Hypertensive disorders in pregnancy and subsequently measured cardiovascular risk factors.
To study the association of hypertensive pregnancy disorders with modifiable risk factors for cardiovascular and metabolic diseases and to estimate the feasibility for early detection and prevention. This was a prospective study of 15,065 women with a first singleton birth between 1967 and 1995, who later participated in a population study that included standardized measurements of blood pressure, serum lipids, and body mass index (BMI). Women with a history of hypertensive disorders in pregnancy (preeclampsia or gestational hypertension) had higher BMI, higher blood pressure, and unfavorable levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Preeclampsia was associated with substantially higher risk of developing diabetes (odds ratio 3.8, 95% confidence interval [CI] 2.1-6.6), and if the hypertensive disorder occurred in more than one pregnancy, or in a relatively late pregnancy, the associations with later cardiovascular risk factors were substantially stronger. Thus, women with two episodes of preeclampsia were approximately 10 times more likely to use blood pressure medication at follow-up (adjusted odds ratio, 11.6, 95% CI 7.1-26.3), and in women with gestational hypertension in three consecutive pregnancies, systolic pressure was on average 27 mm Hg (95% CI 18-37 mm Hg) higher, and diastolic pressure was 12 mm Hg (95% CI 5-19 mm Hg) higher, compared with women without a history of hypertensive disorders. Adjustment for current body mass index partly attenuated these associations, suggesting that BMI may play an important mediating role. Women with a history of hypertensive disorders in pregnancy, and particularly women with recurrent pregnancy disorders, should be candidates for intervention intended to prevent premature cardiovascular disease. II.


Oral L-carnitine supplementation increases trimethylamine-N-oxide but reduces markers of vascular injury in hemodialysis patients.
Food or supplement-derived L-carnitine is changed to trimethylamine (TMA) by interstinal microbiota, which is further metabolized to trimethylamine-N-oxide (TMAO), being involved in the promotion of atherosclerosis in animal models. Meanwhile, carnitine deficiency has played a role in accelerated atherosclerosis in hemodialysis (HD) patients. However, effects of oral L-carnitine supplementation on circulating levels of TMAO and markers of vascular injury and oxidative stress in patients on HD remain unclear. In this study, we addressed the issue. Thirty-one HD patients with carnitine deficiency were treated with oral L-carnitine (900 mg/d) for 6 months. At baseline and after treatment, clinical variables including circulating levels of carnitine fractions, TMA, TMAO, advanced glycation end products (AGE), soluble forms of intracellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and malondialdehyde (MDA) were measured. Oral L-carnitine supplementation significantly increased total, free, acyl carnitine, and plasma TMA and TMAO levels, whereas it decreased markers of vascular injury and oxidative stress such as sICAM-1, sVCAM-1, and MDA levels. TMA and TMAO levels at baseline were correlated with each other, and free carnitine was independently associated with TMAO levels. Furthermore, change in AGE values from baseline ([INCREMENT]AGE) was positively correlated with [INCREMENT]sICAM-1 (P = 0.043) and was a sole independent determinant of [INCREMENT]sICAM-1 (R = 0.133, P = 0.043). This study demonstrated that although oral L-carnitine supplementation was associated with increased TMAO levels, it might be beneficial on vascular injury in patients on HD. Vasculoprotective properties of L-carnitine supplementation in HD patients might be ascribed partly to its inhibitory actions on AGE.


Etiology and Risk Factors for Infectious Keratitis in South Texas.
To determine the causative organisms and associated risk factors for infectious keratitis in South Texas. This retrospective study was performed at a tertiary teaching hospital system in South Texas. Medical records of all patients who presented with infectious keratitis from 2012 to 2018 were reviewed. Only patients with culture-proven bacterial, fungal, and Acanthamoeba keratitis were included. In total, 182 eyes of 181 patients had culture-proven bacterial, fungal, or Acanthamoeba keratitis. The age of patients ranged from 3 to 93 years, with a mean of 48.3 ± 20.8 years. The most common etiologic agent was bacteria, with 173 bacterial cultures (95.1%) recovered, followed by 13 fungal cultures (7.1%), and 3 Acanthamoeba cultures (1.6%). Of the 218 bacterial isolates, coagulase-negative Staphylococcus was the most common (25.7%), followed by Pseudomonas aeruginosa (23.4%), Staphylococcus aureus (11.0%), and Moraxella (7.8%). Fusarium was the most common fungal isolate (46.2%). The most common risk factors for infectious keratitis included contact lens wear (32.4%), underlying corneal disease (17.6%), trauma (14.3%), and ocular surface disease (13.7%). Bacteria are the most common cause of infectious keratitis in this patient population, with coagulase-negative Staphylococcus and Pseudomonas as the most common isolates. The prevalence of culture-positive fungal keratitis is significantly lower than that of bacterial keratitis. Contact lens wear is the most common risk factor associated with infectious keratitis in South Texas.


Ocular metastases from breast carcinoma: a report of two cases.
Breast carcinoma metastases to the eye occur more frequently than is clinically recognized. The prevalence of this lesion is not appreciated because of the dominant clinical picture of metastases occurring in other organs or because a number of eye lesions are small and asymptomatic. With the increasing length of survival, more breast cancer patients will require care for ocular metastases. A thorough ophthalmic evaluation, aided by computed tomography or magnetic resonance imaging, usually confirms the diagnosis. Rapid progression of a lesion demands emergency therapy since the dysfunction produced by progressive disease may not otherwise be corrected. Early diagnosis of ocular metastases in patients with breast cancer is important because timely treatment may improve vision and quality of life in the time remaining to patients. Experience with two cases of metastases to the eye from breast cancer are presented, with a review of the literature.


Further evidence suggesting a role for variation in ARHGAP29 variants in nonsyndromic cleft lip/palate.
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect of complex etiology. Several genes have been implicated in the etiology of NSCL/P, although only a few have been replicated across datasets. ARHGAP29 was suggested as a candidate gene for NSCL/P as it is located in close proximity to ABCA4 (1p22), a gene previously identified in a genome-wide association study of NSCL/P. Rare, potentially damaging, coding variants in ARHGAP29 were found in NSCL/P cases, and its expression was detected during murine craniofacial development. In this study, we investigated whether variations in ARHGAP29 were associated with NSCL/P in our family based dataset. Five single-nucleotide polymorphisms (SNPs) flanking and within ARHGAP29 were genotyped in our NSCL/P datasets consisting of simplex and multiplex families of non-Hispanic white (NHW, primarily European) and Hispanic ethnicities. Results showed strong association of three ARHGAP29 SNPs with NSCL/P in the NHW families. Two intronic SNPs (rs1541098 and rs3789688) showed strong association with NSCL/P in all NHW families (p = 0.0005 and p = 0.0002, respectively), and simplex NHW families (p = 0.003 for both SNPs). A SNP in the 3' untranslated region (rs1576593) also showed strong association with NSCL/P in all NHW families (p = 0.002), and the multiplex subset (p = 0.002). ARHGAP29 SNP haplotypes were also associated with NSCL/P. Evidence of gene-gene interaction was found between ARHGAP29 and additional cleft susceptibility genes. This study further supports ARHGAP29 as a candidate gene for human NSCL/P in families of Caucasian descent.


