Posterior Endoscopic Cervical Foraminotomy.
Unilateral cervical nerve root compression causing radiculopathy, which does not improve with conservative measures, is safely and effectively treated with surgery. Both anterior and posterior approaches have been described. Overall results from either of these broad categories of approaches are equivalent. Posterior approaches target the cervical root compression directly and allow decompression by widening the neural foramen and/or removing a lateral disc fragment. Following success of the open technique, variations of this technique were introduced to minimize approach-related complications.


[Diabetes and acute coronary syndromes: a practical approach].
Type 2 diabetes is currently recognized as an important risk factor for cardiovascular morbidity and mortality, particularly in patients admitted with acute coronary syndromes (ACS). The aim of this paper is to characterize, in a systematic way, how to approach diabetes and ACS, regarding prognosis, risk stratification and short and long-term prognosis, therefore contributing to improve good clinical practices regarding diabetes and ACS. Diabetes is an important cardiovascular risk factor, being diabetics an important ACS subpopulation. A comprehensive diabetes and ACS management, including early and complete revascularization, systematic OGTT performance in patients lacking a previous diagnosis of diabetes and a particular focus on identifying and decreasing comorbidities and risk factors, as well as in optimizing antidiabetic, antithrombotic and anti-ischemic medication, using cardiac rehabilitation and the multidisciplinary promotion of therapeutic compliance and healthy lifestyles are key factors in a successful strategy to optimize prognosis of ACS in diabetics.


In vitro and in vivo anti-diabetic and hepatoprotective effects of edible pods of Parkia roxburghii and quantification of the active constituent by HPLC-PDA.
Parkia roxburghii G. Don. is a traditional medicinal plant and its pods are extensively used as food and medicine. It is believed by the traditional healers to have medicinal properties to treat diabetes, hypertension and urinary tract infections (Jamaluddin et al., 1994). The methanolic extract of pods of P roxburghii and fractions were screened for their α-glucosidase and α-amylase inhibitory activity. Anti-hyperglycemic effects were studied on streptozotocin (45mg/kg b.w.) induced diabetes in albino rats (seven groups, n=7 n=6), using different doses for 14 days. Plasma glucose concentration (HbA1c) was analysed using whole blood, while SGOT, SGPT, TG, TC and uric acid were analysed using serum, employing commercial kits. Quantitative analysis of the major active constituent was carried out by HPLC-PDA. Bioactivity guided chemical investigation of the edible pods of P roxburghii identified sub-fraction EA-Fr 5 which significantly inhibited α-glucosidase (IC50 0.39±0.06 µgmL(-1)), reduced the blood glucose level to normal, and lowered the elevated levels of liver function enzymes SGOT and SGPT in STZ-induced diabetic rats. EA-Fr 5 was found to contain epigallocatechin gallate (1) and hyperin (2) which exhibited significantly higher α-glucosidase inhibitory potency with IC50 0.51±0.09 and 0.71±0.03µM respectively. EA-Fr 5 contained 379.82±2.90mg/g of EGCG, the major active constituent which manifests a broad spectrum of biological activities. The present investigation for the first time reports the occurrence of EGCG and hyperin in P roxburghii and substantiates the traditional use of pods of P roxburghii as dietary supplement for management of diabetes with significantly promising α-glucosidase inhibitory potency and anti-hyperglycemic as well as hepatoprotective effects.


Iota-Carrageenan-based biodegradable Ag0 nanocomposite hydrogels for the inactivation of bacteria.
In this paper, we report the synthesis and characterization of Iota-Carrageenan based on a novel biodegradable silver nanocomposite hydrogels. The aim of study was to investigate whether these hydrogels have the potential to be used in bacterial inactivation applications. Biodegradable silver nanocomposite hydrogels were prepared by a green process using acrylamide (AM) with I-Carrageenan (IC). The silver nanoparticles were prepared as silver colloid by reducing AgNO3 with leaf extracts of Azadirachta indica (neem leaf) that (Ag(0)) formed the hydrogel network. The formation of biodegradable silver nanoparticles in the hydrogels was characterized using UV-vis spectroscopy, thermo gravimetrical analysis, X-ray diffractometry studies, scanning electron microscopy and transmission electron microscopy studies. In addition, swelling behavior and degradation properties were systematically investigated. Furthermore, the biodegradable silver nanoparticle composite hydrogels developed were tested for antibacterial activities. The antibacterial activity of the biodegradable silver nanocomposite hydrogels was studied by inhibition zone method against Bacillus and Escherichia coli, which suggested that the silver nanocomposite hydrogels developed were effective as potential candidates for antimicrobial applications. Therefore, the inorganic biodegradable hydrogels developed can be used effectively for biomedical application.


Natural history of cervical intraepithelial neoplasia during pregnancy.
It is uncertain whether pregnancy influences the natural history of cervical intraepithelial neoplasia (CIN). Our aim was to evaluate the evolution of CIN in pregnant women. Prospective study. Department of Obstetrics and Gynaecology, University of Insubria, Italy. Women with histological CIN during pregnancy. Between 2003 and 2007, women with an abnormal Pap-smear during pregnancy underwent colposcopy. Patients with histological CIN were followed during pregnancy with colposcopy every 8 weeks and post-partum evaluation was scheduled 3-6 months after delivery. Women with post-partum histological diagnosis of CIN 2-3 underwent conization. To understand the impact of pregnancy on the evolution of CIN, women with CIN 1 discovered during pregnancy were compared to a group of non-pregnant fertile patients with first diagnosis of CIN 1. A total of 78 women were included: 36 (46.2%) with CIN 2-3 and 42 (53.8%) with CIN 1. In women with CIN 2-3, no invasion was suspected during pregnancy and at post-partum evaluation, no invasive or microinvasive cancer, and 19 (52.7%) persistent CIN 2-3, and 17 (47.3%) regressions were diagnosed. In the group of CIN 1, we recorded six (14.3%) progressions to CIN 2-3, seven (16.6%) persistent CIN 1 and 29 (69%) regressions. The control group of non-pregnant women had a lower regression rate (37/76: 48.7%) in comparison to pregnant women (p=0.03). Expectant management for CIN 2-3 diagnosed during gestation is safe. When discovered during pregnancy, CIN 1 has a significantly higher tendency to spontaneous regression in comparison to non-pregnant condition.


Gene signatures of tumor inflammation and epithelial-to-mesenchymal transition (EMT) predict responses to immune checkpoint blockade in lung cancer with high accuracy.
Treatment of non-small cell lung cancer (NSCLC) with immune checkpoint blockade (ICB) has resulted in striking clinical responses, but only in a subset of patients. The goal of this study was to evaluate transcriptional signatures previously reported in the literature in an independent cohort of NSCLC patients receiving ICB. This retrospective study analyzed transcriptional profiles from pre-treatment tumor samples of 52 chemotherapy-refractory advanced NSCLC patients treated with anti-PD1/PD-L1 therapy. Gene signatures based on published reports were created and examined for their association with response to therapy and progression-free and overall survival (PFS, OS). Two signatures predicting response and outcomes were identified. One reflected the degree of immune infiltration and upregulation of interferon-gamma-induced genes. A second reflected the EMT status. Compared to those not responding to therapy, patients whose tumors responded to ICB had higher scores in an inflammatory gene signature (6.0 ± 2.9 vs -5.5 ± 3.4, p = 0.014) or a more epithelial phenotype (-1.7 ± 1.0 vs 2.1 ± 1.2, p = 0.016). Both signatures demonstrated a satisfactory predictive accuracy for response: AUC of 0.69 (95% CI: 0.54, 0.84) for the inflammatory and 0.70 (95% CI: 0.55, 0.85) for EMT signatures, respectively. A weighted score combining EMT and inflammatory signatures showed increased predictive value with AUC of 0.92 (95% CI: 0.85, 0.99). Kaplan-Meier curves for patients above and below the median combined score showed a significant separation for PFS and OS (all p < 0.01, log rank test). The EMT/Inflammation signature score may be useful in directing checkpoint inhibitor therapy in lung cancer and suggests that reversal of EMT might augment efficacy of ICB.


[Histiocytoses: General classification and molecular criteria].
Histiocytoses are rare and heterogeneous disease sharing histology, characterized by accumulation of histiocytes. They may be inherited or sporadic, and related to the accumulation of endo- or exogenous material in macrophages or to macrophage activation. Recent discoveries have shown that some histiocytoses, such as Langerhans cell histiocytosis or Erdheim-Chester disease, previously considered as idiopathic or inflammatory were clonal myeloid proliferations. This review presents the general classification of histiocytoses, and describes diagnostic and molecular criteria of idiopathic histiocytoses and histiocytic neoplasms.


The clinical impact of Stenotrophomonas maltophilia bacteremia on the 30-day mortality rate in patients with hematologic disorders: a single-institution experience.
Stenotrophomonas maltophilia (SM) is an important nosocomial pathogen, particularly in immunocompromised patients due to their adverse antimicrobial susceptibility pattern. The objective of this article was to investigate the clinical impact of SM bacteremia on the 30-day mortality rate and identify the risk factors of the cause of mortality in patients with hematologic disorders. We retrospectively reviewed the clinical data in patients diagnosed with hematological disorders and SM bacteremia over an 8-year period from July 2010 to July 2018 at a 248-bed hematology department. We compared patients' clinical characteristics and outcomes between the non-survivor and survivor groups. The overall incidence of SM bacteremia was 25.1 per 10,000 admissions. There were 59 patients (median age: 35 years; 57.6% males) included in the study with an overall SM bacteremia-related 30-day mortality of 44.1%. Multi-drug resistance was common. In vitro susceptibility is higher to ceftazidime (72.9%), ciprofloxacin (66.1%) and cefoperazone/sulbactam (59.3%). The risk factors identified in the univariate analysis were catheter re-implantation, accompanying polymicrobial infection, inadequate initial antimicrobial treatment, APACHE II score, temperature > 39 °C, septic shock, respiratory failure, and non-remission post treatment for primary diseases. Multivariate analysis further confirmed that inadequate initial antimicrobial treatment, respiratory failure, and non-remission after treatment for hematological diseases are independent risk factors associated with mortality (P = 0.001, 0.002 and 0.007, respectively). Our study suggests that SM bacteremia is highly associated with increased mortality in patients with hematologic diseases. Early detection, prompt comprehensive management including initiation of combined sensitive antibiotics, respiratory monitoring and support, platelet infusion, and strategies to improve patients' remission status are recommended to improve the overall survival in patients with SM bacteremia.


