate. We, therefore, develop an approach for controlling false identification rate using the distribution of the difference between the first and the second highest spectral similarity scores. We further propose a model-based approach to achieving a desired true positive rate. The developed method is applied to the NIST mass spectral library and its performance is compared with the conventional approach that uses only the maximum spectral similarity score. The results show that the developed method achieves a significantly higher F1 score and positive predictive value than those of the conventional approach.


Molecular analysis of the Drosophila nuclear lamin gene.
A complete nucleotide sequence of a 4.2-kb genomic fragment containing the Drosophila lamin gene and flanking sequences is presented. Primer extension experiments and sequence analysis revealed that transcription starts from a single promoter. The lamin maternal 2.8-kb transcript and the 3.0-kb zygotic transcript are generated from two alternative polyadenylation sites. The gene contains four exons. The first intron is 7 bp upstream of the first AUG site. The two other introns are located within the alpha-helical rod domain of the protein: one in coil 1B in the 42-amino-acid domain that is absent in vertebrate cytoplasmic intermediate filament proteins and the other in coil 2 at a position different from intron positions within the vertebrate intermediate filament genes. Together with the sequence homology analysis, the data suggest either that the lamin gene was the ancestral gene of intermediate filament genes or that the lamin gene diverged from other intermediate filament genes early in evolution.


Ischemic preconditioning affects interleukin release in fatty livers of rats undergoing ischemia/reperfusion.
The present study evaluates the effect of ischemic preconditioning on interleukin-1 (IL-1) and interleukin-10 (IL-10) generation following hepatic ischemia/reperfusion (I/R) in normal and steatotic livers as well as the role of nitric oxide (NO) in this process. Increased IL-1beta and IL-10 levels were observed in normal livers after I/R. Steatotic livers showed higher IL-1beta levels than normal livers, and IL-10 at control levels. The injurious role of IL-1beta and the benefits of IL-10 on hepatic I/R injury was shown with the use of IL-1 receptor antagonist (IL-1ra), anti-IL-10 polyclonal antibody against IL-10 (anti-IL-10) and exogenous IL-10. The effective dose of these treatments was different in both types of livers. Preconditioning prevented IL-1beta release and increased IL-10 generation after I/R in normal and steatotic livers. IL-1beta or anti-IL-10 pretreatments reversed the benefits of preconditioning. IL-1beta action inhibition in a preconditioned group that was pretreated with anti-IL-10 did not modify the benefits of preconditioning. In addition, anti-IL-10 pretreatment in the preconditioned group resulted in IL-1beta levels comparable to those observed after I/R. NO inhibition eliminated the benefits of preconditioning on IL-10 release, IL-1beta levels, and hepatic injury. In conclusion, preconditioning, through IL-10 overproduction, inhibits IL-1beta release and the ensuing hepatic I/R injury in normal and steatotic livers. IL-10 generation induced by preconditioning could be mediated by NO.


Dynamics of bovine respiratory syncytial virus infections: a longitudinal epidemiological study in dairy herds.
To study the epidemiology of respiratory syncytial virus (RSV) infections during the year, the incidences of primary infections and reinfections were monitored by titrating antibodies to bovine RSV (BRSV) in cattle above 2 months of age in 6 dairy herds in the Netherlands. From August 1990 until September 1991, 884 cattle were sampled at one-month intervals. A total of 155 cattle, most under two years of age, had a primary antibody response. Antibody rises were found in 259 cattle of all ages. The highest incidences of BRSV infections were found in one period either in autumn or winter. In other seasons, primary infections were rare, whereas reinfections were not uncommon. In 5 out of the 6 herds, two seronegative sentinel calves were introduced at the end of the winter and none developed specific antibodies before the next winter. The observations strongly suggest that, in spite of regular reinfections, BRSV circulates during spring or summer at a very low level or not at all. Persistent BRSV infection in a number of cows might be a means for the virus to survive during summer, but a steady rate of reinfection of seropositive cows throughout the year at a low level might also maintain a reservoir of infectious virus. This study adds to the knowledge of frequency and timings of primary infections and reinfections of BRSV and it might contribute to the study of these issues of human RSV.