Porous silicon platform for optical detection of functionalized magnetic particles biosensing.
The physical properties of porous materials are being exploited for a wide range of applications including optical biosensors, waveguides, gas sensors, micro capacitors, and solar cells. Here, we review the fast, easy and inexpensive electrochemical anodization based fabrication porous silicon (PSi) for optical biosensing using functionalized magnetic particles. Combining magnetically labeled biomolecules with PSi offers a rapid and one-step immunoassay and real-time detection by magnetic manipulation of superparamagnetic beads (SPBs) functionalized with target molecules onto corresponding probe molecules immobilized inside nano-pores of PSi. We first give an introduction to electrochemical and chemical etching procedures used to fabricate a wide range of PSi structures. Next, we describe the basic properties of PSi and underlying optical scattering mechanisms that govern their unique optical properties. Finally, we give examples of our experiments that demonstrate the potential of combining PSi and magnetic beads for real-time point of care diagnostics.


Gut Microbiome Profiles Are Associated With Type 2 Diabetes in Urban Africans.
Gut dysbiosis has been associated with several disease outcomes including diabetes in human populations. Currently, there are no studies of the gut microbiome composition in relation to type 2 diabetes (T2D) in Africans. Here, we describe the profile of the gut microbiome in non-diabetic adults (controls) and investigate the association between gut microbiota and T2D in urban West Africans. Gut microbiota composition was determined in 291 Nigerians (98 cases, 193 controls) using fecal 16S V4 rRNA gene sequencing done on the Illumina MiSeq platform. Data analysis of operational taxonomic units (OTU) was conducted to describe microbiome composition and identify differences between T2D and controls. The most abundant phyla were Firmicutes, Actinobacteria, and Bacteroidetes. Clostridiaceae, and Peptostreptococcaceaea were significantly lower in cases than controls (p < 0.001). Feature selection analysis identified a panel of 18 OTUs enriched in cases that included Desulfovibrio piger, Prevotella, Peptostreptococcus, and Eubacterium. A panel of 17 OTUs that was enriched in the controls included Collinsella, Ruminococcus lactaris, Anaerostipes, and Clostridium. OTUs with strain-level annotation showing the largest fold-change included Cellulosilyticum ruminicola (log2FC = -3.1; p = 4.2 × 10-5), Clostridium paraputrificum (log2FC = -2.5; p = 0.005), and Clostridium butyricum (log2FC = -1.76; p = 0.01), all lower in cases. These findings are notable because supplementation with Clostridium butyricum and Desulfovibrio piger has been shown to improve hyperglycemia and reduce insulin resistance in murine models. This first investigation of gut microbiome and diabetes in urban Africans shows that T2D is associated with compositional changes in gut microbiota highlighting the possibility of developing strategies to improve glucose control by modifying bacterial composition in the gut.


Obesity and metabolic syndrome in circadian Clock mutant mice.
The CLOCK transcription factor is a key component of the molecular circadian clock within pacemaker neurons of the hypothalamic suprachiasmatic nucleus. We found that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia. Expression of transcripts encoding selected hypothalamic peptides associated with energy balance was attenuated in the Clock mutant mice. These results suggest that the circadian clock gene network plays an important role in mammalian energy balance.


Long-Term Clinical Course of Patients After Decompression and Posterior Instrumented Fusion Surgery for Thoracic Ossification of the Posterior Longitudinal Ligament: An Average Follow-Up of 18 years.
Retrospective observational study. To evaluate the long-term recurrence rates and functional status of patients with thoracic ossification of the posterior longitudinal ligament (OPLL) after decompression and posterior fusion surgery. Thirty-seven consecutive patients who underwent posterior thoracic spine surgery at a single institution were retrospectively reviewed. The long-term neurological and functional outcomes of 25 patients who were followed up for ≥10 years after surgery were assessed. Factors associated with the recurrence of myelopathy were also analyzed. The mean preoperative Japanese Orthopaedic Association score was 3.7, which improved to 6.5 at postoperative year 2 and declined to 6.0 at a mean follow-up of 18 years. No patient experienced a relapse of myelopathy due to OPLL within the instrumented spinal segments. However, 15 (60%) patients experienced late neurological deterioration, 10 of whom had a relapse of myelopathy due to OPLL or ossification of the ligamentum flavum (OLF) in the region outside the primary operative lesion, while 4 developed myelopathy due to traumatic vertebral fracture of the ankylosed spine. Young age, a high body mass index, and lumbar OPLL are likely associated with late neurological deterioration. Decompression and posterior instrumented fusion surgery is a reliable surgical procedure with stable long-term clinical outcomes for thoracic OPLL. However, as OPLL may progress through the spine, attention should be paid to the recurrence of paralysis due to OPLL or OLF in regions other than the primary operative lesion and vertebral fractures of the ankylosed spine after surgery for thoracic OPLL.


Phenotypical and Myopathological Consequences of Compound Heterozygous Missense and Nonsense Variants in SLC18A3.
Presynaptic forms of congenital myasthenic syndromes (CMS) due to pathogenic variants in SLC18A3 impairing the synthesis and recycling of acetylcholine (ACh) have recently been described. SLC18A3 encodes the vesicular ACh transporter (VAChT), modulating the active transport of ACh at the neuromuscular junction, and homozygous loss of VAChT leads to lethality. Exome sequencing (ES) was carried out to identify the molecular genetic cause of the disease in a 5-year-old male patient and histological, immunofluorescence as well as electron- and CARS-microscopic studies were performed to delineate the muscle pathology, which has so far only been studied in VAChT-deficient animal models. ES unraveled compound heterozygous missense and nonsense variants (c.315G>A, p.Trp105* and c.1192G>C, p.Asp398His) in SLC18A3. Comparison with already-published cases suggests a more severe phenotype including impaired motor and cognitive development, possibly related to a more severe effect of the nonsense variant. Therapy with pyridostigmine was only partially effective while 3,4 diaminopyridine showed no effect. Microscopic investigation of the muscle biopsy revealed reduced fibre size and a significant accumulation of lipid droplets. We suggest that nonsense variants have a more detrimental impact on the clinical manifestation of SLC18A3-associated CMS. The impact of pathogenic SLC18A3 variants on muscle fibre integrity beyond the effect of denervation is suggested by the build-up of lipid aggregates. This in turn implicates the importance of proper VAChT-mediated synthesis and recycling of ACh for lipid homeostasis in muscle cells. This hypothesis is further supported by the pathological observations obtained in previously published VAChT-animal models.


