Antithrombin III Glasgow: a variant with increased heparin affinity and reduced ability to inactivate thrombin, associated with familial thrombosis.
A functional antithrombin III (AT III) deficiency has been identified in two generations of a family with a high incidence of thrombosis. The deficiency presented as approximately 50% reduction in heparin cofactor activity compared to its antigen concentration. No abnormality was detected by crossed immunoelectrophoresis in the presence or absence of heparin. Plasma from the propositus was precipitated with dextran sulphate, applied to heparin-Sepharose and the AT III stepwise eluted with NaCl. The AT III had a reduced ability to inactivate thrombin, when this was monitored by substrate hydrolysis or by SDS polyacrylamide gel electrophoresis. Its mobility was normal by the latter technique using 10-20% gradient gels under reducing and non-reducing conditions. AT III from the patient was reapplied to heparin-Sepharose and eluted with a NaCl gradient. An active pool eluted in the same NaCl concentration range used to purify normal AT III, while predominantly inactive AT III eluted at higher NaCl concentrations. It is concluded that this variant, designated AT III Glasgow, has increased affinity for heparin but reduced ability to inactivate thrombin.


Ten years' follow-up after iliococcygeus fixation for the treatment of apical vaginal prolapse.
Various surgical techniques have been described for vaginal vault prolapse repair, but the best surgical approach is still to be proven. The aim of this study is to report the long-term objective and subjective outcomes of women who underwent iliococcygeus fixation for the treatment of vaginal vault prolapse with a minimum follow-up of 10 years. Women with symptomatic vaginal vault prolapse (Pelvic Organ Prolapse Quantification [POP-Q] stage ≥ 2) who had previously undergone hysterectomy for any reason were prospectively enrolled and treated with iliococcygeus fixation. Subjective success was defined as Patient Global Impression of Improvement (PGI-I) ≤ 2 and an absence of bulging symptoms. Objective success was defined as stage of prolapse < 2 in all compartments. Overall success rate was defined as women without prolapse symptoms, PGI-I ≤ 2, stage of prolapse < 2, and no need for other surgery. Prolpase Quality of Life (P-QOL) questionnaires were completed at the preoperative visit and at every follow-up visit. Multiple logistic regression was performed to identify factors involved in the risk of recurrent POP. After a median (range) follow-up of 120 (120-132) months, the subjective, objective, and overall cure rates were 82% (32/39), 74.4% (29/39), and 74.4% (29/39), respectively. Only stage IV vault descensus independently predicted POP recurrence after ICG (OR: 7.66 [95% CI: 1.21-9.02]; p < 0.001). Iliococcygeus fixation seems to be a safe and effective option for the treatment of vaginal vault prolapse at 10 years' follow-up.


Multi-steroid profiling by UHPLC-MS/MS with post-column infusion of ammonium fluoride.
Multi-steroid profiling is a powerful analytical tool that simultaneously quantifies steroids from different biosynthetic pathways. Here we present an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) assay for the profiling of 23 steroids using post-column infusion of ammonium fluoride. Following liquid-liquid extraction, steroids were chromatographically separated over 5 min using a Phenomenex Luna Omega C18 column and a water (0.1 % formic acid) methanol gradient. Quantification was performed on a Waters Acquity UHPLC and Xevo® TQ-XS mass spectrometer. Ammonium fluoride (6 mmol/L, post-column infusion) and formic acid (0.1 % (vol/vol), mobile phase additive) were compared as additives to aid ionisation. Post-column infusion of ammonium fluoride enhanced ionisation in a steroid structure-dependent fashion compared to formic acid (122-140 % for 3βOH-Δ5 steroids and 477-1274 % for 3-keto-Δ4 steroids). Therefore, we analytically validated post-column infusion of ammonium fluoride. Lower limits of quantification ranged from 0.3 to 3 nmol/L; All analytes were quantifiable with acceptable accuracy (bias range -14 % to 11.9 % for 21/23, -21 % to 11.9 % for all analytes). Average recovery ranged from 91.6 % to 113.6 % and average matrix effects from -29.9 % to 19.9 %. Imprecision ranged from 2.3 % to 23 % for all analytes and was < 15 % for 18/23 analytes. The serum multi-steroid profile of 10 healthy men and 10 healthy women was measured. UHPLC-MS/MS with post-column infusion of ammonium fluoride enables comprehensive multi-steroid profiling through enhanced ionisation particularly benefiting the detection of 3-keto-Δ4 steroids.


Abuse Potential of Oral Phendimetrazine in Cocaine-dependent Individuals: Implications for Agonist-like Replacement Therapy.
Phendimetrazine is a prodrug for the monoamine releaser phenmetrazine-a drug with known abuse potential. Preclinical studies suggest that phendimetrazine has limited abuse potential and may have promise as an agonist-like replacement therapy for cocaine dependence. This study evaluated the abuse potential of phendimetrazine in humans. Nine cocaine-dependent individuals (N = 9) were enrolled to investigate the abuse potential of phendimetrazine and d-amphetamine, using a double-blind, placebo-controlled, within-subject design. Subjective and cardiovascular effects of oral phendimetrazine (35, 70, and 105 mg), d-amphetamine (10, 20, and 30 mg), and placebo were assessed in quasi-random order across 8 sessions lasting for approximately 8 hours each. d-Amphetamine (20 and 30 mg) significantly increased cardiovascular measures in a time and dose-related manner, but phendimetrazine did not systematically alter cardiovascular measures. Although d-amphetamine and phendimetrazine significantly increased ratings indicative of abuse potential (eg, drug liking) and stimulant-like effects relative to placebo, these increases were generally small in magnitude, with phendimetrazine producing significant effects on fewer abuse-related measures and at fewer time points than d-amphetamine. These preliminary findings suggest that oral phendimetrazine and d-amphetamine may have limited abuse potential in cocaine-dependent individuals. These findings collectively emphasize that the clinical utility of medications to treat cocaine-use disorders should be weighed carefully against their potential for abuse and diversion, with careful attention paid to evaluating abuse potential in a clinically relevant population of interest. Future studies are needed to further elucidate the potential utility of phendimetrazine as an agonist-like replacement therapy for cocaine dependence.


Skeletal muscle-derived cell implantation for the treatment of sphincter-related faecal incontinence.
In an earlier pilot study with 10 women, we investigated a new approach for therapy of faecal incontinence (FI) due to obstetric trauma, involving ultrasound-guided injection of autologous skeletal muscle-derived cells (SMDC) into the external anal sphincter (EAS), and observed significant improvement. In the current study, we tested this therapeutic approach in an extended patient group: male and female patients suffering from FI due to EAS damage and/or atrophy. Furthermore, feasibility of lower cell counts and cryo-preserved SMDC was assessed. In this single-centre, explorative, baseline-controlled clinical trial, each patient (n = 39; mean age 60.6 ± 13.81 years) received 79.4 ± 22.5 × 106 cryo-preserved autologous SMDC. Changes in FI parameters, Fecal Incontinence Quality of Life (FIQL), anorectal manometry and safety from baseline to 1, 6 and 12 months post implantation were evaluated. SMDC used in this trial contained a high percentage of myogenic-expressing (CD56+) and muscle stem cell marker-expressing (Pax7+, Myf5+) cells. Intervention was well tolerated without any serious adverse events. After 12 months, the number of weekly incontinence episodes (WIE, primary variable), FIQL and patient condition had improved significantly. In 80.6% of males and 78.4% of females, the WIE frequency decreased by at least 50%; Wexner scores and severity of FI complaints decreased significantly, independent of gender and cause of FI. Injection of SMDCs into the EAS effectively improved sphincter-related FI due to EAS damage and/or atrophy in males and females. When confirmed in a larger, placebo-controlled trial, this minimal invasive procedure has the potential to become first-line therapy for FI. EU Clinical Trials Register, EudraCT 2010-023826-19 (Date of registration: 08.11.2010).


Experimental scrapie in rats: first electrophysiological observations.
Scrapie was transmitted (1st passage) to various strains of rats through intracerebral (IC) inoculation of sheep-scrapie, mouse-scrapie and hamster-scrapie brains. For the 2nd passage, Wistar rats were chosen and inoculated IC with rat-scrapie brain from the 1st passage. Three groups of 12 rats were considered (S for sheep, M for mouse, H for hamster). Electrodes were chronically implanted for EEG recording. From 100 to 110 days after inoculation, EEG abnormalities were observed, consisting of spindle-shaped bursts of diphasic spikes sporadically occurring during quiet wakefulness. Between 130 and 230 days, EEG signs diversified and became more pronounced. Simultaneously, changes occurred in the sleep-wakefulness cycle: active wakefulness decreased and was replaced by quiet wakefulness (rats were motionless , as if prostrate ). Slow wave sleep diminished, giving way to an unstable low voltage sleep. EEG disturbances clearly preceded the onset of the clinical signs (the latter appearing at about the 8th month). The disease was fairly similar in the S, M and H groups. The interest of the experimental scrapie rat model is discussed in the framework of current research on the neurophysiology of the subacute spongiform encephalopathies.


Cardiovascular and renal health: Preeclampsia as a risk marker.
Cardiovascular (CVD) and chronic kidney disease (CKD) in women have unique risk factors related to hormonal status and obstetric history that must be taken into account. Pregnancy complications, such as preeclampsia (PE), can reveal a subclinical predisposition for the development of future disease that may help identify women who could benefit from early CVD and CKD prevention strategies. Review of PE and its association with future development of CVD and CKD. Multiple studies have established an association between PE and the development of ischemic heart disease, chronic hypertension, peripheral vascular disease, stroke and CKD. It has not been sufficiently clarified if this relation is a causal one or if it is mediated by common risk factors. Nevertheless, the presence of endothelial dysfunction and thrombotic microangiopathy during pregnancies complicated with PE makes us believe that PE may leave a long-term imprint. Early identification of women who have had a pregnancy complicated by PE becomes a window of opportunity to improve women's health through adequate follow-up and targeted preventive actions. Oxidative stress biomarkers and vascular ultrasound may play a key role in the early detection of this arterial damage. The implementation of preventive multidisciplinary targeted strategies can help slow down CVD and CKD's natural history in women at risk through lifestyle modifications and adequate blood pressure control. Therefore, we propose a series of recommendations to guide the prediction and prevention of CVD and CKD throughout life of women with a history of PE.