Liposomal enhancement of the immunogenicity of adenovirus type 5 hexon and fiber vaccines.
Immunogenicity of adenovirus capsid proteins carried in liposomes was comparable to that with equivalent doses administered in Freund adjuvant, and both forms were more potent than aqueous vaccines.


Perioperative mortality in patients with myelodysplastic syndrome.
Myelodysplastic syndrome (MDS) is a conglomerate of diseases in which bone marrow-derived cells die before or shortly after entering circulation. We sought to define the perioperative mortality in MDS patients. We reviewed our experience of all persons treated for MDS at our institution over the past 15 years. Demographic and survival information were collected, and those who underwent any procedure requiring general anesthesia were defined as the operative subgroup. Of 169 patients identified, 39 (23%) were in the operative subgroup. The median survival was 17.8 months. The mortality rate for the operative group was 23% (N = 9) and 30.8% (N = 12) at 30 and 60 days post-procedure. Twenty-three patients (59%) had an urgent/emergent indication for operation, which was associated with higher 60-day mortality (N = 12, 48%) compared to those with elective indications (N = 1, 7%) (P = 0.037, Chi-square). Several other factors (age, gender, International Prognostic Score, MDACC score, and major/minor procedure type) were not associated with perioperative mortality. Outcomes in MDS patients are poor with expected survival less than 2 years and high postoperative mortality in the setting of urgent/emergent operations. While maybe not prohibitive, we believe it is an imperative part of the informed consent process particularly for urgent/emergent procedures.


Herpes simplex virus type 1 replication and recombination.
Herpesviruses are a very interesting model for studying DNA replication in eukaryotic systems since they encode most of the proteins required for this process. These include a protein that specifically binds to the virus origin of DNA synthesis, a single-stranded DNA binding protein, an heterotrimeric helicase-primase and an heterodimeric DNA polymerase holoenzyme. Although the virus genome contains three origins of DNA synthesis, replication proceeds through the generation of high molecular mass concatemeric replicative intermediates reminiscent of rolling circles. In addition, herpesviruses are highly recombinogenic and are useful models to study homologous recombination. Homologous recombination and replication of the virus genome appear to be tightly coupled and interrelated processes.


Domain organization and phylogenetic analysis of proteins from the chitin deacetylase gene family of Tribolium castaneum and three other species of insects.
A bioinformatics investigation of four insect species with annotated genome sequences identified a family of genes encoding chitin deacetylase (CDA)-like proteins, with five to nine members depending on the species. CDAs (EC 184.108.40.206) are chitin-modifying enzymes that deacetylate the beta-1,4-linked N-acetylglucosamine homopolymer. Partial deacetylation forms a heteropolysaccharide that also contains some glucosamine residues, while complete deacetylation produces the homopolymer chitosan, consisting exclusively of glucosamine. The genomes of the red flour beetle, Tribolium castaneum, the fruit fly, Drosophila melanogaster, the malaria mosquito, Anopheles gambiae, and the honey bee, Apis mellifera contain 9, 6, 5 and 5 genes, respectively, that encode proteins with a chitin deacetylase motif. The presence of alternative exons in two of the genes, TcCDA2 and TcCDA5, increases the protein diversity further. Insect CDA-like proteins were classified into five orthologous groups based on phylogenetic analysis and the presence of additional motifs. Group I enzymes include CDA1 and isoforms of CDA2, each containing in addition to a polysaccharide deacetylase-like catalytic domain, a chitin-binding peritrophin-A domain (ChBD) and a low-density lipoprotein receptor class A domain (LDLa). Group II is composed of CDA3 orthologs from each insect species with the same domain organization as group I CDAs, but differing substantially in sequence. Group III includes CDA4s, which have the ChBD domain but do not have the LDLa domain. Group IV comprises CDA5s, which are the largest CDAs because of a very long intervening region separating the ChBD and catalytic domains. Among the four insect species, Tribolium is unique in having four CDA genes in group V, whereas the other insect genomes have either one or none. Most of the CDA-like proteins have a putative signal peptide consistent with their role in modifying extracellular chitin in both cuticle and peritrophic membrane during morphogenesis and molting.