α-Fe2O3 mediated periodate activation for selective degradation of phenolic compounds via electron transfer pathway under visible irradiation.
Periodate (PI)-photoactivated advanced oxidation process (AOP) has recently received increasing attention for the removal of micropollutants from water. However, periodate is mainly driven by high-energy ultraviolet light (UV) in most cases, and few studies have extended it to the visible range. Herein, we proposed a new PI visible light activation system employing α-Fe2O3 as catalyst. It is completely different from traditional PI-AOP based on hydroxyl radicals (•OH) and iodine radical (•IO3). The vis-α-Fe2O3/PI system can selectively degrade the phenolic compounds via non-radical pathway under the visible range. Notably, the designed system not only shows a well pH tolerance and environmental stability, but also exhibits a strong substrate-dependent reactivity. Both quenching experiments and electron paramagnetic resonance (EPR) experiments demonstrate that photogenerated holes are the main active species in this system. Moreover, a series of photoelectrochemical experiments reveal that PI can effectively inhibit the carrier recombination on the α-Fe2O3 surface, thereby improving the utilization of photogenerated charges and increasing the number of photogenerated holes, which effectively reacts with 4-CP through electron transfer way. In a word, this work proposes a cost-effective, green and mild mean to activate PI, and provides a facile way to solve the fatal shortcomings (i.e., inappropriate band edge position, rapid charge recombination and short hole diffusion length) of traditional iron oxide semiconductor photocatalysts.


Dietary Ethanolamine Plasmalogen Alleviates DSS-Induced Colitis by Enhancing Colon Mucosa Integrity, Antioxidative Stress, and Anti-inflammatory Responses via Increased Ethanolamine Plasmalogen Molecular Species: Protective Role of Vinyl Ether Linkages.
Dietary ethanolamine plasmalogen (PlsEtn) has been reported to have several health benefits; however, its functional role during colon pathophysiology remains elusive. The present study investigated the anticolitis effect of dietary ethanolamine glycerophospholipids (EtnGpls) with high PlsEtn from ascidian muscle (86.2 mol %) and low PlsEtn from porcine liver (7.7 mol %) in dextran sulfate sodium (DSS)-induced colitis in mice. Dietary EtnGpls lowered myeloperoxidase activity, thiobarbituric acid-reactive substances, proinflammatory cytokines and proapoptosis-related protein levels in colon mucosa after 16 days of DSS treatment, with ascidian muscle (0.1% EtnGpl in diet) showing higher suppression than porcine liver (0.1% EtnGpl in diet). Moreover, dietary EtnGpls suppressed DSS symptoms after 38 days of DSS treatment as evidenced by increased body weight, colon length, and ameliorated colon mucosa integrity. Additionally, dietary EtnGpls elevated short-chain fatty acid production in DSS-treated mice. Altogether, these results indicate the potential of utilizing diets with abundant PlsEtn for the prevention of colon inflammation-related disorders.


The effect of distraction on the Word Memory Test and Test of Memory Malingering performance in patients with a severe brain injury.
This research compares the performance of a sample of non-litigating participants with severe brain injury on both the WMT and TOMM under conditions of (1) full effort, (2) distraction, or (3) simulated malingering. The study included 60 participants with a severe brain injury and used restricted randomization to assign participants to the groups. Following Craik (1982) an auditory distraction task was used during the learning phase of each test in the distraction group, while a scenario adapted from Tombaugh (1997) was used to encourage simulation of memory impairment in the simulated malingering group. The results of this study clearly showed that while both tests demonstrated excellent sensitivity, the false positive rates for the WMT were significantly greater than those for the TOMM. It was concluded that the so-called "effort" components of the WMT required more cognitive capacity than was previously believed.


Ultra-processed food consumption patterns among older adults in the Netherlands and the role of the food environment.
To describe the patterns of ultra-processed foods (UPFs) consumption in the Netherlands; to test if exposure to the food environment is associated with UPFs consumption; and if this association differed across educational levels and neighbourhood urbanisation. Cross-sectional study using 2015-data of 8104 older adults from the Dutch EPIC cohort. Proportion of UPFs consumption was calculated from a validated food-frequency questionnaire. Exposure to the food environment was defined as proximity and availability of supermarkets, fast-food restaurants, full-service restaurants, convenience stores, candy stores and cafés. Consumption of UPFs was expressed as both percentage of total grams and total kilocalories. The study population was aged 70(± 10 SD) years and 80.5% was female. Average UPFs consumption was 17.8% of total food intake in grams and 37% of total energy intake. Those who consumed greater amounts of UPFs had a poorer overall diet quality. Adjusted linear regression models showed that closer proximity and larger availability to any type of food retailer was associated with lower UPFs consumption (both in grams and kilocalories). Somewhat stronger significant associations were found for proximity to restaurants (β = - 1.6%, 95% confidence interval (CI) = - 2.6; - 0.6), and supermarkets (β = - 2.2%, 95%CI = - 3.3; - 1.1); i.e., Individuals living within 500 m from the closest supermarket, as compared to 1500 m, had 2.6% less calories from UPFs. No differences were found on analyses stratified for urbanisation and education. Using various measures of exposure to the food environment, we found that exposure to restaurants and supermarkets was associated with somewhat lower consumption of UPFs.


Synthesis of bacterial magnetic particles during cell cycle of Magnetospirillum magneticum AMB-1.
We investigated the relationship between the synthesis of bacterial magnetic particles (BMPs) and the transcription of magA gene-encoding iron transport protein using synchronous culture of Magnetospirillum magneticum AMB-1. Synchronously cultured cells were subjected to transmission electron microscopic observation and fluorescence in situ hybridization. The average number of BMPs slowly increased in the cell with increasing cell size. A sharp increase in BMPs occurred just before cell division and resulted in maximum BMP production of 30 particles/cell. The transcription of magA was regulated immediately before and after cell division.


Zika virus induced cellular remodelling.
Zika virus (ZIKV) has been associated with morbidities such as Guillain-Barré, infant microcephaly, and ocular disease. The spread of this positive-sense, single-stranded RNA virus and its growing public health threat underscore gaps in our understanding of basic ZIKV virology. To advance knowledge of the virus replication cycle within mammalian cells, we use serial section 3-dimensional electron tomography to demonstrate the widespread remodelling of intracellular membranes upon infection with ZIKV. We report extensive structural rearrangements of the endoplasmic reticulum and reveal stages of the ZIKV viral replication cycle. Structures associated with RNA genome replication and virus assembly are observed integrated within the endoplasmic reticulum, and we show viruses in transit through the Golgi apparatus for viral maturation, and subsequent cellular egress. This study characterises in detail the 3-dimensional ultrastructural organisation of the ZIKV replication cycle stages. Our results show close adherence of the ZIKV replication cycle to the existing flavivirus replication paradigm.


Patient-Reported Outcomes After Tetralogy of Fallot Repair.
Comprehensive assessment of tetralogy of Fallot (TOF) outcomes extends beyond morbidity and mortality to incorporate patient-reported outcomes (PROs), including quality of life (QOL) and health status (HS). This study explored PROs in adolescents and adults with TOF and delineated variables associated with PROs. This was a cross-sectional observational study within a larger prospective registry of adolescents and adults with repaired TOF and moderate or greater pulmonary regurgitation from North America, Europe, and Asia. Participants completed PROs, including a QOL linear analogue scale (QOL-LAS) and an HS visual analogue scale (HS-VAS). Scores were classified according to age cohorts: <18, 18 to 25, 26 to 40, and >40 years. The study included 607 patients (46.3% female; median age 28.5 years). Median QOL-LAS scores (0-100) were similar across age cohorts (85, 80, 80, 80; P = 0.056). Median HS-VAS scores (0-100) were lowest for the oldest cohort (77) compared with the 3 younger cohorts (85, 80, 80) (P = 0.004). With advancing age, there were increased reports of poor mobility (P < 0.001) and pain or discomfort (P = 0.004); problems in these dimensions were reported by 19.1% and 37.2% of patients aged >40 years, respectively. Of factors associated with superior PROs on multivariable regression modeling (ie, being White, being nonsyndromic, having employment, and having better left ventricular function; P < 0.05), asymptomatic status (functional class I) was the variable associated with the greatest number of QOL and HS measures (P < 0.001). Strategies to improve TOF outcomes should consider PROs alongside conventional clinical variables. Factors associated with poorer PROs represent opportunities to intervene to improve the lives of patients with TOF.


Vitexin protects against cardiac hypertrophy via inhibiting calcineurin and CaMKII signaling pathways.
Vitexin is a flavone glycoside isolated from the leaf of Crataeguspinnatifida Bunge, the utility of which has been demonstrated in several cardiovascular diseases. However, its role in cardiac hypertrophy remains unclear. In the present study, we aimed to determine whether vitexin prevents cardiac hypertrophy induced by isoproterenol (ISO) in cultured neonatal rat ventricular myocytes in vitro and pressure overload-induced cardiac hypertrophy in mice in vivo. The results revealed that vitexin (10, 30, and 100 μM) dose-dependently attenuated cardiac hypertrophy induced by ISO in vitro. Furthermore, vitexin (3, 10, and 30 mg kg(-1)) prevented cardiac hypertrophy induced by transverse aortic constriction as assessed by heart weight/body weight, left ventricular weight/body weight and lung weight/body weight ratios, cardiomyocyte cross-sectional area, echocardiographic parameters, and gene expression of hypertrophic markers. Further investigation demonstrated that vitexin inhibited the increment of the resting intracellular free calcium induced by ISO. Vitexin also inhibited the expression of calcium downstream effectors calcineurin-NFATc3 and phosphorylated calmodulin kinase II (CaMKII) both in vitro and in vivo. Taken together, our results indicate that vitexin has the potential to protect against cardiac hypertrophy through Ca2+-mediated calcineurin-NFATc3 and CaMKII signaling pathways.


Regulation of secretion and enzymatic activity of lipoprotein lipase by C-mannosylation.
Lipoprotein lipase (LPL) is a crucial enzyme in lipid metabolism and transport, and its enzymatic deficiency causes metabolic disorders, such as hypertriglyceridemia. LPL has one predicted C-mannosylation site at Trp417. In this study, we demonstrated that LPL is C-mannosylated at Trp417 by mass spectrometry. Furthermore, by using wild-type and a C-mannosylation-defective mutant of LPL-overexpressing cell lines, we revealed that both secretion efficiency and enzymatic activity of C-mannosylation-defective mutant LPL were lower than those of wild-type. These data suggest the importance of C-mannosylation for LPL functions.