Kinetic analysis of simultaneous denitrification and biomineralization of novel Acinetobacter sp. CN86.
A novel aerobic denitrification and biomineralization strain CN86 was isolated from the Qu Jiang artificial lake. Based on phylogenetic characteristics, the isolated strain was identified as Acinetobacter species. Strain CN86 was confirmed to have the ability to perform simultaneous denitrification and biomineralization. Exponential decay equation was used for the matching of kinetic processes on denitrification and biomineralization. A highest nitrate removal rate was achieved at the pH7.0, organic concentration of 1.5g/L and temperature of 30°C. An optimal hardness removal rate was obtained at the pH9.0, organic concentration of 2.0g/L and temperature of 30°C. Strain CN86 is a suitable candidate for the simultaneous removal of nitrate and hardness in groundwater treatment.


Massive hemoptysis in Loeys-Dietz syndrome.
We describe four unrelated individuals with Loeys-Dietz syndrome (LDS) who presented with massive hemoptysis of unknown etiology. LDS is an autosomal dominant connective-tissue disorder characterized by altered cardiovascular, craniofacial, and skeletal development that is attributed to mutations in the TGFBR1, TGFBR2, SMAD3, or TGFB2 genes. Massive hemoptysis (MH) is a rare and often fatal pulmonary medical emergency. This is the first report of MH in individuals with LDS and establishes it as part of the LDS spectrum. It compels providers to educate their LDS patients on MH, although much investigation needs to be done to determine etiology and appropriate treatment for this newly described LDS feature.


Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM.
X chromosome-linked immunodeficiency with hyper-IgM (HIGM1, MIM number 308230) is a rare disorder characterized by recurrent bacterial infections, very low or absent IgG, IgA and IgE, and normal to increased IgM and IgD serum levels. HIGM1 has been suggested to result from ineffective T-cell help for B cells. We and others have identified a novel, TNF-related activation protein (TRAP) that is exclusively expressed on the surface of stimulated T cells. TRAP, a type II transmembrane protein of M(r) 33,000, is the physiological ligand for CD40 (refs 5-8). Crosslinking of CD40 on B cells induces, in the presence of lymphokines, immunoglobulin class switching from IgM to IgG, IgA or IgE. Mapping of the TRAP gene to the X-chromosomal location q26.3-q27.1 (ref. 6) suggested a causal relationship to HIGM1, which had previously been assigned to Xq26 (refs 12-14). Here we present evidence that point mutations in the TRAP gene give rise to nonfunctional or defective expression of TRAP on the surface of T cells in patients with HIGM1. The resultant failure of TRAP to interact with CD40 on functionally intact B cells is responsible for the observed immunoglobulin isotype defect in HIGM1.


Deficient collagen-induced activation in the newborn platelet.
We have investigated the impaired secretion response of neonatal platelets. We compared the response of washed neonatal and adult platelets to thrombin and collagen, and to specific activators of calcium flux (inositol trisphosphate) and protein kinase C activation (oleoyl-acetyl glycerol). Neonatal platelets show no impairment of aggregation, secretion of [14C]serotonin or phosphorylation of specific intracellular proteins in response to thrombin, inositol trisphosphate, or oleoyl-acetyl glycerol. However, neonatal platelets have a markedly decreased response to collagen. To further evaluate this deficient response, we examined specific aspects of the collagen activation pathway. Collagen-platelet interaction as measured by adhesion of platelets to collagen-coated dishes showed no difference in adhesion of neonatal platelets compared to adult controls (20.1 +/- 11.6 versus 18.6 +/- 9.3%). The presence of GPIa/IIa, a Mg2(+)-dependent collagen receptor, was evaluated by flow cytometric analysis of binding of fluorescein-tagged monoclonal antibody, 6F1 (directed against GPIa/IIa). There was no difference either in the percent of platelets that bound antibody (80 versus 81%) or in the mean fluorescence intensity of the adult and neonatal samples. Phosphoinositide hydrolysis was decreased in neonatal platelets in response to collagen but normal in response to thrombin. Neonatal platelets released more arachidonic acid than adult platelets in response to thrombin (29.5 +/- 3.2 versus 19.6 +/- 1.8%) but less than adult platelets in response to 10 micrograms/mL collagen (3.2 +/- 1.1 versus 9.3 +/- 3.0%).(ABSTRACT TRUNCATED AT 250 WORDS)


Blunt pancreatic trauma: evaluation with MDCT technology.
The purpose of this paper is to determine the relative frequency of multi-detector CT (MDCT) findings of pancreatic injury in blunt trauma and to determine their diagnostic accuracy in predicting main pancreatic duct injury. Fifty-three patients (31 male, 22 female; mean 44.1 years) with blunt trauma and admission MDCT findings suspicious for pancreatic injury or who underwent MDCT and had a discharge diagnosis of pancreatic trauma were included in this study. Two radiologists reviewed all images and recorded findings suspicious for pancreatic injury, which were subsequently compared to surgical findings to generate diagnostic accuracy. MDCT imaging findings suggestive of pancreatic injury included low attenuation peripancreatic fluid (n = 51), hyperattenuating peripancreatic fluid (n = 13), pancreatic contusion (n = 7), active hemorrhage (n = 2), and pancreatic laceration (n = 16). Diagnostic accuracy of the various imaging findings varied for diagnosing main duct injury; there were highly sensitive, nonspecific imaging findings such as the presence of low attenuation peripancreatic fluid (sensitivity, 100 %; specificity 4.9 %) as well as insensitive, specific findings such as visualizing a pancreatic laceration involving >50 % of the parenchymal width (sensitivity, 50 %; specificity, 95.1 %). In the setting of blunt abdominal trauma, MDCT imaging findings can be grouped into two categories for determining integrity of the main pancreatic duct: indirect, highly sensitive but nonspecific findings and direct, specific but insensitive findings. Awareness of the clinical implications of the various MDCT imaging findings of pancreatic trauma is useful in interpreting their significance.


Bovine and human pineal glands contain substantial quantities of endothelial cell stimulating angiogenic factor.
Using a quantitative assay the amount of a low Mr endothelial cell stimulating angiogenesis factor (ESAF) has been determined in human pineal glands and bovine brain, retina, pineal gland, liver and kidney. Pineal glands contain approximately ten times as much ESAF as the retina or grey and white matter from the cerebral cortex and a hundred times as much as highly vascular tissues such as liver and kidney. The relevance of these findings to the highly vascular nature of the pineal gland is discussed.


Tracheoesophageal fistula and anomalies of thoracic vessels: their occurrence in a case of congenital rubella.
Virologic, gross, and microscopic studies of rubella embryopathy were performed. The presence of esophageal atresia with tracheal fistula allied with anomalies of the thoracic vessels were seen. We believe that both the mechanical action of the anomalous vessels on the developing organ, and the vascular degenerative aortic lesions, which are identical to those described in rubella syndrome, are probable causes of the esophageal malformation.


Family interactions of schizophrenic and schizoaffective patients: determinants of relatives' negativity.
Videotaped family problem-solving interactions of 57 schizophrenic or schizoaffective patients and their relatives were examined for predictors of negativity of their communication behavior. Ratings of patients' behaviors and independent assessments of patients' symptomatology were used to predict the negativity of relatives in the videotaped interaction. The results indicated that severity of symptomatology was not related to relatives' negativity. Patients' social skill, as independently assessed by a role-play test, also was not associated with relatives' negativity. The regression results suggest that with both members of a patient-relative dyad, the quality of communication in a discussion is related to the other participant's level of negativity.


Prognostic significance of tumour angiogenesis in schistosoma-associated adenocarcinoma of the urinary bladder.
To report on tumour angiogenesis and its relationship with morphological variables and prognosis in adenocarcinoma of the urinary bladder associated with schistosomiasis. Fifty-five vesical adenocarcinomas were evaluated from 30 men and 25 women (mean age 47.2 years, sd 8.7, range 30-65) who were followed up after radical cystectomy and urinary diversion for a mean (sd, range) of 61 (43.5, 2.7-159.5) months. Vessels were stained immunohistochemically using an antibody to the platelet endothelial cell-adhesion molecule CD31. Microvessels were counted in active areas of angiogenesis within the tumours (at x250) and the microvessel density (MVD) quantified using the mean of three counts. Treatment failure was defined as death from cancer or the development of local recurrence or distant metastasis. Kaplan-Meier survival curves and Cox's proportional hazard model were used to assess survival. The overall 5- and 10-year survival rates were 57% and 51%, respectively. The presence of lymph node metastasis and high mean vascular density (> 26) were significantly associated with a poor prognosis. The 5-year survival for patients with negative lymph nodes was 66% while no patients with positive nodes survived for 5 years (P < 0.001); the survival was 72% for patients with a low MVD and 33% for those with a high MVD (P = 0.0016). From individual results plotted against vascularity in lymph node-negative patients, there was a significantly better outcome for those with a low MVD (< or = 26; P = 0.0099); this significance was maintained on multivariate analysis. However, there was no significant relationship between angiogenesis and the different clinicopathological factors apart from the grade (P = 0.03); tumour stage, grade and DNA profile had no significant effect on survival in these patients. These findings suggest that assessing angiogenesis using the MVD provides an independent predictor of survival in patients with adenocarcinoma of the urinary bladder.


Two doses of the Pfizer-BioNTech vaccine, two different side effects: Skin and eye.
A 47-year-old male patient presented to our clinic with the complaints of eye pain, reduced vision and redness in the right eye three days after administration of the second dose of the Pfizer-BioNTech vaccine. The patient was diagnosed with uveitis associated with the Pfizer-BioNTech vaccine and inflammatory glaucoma due to the uveitis. In addition, an erythematous, morbilliform rash had developed three days after the first dose of the vaccine. This is the first case report in the literature to show both skin and eye side effects after the Pfizer-BioNTech vaccine.


T2 heterogeneity: a novel marker of microstructural integrity associated with cognitive decline in people with mild cognitive impairment.
Early Alzheimer's disease (AD) diagnosis is vital for development of disease-modifying therapies. Prior to significant brain tissue atrophy, several microstructural changes take place as a result of Alzheimer's pathology. These include deposition of amyloid, tau and iron, as well as altered water homeostasis in tissue and some cell death. T2 relaxation time, a quantitative MRI measure, is sensitive to these changes and may be a useful non-invasive, early marker of tissue integrity which could predict conversion to dementia. We propose that different microstructural changes affect T2 in opposing ways, such that average 'midpoint' measures of T2 are less sensitive than measuring distribution width (heterogeneity). T2 heterogeneity in the brain may present a sensitive early marker of AD pathology. In this cohort study, we tested 97 healthy older controls, 49 people with mild cognitive impairment (MCI) and 10 with a clinical diagnosis of AD. All participants underwent structural MRI including a multi-echo sequence for quantitative T2 assessment. Cognitive change over 1 year was assessed in 20 participants with MCI. T2 distributions were modelled in the hippocampus and thalamus using log-logistic distribution giving measures of log-median value (midpoint; T2μ) and distribution width (heterogeneity; T2σ). We show an increase in T2 heterogeneity (T2σ; p < .0001) in MCI compared to healthy controls, which was not seen with midpoint (T2μ; p = .149) in the hippocampus and thalamus. Hippocampal T2 heterogeneity predicted cognitive decline over 1 year in MCI participants (p = .018), but midpoint (p = .132) and volume (p = .315) did not. Age affects T2, but the effects described here are significant even after correcting for age. We show that T2 heterogeneity can identify subtle changes in microstructural integrity of brain tissue in MCI and predict cognitive decline over a year. We describe a new model that considers the competing effects of factors that both increase and decrease T2. These two opposing forces suggest that previous conclusions based on T2 midpoint may have obscured the true potential of T2 as a marker of subtle neuropathology. We propose that T2 heterogeneity reflects microstructural integrity with potential to be a widely used early biomarker of conditions such as AD.