Asymmetric synthesis of substituted prolines from delta-amino beta-ketoesters. Methyl (2S,5R)-(+)-5-phenylpyrrolidine-2-carboxylate.
[reaction: see text]. Metal carbenoid chemistry is used to convert delta-amino beta-ketoesters into 5-substituted 3-oxo prolines, which expands the utility of this class of polyfunctionalized chiral building blocks.


Analysis of Rotterdam Study cohorts confirms a previously identified RIPOR2 in-frame deletion as a prevalent genetic factor in phenotypically variable adult-onset hearing loss (DFNA21) in the Netherlands.
A 12-nucleotide RIPOR2 in-frame deletion was recently identified as a relatively common and highly penetrant cause of autosomal dominant non-syndromic sensorineural hearing loss, type DFNA21, in the Netherlands. The associated hearing phenotype is variable. The allele frequency (AF) of 0.039% of this variant was determined in a local cohort, and the reported phenotype may be biased because studied families were identified based on index patients with hearing loss (HL). In this study, we determine the AF in a cohort from a different geographical region of the Netherlands. Additionally, we examine the hearing phenotype in individuals with the variant but not selected for HL. The AF was determined in participants of the Rotterdam Study (RS), a large cohort study. The phenotype was characterised using individual clinical hearing data, including audiograms. The observed AF in the RS cohort was 0.072% and not statistically significantly different from the previously observed 0.039%. The AF in the two cohorts combined was 0.052%. Consistent with previous findings, we found a highly variable audiometric phenotype with non-penetrance of HL in 40% of subjects aged 55-81, which is higher than the 10% at age 50 previously observed. We found an overall higher AF and lower penetrance than previously reported, confirming that DFNA21 is relatively common in the Netherlands. This supports its potential suitability as a target for therapeutic development. Studying possible modifying factors is essential to explain the phenotypical variability and to identify patients eligible for such a therapy.


Buccal Bone Thickness Overlying Maxillary Anterior Teeth: A Clinical and Radiographic Prospective Human Study.
The aim of this work was to measure the facial bone thickness overlying maxillary anterior teeth according to the periodontal biotype, the tooth position, and the bucco-palatal inclination of the tooth. CBCTs of 47 patients were included. The periodontal biotype and the bucco-palatal inclination were examined for all maxillary anterior teeth as well as the sagittal tooth position according to the classification of Kan et al. Buccal bone thickness was measured at 4, 6, 8, and 10 mm apical to the cement-enamel junction (CEJ). At 4 mm from the CEJ, mean buccal bone thickness was 1.0 mm for all teeth and it decreased gradually and significantly in apical direction (6, 8, and 10 mm). A thin biotype was associated with a labial plate thickness half that of a thick biotype at all 4 distances from the CEJ. Class IV of Kan et al classification presented the thinnest facial bone (0.32-0.54 mm), whereas Class III demonstrated the thickest one (1.26-2.09 mm) at all distances from the CEJ. At 10 mm from the CEJ, the facial bone thickness increased with the vestibulo-palatal inclination of the tooth. A thin facial bone wall overlies almost all maxillary anterior teeth.


Managing terror. Public health officials learn lessons from bioterrorism attacks.
When a photo-journalist presented with the first case of inhalation anthrax in the United States in 23 years, it marked the worse case of biological terrorism in our nation's history. It also marked a significant management challenge for numerous local, state and federal officials. Review what was learned and how we can better prepare for future attacks.