Assessment of the mercury-selenium antagonism in rainbow trout fish.
This study aims at the assessment of mercury (Hg)-selenium (Se) antagonism in fish. For this purpose, rainbow trout fish (Oncorhynchus mykiss) were exposed to methylmercury (MeHg) under controlled conditions, in the presence or absence of selenomethionine (SeMet) using an in-house prepared diet (enriched with MeHg and SeMet at 0.2 μg/g and 5.0 μg/g, respectively). The total duration of the exposure study was 3 months. Fish was sampled and analysed for total Se (SeT) and total mercury (HgT) content after 1, 2 and 3 months of exposure. Six feeding protocols were compared, depending on the exposure type: (i) no MeHg nor SeMet exposure (control group); (ii) exposure to SeMet solely; (iii) exposure to MeHg solely; (iv) exposure to both MeHg and SeMet; (v) exposure first to MeHg during 1 month and then to SeMet during 2 months and (vi), exposure to SeMet during 1 month and then to MeHg for 2 months. The levels of SeT and HgT in the fish (control and supplemented with MeHg/SeMet) were measured by inductively coupled plasma-mass spectrometry (ICPMS). Steadily (linear) bioaccumulation of MeHg in the fish muscle occurred when the fish were exposed individually to this species during the period. The bioaccumulation of MeHg is diminished when the fish are firstly exposed to SeMet and then to MeHg, hence indicating the MeHg detoxification due to SeMet supplementation.


Cancer associated fibroblasts (CAFs) are activated in cutaneous basal cell carcinoma and in the peritumoural skin.
Cutaneous basal cell carcinoma (BCC) is the commonest cancer worldwide. BCC is locally invasive and the surrounding stromal microenvironment is pivotal for tumourigenesis. Cancer associated fibroblasts (CAFs) in the microenvironment are essential for tumour growth in a variety of neoplasms but their role in BCC is poorly understood. Material included facial BCC and control skin from the peritumoural area and from the buttocks. With next-generation sequencing (NGS) we compared mRNA expression between BCC and peritumoural skin. qRT-PCR, immunohistochemical and immunofluorescent staining were performed to validate the NGS results and to investigate CAF-related cyto-and chemokines. NGS revealed upregulation of 65 genes in BCC coding for extracellular matrix components pointing at CAF-related matrix remodeling. qRT-PCR showed increased mRNA expression of CAF markers FAP-α, PDGFR-β and prolyl-4-hydroxylase in BCC. Peritumoural skin (but not buttock skin) also exhibited high expression of PDGFR-β and prolyl-4-hydroxylase but not FAP-α. We found a similar pattern for the CAF-associated chemokines CCL17, CCL18, CCL22, CCL25, CXCL12 and IL6 with high expression in BCC and peritumoural skin but absence in buttock skin. Immunofluorescence revealed correlation between FAP-α and PDGFR-β and CXCL12 and CCL17. Matrix remodeling is the most prominent molecular feature of BCC. CAFs are present within BCC stroma and associated with increased expression of chemokines involved in tumour progression and immunosuppression (CXCL12, CCL17). Fibroblasts from chronically sun-exposed skin near tumours show gene expression patterns resembling that of CAFs, indicating that stromal fibroblasts in cancer-free surgical BCC margins exhibit a tumour promoting phenotype.


Oxidative stress resistance in Deinococcus radiodurans.
Deinococcus radiodurans is a robust bacterium best known for its capacity to repair massive DNA damage efficiently and accurately. It is extremely resistant to many DNA-damaging agents, including ionizing radiation and UV radiation (100 to 295 nm), desiccation, and mitomycin C, which induce oxidative damage not only to DNA but also to all cellular macromolecules via the production of reactive oxygen species. The extreme resilience of D. radiodurans to oxidative stress is imparted synergistically by an efficient protection of proteins against oxidative stress and an efficient DNA repair mechanism, enhanced by functional redundancies in both systems. D. radiodurans assets for the prevention of and recovery from oxidative stress are extensively reviewed here. Radiation- and desiccation-resistant bacteria such as D. radiodurans have substantially lower protein oxidation levels than do sensitive bacteria but have similar yields of DNA double-strand breaks. These findings challenge the concept of DNA as the primary target of radiation toxicity while advancing protein damage, and the protection of proteins against oxidative damage, as a new paradigm of radiation toxicity and survival. The protection of DNA repair and other proteins against oxidative damage is imparted by enzymatic and nonenzymatic antioxidant defense systems dominated by divalent manganese complexes. Given that oxidative stress caused by the accumulation of reactive oxygen species is associated with aging and cancer, a comprehensive outlook on D. radiodurans strategies of combating oxidative stress may open new avenues for antiaging and anticancer treatments. The study of the antioxidation protection in D. radiodurans is therefore of considerable potential interest for medicine and public health.


Inhibition of smooth-muscle myosin-light-chain phosphatase by Ruthenium Red.
Ruthenium Red (RuR) is widely used as an inhibitor of ryanodine receptor Ca(2+) release channels, but has additional effects such as the induction of Ca(2+) sensitization of contraction of permeabilized smooth muscles. To address the mechanism underlying this process, we examined the effects of RuR on contractility in permeabilized guinea-pig ileum and on the activity of myosin-light-chain phosphatase (MP). RuR increased the force at submaximal [Ca(2+)] (pCa 6.3) approx. 4-fold. This effect was not observed after thiophosphorylation of MP. RuR also seemed capable of preventing the thiophosphorylation of MP, suggesting a direct interaction of RuR with MP. Consistent with this possibility, smooth-muscle MP was inhibited by RuR in a concentration-dependent manner (IC(50) 23 microM). Exogenous calmodulin significantly increased RuR-induced contraction at pCa 6.3 but had little effect on contraction induced by microcystin at this [Ca(2+)]. Ca(2+)-independent contraction was induced by RuR (EC(50) 843 microM) and by microcystin (EC(50) 59 nM) but the maximal force induced by RuR was smaller than that induced by microcystin. The addition of 300 microM RuR enhanced the contraction induced by 30 nM microcystin but markedly decreased that induced by 1 microM microcystin. Such a dual action of RuR on microcystin-induced effects was not observed in experiments using purified MP. We conclude that the RuR-induced Ca(2+) sensitization of smooth-muscle contraction is due to the direct inhibition of MP by RuR.