A lightweight neural network with multiscale feature enhancement for liver CT segmentation.
Segmentation of abdominal Computed Tomography (CT) scan is essential for analyzing, diagnosing, and treating visceral organ diseases (e.g., hepatocellular carcinoma). This paper proposes a novel neural network (Res-PAC-UNet) that employs a fixed-width residual UNet backbone and Pyramid Atrous Convolutions, providing a low disk utilization method for precise liver CT segmentation. The proposed network is trained on medical segmentation decathlon dataset using a modified surface loss function. Additionally, we evaluate its quantitative and qualitative performance; the Res16-PAC-UNet achieves a Dice coefficient of 0.950 ± 0.019 with less than half a million parameters. Alternatively, the Res32-PAC-UNet obtains a Dice coefficient of 0.958 ± 0.015 with an acceptable parameter count of approximately 1.2 million.


Amanita phalloides poisoning and treatment with silibinin in the Australian Capital Territory and New South Wales.
To report the frequency and clinical outcomes of Amanita phalloides poisoning in the Australian Capital Territory and New South Wales, and the treatments used (including silibinin). Retrospective case series of patients admitted to public hospitals in Canberra and Sydney for suspected A. phalloides poisoning between 1999 and 2012 (identified from hospital records and calls to the New South Wales Poisons Information Centre). Frequency of poisoning and the clinical outcomes. Twelve patients presented with a history suggesting A. phalloides poisoning, 10 with probable poisoning and two with possible poisoning. Eight of those with probable poisoning developed significant hepatotoxicity and four died. Silibinin was administered to nine of those with probable poisoning (the other presented before 2005). Maintaining silibinin supply became a challenge during two clusters of poisoning. Eight of the patients with probable poisoning were not long-term residents of the ACT, and six were immigrants from Asia. The mortality rate due to A. phalloides poisoning in this case series was high despite treatment according to current standards, including use of silibinin, and the frequency of hepatotoxicity was more than double that for the previous decade. Ongoing public health campaigns are required.


Spontaneous twisting of an implanted pacemaker electrode in three cases.
We present three cases of an unusual pacing lead aberration occurring at different times after implantation. In the first patient, the electrode was twisted close to the pacemaker, and dislodgment occurred on the 40th postoperative day. In the second case, there was only proximal twisting of the electrode. In the third case the electrode was twisted in two places: proximal to the pacemaker, and distal, within the right atrium. The complication was managed successfully by reimplanting the same electrode after stiffening the lead near the generator with a portion of the stylet.


Forskolin requires more than the catalytic unit to activate adenylate cyclase.
Forskolin, a natural diterpene, is a novel, potent activator of a variety of adenylate cyclase systems; its mechanism and site of action are still disputed. We report here that, while forskolin activates liver adenylate cyclase up to 15-fold, it does not activate cyclase of ram sperm which comprises a pure catalytic subunit. However, forskolin activation of sperm adenylate cyclase activity could be observed after reconstitution with the regulatory component-enriched membrane from human erythrocytes. The diterpene weakly (3-5-fold) activated the cytosolic, soluble cyclase found in rat and ram tests, but this effect was lost when the cyclase was purified by gel chromatography. Our data are not compatible with the hypothesis that forskolin acts directly on the catalytic subunit, but rather suggest that it acts via another regulatory component, part of, or different from, the GTP-binding regulatory complex.


Percutaneous tracheostomy.
Elective tracheostomy is commonly performed on patients in intensive care units who require assisted ventilation for more than 1-2 weeks. Percutaneous dilatational techniques have recently been developed which allow tracheostomies to be performed at the bedside. These compare favourably with conventional techniques.


Some considerations on the estimation of steady state apparent volume of distribution and the relationships between volume terms.
Application of statistical moment theory to four methods which do not involve detailed compartmental analysis for the determination of Vss shows them to be equal. Assuming drug to be eliminated exclusively from the central compartment results in the minimum value of Vss being determined. A method for determining the maximum possible value of Vss is shown which uses AUC, dose (iv), and the exponents which describe the plasma-concentration time curve. The relationships between the volume terms Vextrap, Varea and Vss are discussed in terms of moment theory.


Direct in situ thermometry: Variations in reciprocal-lattice vectors and challenges with the Debye-Waller effect.
Conventional in situ transmission electron microscopy (TEM) enables the atomic-scale study of dynamic materials processes on millisecond time scales. Specimen holders capable of being heated to over 1000°C have provided insight into myriad processes, including nanoscale thermal transport, structural phase transitions, and catalytic reactions. In order for such studies to be accurate and precise, direct determination of the specimen temperature - rather than the heating-element temperature - is critical. Further, such methods should be versatile in that any temperature across a wide range may be measured, irrespective of single-indicator properties specific to the specimen (e.g., first-order phase transition, melting point, etc.). Here, we describe a rigorous approach to direct, in situ thermometry of TEM specimens that exploits lattice thermal expansion and the resultant decrease in diffraction-vector magnitude in reciprocal space. Via sub-pixel measurement of reciprocal-lattice-vector magnitudes, picometer increases in lattice parameters are measured over a continuous temperature range and compared to those expected from the coefficient of thermal expansion. Statistical treatment of several experimental trials conducted on nanostructured aluminum thin films shows excellent agreement with both theory and (indirect) measurement of the in situ heating holder. Additionally, we illustrate how uncontrolled, thermally-induced variation in single-crystal orientation leads to modulation of the excitation error and, therefore, the Bragg-spot intensities resulting in a convolution of heating and tilting effects, thus complicating temperature determination via the Debye-Waller effect.


Aboriginal and Torres Strait Islander children with obesity: A review of programmes for children and young people aged 5-17 years.
A literature review of overweight and obesity prevention and management programmes for Australian Aboriginal and Torres Strait Islander children 5-17 years to inform a co-design weight management intervention in an urban Aboriginal community. Systematic searching of PubMed, Science Direct, Lowitja LitSearch and hand-searching of references, government and Aboriginal websites. Programmes were categorised as including nutrition and food literacy, cooking skills, health education and cultural components. Quality was assessed against the CREATE QAT Tool. Eight programmes, including two evaluations and six programme descriptions, were identified. Interventions ranged in duration from 1 day to 10 weeks involving nutrition education, health information, cooking skills, exercise and cultural content. There were no significant reductions in weight outcomes, although there were reported positive health changes to the children including a reduction in waist circumference and an increase in exercise levels. Insights for future research include effective co-design with community and the delivery of flexible content through an Aboriginal-led, multifaceted programme. There is limited evidence for the prevention and management of weight in Aboriginal children with overweight and obesity. Future research efforts should include more time-intensive, multifaceted, community-run programmes that are supported by medical, advocacy and evaluation expertise from health services.


[Classification of disposable medical plastics and search for alternatives without polyvinyl chloride in the Hospital Virgen de las Nieves (Granada, Spain)].
To identify and classify disposable hospital products containing polyvinyl chloride (PVC), including the search and evaluation of cost-effective sustainable alternative products free of PVC. A descriptive observational analysis was performed, after classifying the latest research in major databases, and disposable products that could contain PVC. These were divided into 5 groups: cannulas, catheters, tubes, bags, and equipment, purchased in the period 2008-2009, differentiating between the technical and economic assessment of the materials. In the analysis of the composition of 492 articles selected, 234 (47.5%) contained PVC, and 19.4% were considered PVC-free alternatives, with only 11.3% of these being economically viable. This study highlights the advantages of the classification of PVC products, by showing that safe and efficient alternatives exist for some product lines that are consistent with patient safety and quality in the work by doctors.


A blast without power - cell death induced by the tuberculosis-necrotizing toxin fails to elicit adequate immune responses.
In this study, we deploy a doxycycline-dependent suicide switch integrated in a tumor challenge model. With this experimental setup, we characterized the immunological consequences of cells dying by four distinct cell death stimuli in vivo. We observed that apoptotic cell death induced by expression of the truncated form of BH3 interacting-domain death agonist (tBid) and a constitutively active form of caspase 3 (revC3), respectively, showed higher immunogenicity than cell death induced by expression of the tuberculosis-necrotizing toxin (TNT). Our data indicate that the early release of ATP induces the silent clearance of dying cells, whereas the simultaneous presence of 'find me' signals and danger-associated molecular patterns (DAMPs) promotes inflammatory reactions and increased immunogenicity. This proposed model is supported by findings showing that the production and release of high concentrations of IL-27 by bone-marrow-derived macrophages (BMDM) is limited to BMDM exposed to those forms of death that simultaneously released ATP and the DAMPs heat-shock protein 90 (HSP90) and high-mobility group box-1 protein (HMGB1). These results demonstrate that the tissue microenvironment generated by dying cells may determine the subsequent immune response.


Antiviral properties of cobalt(III)-complexes.
We have investigated the potential antiviral activity of three cobalt(III) compounds. Two compounds, Co(III)-cyclen-methylbenzoic acid and its methyl ester derivative, are based on the macrocyclic chelator, cyclen, and were synthesized in our laboratory. Both compounds have been shown to bind tightly to nucleic acids and to hydrolyze phosphodiester bonds. However, neither compound exhibited any significant antiviral activity in an in vitro model of Sindbis virus replication. In contrast, a third compound, Co(III)hexammine, significantly inhibited Sindbis virus replication in baby hamster kidney (BHK) cells in a dose- and time-dependent manner. In plaque assays, the incubation of Co(III)hexammine with Sindbis virus resulted in a dose-dependent decrease in virus replication when measured at both 24 and 48-h post-infection. Over the concentration range of 0-5mM Co(III)hexammine, the IC(50) for the inhibition of viral replication was determined to be 0.10+/-0.04mM at 48h. Additionally, when BHK cell monolayers were pretreated with Co(III)hexammine for 6h prior to Sindbis infection, optimal cellular morphology and plasma membrane integrity were observed at 0.6-1.2mM Co(III)hexammine. Analysis by flow cytometry confirmed that Co(III)hexammine mediated a concomitant dose-dependent increase in BHK cell viability and a decrease in the percentage of Sindbis virus-infected cells (IC(50)=0.13+/-0.04mM). Our findings demonstrate for the first time that Co(III)hexammine possesses potent antiviral activity. We discuss our findings within the context of the ability to further functionalize Co(III)hexammine to render it a highly specific antiviral therapeutic reagent.