AIRO GORTEC consensus on postoperative radiotherapy (PORT) in low-intermediate risk early stages oral squamous cell cancers (OSCC).
Evidence on the efficacy of postoperative radiotherapy (PORT) in low-intermediate risk squamous cell carcinoma of the oral cavity (OSCC) remains inconclusive. Members of a task force from two national radio-oncology Associations (AIRO and GORTEC) defined 14 clinically relevant questions to identify "gray areas" pertinent to the indication for PORT in this clinical setting. Consequently, a literature review was performed on the topic. The resulting statements were then rated by an Expert Panel (EP) using a modified Delphi method. Only radiation oncologists were part of the discussion and voting on the scenarios. There was agreement on the 14 statements at the first round of voting. The task force then decided to propose clinical cases for the two more controversial statements that had received a lower agreement to better capture the Experts' attitudes. The clinical cases highlighted a more significant decisional heterogeneity. However, the good level of consensus reached among the two Associations gives relevant support in informing clinical choices while acknowledging general indications cannot fit all clinical situations and do not replace multidisciplinary discussion.


Added Value of Contrast-Enhanced T1-Weighted and Diffusion-Weighted Sequences for Characterization of Incidental Findings on Whole Body Magnetic Resonance Imaging in Plasma-Cell Disorders.
Whole body magnetic resonance imaging (WBMRI) is currently recommended by guidelines for the assessment of myeloma. This will inevitably result in incidental findings. We aimed to assess the frequency of extraskeletal incidental findings and the added value of contrast-enhanced (CE) T1-weighted (T1-W) and diffusion-weighted (DWI) sequences for their characterization in a single WBMRI examination. We performed 1.5 T WBMRI in 100 patients (53 female; median age, 65 years) with plasma-cell disorders from January 2014 to July 2017. T2-weighted sequences were reviewed initially for incidental findings, followed by sequential review of T1-W, CE T1-W, and DWI sequences for lesion characterization. Descriptive statistics were undertaken. A total of 348 incidental findings were detected in 97 (97%) of 100 patients; only 38 (10.9%) of 348 findings were indeterminate. T1-W sequences increased diagnostic confidence in the characterization of 12 (31.6%) of 38; CE T1-W sequences in the characterization of 16 (50%) of 32; and DWI increased diagnostic confidence in 21 (55.3%) of 38 compared to the T2-weighted sequence alone. Incidental findings are common, but the majority are of no clinical consequence. No additional cancers were noted in our series. DWI and CE T1-W sequences increased diagnostic confidence in 50% of indeterminate findings and may reduce the need for further investigation.


Breast consciousness in American society and it's effect on the American woman's adaptation to mastectomy.
The American Cancer Society estimates that more than a hundred thousand American women develop breast cancer every year. Mastectomy is the treatment of choice. While this surgery performs a gratifying service by saving a woman's life, her appreciation is muted by the price she must pay--the loss of a breast and permanent disfigurement. Within the value system of American culture, that price is a considerable one. This paper will attempt to interpret that cost.


[Abdominal wall endometrioma in the cesarean section scar].
The study presents a retrospective review of patients diagnosed with abdominal wall endometrioma in the cesarean section scar between the years 2001-2006. The study presented age symptoms, size of tumor, time between cesarean section and symptoms, results of treatment. Between 2001-2006, 34 patients, all of which suffered from abdominal pain and palpable mass, were diagnosed and treated in our hospital. In 8 cases the disease returned and reoperation was necessary. In one case we observed adenocarcinoma papillare. Endometriosis in postoperative abdominal wall scar after cesarean section is rarely observed. Because to the fact that the number of cesarean sections is constantly increasing, this complication becomes more frequent. The treatment of choice is surgical resection.


Why do some ME/CFS patients benefit from treatment with sodium dichloroacetate, but others do not?
Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is an enigmatic disease the pathogenesis of which remains elusive. Pragmatic proof-of-principle of the hypothetical mechanisms causing the clinical symptoms has been delivered, but it is hard to explain why some patients do respond favourably to treatment with sodium dichloroacetate (DCA), which enhances the activity of the mitochondrial enzyme pyruvate dehydrogenase, but other patients experience no benefit from this substance. In a prospective trial including 35 ME/CFS patients, logistic regression analysis with stepwise elimination has identified 6 pre-treatment characteristics allowing for the differentiation between responders (n = 13) and non-reponders (n = 22) with high accuracy (P < 0.0001; area under the ROC-curve = 0.92). A formula was derived generating the probability of belonging to the group of responders. This finding may assist in selecting ME/CFS patients suitable for treatment with DCA, but requires further studies as to the predictive capacity of the derived formula.