The electrocardiogram signal of Seba's short-tailed bat, Carollia perspicillata.
A number of studies have successfully used electrocardiogram (ECG) signals to characterize complex physiological phenomena such as associative learning in bats. However, at present, no thorough characterization of the structure of ECG signals is available for these animals. The aim of the present study was to quantitatively characterize features of the ECG signals in the bat species Carollia perspicillata, a species that is commonly used in neuroethology studies. Our results show that the ECG signals of C. perspicillata follow the typical mammalian pattern, in that they are composed by a P wave, QRS complex and a T wave. Peak-to-peak amplitudes in the bats' ECG signals were larger in measuring configurations in which one of the electrodes was attached to the right thumb. In addition, large differences in the instantaneous heart rate (HR) distributions were observed between ketamine/xylazine anesthetized and awake bats. Ketamine/xylazine might target the neural circuits that control HR, therefore, instantaneous HR measurements should only be used as physiological marker in awake animals.


A crisis in my community? Local-level awareness of the opioid epidemic and political consequences.
The opioid epidemic has had a profound effect on American public health, and studies suggest it has had a profound effect on American politics as well. Research suggests a relationship between the severity of the opioid crisis in a community and aggregate-level political behavior, including voting for Donald Trump in 2016, but there is very little individual-level data establishing the mechanism for this relationship. Using a question on a nationally representative survey fielded after the 2018 election, we explore Americans' perceptions of the severity of the opioid epidemic in their community, and whether these perceptions predict political behavior and attitudes. We find that relative estimates of local opioid overdoses are significantly influenced by the actual county-level overdose death rate, and that the relationship between reality and perception is strongest for the most knowledgeable and informed citizens. There is also evidence that the social construction of the opioid epidemic as a crisis primarily affecting White suburban or rural Americans affects these perceptions, as both White and non-urban respondents are significantly more attentive to objective mortality rates than others. Turning to political behavior, we find no evidence that these estimates affected validated voter turnout or U.S. House vote choice in the 2018 midterm election. Assessing public approval outcomes, we found a nonlinear effect of these estimates on support for President Trump, a pattern which is partially consistent with the existing literature. We also observed that those who believed the opioid epidemic to be worse than average in their communities reported lower approval of their state legislatures, though we found no such relationship for ratings of governors. These findings raise important questions about the micro-level mechanisms that link aggregate-level public health with political outcomes.


Microarray-based assay for the detection of genetic variations of structural genes of West Nile virus.
Adaptation through fixation of spontaneous mutations in the viral genome is considered to be one of the important factors that enable recurrent West Nile virus (WNV) outbreaks in the U.S. Genetic variations can alter viral phenotype and virulence, and degrade the performance of diagnostic and screening assays, vaccines, and potential therapeutic agents. A microarray assay was developed and optimized for the simultaneous detection of any nucleotide mutations in the entire structural region of WNV in order to facilitate public health surveillance of genetic variation of WNV. The DNA microarray consists of 263 oligonucleotide probes overlapping at half of their lengths which have been immobilized on an amine-binding glass slide. The assay was validated using 23 WNV isolates from the 2002-2005 U.S. epidemics. Oligonucleotide-based WNV arrays detected unambiguously all mutations in the structural region of each one of the isolates identified previously by sequencing analysis, serving as a rapid and effective approach for the identification of mutations in the WNV genome.


Meta-analysis: capsule enteroscopy vs. conventional modalities in diagnosis of small bowel diseases.
Prospective trials support the role of capsule enteroscopy as an improvement in diagnosing mucosal lesions in the small bowel. To determine the diagnostic yield and safety of capsule enteroscopy vs. alternative diagnostic modalities (such as push enteroscopy, small bowel follow-through or enteroclysis) in patients with small bowel diseases. A search for prospective studies comparing capsule enteroscopy vs. other diagnostic tests in adults was performed between 1966 and 2005. Selected articles were included in a meta-analysis. Three analyses were run separately, all included studies and studies having occult gastrointestinal bleeding or Crohn's disease as main outcome. Seventeen studies (526 patients) met inclusion criteria. The rate difference (i.e. the absolute pooled difference in the rate of positive findings) between capsule enteroscopy and alternative modalities for small bowel disease was 41% (95% CI 35.6-45.9); 37% (95% CI 29.6-44.1) for occult gastrointestinal bleeding; and 45% (95% CI 30.9-58.0) for Crohn's disease. Failure to visualize the caecum occurred in 13%, significantly more often in occult bleeders (17%) than in patients with Crohn's disease (8%) (P < 0.006). Adverse events were recorded in 29 patients (6%). Capsule retention was more frequent in patients with Crohn's disease (3% vs. 1%, OR 4.37). Capsule enteroscopy proved significantly superior to push enteroscopy and small bowel radiology in the diagnosis of ileal diseases. Capsule enteroscopy is safe, though prior radiology is still necessary to rule out small bowel strictures in patients with known or suspected Crohn's disease.


Sodium channel inactivation kinetics of rat sensory and motor nerve fibres and their modulation by glutathione.
Na+ channel currents of rat motor and sensory nerve fibres were studied with the patch-clamp technique on enzymatically demyelinated axons. Differences between motor and sensory fibres in multi-channel inactivation kinetics and the gating of late single-channel currents were investigated. In the axon-attached mode, inactivation of multi-channel Na+ currents in sensory axons was best fitted with a single time constant while for motor axons two time constants were needed. Late single-channel currents in sensory axons were characterized by short openings whereas motor axons exhibited additional long single-channel openings. In contrast, in excised, inside-out membrane patches, no differences between motor and sensory fibres were found; in both types of fibre inactivation of multi-channel Na+ currents proceeded with two time constants and late single-channel currents showed short and long openings. After application of the reducing agent glutathione to the cytoplasmic side of excised inside-out patches, inactivation of Na+ currents in both motor and sensory fibres proceeded with a single, fast exponential time constant and late currents appeared with short openings only. These data indicate that the axonal metabolism may contribute to the different inactivation kinetics of Na+ current in motor and sensory nerve fibres.


Guerin sign in midfacial fractures.
We report a patient with multiple fractures of the midface and Guerin sign bilaterally after maxillofacial trauma. To the best of our knowledge, this is the first time that this rare presentation of Guerin sign has been published.


On-treatment HBV DNA level could predict HBeAg seroclearance in patients with HBeAg-positive chronic hepatitis B with entecavir therapy.
Hepatitis B e antigen (HBeAg) status is associated with clinical outcomes, and seroconversion of HBeAg is one of the treatment goals. In this study, we determined the association of on-treatment serum hepatitis B virus (HBV) DNA levels in HBeAg-positive chronic hepatitis B patients who were receiving entecavir (ETV) treatment. A retrospective cohort study was conducted involving 135 (78 male and 57 female; mean age, 42.3 ± 13 years) patients with HBeAg-positive chronic hepatitis B (CHB). Between August 2008 and March 2014, each patient was treated with ETV for at least 96 weeks, and their HBV DNA levels were evaluated every 3-6 months. HBeAg seroclearance at the 96th week was defined as an absence of serum HBeAg within 96 weeks after ETV treatment. Univariate and multivariate logistic regression analysis was used to identify the predictors of 96th week HBeAg seroclearance, and a multivariable model was constructed. Among the 135 ETV-treated HBeAg-positive CHB patients, 37 patients achieved HBeAg seroclearance (Group 1), whereas 98 patients had persistent HBeAg-positive status (Group 2) at the 96th week check-up. The baseline laboratory data was not significantly different between both the two groups. At the 24th and 48th weeks, there were significant differences between Group 1 and Group 2 in the percentage of patients with HBV DNA levels < 20 IU/mL [17/77 (22.1%) and 11/23 (47.8%), p = 0.032; 45/89 (50.6%) and 26/35 (74.3%), p = 0.028, respectively). Our study demonstrated that HBV DNA levels < 20 IU/mL at the 24th and 48th weeks could predict serum HBeAg loss in ETV-treated HBeAg-positive patients with CHB.


Efficacy of early goal-directed therapy using FloTrac/EV1000 to improve postoperative outcomes in patients undergoing off-pump coronary artery bypass surgery: a randomized controlled trial.
Early goal-directed therapy (EGDT) using FloTrac reduced length of stay (LOS) in intensive care (ICU) and hospital among patients undergoing coronary artery bypass graft (CABG) with a cardiopulmonary bypass. However, this platform in off-pump CABG (OPCAB) has received scant attention, so we evaluated the efficacy of EGDT using FloTrac/EV1000 as a modality for improving postoperative outcomes in patients undergoing OPCAB. Forty patients undergoing OPCAB were randomized to the EV1000 or Control group. The Control group received fluid, inotropic, or vasoactive drugs (at the discretion of the attending anesthesiologist) to maintain a mean arterial pressure 65-90 mmHg; central venous pressure 8-12 mmHg; urine output ≥ 0.5 mL kg-1 h-1; SpO2 > 95%; and hematocrit ≥ 30%. The EV1000 group achieved identical targets using information from the FloTrac/EV1000. The goals included stroke volume variation < 13%; cardiac index (CI) of 2.2-4.0 L min-1 m-2; and systemic vascular resistance index of 1500-2500 dynes s-1 cm-5 m-2. The EV1000 group had a shorter LOS in ICU (mean difference - 1.3 d, 95% CI - 1.8 to - 0.8; P < 0.001). The ventilator time for both groups was comparable (P = 0.316), but the hospital stay for the EV1000 group was shorter (mean difference - 1.4 d, 95% CI - 2.1 to - 0.6; P < 0.001). EGDT using FloTrac/EV1000 compared to conventional protocol reduces LOS in ICU and hospital among patients undergoing OPCAB. Trial registration This study was retrospectively registered at www. gov (NCT04292951) on 3 March 2020.


Application Areas of Intermittent Pneumatic Compression in the Prevention of Deep Vein Thrombosis During Dixon Surgery: A Randomized, Controlled Trial.
Deep vein thrombosis (DVT) is common in the lithotomy position after laparoscopic surgery. Intermittent pneumatic compression (IPC) plays an important role in DVT prevention. However, few studies have compared the different compression areas of IPC application. It was hypothesized that the location of the compression sleeves could have an impact on the effects of thromboprophylaxis. In this randomized, controlled trial performed from August 2020 to March 2021, 164 patients scheduled to undergo laparoscopic Dixon surgery were randomly assigned to one of four groups, based on the bilateral placement of compression sleeves during surgery: feet, calves, thighs, or control (no IPC). Both lower extremities were monitored for DVT on days 1 and 7 after surgery, using ultrasonographic assessment of mean blood velocity, blood flow volume, and diameter of the common femoral veins. Thrombosis-related hematologic analysis was performed. On day 1 after surgery, IPC of the feet or calves was associated with a reduced prevalence of DVT compared with controls (both: P = 0.024; OR = 0.09; 95% CI, 0.01-0.72), while IPC of the thighs had no significant benefit (P = 0.781; OR = 0.86; 95% CI, 0.29-2.55). The prevalence of DVT in the left extremity was lower with IPC of the feet and calves compared with controls (both, P = 0.048). The mean blood velocity in the common femoral vein was significantly increased after surgery with IPC of the left and right feet (P = 0.006 and 0.007, respectively) and calves (P = 0.011 and P = 0.026, respectively) compared with controls. Similarly, the volume of blood flow in the left common femoral vein was greater with IPC of the feet and calves (P = 0.03 and 0.027, respectively). However, on day 7 after surgery, the between-group differences in the prevalences of DVT and hematologic indicators of thrombosis were not significant. On day 1 after surgery, IPC application at the feet or calves facilitated venous return and, hence, reduced the prevalence of DVT, especially in the left extremities. However, there were no significant differences in the prevalences of DVT or thrombosis-related hematologic indicators among the four groups on the day 7 after surgery. Chinese Clinical Trial Registration identifier: ChiCTR2000035325.