Utilizing UVA-1 Phototherapy.
There is a long history of utilization of phototherapy for treatment of skin conditions. Because of its longer wavelength, UVA1 phototherapy is able to penetrate into the dermis and subcutis. This depth of penetration, combined with its unique immunomodulating properties, makes UVA1 an effective treatment modality for many immune-mediated skin diseases. In some cases, it performs better than other types of phototherapy.


Charcot arthropathy of the spine in long-standing paraplegia.
Three cases of Charcot spinal arthropathy in long-standing (greater than 20 years) paraplegia are presented. In this group of patients with other known chronic infections, the differential diagnosis strongly favored osteomyelitis. Scanning techniques including technetium 99, indium 111, and computed tomography (CT) were used in the extensive work-up and were helpful, although not diagnostic. Closed needle and, in two cases, open biopsies eventually confirmed the diagnosis. The possible occurrence of this neuroarthropathy long after the onset of nonprogressive paraplegia should be kept in mind by those treating spinal cord injured patients.


Role of statistics in toxicogenomics.
In this chapter, we provide a structured approach to the statistical analysis of toxicogenomic data, from the assessment of data quality to data exploration, gene and pathway level analysis, and finally predictive model building. This type of analysis approach can yield toxicogenomic models that provide validated and reliable information about the toxicity of compounds. In addition, we provide study design recommendations for genomic studies in toxicology, covering areas of power, sample size, the need for replicates, and the issue of sample pooling.


Undiagnosed Hypertension in Vancouver's Punjabi Sikh Community: A Cross-Sectional Study.
South Asians bear a greater burden of cardiovascular disease (CVD) compared to other ethnic groups and hypertension is a major modifiable risk factor. The purpose of this study was to examine rates and predictors of uncontrolled blood pressure among an immigrant Punjabi Sikh community in Vancouver. We recruited 350 adults (40% women; mean age 67.3 ± 11.9 years) across 5 Sikh temples and measured blood pressure, heart rate, height, weight, waist circumference, socio-demographic background, and health history. 42% of participants had uncontrolled blood pressure of which one-third reported no previous history of hypertension. Based on modified cut-offs for South Asians, the mean waist circumferences across groups were well above target and 50% classified as obese. A higher percentage in the uncontrolled group (vs. controlled group) were of an older age, had a diabetes history and reported a physically active lifestyle. Findings suggest more efforts are needed to reduce the rates of uncontrolled blood pressure in this community. Interventions such as blood pressure drives, community-based outreach programs, and physical activity and dietary interventions should be explored to lower this CVD risk factor in this community.


The Interplay Between Sex, Ethnicity, and Adipose Tissue Characteristics.
The obesity epidemic in the USA affects disproportionately women and the ethnic minorities. On the other hand, female sex is traditionally associated with a favorable fat distribution preferentially in the subcutaneous depots of the lower body and with improved endocrine and metabolic function of the adipose tissue. However, these data are derived from predominantly non-Hispanic white populations. This review discusses fat distribution patterns in women of diverse ethnic backgrounds, together with data on the release of adipokines from adipose tissue in these populations. Very little information is available on how the metabolic function of the adipocyte differs depending on ethnicity. Thus, it becomes clear that future clinical and translational research should explicitly discuss and take into account the sex and ethnic background of the populations studied.


Vulvoperineal Hidradenitis Suppurativa: Diagnosis, Treatment, and Management of Deformities.
Hidradenitis suppurativa (HS) is a chronic, inflammatory disorder affecting skin of intertriginous areas that is often encountered and treated by nondermatologic specialists. The purpose of this literature review is to provide a comprehensive, clinical source of information on HS as it relates to incidence of disease, pathophysiology, diagnosis, and overall management of this condition. Sources were obtained through a comprehensive literature search using PubMed and PMC. Various terms were used to query the database, including "hidradenitis suppurativa," "pathogenesis," "prevalence," "management," "surgery," "perineal," and "vulva." Underreported prevalence and unknown pathogenesis have subsequently led to variable approaches in clinical management, often employing a combination of medical and surgical management. Early diagnosis and treatment of HS may lead to better disease control and minimize patients' associated morbidity related to disease. Knowledge of vulvoperineal hidradenitis is necessary for gynecologists and primary care physicians to ensure early diagnosis, management, and referral for optimal patient outcomes.


Pushing the Upper Limit of Nucleophilicity Scales by Mesoionic N-Heterocyclic Olefins.
A series of mesoionic, 1,2,3-triazole-derived N-heterocyclic olefins (mNHOs), which have an extraordinarily electron-rich exocyclic CC-double bond, was synthesized and spectroscopically characterized, in selected cases by X-ray crystallography. The kinetics of their reactions with arylidene malonates, ArCH=C(CO2 Et)2 , which gave zwitterionic adducts, were investigated photometrically in THF at 20 °C. The resulting second-order rate constants k2 (20 °C) correlate linearly with the reported electrophilicity parameters E of the arylidene malonates (reference electrophiles), thus providing the nucleophile-specific N and sN parameters of the mNHOs according to the correlation lg k2 (20 °C)=sN (N+E). With 21<N<32, the mNHOs are much stronger nucleophiles than conventional NHOs. Some mNHOs even excel the reactivity of mono- and diacceptor-substituted carbanions. It is exemplarily shown that the reactivity parameters thus obtained allow to calculate the rate constants for mNHO reactions with further Michael acceptors and predict the scope of reactions with other electrophilic reaction partners including carbon dioxide, which gives zwitterionic mNHO-carboxylates. The nucleophilicity parameters N correlate linearly with a linear combination of the quantum-chemically calculated methyl cation affinities and buried volumes of mNHOs, which offers a valuable tool to tailor the reactivities of strong carbon nucleophiles.


Microalgae-based bioremediation of water contaminated by pesticides in peri-urban agricultural areas.
The present study evaluated the capacity of a semi-closed, tubular horizontal photobioreactor (PBR) to remove pesticides from agricultural run-off. The study was carried out in summer (July) to study its efficiency under the best conditions (highest solar irradiation). A total of 51 pesticides, including 10 transformation products, were selected and investigated based on their consumption rate and environmental relevance. Sixteen of them were detected in the agricultural run-off, and the estimated removal efficiencies ranged from negative values, obtained for 3 compounds, namely terbutryn, diuron and imidacloprid, to 100%, achieved for 10 compounds. The acidic herbicide MCPA was removed by 88% in average, and the insecticides 2,4-D and diazinon showed variable removals, between 100% and negative values. The environmental risk associated to the compounds still present in the effluent of the PBR was evaluated using hazard quotients (HQs), calculated using the average and highest measured concentrations of the compounds. HQ values > 10 (meaning high risk) were obtained for imidacloprid (21), between 1 and 10 (meaning moderate risk) for 2,4-D (2.8), diazinon (4.6) and terbutryn (1.5), and <1 (meaning low risk) for the remaining compounds diuron, linuron and MCPA. The PBR treatment yielded variable removals depending on the compound, similarly to conventional wastewater treatment plants. This study provides new data on the capacity of microalgae-based treatment systems to eliminate a wide range of priority pesticides under real/environmental conditions.


Fast imaging of phosphocreatine in the normal human myocardium using a three-dimensional RARE pulse sequence at 4 Tesla.
To investigate the use of a three-dimensional rapid acquisition with relaxation enhancement (RARE) pulse sequence for direct acquisition of phosphocreatine (PCr) images of the human myocardium. A short elliptical birdcage radiofrequency (RF) body coil was constructed to produce a uniform flip angle throughout the chest cavity. In vivo images using a spectrally-selective RARE sequence with a spatial resolution of 1.2 cm x 1.2 cm x 2.5 cm (4 cm(3)) were acquired in nine minutes and 40 seconds. Scans of phantoms demonstrated excellent spectral selectivity. The signal-to-noise ratio in the myocardium ranged from 12.6 in the anterior wall to 5.3 in the mid septum. This study demonstrates that PCr data can be acquired using a three-dimensional RARE sequence with greater spatial and temporal resolution than spectroscopic techniques.


In situ generated O-glycan core 1 structure as substrate for Gal(beta 1-3)GalNAc beta-1,6-GlcNAc transferase.
beta-Galactosidase from bovine testes was used in a one pot reaction together with a recombinant beta-1,6-GlcNAc transferase for the synthesis of GlcNAc(beta 1-6)GalNAc(alpha 1-OBn) (core 6-Bn). The galactosidase, which reversibly links galactose via a (beta 1-3) linkage to N-acetylgalactosamine, provides the substrate for the GlcNAc transferase in situ. The synthesis was carried out with a yield > 90%.


Action of mefloquine on agonist-induced contractions of the guinea-pig isolated ileum.
1. Responses of the guinea-pig isolated ileum to cumulative concentrations of acetylcholine (ACh), histamine (H), and prostaglandin E2 (PGE2) were obtained in the presence or absence of mefloquine or quinine. 2. The effects of increasing the external calcium concentration and the presence of a low concentration (1.8 nmol/l) of PGE2 on the mefloquine- and quinine-induced inhibition of the ACh cumulative dose-response curves were also investigated. 3. Mefloquine (1-10 mumol/l) and quinine (50-100 mumol/l) both caused a dose-dependent non-parallel right shift of the log concentration-response curve of every agonist. Mefloquine is a more potent inhibitor of PGE2-induced responses whereas quinine inhibited all three agonist-induced responses to the same extent. 4. Increasing the external calcium concentration enhanced the inhibitory effects of both drugs on ACh-induced responses. Pre-incubation with 1.8 nmol/l PGE2 had a similar effect. 5. The actions of mefloquine on ACh- and H-induced contractions are non-specific, like other antimalarials, but its greater inhibitory action on PGE2 may involve a more complex effect.