A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability and pharmacokinetics.
Oral itraconazole has variable pharmacokinetics and risks of adverse events associated with high plasma exposure. An inhalation formulation of itraconazole (PUR1900) is being developed to treat allergic bronchopulmonary aspergillosis, an allergic inflammatory disease occurring in asthmatics and patients with cystic fibrosis. A 3-part, open-label Phase 1 study was conducted to evaluate safety, tolerability and pharmacokinetics of PUR1900. Healthy volunteers (n = 5-6/cohort) received either single (Part 1) or multiple (Part 2) ascending doses of PUR1900 for up to 14 days. In Part 3 stable, adult asthmatics received a single dose of 20 mg PUR1900 or 200 mg of oral Sporanox (itraconazole oral solution) in a 2-period randomized cross-over design. Itraconazole plasma and sputum concentrations were evaluated. None of the adverse events considered as at least possibly related to study treatment were moderate or severe, and none were classed as serious. The most common was the infrequent occurrence of mild cough. Itraconazole plasma exposure increased with increasing doses of PUR1900. After 14 days, PUR1900 resulted in plasma exposure (area under the concentration-time curve up to 24 h) 106- to 400-fold lower across doses tested (10-35 mg) than steady-state exposure reported for oral Sporanox 200 mg. In asthmatics, PUR1900 geometric mean maximum sputum concentrations were 70-fold higher and geometric mean plasma concentrations were 66-fold lower than with oral Sporanox. PUR1900 was safe and well-tolerated under the study conditions. Compared to oral dosing, PUR1900 achieved higher lung and lower plasma exposure. The pharmacokinetic profile of PUR1900 suggests the potential to improve upon the efficacy and safety profile observed with oral itraconazole.


Staff perception of aggressive behaviour in community services for adults with intellectual disabilities.
Experiencing aggressive behaviour has been associated with increased stress and turnover among staff who support adults with intellectual disabilities. Incident perception is a strong predictor of psychological outcomes after trauma but has not been studied in this staff group. This study clustered exposure to aggression and endorsement of emotional difficulties among 386 community residential group home staff and evaluated the contribution of four behavioural topographies to staff-rated perceived severity. Staff exposure varied considerably. Perceived severity correlated with subjective emotional difficulties. High perceived severity was associated with daily exposure, aggression towards others causing injury, and property aggression causing injury or damage. Therefore, the role the staff plays, whether a witness or target, may impact their experience.


The positive impact of laparoscopic adrenalectomy on complications of adrenal surgery.
This study was conducted to determine whether laparoscopic adrenalectomy (LA) has had a positive impact on the incidence and nature of adrenalectomy-related complications, as compared with the prelaparoscopic era. All English language reports of patients undergoing either open adrenalectomy (OA) or LA from 1980 to 2000 were identified by Medline search. Reports were analyzed for the frequency and type of complications, with a minimum of 10 cases or studies required for inclusion. Complications were stratified by type and/or organ system involved, and groups were compared statistically using generalized linear model methods. Complications were tabulated from 50 studies of LA involving 1,522 patients and 48 studies of OA comprising 2,273 patients. Among the reports, 22 compared LA and OA within a single institution. The total reported complication rate was 25.2% with LA versus 10.9% with OA (p < or = 0.0001). The incidence of bleeding complications was higher with LA (4.7%) than OA (3.7%) (p < or = 0.0001). As compared with LA, OA had a significantly higher incidence of associated organ injury (2.4% vs 0.7%), mainly to the spleen, and more wound (6.9% vs 1.4%), pulmonary (5.5% vs 0.9%), cardiac (1.6% vs 0.3%), and infectious (5.8% vs 1.6%) complications (p < or = 0.0001). No significant differences in gastrointestinal, thromboembolic, or neurologic complications were seen. The mortality rate was 0.3% after LA and 0.9% after OA. The difference was not significant. Laparoscopic adrenalectomy has resulted in fewer adrenalectomy-related complications than seen historically with OA. Fewer wound and pulmonary complications and a reduced incidence of incidental splenectomy are primarily responsible for this improved outcome.