Combining individual patient data from randomized and non-randomized studies to predict real-world effectiveness of interventions.
Meta-analysis of randomized controlled trials is generally considered the most reliable source of estimates of relative treatment effects. However, in the last few years, there has been interest in using non-randomized studies to complement evidence from randomized controlled trials. Several meta-analytical models have been proposed to this end. Such models mainly focussed on estimating the average relative effects of interventions. In real-life clinical practice, when deciding on how to treat a patient, it might be of great interest to have personalized predictions of absolute outcomes under several available treatment options. This paper describes a general framework for developing models that combine individual patient data from randomized controlled trials and non-randomized study when aiming to predict outcomes for a set of competing medical interventions applied in real-world clinical settings. We also discuss methods for measuring the models' performance to identify the optimal model to use in each setting. We focus on the case of continuous outcomes and illustrate our methods using a data set from rheumatoid arthritis, comprising patient-level data from three randomized controlled trials and two registries from Switzerland and Britain.


Incidental prostate cancer revisited: early outcomes after holmium laser enucleation of the prostate.
Incidental prostate cancer (PCa) after treatment of benign prostate hyperplasia (BPH) is becoming less common. This is a result of the changing patterns of BPH treatment. The purpose of the present research was to re-examine the clinical outcomes and importance of cT1a and cT1b PCa in a contemporary cohort after holmium laser enucleation of the prostate (HoLEP). All patients with newly diagnosed PCa after HoLEP were retrospectively identified. Pre- and postoperative prostate-specific antigen (PSA), biopsy history, pathological features and disease progression were examined. Patients were matched to a control group with benign pathology for outcome comparisons. The database consisted of 240 consecutive patients, aged 52-90 years with prostate sizes from 25 to 375 cm(3) . A total of 28 patients were identified with incidental PCa (14 cT1a and 14 cT1b). Median follow up was 11 months and 13 months for cT1a and cT1b, respectively. Hospitalization time, catheterization time, complications and functional outcomes were similar. Three patients with cT1b required additional treatment as a result of PSA progression. All other cancers are being closely followed. The functional benefits of HoLEP are well established. The incidental PCa detection rate of 11.7% shows the potential benefit of pathological analysis. Just 10.7% of these patients received additional treatment, but this might be significant as these patients would otherwise go untreated. The impact on disease-specific survival and progression requires a longer follow up.


Kinetic impairment of nitrogen and muscle glutamine metabolisms in old glucocorticoid-treated rats.
Aged rats are more sensitive to injury, possibly through an impairment of nitrogen and glutamine (Gln) metabolisms mediated by glucocorticoids. We studied the metabolic kinetic response of adult and old rats during glucocorticoid treatment. The male Sprague-Dawley rats were 24 or 3 mo old. Both adult and old rats were divided into 7 groups. Groups labeled G3, G5, and G7 received, by intraperitoneal injection, 1.50 mg/kg of dexamethasone (Dex) for 3, 5, and 7 days, respectively. Groups labeled G3PF, G5PF, and G7PF were pair fed to the G3, G5, or G7 groups and were injected with an isovolumic solution of NaCl. One control group comprised healthy rats fed ad libitum. The response to aggression induced specifically by Dex (i.e., allowing for variations in pair-fed controls) appeared later in the aged rats (decrease in nitrogen balance from day 1 in adults but only from day 4 in old rats). The adult rats rapidly adapted to Dex treatment, whereas the catabolic state worsened until the end of treatment in the old rats. Gln homeostasis was not maintained in the aged rats; despite an early increase in muscular Gln synthetase activity, the Gln pool was depleted. These results suggest a kinetic impairment of both nitrogen and muscle Gln metabolisms in response to Dex with aging.


[Morbidity and mortality in surgery for gastric cancer].
Surgery stays as the only effective therapy against gastric cancer. Several factors have been postulated to influence morbidity and mortality risk in gastric cancer surgery. Determine morbidity and mortality of gastric cancer surgery and establish risk factors. We reviewed the charts of patients who underwent surgery for gastric adenocarcinoma. Morbidity and mortality is reported. Demographic factors, preoperative physical evaluation, biochemical parameters, surgical technique and tumor biology were analyzed as risk factors for morbidity and mortality. During a seven year period, 120 patients were operated for gastric cancer. Median age was 58.07 years. Subtotal gastrectomy was the most common surgical procedure in 51 patients (42.5%). Morbidity was 26.66% (n = 32). Medical most common complication was renal failure (n = 6, 14.63%) and surgical most common complication was wound infection (n = 7, 17.07%). Mortality was 13.33% (n = 16). Statistically significant risk factors for morbidity were age, ECOG status, Goldman Cardiac Risk Index and a total lymphocyte count. Statistically significant risk factors for mortality were Goldman Cardiac Risk Index, albumin, creatinine, and total lymphocyte count. Morbidity and mortality after gastric cancer surgery is influenced by preoperative conditions of patients.


Regeneration of alpha-tocopherol in human low-density lipoprotein by green tea catechin.
Oxidative modification of low-density lipoproteins (LDL) may play an important role in the development of atherosclerosis. alpha-Tocopherol functions as a major antioxidant in human LDL. The present study was to test whether green tea catechins (GTC) would protect or regenerate alpha-tocopherol in human LDL. The oxidation of LDL incubated in sodium phosphate buffer (pH 7.4, 10 mM) was initiated by addition of 1.0 mM of 2,2'-azobis(2-amidinopropane) dihydrochloride at 40 degrees C. It was found that alpha-tocopherol was completely depleted within 1 h. Under the same experimental conditions, the longjing GTC extracts demonstrated a dose-dependent protective activity to alpha-tocopherol in LDL at concentrations ranging from 2 to 20 microM. Four pure epicatechin derivatives showed varying protective activity against depletion of alpha-tocopherol in LDL with (-)-epigallocatechin (EGC) and (-)-epigallocatechin gallate (EGCG) being less effective than (-)-epicatechin (EC) and (-)-epicatechin gallate (ECG). The results showed that addition of longjing GTC extracts, EC, ECG, and EGCG at 5, 10, and 15 min to the incubation mixture demonstrated a gradual regeneration of alpha-tocopherol in human LDL.