A simple subcritical chromatographic test for an extended ODS high performance liquid chromatography column classification.
This paper describes a new test designed in subcritical fluid chromatography (SFC) to compare the commercial C18 stationary phase properties. This test provides, from a single analysis of carotenoid pigments, the absolute hydrophobicity, the silanol activity and the steric separation factor of the ODS stationary phases. Both the choice of the analytical conditions and the validation of the information obtained from the chromatographic measurements are detailed. Correlations of the carotenoid test results with results obtained from other tests (Tanaka, Engelhard, Sander and Wise) performed both in SFC and HPLC are discussed. Two separation factors, calculated from the retention of carotenoid pigments used as probe, allowed to draw a first classification diagram. Columns, which present identical chromatographic behaviors are located in the same area on this diagram. This location can be related to the stationary phase properties: endcapping treatments, bonding density, linkage functionality, specific area or silica pore diameter. From the first classification, eight groups of columns are distinguished. One group of polymer coated silica, three groups of polymeric octadecyl phases, depending on the pore size and the endcapping treatment, and four groups of monomeric stationary phases. An additional classification of the four monomeric groups allows the comparison of these stationary phases inside each group by using the total hydrophobicity. One hundred and twenty-nine columns were analysed by this simple and rapid test, which allows a comparison of columns with the aim of helping along their choice in HPLC.


An Unusual Occurrence of Uterine Metastases in a Case of Invasive Ductal Breast Carcinoma.
Breast cancer is the most frequent cancer in women and has a high proclivity for metastasizing, yet it seldom affects gynaecological organs. We present a case of invasive ductal carcinoma of the breast that metastasized to the uterus following initial curative treatment. Our patient was taking tamoxifen, which can induce endometrial hyperplasia and make diagnosis more complicated.


Isolation of TPO-dependent subclones from the multipotent 32D cell line.
Using thrombopoietin (TPO), as selective pressure, several TPO-dependent clones were isolated from the murine multipotential IL-3-dependent cell line 32D. Four of them were fully characterized. They depended on TPO for survival and proliferation and, although retaining the capacity to grow in IL-3, did not respond to either EPO, G-CSF or GM-CSF. 32D TPO cells were heterogeneous in morphology and ranged from small cells, with a DNA content nearly tetraploid and a modal chromosome no. 66, to cells 50-75 microm in diameter containing multiple (up to 5-6) interconnected nuclei with a clear megakaryocyte (Mk) morphology by electron microscopy. Cell sorter isolation and single cell cloning experiments indicated that the small cells were those capable to proliferate in TPO and to generate the larger ones over time. 32D TPO cells expressed Mk-specific markers by FACS (CD41, CD61 and 2D5) and RT-PCR (acetyl cholinesterase E and platelet factor 4) and their unique profile, by gene array analysis, included expression of urokinase plasminogen activator surface receptor (CD87 or uPAR), plasminogen activator inhibitor and coagulation factor II (thrombin) receptor (Cf2r). In addition, by quantitative RT-PCR, 32D TPO clones expressed levels of Gata1 similar to those expressed by freshly isolated Mks (DeltaCt approximately 4.7 in both cases). In conclusion, the 32D TPO subclones described here are among the few pure Mk cell lines isolated so far and, for their unique properties, may prove themselves as a useful model to study Mk differentiation.


Immunofluorescence studies on proteins B23 and C23 in nucleoli of human lymphocytes.
Nucleoli of normal and leukemic lymphocytes were studied by cytochemical and immunofluorescence methods to provide more information on the nucleolar presence and distribution of proteins B23 and C23. Annular nucleoli of human lymphocytes represent a very convenient subject for such studies, since they consist of one centrally located large fibrillar center surrounded by RNP components. In such nucleoli, protein C23 was present mainly in the central nucleolar region and protein B23 was found mostly in the periphery. The nucleolar area immunostained for protein B23 was usually larger than that stained for protein C23. The distribution of protein C23 appeared to be similar to that of intensely stained nucleolar argyrophilic components. No substantial differences were found between the distribution of proteins B23 and C23 in nucleoli of normal and leukemic lymphocytes. In lymphocytes of patients treated with chemotherapy, the immunofluorescence was diminished for protein B23 and particularly so for protein C23.


The impact of COVID-19 pandemic on the cardiology services in Northern Jordan.
The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, has rapidly spread worldwide starting from China in late 2019. The first case in Jordan was reported on March 2, 2020. The Jordanian government made many transformations to address this crisis. As we are the only referral cardiology center for percutaneous coronary intervention (PCI) in the north of Jordan, we made multiple adjustments to confront COVID-19 challenges. We emphasize that there is an urgent need to update all procedures and therapeutic activities that are performed in the Cath-Lab to minimize the risks for both the patients and the health care providers during the pandemic of COVID-19.


Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells.
We investigated the molecular mechanisms responsible for fisetin-induced apoptosis in U266 cells. Fisetin elicited the cytotoxicity in U266 cells, manifested as an increased fraction of the cells with sub-G1 content or stained positively with TUNEL labeling. Fisetin enhanced caspase-3 activation, downregulation of Bcl-2 and Mcl-1(L), and upregulation of Bax, Bim and Bad. Fisetin activated AMPK as well as its substrate acetyl-CoA carboxylase (ACC), along with a decreased phosphorylation of AKT and mTOR. Fisetin also stimulated generation of ROS in U266 cells. Conversely, compound C or N-acetyl-L-cystein blocked fisetin-induced apoptosis. Our data suggest that fisetin-induced apoptosis in U266 cells is through ROS and AMPK pathways.


Comparison of the Levels of Transforming Growth Factor-β1 in Tear Fluid in Patients with High Myopia after Transepithelial Photorefractive Keratectomy and Laser Subepithelial Keratomileusis (LASEK).
We compared the level of transforming growth factor-β1 (TGF-β1) in the tear fluid of 20 patients with high myopia who underwent transepithelial photorefractive keratectomy (T-PRK) in one eye and laser subepithelial keratomileusis (LASEK) in the contralateral eye. Tear fluid samples were collected with scaled microcapillary tubes before (day 0) and on days 1, 3, and 5 after surgery. The release of TGF-β1 was determined by multiplying the concentration of TGF-β1 by capillary tear fluid flow. Corneal haze was also evaluated in 1, 3, and 6 months after surgeries. The median TGF-β1 release after T-PRK and LASEK differed significantly on days 1 and 3 (p<0.005) and on day 5 (p<0.05). The mean corneal haze score after T-PRK and LASEK also significantly differed in 1 month (p<0.005), but no significant differences in this parameter were revealed at later terms. Thus, the level of TGF-β1 in the tear fluid after T-PRK was lower than after LASEK, which can be the cause of less pronounced corneal haze in 1 month after surgery.


Detection of human telomerase reverse transcriptase mRNA in urine of patients with bladder cancer: evaluation of an emerging tumor marker.
To assess the value of the telomerase enzyme as a bladder cancer detection marker, we investigated the expression of the catalytic subunit of the complex (human telomerase reverse transcriptase [hTERT]) in the urine of patients with malignant or benign urinary lesions, as well as of healthy individuals, and compared the results with urine cytology. Spontaneously voided samples were obtained from two groups of subjects: group 1, 146 previously untreated patients with a histologic diagnosis of transitional cell carcinoma or other urothelial neoplasm; and group 2, 128 control individuals, either healthy or with a nonmalignant bladder disease. Total RNA extracts from sedimented urothelial cells were analyzed by a reverse transcriptase-polymerase chain reaction assay for the presence of a 146-bp hTERT transcript. Urine samples were also examined by standard cytology. Expression of hTERT was detected in 134 (92%) of 146 patients with bladder cancer, and only 64 (44%) yielded a positive result by cytology (P <0.001). The sensitivity advantage of the former technique became particularly evident in the detection of low-grade transitional cell carcinoma (93% versus 28%, P <0.001). Accordingly, the negative predictive value of the molecular assay was markedly greater than the one calculated for cytologic screening (91% versus 60%). On the other hand, both methods were at least 96% specific, with their positive predictive indexes exceeding 94%. Our findings suggest that the assessment of hTERT expression in urine sediments represents a reliable tool for the detection of primary urothelial neoplasms, equally specific, yet far more sensitive, than conventional cytology.


Glutamine supplementation.
Intravenous glutamine supplementation is standard care when parenteral nutrition is given for critical illness. There are data of a reduced mortality when glutamine supplementation is given. In addition, standard commercial products for parenteral nutrition do not contain any glutamine due to glutamine instability in aqueous solutions. For the majority of critical ill patients who are fed enterally, the available evidence is insufficient to recommend glutamine supplementation. Standard formulation of enteral nutrition contains some glutamine: 2-4 g/L. However, this dose is insufficient to normalize glutamine plasma concentration.Plasma concentration of glutamine is low in many patients with critical illness and a low level is an independent risk factor for mortality. A low plasma glutamine concentration is the best indicator of glutamine depletion. Data are emerging about how the endogenous production of glutamine is regulated. We know that skeletal muscle is the major producer of glutamine and that a part of the profound depletion of skeletal muscle seen in critical illness is a reflection of the need to produce glutamine.Glutamine is utilized in rapidly dividing cells in the splanchnic area. Quantitatively most glutamine is oxidized, but the availability of glutamine in surplus is important for the de novo synthesis of nucleotides and necessary for cell division and protein synthesis. More knowledge about the regulation of the endogenous production of glutamine is needed to outline better guidelines for glutamine supplementation in the future.


ζ-Glycine: insight into the mechanism of a polymorphic phase transition.
Glycine is the simplest and most polymorphic amino acid, with five phases having been structurally characterized at atmospheric or high pressure. A sixth form, the elusive ζ phase, was discovered over a decade ago as a short-lived intermediate which formed as the high-pressure ∊ phase transformed to the γ form on decompression. However, its structure has remained unsolved. We now report the structure of the ζ phase, which was trapped at 100 K enabling neutron powder diffraction data to be obtained. The structure was solved using the results of a crystal structure prediction procedure based on fully ab initio energy calculations combined with a genetic algorithm for searching phase space. We show that the fate of ζ-glycine depends on its thermal history: although at room temperature it transforms back to the γ phase, warming the sample from 100 K to room temperature yielded β-glycine, the least stable of the known ambient-pressure polymorphs.