Gut microbiome profiles and associated metabolic pathways in patients of adult-onset immunodeficiency with anti-interferon-gamma autoantibodies.
Autoantibodies against interferon-gamma (AutoAbs-IFN-γ) can cause the immunodeficiency condition following various opportunistic infections. Gut microbiota can affect the human immune system in many ways. Many studies have shown that gut dysbiosis was associated with some immune diseases, such as autoimmune diseases and human immunodeficiency virus (HIV) infection, while its relationship at anti-IFN-γ AAbs remains unknown. We aimed to identify the anti-IFN-γ AAbs specific microbiome and the possible association with immunodeficiency. We profiled fecal microbiome for two cohorts of forty subjects, including seven patients with anti-IFN-γ AAbs and 33 individuals with competent immune. The study shows that patients with anti-IFN-γ AAbs have characterized the gut microbiome and have lower alpha diversity indexes than healthy controls (HC). There are significant differences in the microbiome structure at both the family and genera level between the two cohorts. The anti-IFN-γ AAbs cohort featured some microbiome such as Clostridium, including the possible opportunistic pathogen and fewer genera including Bacteroides, Ruminococcus, and Faecalibacterium, some of them with possible immune-related genera. The PICRUSt2 pathway demonstrated the decreased abundance of some immune-related pathways and one potential pathway related to the immune alternations in the anti- IFN-γ AAbs cohort. This was the first study to examine the gut microbiome characteristics in patients with anti-IFN-γ AAbs. It could be involved in the pathogenesis of anti-IFN-γ AAbs and contribute to the derived immune condition in this disease. This could lead to new strategies for treating and preventing patients suffering from this disease.


A 10-year follow-up study of 97 epileptics.
1) Of 267 patients with epilepsy who were examined in our clinic during the period between 1964 and 1966, 97 were investigated in a 10-year follow-up study. The patients were selected according to the following criteria: the age of onset of seizures was 10 years or older and the follow-up period was 10 years after the onset of seizures. Of the 97 patients, 36 were followed up by mail. 2) In the adult 10-year follow-up study, seizures disappeared in 43.3%, decreased in 34.0%, remained unchanged in 16.5%, and were aggravated in 6.2% of the 97 patients. Comparing the five-year follow-up study with the present study, the rate of cases which were free of seizures for three years was 22.7% in the five-year study and 43.3% in this study. The seizures were controlled for at least three years in 22.9% of the cases with partial seizure and in 63.3% of the cases with generalized seizure. The worst prognoses were found in cases with versive seizure in which the seizure was unchanged and/or aggravated in 4 (44.4%) of 9 cases. Of 16 cases with psychomotor seizure, 25% were unchanged or aggravated. 3) Comparing the impaired consciousness seizure with the psychomotor seizure, there was a tendency for the psychomotor seizures to remain as a single type of partial seizure, while the impaired consciousness seizure tended to develop easily into a secondarily generalized seizure. 4) Of the 97 patients, three were personality disorders in 19 cases (19.6%), episodic psychotic state in 2 cases (2.1%), and mental retardation in 6 cases (6.2%). Disorders of mood, irritability and explosiveness associated with personality disorders were improved in three of six cases whose seizures disappeared. Personality disorders were found in half of those cases with partial complex seizures. No correlation was found between mental symptoms and the prognosis of seizures. 5) The EEG was improved in 15 (27.8%) of a total of 54 cases, unchanged in 35 (64.8%) and aggravated in 4 (7.4%). In comparing the prognosis of clinical seizure with changes in the EEG, the seizures improved in 40 (74.1%) of the cases, whereas the EEG improved in only 15 (27.8%) of 54 cases. Most of the clinical seizures were controlled or decreased, whether the EEG improved or not.