Generating photo-realistic training data to improve face recognition accuracy.
Face recognition has become a widely adopted biometric in forensics, security and law enforcement thanks to the high accuracy achieved by systems based on convolutional neural networks (CNNs). However, to achieve good performance, CNNs need to be trained with very large datasets which are not always available. In this paper we investigate the feasibility of using synthetic data to augment face datasets. In particular, we propose a novel generative adversarial network (GAN) that can disentangle identity-related attributes from non-identity-related attributes. This is done by training an embedding network that maps discrete identity labels to an identity latent space that follows a simple prior distribution, and training a GAN conditioned on samples from that distribution. A main novelty of our approach is the ability to generate both synthetic images of subjects in the training set and synthetic images of new subjects not in the training set, both of which we use to augment face datasets. By using recent advances in GAN training, we show that the synthetic images generated by our model are photo-realistic, and that training with datasets augmented with those images can lead to increased recognition accuracy. Experimental results show that our method is more effective when augmenting small datasets. In particular, an absolute accuracy improvement of 8.42% was achieved when augmenting a dataset of less than 60k facial images.


Variations in N-linked glycosylation of glycosylation-dependent cell adhesion molecule 1 (GlyCAM-1) whey protein: Intercow differences and dietary effects.
In bovine milk serum, the whey proteins with the highest N-glycan contribution are lactoferrin, IgG, and glycosylation-dependent cellular adhesion molecule 1 (GlyCAM-1); GlyCAM-1 is the dominant N-linked glycoprotein in bovine whey protein products. Whey proteins are base ingredients in a range of food products, including infant formulas. Glycan monosaccharide composition and variation thereof may affect functionality, such as the interaction of glycans with the immune system via recognition receptors. It is therefore highly relevant to understand whether and how the glycosylation of whey proteins (and their functionality) can be modulated. We recently showed that the glycoprofile of GlyCAM-1 varies between cows and during early lactation, whereas the glycoprofile of lactoferrin was highly constant. In the current study, we evaluated intercow differences and the effects of macronutrient supply on the N-linked glycosylation profiles of the major whey proteins in milk samples of Holstein-Friesian cows. Overall, approximately 60% of the N-glycan pool in milk protein was sialylated, or fucosylated, or both; GlyCAM-1 contributed approximately 78% of the total number of glycans in the overall whey protein N-linked glycan pool. The degree of fucosylation ranged from 44.8 to 73.3% between cows, and this variation was mainly attributed to the glycans of GlyCAM-1. Dietary supplementation with fat or protein did not influence the overall milk serum glycoprofile. Postruminal infusion of palm olein, glucose, and essential AA resulted in shifts in the degree of GlyCAM-1 fucosylation within individual cows, ranging in some cases from 50 to 71% difference in degree of fucosylation, regardless of treatment. Overall, these data demonstrate that the glycosylation, and particularly fucosylation, of GlyCAM-1 was variable, although these shifts appear to be related more to individual cow variation than to nutrient supply. To our knowledge, this is the first report of variation in glycosylation of a milk glycoprotein in mature, noncolostral milk. The functional implications of variable GlyCAM-1 fucosylation remain to be investigated.


Cost-effectiveness analysis of fecal microbiota transplantation for recurrent Clostridium difficile infection.
Clostridium difficile infection (CDI) places a high burden on the US healthcare system. Recurrent CDI (RCDI) occurs frequently. Recently proposed guidelines from the American College of Gastroenterology (ACG) and the American Gastroenterology Association (AGA) include fecal microbiota transplantation (FMT) as a therapeutic option for RCDI. The purpose of this study was to estimate the cost-effectiveness of FMT compared with vancomycin for the treatment of RCDI in adults, specifically following guidelines proposed by the ACG and AGA. We constructed a decision-analytic computer simulation using inputs from the published literature to compare the standard approach using tapered vancomycin to FMT for RCDI from the third-party payer perspective. Our effectiveness measure was quality-adjusted life years (QALYs). Because simulated patients were followed for 90 days, discounting was not necessary. One-way and probabilistic sensitivity analyses were performed. Base-case analysis showed that FMT was less costly ($1,669 vs $3,788) and more effective (0.242 QALYs vs 0.235 QALYs) than vancomycin for RCDI. One-way sensitivity analyses showed that FMT was the dominant strategy (both less expensive and more effective) if cure rates for FMT and vancomycin were ≥70% and <91%, respectively, and if the cost of FMT was <$3,206. Probabilistic sensitivity analysis, varying all parameters simultaneously, showed that FMT was the dominant strategy over 10, 000 second-order Monte Carlo simulations. Our results suggest that FMT may be a cost-saving intervention in managing RCDI. Implementation of FMT for RCDI may help decrease the economic burden to the healthcare system.


Effects of an interdependent group contingency on the transition behavior of middle school students with emotional and behavioral disorders.
An ABAB design was used to evaluate the effectiveness of an interdependent group contingency with randomized components to improve the transition behavior of middle school students identified with emotional and behavioral disorders (EBDs) served in an alternative educational setting. The intervention was implemented by one teacher with three classes of students, and the dependent variable was the percentage of students ready to begin class at the appropriate time. Data revealed significant improvements in student behavior, providing support for implementation of group contingencies for students with EBDs in alternative educational settings and an example of feasible procedures and data collection methods. (PsycINFO Database Record


A functional immature model of chronic partial ureteral obstruction.
The most common nonlethal congenital anomaly of the urinary tract is ureteral obstruction without dysplasia. Although rarely progressive, the morbidity associated with metabolic and surgical management is considerable. Our study was designed to measure local and systemic pathophysiologic mechanisms in an immature model of chronic partial unilateral ureteral obstruction (UUO) after completion of glomerulogenesis. A partial UUO was created by the method of "psoas wrap" in young male weanling rats. Control animals were sham operated. Three groups were divided as follows: sham (N= 15), UUO (N= 18), and UUO + angiotensin-converting enzyme (ACE) (N= 16) inhibitor, enalapril. Renal glomerular and tubular functions were determined by creatinine and uric acid clearances. Diuresis was assessed by urine volume, osmolality, and fractional solute excretions from samples above and below the obstruction. Proteinuria was determined by the urine protein/creatinine ratio (Up/c). Proteinuria was attenuated in UUO + ACE-treated animals. The hyperuricemia of the immature UUO animals was avoided by an increase in the clearance of uric acid in the UUO + ACE-treated group. Fractional solute excretions suggested a diversion of diuresis to the contralateral unobstructed kidney. Angiotensin blockade during chronic UUO in young rats affords protection by attenuating proteinuria, promoting uricosuria, and diverting solute diuresis. These data suggest a complex interaction of local and systemic mechanisms unique to the maturing kidney.