Serum immunoglobulin and complement interrelationships in juvenile rheumatoid arthritis.
Patients with juvenile rheumatoid arthritis (JRA) were compared with a matched control group for the presence and levels of IgG, IgM, IgA, IgE, IgD, C3, C4, and rheumatoid factor. In the majority of patients (86.1 to 94.4%) the distributions fell within the normal ranges of the control group. In JRA, older age appears to have a significant relationship for increased IgE levels. Levels of IgE and IgD do not appear to be related to the presence or activity of JRA. Significantly elevated levels of IgG, IgA, and C4 were found in active disease while elevated IgM levels are characteristic of the disease itself.


Outcome-Supervised Deep Learning on Pathologic Whole Slide Images for Survival Prediction of Immunotherapy in Patients with Non-Small Cell Lung Cancer.
Although programmed death-(ligand) 1 (PD-(L)1) inhibitors are marked by durable efficacy in patients with non-small cell lung cancer (NSCLC), approximately 60% of the patients still suffer from recurrence and metastasis after PD-(L)1 inhibitor treatment. To accurately predict the response to PD-(L)1 inhibitors, we presented a deep learning model using a Vision Transformer (ViT) network based on hematoxylin and eosin (H&E)-stained specimens of patients with NSCLC. Two independent cohorts of patients with NSCLC receiving PD-(L)1 inhibitors from Shandong Cancer Hospital and Institute and Shandong Provincial Hospital were enrolled for model training and external validation, respectively. Whole slide images (WSIs) of H&E-stained histologic specimens were obtained from these patients and patched into 1024 × 1024 pixels. The patch-level model was trained based on ViT to identify the predictive patches, and patch-level probability distribution was performed. Then, we trained a patient-level survival model based on the ViT-Recursive Neural Network framework and externally validated it in the Shandong Provincial Hospital cohort. A total of 291 WSIs of H&E-stained histologic specimens from 198 patients with NSCLC in Shandong Cancer Hospital and 62 WSIs from 30 patients with NSCLC in Shandong Provincial Hospital were included in the model training and validation. The model achieved an accuracy of 88.6% in the internal validation cohort and 81% in the external validation cohort. The survival model also remained a statistically independent predictor of survival from PD-(L)1 inhibitors. In conclusion, the outcome-supervised ViT-Recursive Neural Network survival model based on pathologic WSIs could be used to predict immunotherapy efficacy in patients with NSCLC.


Microbiological survey of prepackaged pâté and ham in New Zealand.
To gauge the effectiveness of pâté and ham manufacturers' management of the microbial safety and quality of their products. A survey of 60 batches of prepackaged pâté showed that 41.7% of the batches had aerobic plate counts (APC) exceeding 10(5) CFU g(-1), one of pâté sample contained a Bacillus cereus count of >5000 CFU g(-1) and another contained 1700 CFU g(-1) of Listeria monocytogenes. No other pathogens were isolated from any of the samples. The survey of prepackaged ham showed that only 1% (1/104) of the ham samples were positive for L. monocytogenes (50 CFU g(-1)). The presence of microbial hazards in these foods has generally declined since the early 1990s in New Zealand. Noncomplying APC levels may be due to an over-estimation of product shelf life or poor food handling practices during manufacture. Few of the samples tested contained pathogens at significant levels. The prevalences of L. monocytogenes in pâté and ham were low. The presence of 1700 CFU g(-1) of L. monocytogenes in a pâté sample indicates that occasionally, the population can be exposed to levels of L. monocytogenes above the zero tolerance level set in New Zealand.


Fucosidosis: ultrastructural study of the eye in an adult.
The ocular histopathological and ultrastructural features of fucosidosis in a man who survived to the age of 25 years are reported. Virtually all of the cells of the eye contained cytoplasmic, membrane-bound, and confluent areas of fibrillogranular and multilaminated material. The most striking accumulations were present within the endothelial cells lining blood vessels and corneal endothelium, and the least amount was present in the uveal melanocytes.


Size dependent effect of ZnO nanoparticles on endoplasmic reticulum stress signaling pathway in murine liver.
ZnO nanoparticles (NPs) have been assessed to show adverse effects on the liver, but the molecular mechanisms and the role of nanoparticle properties in these adverse reactions have not been sufficiently studied. In this study, the toxicity of various sizes of ZnO particles (bulk, 90nm, and 30nm) that were ingested orally over a period of 3days were evaluated in mice. The blood biochemistry, hematological analyses, and histopathological evaluation showed that there was apparent toxicity caused by smaller ZnO NPs (30nm) in liver. The smallest ZnO NPs showed highest accumulation in the mice liver. The RT-qPCR data indicated that 30nm ZnO NPs can induce significant endoplasmic reticulum (ER) stress responses. The ER stress marker of PERK, eIF2α, ATF4, Chop, JNK, caspase-12, caspase-9, GRP94, and Bax at the mRNA levels were higher expression in 30nm ZnO NP than that in bulk or 90nm ZnO. These findings implied that the smaller ZnO NPs (30nm) activated ER stress responses that signified severe apoptosis in murine liver.


Bone development in the fetus and neonate: role of the calciotropic hormones.
During embryonic and fetal development much of the skeleton initiates as a cartilaginous scaffold, which is progressively resorbed and replaced by bone. Endochondral bone formation continues until the growth plates fuse during puberty. At all life stages adequate delivery of mineral is required for the skeleton to achieve and maintain appropriate mineral content and strength. During fetal development the placenta actively transports calcium, phosphorus, and magnesium. Postnatally passive and then active absorption from the intestines becomes the main supply of minerals to the skeleton. Animal and human data indicate that fetal bone development requires parathyroid hormone (PTH) and PTH-related protein but not vitamin D/calcitriol, calcitonin, or (possibly) sex steroids. During the postnatal period, when intestinal calcium absorption becomes an active process, skeletal development begins to depend upon vitamin D/calcitriol but this requirement can be bypassed by increasing the calcium content of the diet or by administering intermittent calcium infusions.


Influence of nectar-supply rate on the number of flowers visited by a honeybee on each collecting flight.
The behavior of nectar-collecting honeybees (Apis mellifica) at a glass sugar-water contained and at various plants was observed, and these food sources were compared with regard to duration of the bee's sojourn in the collecting area and the number of single visits per sojourn. Meagre - but continuous - nectar secretion by the flowers of bee-pollinated plants, when combined with a small distance between the individual flowers, results in a high number of flowers visited during a sojourn in the collecting area.


Myelination of jp,jpmsd, and qk axons by normal glia in vitro: ultrastructural and autoradiographic evidence.
Normal optic nerve glia were 'injected' into hypomyelinated mutant jp,jpmsd, and qk cerebellum by co-culturing explants in direct physical contact. Quantitative light microscopic studies demonstrated that such glial injection significantly increased the number of myelin profiles counted in cultures, suggesting that axons in all 3 mutants can accept myelination from competent glia when they are made available. In each mutant, the observed increase in myelination was independent of the ages of donor optic nerves and recipient cultures, but absolutely required positioning of the optic nerve so that direct contact occurred with the mutant cerebellar explants. The additional myelin found near the zone of fusion with the optic nerve morphologically resembled normal, not mutant myelin. Autoradiographs made after [3H]thymidine-labeled normal optic nerve was injected into jpmsd cultures showed that labeled cells had colonized the nearby mutant tissue. Labeled cells identified as oligodendrocytes by ultrastructural criteria were found adjacent to myelin segments near the fusion zone, but direct continuity between processes of these oligodendrocytes and myelin sheaths was not demonstrated. The astrocytes and phagocytic cells which were also labeled had no obvious relationship to myelinated axons. These results provide experimental evidence that the primary abnormalities produced by the three mutations jp,jpmsd, and qk are inherent in their glial cells, probably although not definitely in the oligodendrocytes.


Combined effects of levetiracetam and sodium valproate on paediatric patients with epilepsy: a systematic review and meta-analysis.
To estimate the safety and efficacy of sodium valproate combined with levetiracetam in paediatric patients with epilepsy based on randomized controlled trials (RCTs). The Cochrane Library, PubMed, Web of Science, Chinese Journal Full-Text Database (CNKI), WANGFANG DATA and Sino Med were searched between January 1946 and May 2021. The included literature was randomized controlled clinical trials focusing on sodium valproate combined with levetiracetam in paediatric patients with epilepsy. Two evaluators separately collected the data based on the retrieval strategy, filtered the literature in accordance with the inclusion and exclusion criteria, and summarized the literature that satisfied the criteria. The statistical programme used for the meta-analysis was Stata V14.0. Of 577 original titles screened, data were extracted from 7 studies (617 participants). Compared with sodium valproate alone or sodium valproate combined with topiramate, the application of sodium valproate combined with levetiracetam in the treatment of paediatric epilepsy significantly improved the overall therapeutic effect (RR=1.24, 95% CI: 1.16 to 1.33, p=0.927). The observation group significantly reduced the occurrence of adverse drug reactions (ADRs) (RR=0.54, 95% CI: 0.37 to 0.79, p=0.602). Egger's regression test of the overall therapeutic effect showed no potential publication bias (p=0.122). Based on this meta-analysis, compared with sodium valproate alone or sodium valproate with topiramate, the application of sodium valproate combined with levetiracetam in the treatment of paediatric epilepsy can significantly improve the overall therapeutic effect and simultaneously reduce the occurrence of ADR. Therefore, we recommend sodium valproate combined with levetiracetam for the therapy of paediatric patients with epilepsy.


Functionalized magnetic nanoparticles attenuate cancer cells proliferation: Transmission electron microscopy analysis.
The penetration and transportation of nanoparticles (NPs) inside the cancer cells is critical to study. In this article, cancer cells (HCT-116) were treated with functionalized magnetic NPs for the period of 48 hr and studied their ultrastructure by transmission electron microscopy (TEM). The NPs-treated cells were prepared by chemical fixation and sliced into electron-transparent arbitrary sections (200 × 200 μm2 ) by ultramicrotome. Major events of NPs-cell interaction, such as penetration of NPs, encapsulation of NPs into the intracellular compartments, transportation of NPs, and NPs exit, were examined by TEM to understand the mechanism of cell death. The NPs showed the uniform spherical shape with broad size distribution (100-400 nm), while cells displayed irregular morphology with average diameter ~5 μm. Our results showed the successful penetration of NPs deep into the cell, encapsulation, transportation, and exocytosis. Furthermore, we tested the different concentrations (0, 1.5, 12.5, and 50 μg/ml) of NPs on cancer cells and evaluated the cell viability. Laser confocal microscopy and colorimetric analysis together demonstrated that the cell viability is a dose-dependent phenomenon, where 50 μg/ml specimen showed the highest killing of cancer cells compared to other dosages.