Severe Covid-19 and acute pulmonary hypertension: 24-month follow-up regarding mortality and relationship to initial echocardiographic findings and biomarkers.
Critically ill Covid-19 patients are likely to develop the sequence of acute pulmonary hypertension (aPH), right ventricular strain, and eventually right ventricular failure due to currently known pathophysiology (endothelial inflammation plus thrombo-embolism) that promotes increased pulmonary vascular resistance and pulmonary artery pressure. Furthermore, an in-hospital trans-thoracic echocardiography (TTE) diagnosis of aPH is associated with a substantially increased risk of early mortality. The aim of this retrospective observational follow-up study was to explore the mortality during the 1-24-month period following the TTE diagnosis of aPH in the intensive care unit (ICU). A previously reported cohort of 67 ICU-treated Covid-19 patients underwent an electronic medical chart-based follow-up 24 months after the ICU TTE. Apart from the influence of aPH versus non-aPH on mortality, several TTE parameters were analyzed by the Kaplan-Meier survival plot technique (K-M). The influence of biomarkers for heart failure (NTproBNP) and myocardial injury (Troponin-T), taken at the time of the ICU TTE investigation, was analyzed using receiver-operator characteristics curve (ROC) analysis. The overall mortality at the 24-month follow-up was 61.5% and 12.8% in group aPH and group non-aPH, respectively. An increased relative mortality risk continued to be present in aPH patients (14.3%) compared to non-aPH patients (5.6%) during the 1-24-month period. The easily determined parameter of a tricuspid valve regurgitation, allowing a measurement of a systolic pulmonary artery pressure (regardless of magnitude), was associated with a similar K-M outcome as the generally accepted diagnostic criteria for aPH (systolic pulmonary artery pressure >35 mmHg). The biomarker values of NTproBNP and Troponin-T at the time of the TTE did not result in any clinically useful ROC analysis data. The mortality risk was increased up to 24 months after the initial examination in ICU-treated Covid-19 patients with a TTE diagnosis of aPH, compared to non-aPH patients. Certain individual TTE parameters were able to discriminate 24-month risk of morality.


Sleep-disordered breathing with chronic opioid use.
Chronic opioid use for pain relief or as substitution therapy for illicit drug abuse is prevalent in our societies. In the US, retail distribution of methadone and oxycodone has increased by 824 and 660%, respectively, between 1997 and 2003. Mu-opioids depress respiration and deaths related to illicit and non illicit chronic opioid use are not uncommon. Since 2001 there has been an emerging literature that suggests that chronic opioid use is related to central sleep apnoea of both periodic and non-periodic breathing types, and occurs in approximately 30% of these subjects. The clinical significance of these sleep-related abnormalities are unknown. This review addresses the present knowledge of control of ventilation mechanisms during wakefulness and sleep, the effects of opioids on ventilatory control mechanisms, the sleep-disordered breathing found with chronic opioid use and a discussion regarding the future research directions in this area.


Detection of drug-resistant HIV-1 strains.
Human immunodeficiency virus (HIV-1) encodes proteins essential to its replication cycle. Reverse transcriptase, protease, and viral envelope gp120 are three proteins that have been targeted for antiviral drug development. Eleven inhibitors of reverse transcriptase, seven inhibitors of protease, and one inhibitor of viral envelope binding have been approved for use. Antiretroviral therapy has reversed the mortality rate of HIV-infected persons, but over time, therapy-resistant virus variants may outgrow. A large body of information is now available to relate specific amino acid sequences in the resistant variants to specific drug regimens. Designing therapy to compensate for virus resistance results in improved patient outcomes. The advent of microsequencing technologies paved the way for direct sequencing of DNA products generated by polymerase chain reactions, thus dramatically lowering the cost of HIV gene sequencing. Designing therapy according to genetic analysis of HIV variants will not only also improve clinical outcome, but will also deter the transmission of drug-resistant strains.