Investigation Study of Ultrasound Practitioners' Awareness about Artefacts of Hepatobiliary Imaging in Almadinah Almunawwarah.
To investigate the knowledge and awareness of ultrasound practitioners' concerning ultrasound artefacts in evaluating the hepatobiliary system. This electronic questionnaire-based comparative study involved the ultrasound practitioners' who work in the radiology departments in Almadinah Almunawwarah governmental hospitals during the period from 1 November 2020 to 30 April 2021. Spearman's rho correlation test was used to correlate between knowledge and job, academic qualification, and years of experience. A T-test and cross tabulation test were done to compare the knowledge about artefacts among radiologists and radiologic technologists. This study involved 94 participants distributed as 22 (23.4%) radiologists and 72 (76.6%) radiologic technologists. The results shows that 85%, 71%, 73%, 69%, 54% and 53% of the participants assigned the acoustic shadowing, acoustic enhancement, ring down, side lobe, reverberation and mirror artefacts, as artefacts respectively. However, 68%, 53%, 19%, 19%, 18%, and 40% of the participants gave correct final diagnosis of acoustic shadowing, acoustic enhancement, ring down, side lobes, reverberation, and mirror artifacts, respectively. Spearman's rho correlation test shows significant correlation between participants with more than three years experience and knowledge related mirror artefacts (r=0.328, p=0.001). It shows significant correlation between radiologists with knowledge related mirror artefacts (r=0.367, p<0.001). A significant correlation was found between highly qualified participants and knowledge related mirror artefacts (r=0.336, p=0.001) and side lobe artefacts (r=0.237, p=0.008). The questionnaire-based comparative study of knowledge about artefacts of hepatobiliary ultrasound imaging reveals a high level of Ultrasound practitioners' knowledge in differentiating artefacts from pathology with a high level of knowledge in identifying hepatobiliary acoustic shadowing and acoustic enhancement artefacts. However, insufficient knowledge was noted in identifying mirror, side lobe, reverberation and ring down artefacts. A direct link was found between academic qualification, years of experience and practioners' knowledge among.


Turning flight of bats.
The turning flight of six microchiropteran bat species is described. The bats' abilities to turn tightly were determined by their abilities to fly slowly and to generate high lateral accelerations. Rhinolophus ferrumequinum developed high lateral accelerations by flapping its banked wings while flying at very low speed. Plecotus auritus turned at relatively low speed and at low lateral acceleration. The other species were all moving fast as they turned and generated lateral accelerations either by developing high bank angles or by flapping their wings with low bank angles. There was a significant correlation between wing loading and turning curvature, indicating that low wing loadings improve manoeuvrability.


Toxin production by Bacillus pumilus.
Two strains of Bacillus pumilus (M11 and M38) and one strain each of Bacillus cereus (M27), Bacillus subtilis (M67), and Enterobacter agglomerans (M14) were identified from the air of Lancashire cotton mills. These strains were tested for cytopathic effects in Vero cells; B pumilus and B cereus strains were also examined for haemolytic activity, lecithinase production, and proteolytic action on casein. Rounding and clumping of the Vero cells occurred after the addition of supernatants prepared from B pumilus and B cereus strains; finger-like projections developed in the cells treated with B pumilus supernatants. Minimal effects occurred with B subtilis and E agglomerans. After two hours of exposure B pumilus (M11) produced the greatest effect, but treatment with trypan blue showed that most cells exposed to the M11 strain were still alive after 96 hours of exposure; those exposed to the supernatant prepared from the M38 strain of B pumilus were dead. Sheep erythrocytes were lysed more rapidly by B cereus than by B pumilus, B cereus (strongly positive) had a greater effect on lecithin than either of the B pumilus strains (M38 weakly positive, M11 negative). All hydrolised casein but the effect was more rapid with one of the B pumilus (M11) strains. It is concluded that not only do the toxins of B pumilus differ from those of B cereus, but there are also differences between the toxins produced by the two strains of B pumilus (M11 and M38).


Comments on the effects of dietary trans-fatty acids in humans.
Papers presented at this Workshop report clues which suggest further research on the role of dietary fat in the etiology of some forms of cancer. The research has not yet yielded information which can be used to make responsible dietary recommendations to the public. The suggestion that dietary animal fats are associated with "fat-related" cancers is not well documented. Virtually all of the increase in fat consumption in the United States during the 20th century has been due to vegetable fats. Many of these vegetable oils are partially hydrogenated, resulting in the accumulation of significant amounts of trans-fatty acids in such products as margarines and shortenings. It is suggested that more research attention should be given to the effects of dietary trans-fatty acids on animal physiology.


Psychopathology and symptoms of atrial fibrillation: implications for therapy.
Current guidelines recommend that the choice of AF management strategy be guided by the symptomatic status of the patient when in AF. However, little is known regarding what drives AF symptoms. Several limited studies suggest that psychological distress may be linked with AF symptom severity. A total of 300 patients with documented AF completed a questionnaire assessing general health and well-being, including a comprehensive psychological assessment as well as disease-specific measures of AF symptom severity. AF burden was determined by 1-week continuous looping monitor in a subset of patients. Analysis of covariance was used to determine the association between individual measures of depression, anxiety, and somatization disorder symptom severity with measures of general health status and AF-specific symptom severity, adjusting for important confounders. Patients with worsened severity of depression, anxiety, or somatization disorder symptoms had an associated increase in the severity of symptoms attributed to AF regardless of AF severity scale used (P < 0.0001 for each measure of psychological distress). This association persisted after adjusting for important confounders. Increasing severity of depression and anxiety symptoms were also associated with increased visits to medical care for AF management. Our study demonstrates the consequence of psychological distress on AF-specific symptom severity and healthcare resource utilization. Psychological well-being may strongly influence symptom severity and healthcare utilization. An assessment of psychological distress may be an important adjunct to standard AF management that warrants further study, particularly if symptom relief is the primary goal.


Cyclic testing of meniscal sutures.
Suturing the meniscus has become a standard procedure for repairable tears. Studies investigating the outcome of meniscal sutures report a considerable rate of failures. Regarding the indications, which have been extended to the avascular zones, and regarding some accelerated rehabilitation protocols, the need for further in vitro investigations has become obvious. The aim of this study was to compare different meniscal suture types (vertical and horizontal mattress sutures) and materials (absorbable monofilament PDS 2-0, and nonabsorbable braided Ethibond 2-0 [Ethicon, Somerville, NJ]) under standard and cyclic loading conditions. Testing was performed on medial porcine menisci. In group A, specimens were tested to failure at a cross-head speed of 50 mm/minute. In group B, cyclic testing (100 cycles) was performed first within different load intervals (5 to 20 N and 5 to 40 N). Finally, the specimens were loaded until failure. In both groups, the failure loads were recorded and the failure modes were analyzed. In group A, there was no difference between suture type or suture material, with a mean failure load of 60 N. The failure modes were significantly different for vertical (100% suture failure) and horizontal sutures (50% suture failure) (P <.0001). In group B, 13% of the sutures failed under cyclic loading (7 with 40-N load, 1 with 20-N load). The gap of the sutured tear that appeared within the first load cycles was broader in horizontal sutures (P <.001). During the first cycles, the thread cut through the meniscus tissue and disappeared from the surface (partial tissue failure). There was no difference according to suture material. The ultimate failure loads after cyclic loading did not differ from the values of group A. These results show that meniscal sutures may fail under repetitive loading conditions and that a gap appears between the meniscal margins within the first loading cycles irrespective of the suture type and suture material used. The appearance of the gap and suture disappearance on the meniscal surface because of partial tissue failures (which were more pronounced in the horizontal sutures) confirmed the superior resistance of meniscal tissue to vertical sutures.