Reaction-diffusion models for morphological patterning of hESCs.
In this paper we consider mathematical modeling of the dynamics of self-organized patterning of spatially confined human embryonic stem cells (hESCs) treated with BMP4 (gastruloids) described in recent experimental works (Warmflash in Nat Methods 11:847-854, 2014; Chhabra in PloS Biol 17: 3000498, 2019). In the first part of the paper we use the activator-inhibitor equations of Gierer and Meinhardt to identify 3 reaction-diffusion regimes for each of the three morphogenic proteins, BMP4, Wnt and Nodal, based on the characteristic features of the dynamic patterning. We identify appropriate boundary conditions which correspond to the experimental setup and perform numerical simulations of the reaction-diffusion (RD) systems, using the finite element approximation, to confirm that the RD systems in these regimes produce realistic dynamics of the protein concentrations. In the second part of the paper we use analytic tools to address the questions of the existence and stability of non-homogeneous steady states for the reaction-diffusion systems of the type considered in the first part of the paper.


An 80-Year-Old Man With Respiratory Insufficiency After Intravesical Mycobacterium bovis BCG Immunotherapy.
An 80-year-old man came to the ED with fever, hematuria, and overall discomfort for 1 week. His medical history included a superficial urothelial carcinoma of the bladder for which he was adjunctively treated with intravesical Mycobacterium bovis BCG (bacillus Calmette-Guérin) immunotherapy for several months. The patient was admitted to the hospital and was initially treated with cephalosporins for a suspected complicated urinary tract infection, but his symptoms did not improve. Ten days after the initial admission, the patient developed hypoxemic respiratory failure during an episode of fever and cold chills and was admitted to the ICU.


Association between sputum conversion and in-hospital mortality in elderly patients with pulmonary tuberculosis: a retrospective study.
Non-conversion of sputum culture or smear within 2 months after the start of treatment is a known poor prognostic factor of pulmonary tuberculosis. In elderly patients, sputum conversion may be delayed because of the age-related decline in immune competence. This study aimed to assess how a long interval to sputum conversion predicts in-hospital mortality in elderly patients with pulmonary tuberculosis. Consecutive elderly patients (age > 65 years) who were admitted to our institution for bacteriologically confirmed pulmonary tuberculosis were included. The association between sputum conversion within 30, 60, 90, or 120 days from the start of treatment and in-hospital mortality were analyzed by Cox proportional-hazards regression after adjustment for other potential variables. This study included 262 patients, and 74 patients (28%) died during hospitalization. Multivariate analyses showed that sputum non-conversion within 90 days (adjusted hazard ratio 0.424, 95% CI 0.252-0.712, p = 0.001) or 120 days (0.333, 0.195-0.570, p < 0.001) was independently associated with in-hospital mortality, whereas that within 60 days was not (p = 0.890). In elderly patients with tuberculosis, 2 months may be insufficient when evaluating sputum conversion as a prognostic factor. Sputum non-conversion within 90 days or longer may predict in-hospital mortality more accurately.


Small-for-size partial liver graft in an adult recipient; a new transplant technique.
We report a new technique of adult liver transplantation using a small-for-size graft. In order to avoid graft congestion and failure by overperfusion, we completely diverted the superior mesenteric venous flow by a mesocaval shunt with downstream ligation of the superior mesenteric vein. The recipient recovered well, and the graft had normal histology and function at 5 months follow-up. Given the current scarcity of cadaveric donors, this technique may increase the numbers of adult recipients by using left lobes from cadaveric split liver grafts.


Use of endocanalicular dacryocystorhinostomy with multidiode laser in children.
To evaluate the clinical outcome and efficacy of endocanalicular laser dacryocystorhinostomy using a multidiode laser in cases unresponsive to medical therapy, probing or intubation of pediatric nasolacrimal duct obstruction. Eight children with nasolacrimal duct obstruction were treated with a multidiode laser. The study was prospective, non-randomized, and noncomparative. The patients, 2 (25%) males and 6 (75%) females, ranged in age from 8 to 13 years (mean 11.25±2.43). Surgery was performed under general anesthesia. All procedures were performed using a multidiode laser. The nasal passage was visualized with a 30° nasal video endoscope. In all cases, silicone stents were inserted. The main outcome measure was resolution or improvement of the epiphora and no major laser damage intranasally. Patients were followed for at least 6 months. The endocanalicular laser dacryocystorhinostomy failed in one of the 8 (12.5%) cases, which had been secondary to trauma. The others were due to primary nasolacrimal duct obstruction. External dacryocystorhinostomy was performed on the failed case. None of the cases with primary nasolacrimal duct obstruction had obstruction after the endocanalicular laser dacryocystorhinostomy operation. Endocanalicular laser dacryocystorhinostomy using a multidiode laser appears to be an effective technique in cases unresponsive to medical therapy, probing or intubation of primary nasolacrimal duct obstruction.


Treating Obesity in Preschoolers: A Review and Recommendations for Addressing Critical Gaps.
Developing interventions targeting obesity reduction in preschoolers is an emergent area. Although intensive, multicomponent interventions seem a promising approach to preschool obesity reduction, this review identifies and discusses approaches to 3 critical gaps (poor reach to families from low-income and minority backgrounds, lack of sufficient evidence to determine the most effective and efficient treatment components and approaches to treating obesity in early childhood, and lack of consensus on how best to discern intervention effectiveness) that need to be addressed to advance the preschool obesity literature.


Characterization of high voltage spindles and spatial memory in young, mature and aged rats.
EEG was recorded from rats of three age groups, and high voltage spindles (HVS) were measured during waking immobility. Total mean spindling times in 4- (young), 10- (mature) and 22- (aged) month-old rats were 0.3 +/- 0.1, 20.4 +/- 7.4 and 33.4 +/- 14.9 s, respectively. Spatial memory was assessed in these rats using a discrimination version of the Morris water maze. Performance (as measured by number of choice errors) was compared with the extent of HVS activity by characterizing rats as "spindling" if the total average duration of HVS discharges exceeded 5 s, and "non-spindling" if these discharges averaged less than 5 s. Spindling and nonspindling rats had similar performance during training; however, on a 14-day retention trial, spindling rats had a significantly higher mean error score of 2.8 +/- 0.5 compared with 1.2 +/- 0.3 for nonspindling rats (p = 0.011). These results show that spindling activity increases in mature and aged rats, and that HVS discharges may be an electrophysiological change that parallels the progression of brain dysfunction associated with memory impairment.


Regeneration of normal terminal innervation patterns by central noradrenergic neurons after 5,7-dihydroxytryptamine-induced axotomy in the adult rat.
The regeneration of central adrenergic axons has been followed between 5 days and 18 months after 5,7-dihydroxytryptamine(5,7-DHT)-induced axotomy in the adult rat, using fluorescence histochemistry in combination with noradrenaline (NA) determinations and [3H]NA uptake measurements. The axonal and terminal degeneration caused by the 5,7-DHT treatment (150 micrograms intraventricularly) was, by 1--2 weeks after injection, accompanied by a 70% reduction of NA in the forebrain and 30% reduction in the brain stem, and by 43--85% reductions in the [3H]NA uptake capacity in various regions of the brain and spinal cord. Signs of sprouting of the drug-lesioned axons were evident along the terminal axon segments at 5 days after treatment. The sprouts increased rapidly in length and number during the subsequent weeks and by 2--6 months after injection new NA terminal systems of relatively normal density and distribution had been re-established in many initially denervated regions. In parallel there was a recovery of endogenous NA and [3H]NA uptake to the pre-injection levels in the brain, and to levels 50--75% of normal in the cervical and thoracic spinal cord. Four successive phases of the regeneration process are distinguished: (1) primary sprouting from the lesioned NA axon stumps, occurring within the first week after treatment; (2) seemingly random growth and proliferation of the newly formed sprouts during the second and third weeks; (3) directed, forward growth of some of the sprouts leading to a partial restoration of the original fibre paths, branching patterns and terminal networks within 3--6 months; (4) a concomitant removal of at least part of the abnormally directed sprouts. Although the original fibre architecture was quite accurately restored in many areas the regeneration was not always correct. Hyperinnervation patterns and abnormal terminal arrangements were often formed, and in the spinal cord the down-growth of the regenerating axons occurred predominantly along a route that is inconspicuous in the normal rat. It is concluded that at least certain types of central neurons regenerate very efficiently provided the conditions are favourable, and that under such conditions axonal regeneration in the mammalian CNS is subjected to regulatory mechanisms that can be very precise. The results provide evidence that the adult mammalian CNS possesses mechanisms for axonal guidance which allow the accurate regeneration of lesioned axonal tracts and branching patterns, as well as mechanisms of recognition making possible the re-establishment of the original terminal connections.


Combined effects of P25 TiO2 nanoparticles and disposable face mask leachate on microalgae Scenedesmus obliquus: analysing the effects of heavy metals.
Disposable surgical face masks extensively used during the COVID-19 outbreak would release microplastics into the aquatic environment. The increasing usage of titanium dioxide nanoparticles (nTiO2) in various consumer items has led to its ubiquitous presence in freshwater systems. This study determined the quantity and kind of microplastics discharged from disposable surgical face masks. The mask-leached microplastics were identified to be polypropylene of varying shapes and sizes, spanning from 1 μm to 15 μm. In addition, heavy metals like Cd, Cr, and Hg leached from the face masks were quantified. Four concentrations of nTiO2, 0.5, 1, 2, and 4 mg L-1, were mixed with leached solution from the face masks to perform the combined toxicity test on freshwater algae, Scenedesmus obliquus. A dose-dependent decrease in algal cell viability was observed upon treatment with various concentrations of nTiO2 individually. The mixtures of nTiO2 and the leached solution from the face masks exhibited significantly more toxicity in the algal cells than in their pristine forms. nTiO2 promoted increased production of oxidative stress and antioxidant enzyme activities resulting in cellular damage and decreased photosynthesis. These impacts were elevated when the algal cells were treated with the binary mixture. Furthermore, the heavy metal ions leached from face masks also contributed to the toxic effects. Our study shows that the leachates from disposable surgical face masks, combined with nTiO2, may pose a severe environmental threat.


[Normal structure and ultrastructure of the superior cervical ganglion cells in the rat].
It is surprising to ascertain, as did DE LEMNOS and PICK, that the fine structure of rat ganglia has not raised up more interest, If one considers neurons only, S.I.F. and satellite cells are not generally described. Relatively little information is available on the nucleus organization, except nuclear mambran folds (FORSSMANN). Cajal's intranuclear rod shaped inclusions have been omitted or imperfectly studied except by SEITE. However, the presence of the structures testifies the biochemical activity in neurons. In the present ultrastructural investigation, perticular attention was given to the perikaryon fine structure in neurons. Changes in neuronal appearance were estimated in cultures and grafts with reference to morphological features of the perikaryon.