Current State of Dor Yeshorim, Expanded Carrier, and Newborn Screening: Benefits and Limitations.
Availability and accessibility of preconception and prenatal genetic carrier and newborn biochemical and genetic screening have grown exponentially over the past 2 decades and as such, it is challenging for clinicians to keep pace. Although genetic counseling or genetic consultation should be offered to all expectant and new parents for prenatal screening decisions and positive results, benefits and limitations of these tests and results must be known and familiar to perinatal and pediatric clinicians. A brief historical overview of Dor Yeshorim, preconception and prenatal expanded carrier, and newborn screening is presented, followed by discussion about the conditions screened and considerations surrounding the benefits and limitations of these tests in the practice setting.


Adverse Childhood Experiences Are Associated with Unmet Healthcare Needs among Children with Autism Spectrum Disorder.
To explore associations between level of adverse childhood experiences (ACEs) and unmet healthcare needs among children with autism spectrum disorder (ASD) using a population-based sample. Cross-sectional data from the 2011-2012 National Survey of Child Health were analyzed to estimate prevalence of unmet healthcare needs among children with ASD, aged 2-17 years (ASD = 1624; estimated population = 1 174 871). Multivariate Poisson and logistic regression models were used to estimate the relationship between reported ACEs and unmet healthcare needs among children with ASD. After we adjusted for all other variables, children with ASD who experienced 1-2 ACEs and 3+ ACEs were associated with 1.78 (P < .05) and 2.53 (P < .01) times the incidence rate of unmet healthcare needs in comparison with children without ACEs. Compared with children who experienced 0 ACEs, the adjusted odds of any unmet healthcare need were 2.34 (P < .01) and 2.66 (P < .01) for children with 1-2 ACEs and 3 + ACEs, respectively. Although limited to cross-sectional data, our study provides compelling evidence on the link between ACEs and unmet healthcare needs among children with ASD. It advances understanding of risk factors in the child and community context that contribute to health disparities and negatively impact healthcare access and use in this population.


TREATMENT OF HYPOTONY WITH AN INTRAVITREAL GAS BUBBLE.
To describe a case of successful resolution of severe hypotony and choroidal detachments following nonfiltering glaucoma surgery with an intravitreal injection of C 3 F 8 gas after a poor response to topical steroids and cycloplegia. Retrospective chart review of a case report. 89 year-old male presented with a central retinal vein occlusion, hyphema, vitreous hemorrhage and neovascular glaucoma. After initial intravitreal injection of aflibercept he was treated with pars plana vitrectomy with panretinal photocoagulation and endocyclophotocoagulation to the ciliary body, but he continued to have elevated intraocular pressure. Subsequent external cyclophotocoagulation was performed but severe hypotony with inflammation, choroidal detachments, and corneal edema developed one week later without response to cycloplegic and steroid medications. A therapeutic injection of perfluorpropane (C3F8) gas led to resolution of the hypotony and choroid detachment and long-term maintenance of intraocular pressure. An intravitreal gas bubble can be a very useful outpatient procedure to immediately reverse hypotony, resolve choroidal detachment, and decrease associated inflammation. When hypotony does not respond to medical therapy with cycloplegic drops and steroid medications, then an intravitreal gas bubble can rapidly resolve these complications and result in stabilization of intraocular pressure long-term.


Induction of suppressed ADH activity in Drosophila pachea exposed to different alcohols.
Laboratory-reared males of the cactophilic Drosophila pachea exhibit a spontaneous and sex-specific suppression of alcohol dehydrogenase (ADH) activity within 4 days after eclosion. A lack of ADH activity also is usually seen in wild-caught males, although relatively high activity is always seen in female flies. In the present study we examined the effectiveness of different alcohols and related compounds, including several found naturally in necroses of the host cactus, to induce suppressed ADH activity in wild males of D. pachea and to serve as enzyme substrates. The primary alcohols (methanol, ethanol, 1-propanol, 1-butanol, and 1-pentanol), and the secondary alcohols (2-propanol and 2-butanol), each induced activity after 24 h exposure, although to different degrees. 1,2-Propanediol was usually effective as an inducer, but 2,3-butanediol usually was ineffective. Little or no induction was seen with 1-octanol, 2-pentanol, 3-methyl-1-butanol, 3-hydroxy-2-butanone, or acetaldehyde. Although the compounds tested varied in their ability to function as ADH substrates, methanol was the only alcohol that showed no activity staining. Ethanol induction of ADH activity was apparent after 3-6 h exposure and induced activity decreased dramatically within 1 week of flies being placed in an alcohol-free environment. Ethanol exposure did not induce ADH in adult female D. pachea, or in adult males and females of D. acutilabella in which control males show reduced ADH activity compared to females. The implications of the loss of ADH activity in adult males of D. pachea, as they relate to feeding ecology and fitness, are discussed.


Value assessment and heterogeneity: another side to the story.
The founder and president of the Institute for Clinical and Economic Review responds to the commentary on heterogeneity in value assessment.


Visualizations throughout pharmacoepidemiology study planning, implementation, and reporting.
Transparency is increasingly promoted to instill trust in nonrandomized studies using real-world data. Graphics and data visualizations support transparency by aiding communication and understanding, and can inform study design and analysis decisions. However, other than graphical representation of a study design and flow diagrams (e.g., a Consolidated Standards of Reporting Trials [CONSORT] like diagram), specific standards on how to maximize validity and transparency with visualization are needed. This paper provides guidance on how to use visualizations throughout the life cycle of a pharmacoepidemiology study-from initial study design to final report-to facilitate rationalized and transparent decision-making about study design and implementation, and clear communication of study findings. Our intent is to help researchers align their practices with current consensus statements on transparency.


Paraspinal and limb motor neuron involvement within homologous spinal segments in ALS.
We studied the involvement of motor neuron groups innervating paraspinal muscles in amyotrophic lateral sclerosis (ALS) and evaluated the value of paraspinal muscle EMG in the diagnosis of the disease. We used quantitative concentric needle EMG to study denervation and reinnervation in a paraspinal muscle and a limb muscle innervated by the C6 and L5 segments in 32 patients with ALS. As control subjects we studied 11 patients with peripheral neuropathy, and 46 non-neurogenic control subjects. We found similar abnormalities in motor-unit potentials (MUPs) in paraspinal and limb muscles in these two segments in ALS. Fasciculation potentials (FPs) were more frequent in limb muscles than in paraspinal muscles and fibrillations and sharp waves (fibs-sw) were most frequent in tibialis anterior. In peripheral neuropathy paraspinal muscles were normal but tibialis anterior showed very abnormal motor unit potentials. These results are consistent with generalised involvement of motor neurons in motor neuron pools in spinal segments in early stages of ALS progression. However, distally predominant fibrillations indicate susceptibility to ongoing denervation in reinnervated distal axons. Complex FPs of similar morphology to MUP analysis in the same early affected muscle suggests a proximal origin for these FPs at this phase. Our observations emphasize the value of paraspinal muscle EMG in the electrophysiological diagnosis of ALS.


A Vulvar Venous Malformation in a 14-Year-Old Adolescent.
A vulvar venous malformation is a rare condition that can be misdiagnosed as vulvar varicose veins, but they are not the same entity. We describe the case of a 14-year-old nulliparous girl who presented with pelvic discomfort and limited ambulation secondary to a small, purple vulvar mass. The diagnosis was confirmed with the use of invasive imaging techniques after initial conservative management. Clinicians should consider venous malformations in the differential diagnosis of vulvar swelling in adolescents, and an earlier use of phlebography in patients with discordance between workup and symptoms to ensure a prompt diagnosis and decreased patient morbidity.


Bicarbonate use and mortality outcome among critically ill patients with metabolic acidosis: A meta analysis.
The use of sodium bicarbonate in the treatment of metabolic acidosis in critically ill subjects has long been a subject of debate. Despite empiric use in the setting of severe acidemia in critically ill patients, there is little data looking into the role of sodium bicarbonate in the treatment of severe metabolic acidosis in the intensive care unit (ICU) setting. We conducted a comprehensive search of Pubmed and Cochrane Central Register of Controlled Trials addressing bicarbonate use in the metabolic acidosis in the intensive care unit (ICU) setting. We examined mortality as end point. Pooled odds ratios (OR) and their 95% confidence intervals (CI) were calculated for all outcomes using a random-effect model. The final search yielded 202 articles of which all were screened individually. A total of 11 studies were identified but 6 studies were excluded due to irrelevance in mortality outcome and methodology. Analysis was done separately for observational studies and randomized controlled trials. The pooled OR [95% CI] for mortality with bicarbonate use in the observational studies was 1.5 [0.62-3.67] with heterogeneity of 67%, while pooled OR for mortality in the randomized trials was 0.72 [0.49-1.05] (figure 2). In combining all studies, the pooled odds ratio was 0.93 95% [0.69-1.25] but with heterogeneity of 63%. After sensitivity analysis with removing the study done by Kim et al. 2013, heterogeneity was 0% with OR 0.8 [0.59-1.10]. There is no significant difference in mortality in the use of bicarbonate among critically ill patients with high anion gap metabolic acidosis predominantly driven by lactic acidosis.


An audit of cardiac arrest management by extended trained ambulance crew.
To audit the use of extended skills by South Glamorgan Ambulance crew in attempted resuscitations from out-of-hospital cardio-respiratory arrest, in terms of successful discharge of patients from hospital and the accuracy with which agreed protocols were applied. Design-Retrospective analysis of ambulance report forms, electrocardiograph rhythm strips, casualty cards and discharge summaries during 26 months (1st May 1987-30th June 1989). A mixed urban and semi-rural area of 187 square miles with a population of 396,000. There were 274 attempted resuscitations. Seven patients (2.5%) were managed for primary respiratory arrest and 3 were discharged. In 98 patients (35.8%) the initial resuscitation protocol was for ventricular fibrillation: 26 were admitted and 17 were discharged. In 169 patients (61.7%) the initial resuscitation protocol was for asystole or electromechanical dissociation: 11 were admitted and 1 discharged. The majority of patients who were successfully discharged from hospital were those in ventricular fibrillation who responded to defibrillation alone (13 survivors). Drug administration may have played a role in the successful resuscitation of the remainder. Endotracheal intubation was successful in 94.7% and vein cannulation in 87.7% of attempts. There were deviations from the ventricular fibrillation protocol in 27 cases (27.5%) and from the asystole protocol in 27 cases (16.0%). Survival rates for ventricular fibrillation managed by these personnel were satisfactory with early defibrillation. Defibrillation alone was responsible for the majority of successful resuscitations. The additional benefit of drug administration appears small, though potentially important. The majority of patients were in asystole by the time the ambulance arrived. Extended trained crews use their skills effectively. The most important skill is defibrillation. Further studies are required to explain the high proportion of patients found in asystole. The performance of individual ambulance personnel should be assessed prospectively, because agreed resuscitation protocols are not always followed.