Natural Compound from Olive Oil Inhibits S100A9 Amyloid Formation and Cytotoxicity: Implications for Preventing Alzheimer's Disease.
Polyphenolic compounds in the Mediterranean diet have received increasing attention due to their protective properties in amyloid neurodegenerative and many other diseases. Here, we have demonstrated for the first time that polyphenol oleuropein aglycone (OleA), which is the most abundant compound in olive oil, has multiple potencies for the inhibition of amyloid self-assembly of pro-inflammatory protein S100A9 and the mitigation of the damaging effect of its amyloids on neuroblastoma SH-SY5Y cells. OleA directly interacts with both native and fibrillar S100A9 as shown by intrinsic fluorescence and molecular dynamic simulation. OleA prevents S100A9 amyloid oligomerization as shown using amyloid oligomer-specific antibodies and cross-β-sheet formation detected by circular dichroism. It decreases the length of amyloid fibrils measured by atomic force microscopy (AFM) as well as reduces the effective rate of amyloid growth and the overall amyloid load as derived from the kinetic analysis of amyloid formation. OleA disintegrates already preformed fibrils of S100A9, converting them into nonfibrillar and nontoxic aggregates as revealed by amyloid thioflavin-T dye binding, AFM, and cytotoxicity assays. At the cellular level, OleA targets S100A9 amyloids already at the membranes as shown by immunofluorescence and fluorescence resonance energy transfer, significantly reducing the amyloid accumulation in GM1 ganglioside containing membrane rafts. OleA increases overall cell viability when neuroblastoma cells are subjected to the amyloid load and alleviates amyloid-induced intracellular rise of reactive oxidative species and free Ca2+. Since S100A9 is both a pro-inflammatory and amyloidogenic protein, OleA may effectively mitigate the pathological consequences of the S100A9-dependent amyloid-neuroinflammatory cascade as well as provide protection from neurodegeneration, if used within the Mediterranean diet as a potential preventive measure.


[Neuroborreliosis in Chile. Report of a child probably infected by imported pets].
Lyme disease, caused by the spirochete Borrelia burgdorferi, has several clinical manifestations and is transmitted to man by tick bites. In Chile and Latin America, several cases have been reported, but none with immunoblot confirmation or isolation of the infecting organism. We report a 9 year old boy consulting with bilateral facial palsy, polyradiculoneuritis with tetraparesis and meningeal irritation. Cerebrospinal fluid analysis showed increased protein concentration without pleocytosis and negative viral or bacterial cultures. IgM antibodies against Borrelia burgdorferi, were positive by ELISA and were confirmed by immunoblot at the Reference Laboratory of the University of Connecticut. The child had a recent contact with hamsters brought from Germany. The substantiation of Lyme disease existence in Chile should prompt the search and isolation of the causal agent.


A new concept for medical imaging centered on cellular phone technology.
According to World Health Organization reports, some three quarters of the world population does not have access to medical imaging. In addition, in developing countries over 50% of medical equipment that is available is not being used because it is too sophisticated or in disrepair or because the health personnel are not trained to use it. The goal of this study is to introduce and demonstrate the feasibility of a new concept in medical imaging that is centered on cellular phone technology and which may provide a solution to medical imaging in underserved areas. The new system replaces the conventional stand-alone medical imaging device with a new medical imaging system made of two independent components connected through cellular phone technology. The independent units are: a) a data acquisition device (DAD) at a remote patient site that is simple, with limited controls and no image display capability and b) an advanced image reconstruction and hardware control multiserver unit at a central site. The cellular phone technology transmits unprocessed raw data from the patient site DAD and receives and displays the processed image from the central site. (This is different from conventional telemedicine where the image reconstruction and control is at the patient site and telecommunication is used to transmit processed images from the patient site). The primary goal of this study is to demonstrate that the cellular phone technology can function in the proposed mode. The feasibility of the concept is demonstrated using a new frequency division multiplexing electrical impedance tomography system, which we have developed for dynamic medical imaging, as the medical imaging modality. The system is used to image through a cellular phone a simulation of breast cancer tumors in a medical imaging diagnostic mode and to image minimally invasive tissue ablation with irreversible electroporation in a medical imaging interventional mode.


[Anxiety disorders in children and adolescents. Epidemiology, risk factors and intervention].
The article reviews the literature on anxiety disorders in children and adolescents. Anxiety disorders represent one of the most common disorders in children and adolescents, with a life-time prevalence of about 10%. In most studies, significantly more females than males met the diagnosis of anxiety disorders. Some factors that have been commonly found to be associated with anxiety disorders include parental psychopathology, familial dysfunction, negative life events, and behavioral inhibition. Anxiety co-occurs frequently with other disorders; it has a chronic course and most of the anxiety cases are psychosocially impaired in various areas of life. The article ends by giving an overview of various types of intervention strategies commonly used to treat children and adolescents with anxiety disorders.


An okadaic acid-sensitive pathway involved in the phenobarbital-mediated induction of CYP2B gene expression in primary rat hepatocyte cultures.
We have previously demonstrated that specific activation of a cAMP-dependent protein kinase A (PKA) pathway resulted in complete repression of phenobarbital (PB)-inducible CYP gene expression in primary rat hepatocyte cultures. In the current investigation, we examined the role of protein phosphatase pathways as potential co-regulators of this repressive response. Primary rat hepatocytes were treated with increasing concentrations (0.1-25 nM) of okadaic acid, a potent inhibitor of serine/threonine-specific protein phosphatases PP1 and PP2A. PB induction responses were assessed by use of specific hybridization probes to CYP2B1 and CYP2B2 mRNAs. Okadaic acid completely inhibited the PB induction process in a concentration-dependent manner (IC50, approximately 1.5-2 nM). Similar repression was obtained with low concentrations of other highly specific phosphatase inhibitors, tautomycin and calyculin A. In contrast, exposure of hepatocytes to 1-nor-okadaone or okadaol, negative analogs of okadaic acid largely devoid of phosphatase inhibitory activity, was without effect on the PB induction process. At similar concentrations, okadaic acid produced only comparatively weak modulation of the beta-naphthoflavone-inducible CYP1A1 gene expression pathway. In additional experiments, hepatocytes were treated with suboptimal concentrations of PKA activators together with phosphatase inhibitors. Okadaic acid markedly potentiated the repressive effects of dibutyryl-cAMP on the PB induction process. Together, these results indicate that both PKA and protein phosphatase (PP1 and/or PP2A) pathways exert potent and complementary control of the intracellular processes modulating the signaling of PB in cultured primary rat hepatocytes.