Crowded jewel fish show changes in dendritic spine density and spine morphology.
This study demonstrates that neuronal development can be adversely affected by short-term crowding. Compared with uncrowded siblings (15 fish/73-litre), juvenile jewel fish (15 fish/3.6-litre) crowded for 60 days exhibited 50-58% fewer dendritic spines and spines with narrower heads on pyriform interneurons in deep tectal strata. These findings indicate that crowded environments can produce aberrant neuronal development similar to that seen in socially deprived jewel fish.


Experimental otitis media with effusion induced by intratympanic lipid A instillation.
Otitis media with effusion was induced in guinea pigs by intratympanic instillation of lipid A, the lipid moiety of gram-negative bacterial lipopolysaccharide from Salmonella minnesota Re595. Lipid A was chosen as an inducer because of its similar composition among various bacterial species. Animals were killed from the first to 14th day after instillation of various concentrations (0.2, 2, 20, 200 micrograms/ml) of lipid A in 0.5% triethylamine. By 3 days after instillation, all experimental animals developed serous middle ear effusion. The histologic findings included hemorrhage, mucosal edema, capillary engorgement, and migration of infiltrative cells including macrophages, polymorphonuclear neutrophils, and lymphocytes. These findings were most prominent 3 days after instillation, and the recovery of the middle ear epithelium was observed within 14 days. Repeated instillation of lipid A (2 micrograms/ml) at an interval of 14 days reinforced the local response accompanied by serous middle ear effusion. These findings indicate that lipid A can induce the inflammatory changes with middle ear effusion and that lipid A plays an important role in the pathogenesis of otitis media with effusion.


Snowmobile accidents in Northern Sweden.
A total of 129 snowmobile injuries occurring in 117 persons was registered during the winter of 1976-7 in Jämtland, a county of northern Sweden. During that period about 6600 snowmobiles were in use in the district. In 92 cases speed contributed to the cause of the accident. Seventy-five persons were injured when falling off the vehicle or getting caught beneath it. The accidents are analysed and suggestions are made for their prevention.


Effectiveness of teaching general practitioners skills in brief cognitive behaviour therapy to treat patients with depression: randomised controlled trial.
To assess the effectiveness of teaching general practitioners skills in brief cognitive behaviour therapy. Parallel group, cluster randomised, controlled trial of an educational package on cognitive behaviour therapy. General practices in north London. 84 general practitioner principals and 272 patients attending their practices who scored above the threshold for psychological distress on the hospital anxiety and depression scale. A training package of four half days on brief cognitive behaviour therapy. Scores on the depression attitude questionnaire (general practitioners) and the Beck depression inventory (patients). Doctors' knowledge of depression and attitudes towards its treatment showed no major difference between intervention and control groups after 6 months. The training had no discernible impact on patients' outcomes. General practitioners may require more training and support than a basic educational package on brief cognitive behaviour therapy to acquire skills to help patients with depression.


Soman toxication in hypoxia acclimated rats: alterations in brain neuronal RNA and survival.
Effects of prior hypoxia acclimation (14-day at 380 mm Hg) on soman (pinacolyl methylphosphonofluoridate) induced brain neuronal RNA and acetylcholinesterase (AChE) depletion and lethality were monitored in rats following their return to ambient oxygenation. Quantitative cytochemical techniques were used to measure RNA and AChE changes in individual cerebrocortical (Layer III) and striatal (caudate plus putamen) neurons. In ambient Po2 controls, soman eventuated in a moderate diminution of neuronal RNA in both brain regions and severe, dose-dependent suppression of AChE activity. Hypoxia acclimation per se induced RNA alterations as manifested in cortical RNA depletion and increased variability of striatal neuron RNA contents. In hypoxia acclimated rats, the extent of neuronal RNA depletion following soman injection was attenuated in both brain regions, yet there were no discernible differences in saline control AChE levels or in the extent of soman-induced AChE inhibition in ambient control versus hypoxia acclimated treatment groups. Hypoxia acclimated rats, however, were found to be even more susceptible to lethal actions of soman as assessed using 24- and 48-hour survival following a three-point treatment regimen. These data indicate that while compensatory systemic and central metabolic adjustments associated with 14d acclimation to reduced oxygen availability may retard soman-induced neuronal RNA depletion, resistance to lethal or near-lethal soman exposure is not enhanced. It is postulated that hypoxia acclimation is associated with complex adaptive and maladaptive neurophysiological alterations influencing CNS responsiveness to soman toxication, and that detrimental consequences exceed protection afforded by metabolic adaptation.


Parallel processing of appetitive short- and long-term memories in Drosophila.
It is broadly accepted that long-term memory (LTM) is formed sequentially after learning and short-term memory (STM) formation, but the nature of the relationship between early and late memory traces remains heavily debated [1-5]. To shed light on this issue, we used an olfactory appetitive conditioning in Drosophila, wherein starved flies learned to associate an odor with the presence of sugar [6]. We took advantage of the fact that both STM and LTM are generated after a unique conditioning cycle [7, 8] to demonstrate that appetitive LTM is able to form independently of STM. More specifically, we show that (1) STM retrieval involves output from γ neurons of the mushroom body (MB), i.e., the olfactory memory center [9, 10], whereas LTM retrieval involves output from αβ MB neurons; (2) STM information is not transferred from γ neurons to αβ neurons for LTM formation; and (3) the adenylyl cyclase RUT, which is thought to operate as a coincidence detector between the olfactory stimulus and the sugar stimulus [11-14], is required independently in γ neurons to form appetitive STM and in αβ neurons to form LTM. Taken together, these results demonstrate that appetitive short- and long-term memories are formed and processed in parallel.


Morphological and histochemical ageing changes in patellar articular cartilage of the rat.
The aim of this study was to investigate the variation in cartilage characteristics with age. Fresh-frozen cryostat sections of the patellar articular cartilage of the rat were used to demonstrate the enzyme activity of succinate dehydrogenase, lactate dehydrogenase, alkaline phosphatase, and acid phosphatase in the different layers and at different ages. Light microscopic techniques were used to analyse quantitative features such as thickness, cell density and the histological characteristics of the articular cartilage. The results indicate that cell density is significantly affected by age. Furthermore, it depends on the distance from the surface. The most marked decline in cell density occurred between months 3 and 6. The thickness of the articular cartilage also varies with age. The reduction in cartilage thickness was most striking between months 3 and 6. Differentiation into the histological layers is obvious after 3 months. Glycolytic enzymes were strongly reactive in all regions and at all ages, whereas aerobic activity declines with age. The metabolic and morphological changes in ageing cartilage contribute to trophic disorders and deterioration of the functional cartilaginous situation in adult cartilage.


Quality-of-Life Analysis of the German Prospective Multicentre Trial of Single-cycle Adjuvant BEP Versus Retroperitoneal Lymph Node Dissection in Clinical Stage I Nonseminomatous Germ Cell Tumours.
The superiority of one course of bleomycin, etoposide, and cisplatin (BEP) over retroperitoneal lymph node dissection (RPLND) as adjuvant treatment in patients with clinical stage I nonseminomatous germ cell tumours (CSI-NSGCT) in terms of recurrence has been shown. However, studies providing validated prospective quality-of-life (QoL) data in patients with CSI-NSGCT treated with only one cycle of BEP are lacking. To examine and compare QoL issues in patients with CSI-NSGCT after adjuvant treatment. Between 1996 and 2005, we randomly assigned a total of 382 patients with CSI-NSGCT to receive either one course of BEP or RPLND after orchiectomy. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) plus additional scales questionnaire (QLQ-C30+) was completed prospectively according to an a priori schedule, with a final assessment in 2011. We used the Mann-Whitney U test to detect a difference ≥17% on the global QoL item "overall strain." Of 382 patients randomised to receive either one course of BEP (n=191, arm A) or RPLND (n=191, arm B), completed QLQ-C30+ and data on treatment response were available in 162 and 164 patients, respectively. All participants were included for intention-to-treat analysis. We evaluated treatment-related changes in QoL for the follow-up period up to 3 yr after treatment. We observed no significant differences between the treatment groups in any QoL domain except alopecia. Compared to QoL assessments in the general population, both arms had already recovered to normal values in all items by 6 mo. The QoL assessment of this large randomised trial was not able to detect significant differences in QoL scores between patients undergoing RPLND and BEP in a community-based setting. Retroperitoneal lymph node dissection and bleomycin, etoposide, and cisplatin are two adjuvant treatment options for patients with CSI-NSGCT after orchiectomy. Quality of life had already recovered to normal levels in both groups by 6 mo after treatment. No clinically relevant differences were detected.


Anti-influenza virus activity of Chaenomeles sinensis.
This investigation evaluated anti-influenza virus activity of 50% ethanol extract of the fruit of Chaenomeles sinensis K(OEHNE), which is widely used as a traditional Chinese medicine to treat throat diseases. Type A and B influenza viruses were treated with the extract at various concentrations for 1h at room temperature; then the plaque titers of the treated viruses were determined. The neutralizing component in the extract was partially purified using HP20 column chromatography. Treatment with the extract at concentrations greater than 5mg/ml reduced the plaque titers of the both viruses to less than 10% of those of untreated viruses. The treatment inhibited viral hemagglutination activity, too. When the 50mg/ml extract was added to the culture medium after inoculation of the virus, viral NS2 protein synthesis was selectively inhibited and progeny virus was not detected in the infected cell medium. Partial purification showed that the neutralizing component consisted of high molecular weight polyphenols. High molecular weight polyphenols in the fruits of C. sinensis neutralizes influenza virus by inhibiting hemagglutination activity and by suppressing NS2 protein synthesis.


iTRAQ technology-based identification of human peripheral serum proteins associated with depression.
Clinical depression is one of the most common and debilitating psychiatric disorders and contributes to increased risks of disability and suicide. Differentially expressed serum proteins may serve as biomarkers for diagnosing depression. In this study, samples from depressed patients are aggregated into a pool (22×100μL serum was used) and samples from healthy volunteers are aggregated into the other pool (20×100μL serum was used). Isobaric tag for relative and absolute quantitation (iTRAQ) technology and tandem mass spectrometry were employed to screen for differentially expressed serum protein in two separate pools. We identified 472 proteins in the serum samples, and 154 of these presented differences in abundance between the depression and control groups. Ingenuity pathway analysis (IPA) was employed to identify the highest scoring proteins in signaling pathway networks. Finally, four differentially expressed proteins were validated by enzyme-linked immuno sorbent assay (ELISA). Proteomic studies revealed that levels of c-reaction protein (CRP), inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4), serum amyloid A1 (SAA1) and angiopoietin-like 3 (ANGPTL3) were substantially increased in depressed patients compared with the healthy control group. Therefore, these differentially expressed proteins may represent potential markers for the clinical diagnosis of depression.