Sedimentary records of δ(13)C, δ(15)N and organic matter accumulation in lakes receiving nutrient-rich mine waters.
Organic C and total N concentrations, C/N ratios, δ(15)N and δ(13)C values in (210)Pb-dated sediment cores were used to reconstruct historical changes in organic matter (OM) accumulation in three Swedish lakes receiving nutrient-rich mine waters. Ammonium-nitrate-based explosives and sodium cyanide (NaCN) used in gold extraction were the major N sources, while lesser amounts of P originated from apatite and flotation chemicals. The software IsoSource was used to model the relative contribution of soil, terrestrial and littoral vegetation, and phytoplankton detritus in the lake sediments. In one lake the IsoSource modelling failed, suggesting the presence of additional, unknown OM sources. In two of the lakes sedimentary detritus of littoral vegetation and phytoplankton had increased by 15-20% and 20-35%, respectively, since ~1950, when N- and P-rich mine waters began to reach the lakes. Today, phytoplankton is the dominating OM component in these lake sediments, which appears to be a eutrophication effect related to mining operations. Changes in the N isotopic composition of biota, lake water, and sediments related to the use of ammonium-nitrate-based explosives and NaCN were evident in the two studied systems. However, N isotope signals in the receiving waters (δ(15)N~+9‰ to +19‰) were clearly shifted from the primary signal in explosives (δ(15)N-NO3=+3.4±0.3‰; δ(15)N-NH4=-8.0±0.3‰) and NaCN (δ(15)N=+1.1±0.5‰), and direct tracing of the primary N isotope signals in mining chemicals was not possible in the receiving waters. Systems where mine waters with a well known discharge history are a major point source of N with well-defined isotopic composition should, however, be suitable for further studies of processes controlling N isotope signatures and their transformation in aquatic systems receiving mine waters.


Pradimicin S, a new pradimicin analog. II. Isolation and structure elucidation.
Pradimicin S was isolated from the culture filtrate of Actinomadura spinosa AA0851. NMR and MS analyses proved that pradimicin S is the 3'-O-(3''-O-sulfo-beta-D-glucopyranosyl) analog of pradimicin A, a new member of the pradimicin family of antibiotics. Stereochemical assignment was made by correlating pradimicin S with pradimicin L.


GAP-43 mRNA localization in the rat hippocampus CA3 field.
Gene expression of the axonal growth-associated protein, GAP-43, has been studied in the adult rat brain by in situ hybridization histochemistry. This protein is synthesized at high levels in neuronal somata in immature and regenerating neurons, but after establishment of mature synaptic relations its synthesis generally declines sharply, thus providing a marker denoting propensity for exhibiting synaptic plasticity. Detailed examination of the distribution of mRNA for GAP-43 in rat hippocampus is selectively and robustly expressed in the pyramidal neurons of field CA3 and, to a lesser extent, the polymorph neurons of the hilus of the dentate gyrus. Additional hippocampal regions of moderate expression include the tenia tecta and the subicular and entorhinal fields, but CA1 and CA2 are strikingly lower in signal. The significance of this pattern of localization is considered in the context of the phosphorylation of GAP-43 and its role in influencing synaptic events underlying the establishment and maintenance of long-term potentiation and plasticity in the hippocampus.


Skp2: a novel potential therapeutic target for prostate cancer.
Prostate cancer is the most frequently diagnosed tumor in men and the second most common cause of cancer-related death for males in the United States. It has been shown that multiple signaling pathways are involved in the pathogenesis of prostate cancer, such as androgen receptor (AR), Akt, Wnt, Hedgehog (Hh) and Notch. Recently, burgeoning amounts of evidence have implicated that the F-box protein Skp2 (S-phase kinase associated protein 2), a well-characterized oncoprotein, also plays a critical role in the development and progression of prostate cancer. Therefore, this review discusses the recent literature regarding the function and regulation of Skp2 in the pathogenesis of prostate cancer. Furthermore, we highlight that Skp2 may represent an attractive therapeutic target, thus warrants further development of agents to target Skp2, which could have significant therapeutic impact on prostate cancer.


The Elephant Man. Part I.
Joseph Merrick was one of three children. His mother and younger sister were cripples, but their disease is unknown. Joseph's own swellings began to appear in early childhood and he rapidly became so grotesque, that he eventually sought a living as a freak. After an unhappy continental tour, he was given asylum in The London Hospital at the instigation of Mr Frederick Treves, and stayed there until he died. Books, a play and a film have featured his unique story, but each presented it with varying degrees of artistic license. However, contemporary accounts of his condition survive. Both bony abnormalities and substantial soft tissue masses contributed to his deformity. Features of these considered separately suggest neurofibromatosis as a diagnosis, but because the presentation is more extreme than seen in any other recorded patient, other diagnoses have been entertained. In the following three papers, the evidence which supports this diagnosis is reviewed, together with a consideration of the disease affecting his left hip and the manner of his death. This first article reviews the Elephant Man's life story.


Creation, Optimization, and Use of Semi-Synthetic Organisms that Store and Retrieve Increased Genetic Information.
With few exceptions, natural proteins are built from only 20 canonical (proteogenic) amino acids which limits the functionality and accordingly the properties they can possess. Genetic code expansion, i.e. the creation of codons and the machinery needed to assign them to non-canonical amino acids (ncAAs), promises to enable the discovery of proteins with novel properties that are otherwise difficult or impossible to obtain. One approach to expanding the genetic code is to expand the genetic alphabet via the development of unnatural nucleotides that pair to form an unnatural base pair (UBP). Semi-synthetic organisms (SSOs), i.e. organisms that stably maintain the UBP, transcribe its component nucleotides into RNA, and use it to translate proteins, would have available to them new codons and the anticodons needed to assign them to ncAAs. This review summarizes the development of a family of UBPs, their use to create SSOs, and the optimization and application of the SSOs to produce candidate therapeutic proteins with improved properties that are now undergoing evaluation in clinical trials.


Designing and conducting adaptive trials to evaluate interventions in health services and implementation research: practical considerations.
Randomized controlled clinical trials are widely considered the gold standard for evaluating the efficacy or effectiveness of interventions in health care. Adaptive trials incorporate changes as the study proceeds, such as modifying allocation probabilities or eliminating treatment arms that are likely to be ineffective. These designs have been widely used in drug discovery studies but can also be useful in health services and implementation research and have been minimally used. As motivating examples, we use an ongoing adaptive trial and two completed parallel group studies and highlight potential advantages, disadvantages, and important considerations when using adaptive trial designs in health services and implementation research. In addition, we investigate the impact on power and the study duration if the two completed parallel-group trials had instead been conducted using adaptive principles. Compared with traditional trial designs, adaptive designs can often allow one to evaluate more interventions, adjust participant allocation probabilities (e.g., to achieve covariate balance), and identify participants who are likely to agree to enroll. These features could reduce resources needed to conduct a trial. However, adaptive trials have potential disadvantages and practical aspects that need to be considered, most notably outcomes that can be rapidly measured and extracted (e.g., long-term outcomes that take significant time to measure from data sources can be challenging), minimal missing data, and time trends. In conclusion, adaptive designs are a promising approach to help identify how best to implement evidence-based interventions into real-world practice in health services and implementation research.


Household and plot-level survey data on adoption, outcomes, and perceptions of early sown wheat and zero tillage in Northwest India.
This study collected evidence on the use of early sown wheat varieties and complementary zero tillage technologies in Northwest India. Detailed information on farmers' knowledge, adoption decisions, personal experience, and perceptions of early sown wheat and zero tillage technologies were collected at the household level using different survey tools. Additional information on agricultural practices during the Rabi Season 2021/22 were collected at the plot level and geocoded. Overall, the dataset comprises responses from 1206 wheat farmers in 70 villages across 7 districts in Punjab and Haryana that were collected between September and October 2022. The villages were selected using stratified random sampling based on a sampling frame of 1722 communities that had been identified as predominantly wheat growing areas based on remote-sensing data from satellite images. The dataset provides rich information that may be used for assessing the diffusion and impact of recently developed wheat varieties designed for early sowing, identifying barriers to the wider adoption of these technologies, and informing policy making aimed at improving adoption and usage decisions of agricultural innovations.


Duodenal mucosal resurfacing with a GLP-1 receptor agonist increases postprandial unconjugated bile acids in patients with insulin-dependent type 2 diabetes.
Duodenal mucosal resurfacing (DMR) is a new endoscopic ablation technique aimed at improving glycemia and metabolic control in patients with type 2 diabetes mellitus (T2DM). DMR appears to improve insulin resistance, which is the root cause of T2DM, but its mechanism of action is largely unknown. Bile acids function as intestinal signaling molecules in glucose and energy metabolism via the activation of farnesoid X receptor and secondary signaling [e.g., via fibroblast growth factor 19 (FGF19)], and are linked to metabolic health. We investigated the effect of DMR and glucagon-like peptide-1 (GLP-1) on postprandial bile acid responses in 16 patients with insulin-dependent T2DM, using mixed meal tests performed at the baseline and 6 mo after the DMR procedure. The combination treatment allowed discontinuation of insulin treatment in 11/16 (69%) of patients while improving glycemic and metabolic health. We found increased postprandial unconjugated bile acid responses (all P < 0.05), an overall increased secondary bile acid response (P = 0.036) and a higher 12α-hydroxylated:non-12α-hydroxylated ratio (P < 0.001). Total bile acid concentrations were unaffected by the intervention. Postprandial FGF19 and 7-α-hydroxy-4-cholesten-3-one (C4) concentrations decreased postintervention (both P < 0.01). Our study demonstrates that DMR with GLP-1 modulates the postprandial bile acid response. The alterations in postprandial bile acid responses may be the result of changes in the microbiome, ileal bile acid uptake and improved insulin sensitivity. Controlled studies are needed to elucidate the mechanism linking the combination treatment to metabolic health and bile acids.NEW & NOTEWORTHY Glycemic and metabolic improvements are seen in patients with type 2 diabetes after replacing their insulin therapy with DMR and GLP-1. These changes are accompanied by changes in postprandial bile acid concentrations: increased unconjugated and secondary bile acids.