Proteomic Profiling of Native Unpassaged and Culture-Expanded Mesenchymal Stromal Cells (MSC).
Human culture-expanded mesenchymal stromal cells (MSC) are being considered for multiple therapeutic applications because of their regenerative and anti-inflammatory properties. Although a large number of MSC can be propagated from a small initial sample, several lines of evidence indicate that MSC lose their immunosuppressive and regenerative potency aftaer multiple passages. In this report, we use the FACSCAP Lyoplate proteomic analysis system to detect changes in cell surface protein expression of CD45- /CD31- /CD34- /CD73+ /CD105+ stromal cells in unpassaged bone marrow (BM) and through 10 serial culture passages. We provide for the first time a detailed characterization of native unpassaged BM MSC (0.08% of BM mononuclear cells) as well as the changes that occur during the initial expansion. Adipogenic and osteogenic differentiative potential was determined though the serial passages and correlated with immunophenotypic changes and senescence. Among the most prominent were striking decreases in Fas ligand, CD98, CD205, and CD106, accompanied by a gain in the expression of CD49c, CD63, CD98, and class 1 and class 2 major histocompatibility complex (MHC) molecules. Other molecules that are down-modulated with later passage include CD24, CD54, CD59, CD243/P-glycoprotein, and CD273/PD-L2. Early senescence, as defined by the loss of replicative capacity occurring with the loss of differentiative capacity, increase in CDKN2A p16, and increased time to confluence, was accompanied by loss of the motility-associated metalloproteinase CD10 and the proliferation-associated transferrin receptor CD71. Among the strongest statistical associations were loss of MAC-inhibitory protein/CD59, loss of ICAM-1/CD54, and increase in CDKN2A as a function of increasing passage, as well as increased CD10 expression with adipogenic and osteogenic capacities. The data provide a clear set of markers that can be used to assess MSC quality. We suggest that clinically relevant numbers of highly functional low passage MSC can be manufactured starting with large quantities of BM, which are readily available from cadaveric organ donors.


Inflammatory changes associated with circadian variation in pulmonary function in subjects with mild asthma.
Nocturnal enhancement of airway inflammation has been demonstrated in patients with asthma who have a significant drop in pulmonary function at night. To investigate the circadian changes in airway inflammation and their relationship with variations in pulmonary function in subjects with mild atopic asthma. Twelve asthma subjects were admitted to the hospital for two separate 24-h visits. Bronchoalveolar lavage (BAL) was performed at 04:00 hours during one visit, and at 16:00 hours during another visit. BAL cells were analysed for lymphocyte phenotype and the capacity to secrete cytokines following ex vivo stimulation with phytohaemagglutinin (PHA). The numbers of BAL lymphocytes and the percentage of CD4+ T cells were higher at 04:00 hours compared with 16:00 hours. At 04:00 hours, the forced expiratory volume in 1 s (FEV1) was inversely correlated with BAL lymphocytes and CD4+ cells. PHA-induced generation of IL-5 by BAL cells correlated with BAL eosinophils and CD4+ cells. Moreover, there was a linear relationship between the relative change (16:00-04:00 hours) in IL-5 and circadian variation in FEV1. These data suggest that the circadian variation in lung function in asthma is associated with increased airway CD4+ lymphocyte numbers and their capacity to generate IL-5. Furthermore, in mild asthma, these circadian changes appear to fall into a continuous range, suggesting that day/night variations in airway inflammation and lung function occur on a continuum, rather than as an all-or-none phenomenon.


Different palm oil preparations reduce plasma cholesterol concentrations and aortic cholesterol accumulation compared to coconut oil in hypercholesterolemic hamsters.
Several studies have reported on the effect of refined, bleached and deodorized palm oil (RBD-PO) incorporation into the diet on blood cholesterol concentrations and on the development of atherosclerosis. However, very little work has been reported on the influence of red palm oil (RPO), which is higher in carotenoid and tocopherol content than RBD-PO. Thus, we studied the influence of RPO, RBD-PO and a RBD-PO plus red palm oil extract (reconstituted RBD-PO) on plasma cholesterol concentrations and aortic accumulation vs. hamsters fed coconut oil. Forty-eight F1B Golden Syrian hamsters (Mesocricetus auratus) (BioBreeders, Watertown, MA) were group housed (three/cage) in hanging polystyrene cages with bedding in an air-conditioned facility maintained on a 12-h light/dark cycle. The hamsters were fed a chow-based hypercholesterolemic diet (HCD) containing 10% coconut oil and 0.1% cholesterol for 2 weeks at which time they were bled after an overnight fast and segregated into four groups of 12 with similar plasma cholesterol concentrations. Group 1 continued on the HCD, Group 2 was fed the HCD containing 10% RPO in place of coconut oil, Group 3 was fed the HCD containing 10% RBD-PO in place of coconut oil and Group 4 was fed the HCD with 10% reconstituted RBD-PO for an additional 10 weeks. Plasma total cholesterol (TC) and non-high-density lipoprotein-cholesterol (HDL-C) (very low- and low-density lipoprotein) concentrations were significantly lower in the hamsters fed the RPO (-42% and -48%), RBD-PO (-32% and -36%) and the reconstituted RBD-PO (-37% and -41%) compared to the coconut oil-fed hamsters. Plasma HDL-C concentrations were significantly higher by 14% and 31% in hamsters fed the RBD-PO and RPO compared to the coconut oil-fed hamsters. Plasma triglyceride (TG) concentrations were significantly lower in hamsters fed RBD-PO (-32%) and the reconstituted RBD-PO (-31%) compared to the coconut oil-fed hamsters. The plasma gamma-tocopherol concentrations were higher in the coconut oil-fed hamsters compared to the hamsters fed the RPO (60%), RBD-PO (42%) and the reconstituted RBD-PO (49%), while for plasma alpha-tocopherol concentrations, the coconut oil-fed hamsters were significantly higher than only the RPO-fed hamsters (21%). The coconut oil-fed hamsters also had significantly higher plasma lipid hydroperoxide concentrations compared to RBD-PO (112%) and the reconstituted RBD-PO (485%). The hamsters fed the coconut oil diet excreted significantly more fecal total neutral sterols and cholesterol compared to the hamsters fed the RBD-PO (158% and 167%, respectively). The coconut oil-fed hamsters had significantly higher levels of aortic total, free and esterified cholesterol compared to the hamsters fed the RPO (74%, 50% and 225%, respectively), RBD-PO (57%, 48% and 92%, respectively) and the reconstituted RBD-PO (111%, 94% and 94%, respectively). Also, aortic free/ester cholesterol ratio in the aortas of hamsters fed RPO was significantly higher than in those fed the coconut oil (124%). In conclusion, hamsters fed the three palm oil preparations had lower plasma TC and non-HDL-C and higher HDL-C concentrations while accumulating less aortic cholesterol concentrations compared to hamsters fed coconut oil.


A systematic review of quality and consistency of clinical practice guidelines on the primary prevention of food allergy and atopic dermatitis.
With an increasing number of Clinical Practice Guidelines (CPGs) addressing primary prevention of food allergy and atopic dermatitis, it is timely to undertake a comprehensive assessment of the quality and consistency of recommendations and evaluation of their implementability in different geographical settings. We systematically reviewed CPGs from 8 international databases and extensive website searches. Seven reviewers screened records in any language and then used the AGREE II and AGREE REX instruments to critically appraise CPGs published between January 2011 and April 2022. Our search identified 2138 relevant articles, of which 30 CPGs were eventually included. Eight (27%) CPGs were shortlisted based on our predefined quality criteria of achieving scores >70% in the "Scope and Purpose" and "Rigour of Development" domains of the AGREE II instrument. Among the shortlisted CPGs, scores on the "Applicability" domain were generally low, and only 3 CPGs rated highly in the "Implementability" domain of AGREE-REX, suggesting that the majority of CPGs fared poorly on global applicability. Recommendations on maternal diet and complementary feeding in infants were mostly consistent, but recommendations on use of hydrolysed formula and supplements varied considerably. The overall quality of a CPG for Food Allergy and Atopic Dermatitis prevention did not correlate well with its global applicability. It is imperative that CPG developers consider stakeholders' preferences, local applicability, and adapt existing recommendations to each individual population and healthcare system to ensure successful implementation. There is a need for development of high-quality CPGs for allergy prevention outside of North America and Europe. CRD42021265689.


pH-sensitive, serum-stable and long-circulating liposomes as a new drug delivery system.
The lack of stability in blood and the short blood circulation time of pH-sensitive liposomes are major drawbacks for their application in-vivo. To develop pH-sensitive, serum-stable and long-circulating liposomes as drug delivery systems, the impact of polyethylene glycol-derived phosphatidylethanolamine (DSPE-PEG) on the properties of pH-sensitive liposomes was investigated. pH-sensitive liposomes were prepared with dioleoylphosphatidylethanolamine (DOPE) and oleic acid (DOPE/oleic acid liposome) or DOPE and 1,2-dipalmitoylsuccinylglycerol (DOPE/DPSG liposome). The inclusion of DSPE-PEG enhanced the serum stability of both DOPE/oleic acid and DOPE/DPSG liposomes, but also shifted the pH-response curve of pH-sensitive liposomes to more acidic regions and reduced the maximum leakage percentage. The impact of DSPE-PEG, however, was much lower in the DOPE/DPSG liposomes than in the DOPE/oleic acid liposomes. In tumour tissue homogenates, where the pH is lower than normal healthy tissues, the pH-sensitive DOPE/DPSG liposomes released the entrapped markers rapidly, in comparison with pH-insensitive dipalmitoylphosphatidylcholine/cholesterol/DSPE-PEG liposomes. Moreover, the release rate was not affected by the content of DSPE-PEG. The blood circulation time of methotrexate incorporated in DOPE/UDPSG liposomes was significantly prolonged with increasing content of DSPE-PEG. Taken together, the liposomes composed of DOPE, DPSG and DSPE-PEG (up to 5%) were pH sensitive, plasma stable and had a long circulation time in the blood. The complete destabilization of the liposomes at tumour tissues suggests that the liposomes might be useful for the targeted delivery of drugs such as anticancer agents.