Multivariable model of postoperative delirium in cardiac surgery patients: proteomic and demographic contributions.
Delirium following cardiac surgery is common, morbid, and costly, but may be prevented with risk stratification and targeted intervention. Preoperative protein signatures may identify patients at increased risk for worse postoperative outcomes, including delirium. In this study, we aimed to identify plasma protein biomarkers and develop a predictive model for postoperative delirium in older patients undergoing cardiac surgery, while also uncovering possible pathophysiological mechanisms. SOMAscan analysis of 1,305 proteins in the plasma from 57 older adults undergoing cardiac surgery requiring cardiopulmonary bypass was conducted to define delirium-specific protein signatures at baseline (PREOP) and postoperative day 2 (POD2). Selected proteins were validated in 115 patients using the ELLA multiplex immunoassay platform. Proteins were combined with clinical and demographic variables to build multivariable models that estimate the risk of postoperative delirium and bring light to the underlying pathophysiology. A total of 115 and 85 proteins from SOMAscan analyses were found altered in delirious patients at PREOP and POD2, respectively (p<0.05). Using four criteria including associations with surgery, delirium, and biological plausibility, 12 biomarker candidates (Tukey's fold change (|tFC|)>1.4, Benjamini-Hochberg (BH)-p<0.01) were selected for ELLA multiplex validation. Eight proteins were significantly altered at PREOP, and seven proteins at POD2 (p<0.05), in patients who developed postoperative delirium compared to non-delirious patients. Statistical analyses of model fit resulted in the selection of a combination of age, sex, and three proteins (angiopoietin-2 (ANGPT2); C-C motif chemokine 5 (CCL5); and metalloproteinase inhibitor 1 (TIMP1); AUC=0.829) as the best performing predictive model for delirium at PREOP. The delirium-associated proteins identified as biomarker candidates are involved with inflammation, glial dysfunction, vascularization, and hemostasis, highlighting the multifactorial pathophysiology of delirium. Our study proposes a model of postoperative delirium that includes a combination of older age, female sex, and altered levels of three proteins. Our results support the identification of patients at higher risk of developing postoperative delirium after cardiac surgery and provide insights on the underlying pathophysiology. ClinicalTrials.gov ( NCT02546765 ).


Lispro administered by the QS-M Needle-Free Jet Injector generates an earlier insulin exposure.
The aim of this study is to evaluate the pharmacokinetic and pharmacodynamic (PK-PD) profiles of lispro administered by the QS-M needle-free jet injector in Chinese subjects. A randomized, double-blind, double-dummy, cross-over study was performed. Eighteen healthy volunteers were recruited. Lispro (0.2 units/kg) was administered by the QS-M needle-free jet injector or by conventional pen. Seven-hour euglycemic clamp tests were performed. A larger area under the curve (AUCs) of insulin concentration and glucose infusion rate (GIR) during the first 20 minutes after lispro injection by the jet injector compared to the insulin pen was observed (24.91 ± 15.25 vs. 12.52 ± 7.60 mg. kg(-1), P < 0.001 for AUCGIR,0-20 min; 0.36 ± 0.24 vs. 0.10 ± 0.04 U min L(-1), P < 0.001 for AUCINS, 0-20 min). Needle-free injection showed a shorter time to reach maximum insulin concentration (37.78 ± 11.14 vs. 80.56 ± 37.18 min, P < 0.001) and GIR (73.24 ± 29.89 vs. 116.18 ± 51.89 min, P = 0.006). There were no differences in total insulin exposure and hypoglycemic effects between the two devices. Lispro administered by QS-M needle-free injector results in earlier and higher insulin exposure than conventional pen, and a greater early glucose-lowering effect with similar overall potency.


Eight cases of salvage pulmonary resection for residual disease or isolated local recurrence detected after definitive chemoradiotherapy for N2 Stage-IIIA lung cancer.
The concept of salvage pulmonary resection after definitive chemoradiotherapy (dCRT) is not yet commonly accepted in lung cancer treatment. We report our experience of eight patients in whom we performed salvage pulmonary resection for residual disease or isolated locoregional recurrence detected after dCRT. Between 2005 and 2014, we performed salvage pulmonary resection for eight patients with N2 Stage-IIIA non-small cell lung cancer. The patients had initially received dCRT (radiation ≤ 60 Gy), but eventually underwent pulmonary resection with curative intent for residual disease or isolated locoregional recurrence. The postoperative complications, incidence of recurrence, and survival parameters were evaluated. Salvage pulmonary resection was performed in four patients with residual disease and four patients with locoregional recurrence. Complete resection was successfully performed in all eight patients. Postoperative complications were observed in three patients, however, there were no postoperative mortalities. One patient developed local recurrence in a mediastinal lymph node and two patients died. Of the two fatalities, one was related to lung cancer. The estimated 5-year survival rate of the eight patients was 75.0%. We report our experience of salvage pulmonary resection performed for residual disease or isolated locoregional recurrence diagnosed after dCRT in eight patients with locally advanced lung cancer. Although the postoperative complication rate was high, the survival data were favorable. A larger study is needed to confirm the safety and feasibility of salvage pulmonary resection after dCRT.


Trisomy 9p with i(9p) and t(9q18p).
The trisomy 9p syndrome in a 2-year-old girl with moderate mental retardation is presented. She has a unique karyotype with a de novo isochromosome 9p and a translocation between 9q and 18p.


Self-assembled polymeric nanoparticles for percutaneous co-delivery of hydrocortisone/hydroxytyrosol: an ex vivo and in vivo study using an NC/Nga mouse model.
In this study, hydroxytyrosol (HT; a potent antioxidant) was co-administered with hydrocortisone (HC) to mitigate the systemic adverse effects of the latter and to provide additional anti-inflammatory and antioxidant benefits in the treatment of atopic dermatitis (AD). The co-loaded nanoparticles (NPs) prepared had shown different particle sizes, zeta potentials, loading efficiencies, and morphology, when the pH of the chitosan solution was increased from 3.0 to 7.0. Ex vivo permeation data showed that the co-loaded NPs formulation significantly reduced the corresponding flux (17.04μg/cm(2)/h) and permeation coefficient (3.4×10(-3)cm/h) of HC across full-thickness NC/Nga mouse skin. In addition, the NPs formulation showed higher epidermal (1560±31μg/g of skin) and dermal (880±28μg/g of skin) accumulation of HC than did a commercial HC formulation. Moreover, an in vivo study using an NC/Nga mouse model revealed that compared to the other treatment groups, the group treated with the NPs formulation efficiently controlled transepidermal water loss (13±2g/m(2)/h), intensity of erythema (207±12), and dermatitis index (mild). In conclusion, NPs co-loaded with HC/HT is proposed as a promising system for the percutaneous co-delivery of anti-inflammatory and antioxidative agents in the treatment of AD.


Improving greenness and sustainability of standard analytical methods by microextraction techniques: A critical review.
Since environmental awareness has increased in analytical chemistry, the demand for green sample preparation methods continues to grow. Microextractions such as solid-phase microextraction (SPME) and liquid-phase microextraction (LPME) miniaturize the pre-concentration step and are a more sustainable alternative to conventional large-scale extractions. However, the integration of microextractions in standard and routine analysis methods is rare, although these applications are used most frequently and have a role model function. Therefore, it is important to highlight that microextractions are capable to replace large-scale extractions in standard and routine methods. This review discusses the greenness, benefits, and drawbacks of the most common LPME and SPME variants compatible with gas chromatography based on the following key evaluation principles: Automation, solvent consumption, hazards, reusability, energy consumption, time efficiency, and handling. Furthermore, the need to integrate microextractions into standard and routine analytical methods is presented by using method greenness evaluation metrics AGREE, AGREEprep, and GAPI applied to USEPA methods and their replacements.


Prostaglandin E2 receptors in abdominal aortic aneurysm and human aortic smooth muscle cells.
Prostaglandin (PG) E(2) (PGE(2)) appears to have a role in stimulating production of interleukin-6 (IL-6) and apoptosis of smooth muscle cells in diseased aortic tissue. These actions are mediated by cellular receptors for PGE(2) EP receptors. This study was undertaken to identify EP receptors associated with production of IL-6 by aortic explants. Biopsy specimens of abdominal aortic aneurysm were used for explant culture and preparation of messenger RNA. The presence of EP1, EP2, EP3, and EP4 receptors in tissue and cells was investigated with reverse-transcriptase polymerase chain reaction. IL-6 and cyclic adenosine monophosphate were measured with an enzyme-linked immunosorbent assay. PGE(2) or 11-deoxy-PGE(1) (EP 2/3/4 agonist) reversed partially the indomethacin suppression of IL-6 secretion from explant cultures, whereas butaprost (EP2 receptor agonist) and sulprostone (EP 1/3 receptor agonist) had no effect. Aortic biopsy specimens expressed EP2, EP3-III, and EP4 receptors. Aortic smooth muscle cells expressed EP2 receptor and four variants of EP3 receptor, ie, EP3-Ib, EP3-II, EP3-III, and EP3-IV, but PGE(2) did not stimulate secretion of IL-6. In contrast, PGE(2) or 11-deoxy-PGE(1) stimulated secretion of IL-6 from aortic macrophages. In aortic explants, PGE(2) stimulates IL-6 secretion by activation of EP4 receptors, present in macrophages.


The C. elegans lifespan assay toolkit.
Since the discovery of single gene mutations that double its lifespan, the nematode Caenorhabditis elegans has provided remarkable insights into the biology of aging. The precisely measurable lifespan of worms has proven to be an efficient tool to assess the impact of various genetic, physiological and environmental factors on organismal aging. In this article, we describe methods to set up and monitor experiments to determine worm lifespan. We include procedures used for classical, small-scale lifespan assays that are generally performed on solid media, and review recent advances in high-throughput, automated longevity experiments conducted in liquid culture and microfluidic devices. In addition, tools that help analyze this data to obtain survival statistics are summarized, and C. elegans strains that offer particular advantages for lifespan studies are listed.


Vi serology in detection of chronic Salmonella typhi carriers in an endemic area.
A passive haemagglutination assay measuring antibody to highly purified Vi antigen, known to be sensitive and specific for the detection of chronic Salmonella typhi carriers in a non-endemic area, was assessed in an endemic area. A reciprocal serum Vi antibody titre of 160 was found to have a sensitivity of 75%, specificity of 92%, and a high predictive value in screening for chronic S typhi carriers in high-risk population group (eg, women over 40 years). This simple assay can screen for chronic S typhi carriers even in areas where typhoid fever is highly endemic.


The VAS-COG clinic: an out-patient service for patients with cognitive and behavioral consequences of cerebrovascular diseases.
Services dedicated to patients with cognitive and behavioral consequences of cerebrovascular diseases (CVD) are not established. We started an out-patient clinic (the "VAS-COG clinic") to assess patients with psycho-cognitive disturbances related to CVD. The work-up includes a clinical-neuroimaging diagnostic process and the individuation of the best therapeutic strategies as done in patients with neurodegenerative cognitive impairment. We report the results of the first 5 years of activity. Reasons for patient referral were not only cognitive, language, gait, and psychiatric disturbances related to stroke or chronic CVD, but also neuroimaging evidence of vascular encephalopathy and screening for familial microangiopathies. The patients were evaluated with uniformed protocols. From January 2006 to November 2010, we evaluated 403 patients. Of these, 374 (93%; mean age 69.7 years ± 15.0) were considered appropriate for the VAS-COG clinic. The following diagnoses were made: vascular dementia (8.6%), Alzheimer disease (2.1%), mixed dementia (vascular plus degenerative) (4.8%), vascular mild cognitive impairment (MCI) (9.1%), amnesic-MCI (8.0%), mixed-MCI (4.8%), post-stroke depression (2.7%), post-stroke language disturbances (4.5%), subjective memory complaint (1.3%), familiar microangiopathy (31.3%), vascular encephalopathy evidenced by neuroimaging not associated with specific clinical disturbances (15.3%), and other conditions (7.5%). Psycho-cognitive disturbances associated with CVD are heterogeneous. In addition to acute stroke care strategies, long-term assessment of patients with CVD is required. The VAS-COG clinic may represent a model in this regard and might be important for improving the care of patients and offering counseling to their families. The efficacy of this service needs, however, to be proved by successive work.


Hepatitis B third-generation vaccines: improved response and conventional vaccine non-response--evidence for genetic basis in humans.
The lack of response to hepatitis B vaccination remains a problem for those individuals directly at risk of hepatitis B infection, particularly those who work in the health care industry. The factors associated with non-response to hepatitis B vaccination have been investigated in 86 non-responder health care workers who had received multiple 'S' vaccinations without sustained production of anti-HBs. This group received a recently developed hepatitis B vaccine, Hepagene, which included proteins derived from the envelope region of HBV, not present in currently licensed vaccines. The pre-S1 and pre-S2 proteins were included in Hepagene in order to circumvent anti-HBs non-responsiveness which had previously been demonstrated in the inbred mouse model. The inclusion of these additional proteins in Hepagene enabled some seroconverion, from non-responder to responder; however, a proportion of the vaccinees remained non-responders and the reasons for this have been investigated here, with reference to HLA alleles and the demographic predisposition. Here the mechanisms that underlie hepatitis B vaccine non-response have considered the distribution of HLA alleles, age, sex, height and weight in addition to the T-cell responses to Hepagene derived antigens.


The International Standard for Endotoxin: evaluation in an international collaborative study.
An ampouled preparation of bacterial endotoxin, coded 84/650, was evaluated in 35 laboratories in 12 countries for its suitability to serve as the International Standard for Endotoxin. The ampouled preparation was calibrated in terms of the USA National Standard, EC5, in Limulus Amoebocyte Lysate gelation, turbidimetric and chromogenic tests and in rabbit pyrogen tests. On the basis of the results reported here, with the agreement of the participants in the study, and with the authorization of the Expert Committee on Biological Standardization of the World Health Organization, the preparation coded 84/650 was established in 1986 as the International Standard for Endotoxin for Limulus Gelation Tests with an assigned unitage of 14,000 IU of endotoxin per ampoule.


The curious case of SARM1: Dr. Jekyll and Mr. Hyde in cell death and immunity?
Sterile alpha and toll/interleukin-1 receptor motif-containing protein 1 (SARM1) was first identified as a novel ortholog of Drosophila protein CG7915 and was subsequently placed as the fifth member of the human TIR-containing adaptor protein. SARM1 holds a unique position in this family where, unlike other members, it downregulates NFκB activity in response to immunogenic stimulation, interacts with another member of the family, TRIF, to negatively regulate its function, and it also mediates cell death responses. Over the past decade, SARM1 has emerged as one of the primary mediators of programmed axonal degeneration and this robust regulation of axonal degeneration-especially in models of peripheral neuropathy and traumatic injury-makes it an attractive target for therapeutic intervention. The TIR domain of SARM1 possesses an intrinsic NADase activity resulting in cellular energy deficits within the axons, a striking deviation from its other family members of human TLR adaptors. Interestingly, the TIR NADase activity, as seen in SARM1, is also observed in several prokaryotic TIR-containing proteins where they are involved in immune evasion once within the host. Although the immune function of SARM1 is yet to be conclusively discerned, this closeness in function with the prokaryotic TIR-domain containing proteins, places it at an interesting juncture of evolution raising questions about its origin and function in cell death and immunity. In this review, we discuss how a conserved immune adaptor protein like SARM1 switches to a pro-neurodegenerative function and the evolutionarily significance of the process.


Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer's disease and dementia with Lewy bodies.
TAR-DNA-binding protein 43 (TDP-43) has been identified as a major component protein of ubiquitin-positive inclusions in brains from patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. To obtain the precise prevalence of TDP-43 pathology in neurodegenerative disorders, we examined brains from patients with tauopathies and synucleinopathies as well as FTLD-U using immunohistochemical analysis. Consequently, TDP-43-positive inclusions within neurons and oligodendroglia were found in brains from patients with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) in addition to FTLD-U, but not with Parkinson's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration or FTDP-17. The amygdala and hippocampus that were vulnerable to tau or alpha-synuclein pathology demonstrated more severe TDP-43 pathology in AD and DLB cases than in FTLD-U cases. In contrast, in the frontal cortex and basal ganglia that were vulnerable to TDP-43 pathology in FTLD-U, TDP-43 pathology was not observed in AD and DLB cases. Thus, the neuroanatomical distribution of TDP-43 pathology in AD and DLB cases was obviously different from that in FTLD-U cases. Furthermore, a subset of TDP-43-positive inclusions co-existed with neurofibrillary tangles (NFTs) or Lewy bodies (LBs) in the same neurons. Upon double-immunofluorescent labeling analysis, TDP-43 was hardly superimposed with tau, while TDP-43 was partially superimposed with alpha-synuclein, suggesting that neither NFTs nor LBs themselves show TDP-43 immunoreactivity and that TDP-43 pathology found in this study may be related in some way to AD and LB pathology. This study will provide a more in-depth understanding of the various pathogenic pathways leading to neurodegenerative disorders.


Sutureless Tragal Cartilage Island Tympanoplasty: Our Experience.
To evaluate graft take up and hearing improvement using the technique of tragal cartilage island in COM-mucosal type. Prospective study. A total of 258 type 1 tympanoplasty surgeries were done using tragal cartilage island graft from December 2013, to December 2015; in Jubilee Mission Medical College and Research Institute with a follow up of 1 year. Inclusion criteria-all the patients undergoing type 1 tympanoplasty for chronic otitis media (mucosal type, inactive) with an intact ossicular chain by the senior author. The youngest patient was 6 years old and the oldest was 64 years. This pattern was selected for getting a uniform pattern even though cartilage tympanoplasty can be done in other forms of COM also. Graft take up in our study was found to be 96.12% in 1 year of follow up. Closure of tympanic membrane was achieved in 248 of 258 cases. None of the patients showed retraction pockets or cholesteatoma during follow up. The average pre-op AB gap was 21.62 dB which was lowered to 4.22 dB post op. The mean gain in hearing was 17.37 dB. It is worthwhile to consider tragal cartilage island graft as an alternative to temporalis fascia.


Comparison of intravascular ultrasound and magnetic resonance venography in the diagnosis of chronic iliac venous disease.
The diagnosis of chronic iliofemoral venous obstruction (CIVO) can be made with several different modalities. Intravascular ultrasound (IVUS) examination is the gold standard in the diagnosis of CIVO. However, being invasive, it should not be the initial examination to screen patients with CIVO. The aim of this report is to compare the performance of magnetic resonance venography (MRV) with IVUS examination in the diagnosis of CIVO. From January 2016 to December 2020, the records of all patients who underwent preoperative MRV and then IVUS in the evaluation of CIVO were analyzed retrospectively. There were 505 patients who were evaluated by any modality for CIVO. Of these patients, 15% (78) were evaluated by MRV. Patients who had failed a trial of conservative therapy for at least 3 to 6 months and who had disabling and lifestyle-limiting symptoms of CIVO were selected to undergo further evaluation with MRV at the treating physician's discretion. For inclusion in analysis, technically satisfactory IVUS examination and MRV data were mandatory. Data was available for 60 common iliac vein (CIV) segments and 61 external iliac vein (EIV) segments for comparative analysis after appropriate exclusions. The mean age of the patients was 56 ± 15 years. The male to female ratio was 1:2. The distribution of patients across different CEAP classes was as follows: CEAP 3, 28%; CEAP 4, 62%; CEAP 5, 2%; and CEAP 6, 8%. Bland-Altman plots of the mean difference in area between IVUS examination and MRI were 74.1% for CIV and 56.9% for EIV. The sensitivity of MRV was 93% and 100%, and the specificity was 0% and 50% for CIV and EIV, respectively. The positive predictive value was 93% and 86%; the negative predictive value was 0 and 50% for CIV and EIV, respectively. Improvement was noted in clinical parameters (Venous Clinical Severity Score, visual analog pain scale, and grade of swelling) after IVUS examination and stenting after MRV. For the Venous Clinical Severity Score, the score improved from 6.0 ± 2.7 (before the procedure) to 4 ± 2.7 (after the procedure) (P = .0001). There is dimensional disparity between MRV and IVUS examination in the diagnosis of symptomatic CIVO. MRV has a high sensitivity but low specificity when compared with IVUS examination and overestimates the severity of the stenosis in both the EIV and CIV. MRV is not a reliable diagnostic tool for iliac vein stenosis and should not be used for the definitive disposition of patients with CIVO.


Phase II study demonstrating failure of both a five-drug continuous-therapy regimen and a two-drug pulse-therapy regimen in the treatment of metastatic neuroblastoma: Southwest Oncology Group Study 822.
Twenty-six children greater than 1 year of age with previously untreated stage IV neuroblastoma were randomized to receive either a five-drug regimen (prednisone, cyclophosphamide, actinomycin D, vincristine, and daunorubicin) or a two-drug regimen (cyclophosphamide and vincristine). Complete response rates were 6% and 9% for the five-drug and the two-drug regimens respectively. Partial response rates were 13% and 27% for the five-drug and the two-drug regimens respectively. The mean duration of the seven responses was 9 months, and all 26 patients had died within 2 years. Neither regimen was effective for long-term disease control in these children with neuroblastoma.