Hemodynamic Modeling, Medical Imaging, and Machine Learning and Their Applications to Cardiovascular Interventions.
Cardiovascular disease is a deadly global health crisis that carries a substantial financial burden. Innovative treatment and management of cardiovascular disease straddles medicine, personalized hemodynamic modeling, machine learning, and modern imaging to help improve patient outcomes and reduce the economic impact. Hemodynamic modeling offers a non-invasive method to provide clinicians with new pre- and post- procedural metrics and aid in the selection of treatment options. Medical imaging is an integral part in clinical workflows for understanding and managing cardiac disease and interventions. Coupling machine learning with modeling, and cardiovascular imaging, provides faster modeling, improved data fidelity, and an enhanced understanding and earlier detection of cardiovascular anomalies, leading to the development of patient-specific diagnostic and predictive tools for characterizing and assessing cardiovascular outcomes. Herein, we provide a scoping review of translational hemodynamic modeling, medical imaging, and machine learning and their applications to cardiovascular interventions. We particularly focus on providing an intuitive understanding of each of these approaches and their ability to support decision making during important clinical milestones.


Glycosylation sites of influenza viral glycoproteins: characterization of tryptic glycopeptides from the A/USSR(H1N1) hemagglutinin glycoprotein.
Glycosylated tryptic peptides of the hemagglutinin (HA) glycoprotein of influenza A/USSR/90/77(H1N1) virus were separated by a combination of ion-exchange chromatography and gel filtration. Seven different glycosylated tryptic peptide classes were obtained from the HA1 polypeptide, and only one glycosylated peptide was obtained from the HA2 polypeptide. Several of the tryptic fragments of HA1 and the HA2 glycopeptides were sulfated. The nature of the carbohydrate chain in each of the glycosylated tryptic peptides was determined from observations of the incorporation of different sugar precursors and susceptibility to cleavage by the enzyme endoglycosidase H and by compositional analysis by gas chromatography. Such analyses showed that three types of carbohydrate chains were present in HA1 (type I [complex], type II [high mannose], and hybrid type), whereas HA2 contained only type I oligosaccharide chains. The amino acid composition of each of the glycosylated tryptic peptides was also determined.


Kidney growth in children with congenital hypothyroidism.
The effect of hypothyroidism on kidney size has not been studied in children. The aim of this study was to examine the role of congenital hypothyroidism and levothyroxine (L-thyroxine) treatment on renal growth. Forty children with congenital hypothyroidism and 37 healthy controls were prospectively included. The mean age of patients was 8.2+/-4.7 years. Patients had lower height and weight standard deviation scores compared with controls. The mean L-thyroxine initial age and treatment duration were 37.0 and 60.5 months, respectively. In 62.5% of patients, L-thyroxine was initiated after 6 months of age, and 60.0% of patients had severe hypothyroidism. Patients had lower kidney length and total kidney volume compared with controls (P < 0.05). No significant differences were found in kidney volume/body weight and kidney volume/ body height ratios between patients and controls (P > 0.05). Multiple regression analysis showed significant relationship between relative kidney volume and average free thyroxine level (P < 0.05). No significant differences in kidney sizes were found between patients who had L-thyroxine initiated before and after 6 months of age or between mild/moderate and severe hypothyroidism at diagnosis (P > 0.05). In conclusion, normal renal growth can be accomplished with L-thyroxine replacement despite considerable delay in treatment initiation and/or severe hypothyroidism.


Amplified recruitment pressure of biofouling organisms in commercial salmon farms: potential causes and implications for farm management.
The development of biofouling on finfish aquaculture farms presents challenges for the industry, but the factors underlying nuisance growths are still not well understood. Artificial settlement surfaces were used to examine two possible explanations for high rates of biofouling in Norwegian salmon farms: (1) increased propagule release during net cleaning operations, resulting in elevated recruitment rates; and (2) potential reservoir effects of farm surfaces. The presence of salmon farms was associated with consistently and substantially (up to 49-fold) elevated recruitment rates. Temporal patterns of recruitment were not driven by net cleaning. Resident populations of biofouling organisms were encountered on all submerged farm surfaces. Calculations indicate that a resident population of the hydroid Ectopleura larynx, a major biofouling species, could release between 0.3 × 10(9) and 4.7 × 10(9) larvae per farm annually. Such resident populations could form propagule reservoirs and be one explanation for the elevated recruitment pressure at salmon farms.


Best practices of formal new graduate nurse transition programs: an integrative review.
The aim of this review was to identify best practices of formal new graduate nurse transition programs. This information would be useful for organizations in their support and development of formal transition programs for newly hired nurses. An integrative review of the nursing research literature (2000-2011). The literature search included PubMed (MEDLINE), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Excerpta Medica Database (Embase). Studies that dealt with programs geared toward pre-registration nursing students were removed. At least two researchers evaluated the literature to determine if the article met the inclusion and exclusion criteria. The final number of articles included in this review is 47. Cooper's (1989) five-stage approach to integrative review guided the process: problem formulation, data collection, evaluation of data points, data analysis and interpretation, presentation of results. Transition program literature was examined according to four major themes: Education (pre-registration and practice), Support/Satisfaction, Competency and Critical Thinking, and Workplace Environment. This included new graduates' retrospective accounts of their undergraduate education and examination of orientation and formal supports provided beyond the traditional unit orientation period. Transition programs included residencies, internships, mentorships, extended preceptorships, and generic programs. Common elements of programs were a specified resource person(s) for new graduates, mentor (mentorship), formal education, and peer support opportunities. The length, type of education, and supports provided varied considerably among programs, yet the presence of a transition program resulted in improved new graduate nurse retention and cost benefits. The variability in research designs limits the conclusions that can be drawn about best practices in transition programs for new graduate nurses. The presence of a formal new graduate transition program resulted in good retention and improved competency. The stronger evidence suggests that new graduate education should focus on practical skill development, preceptors should receive a level of formal training, formal support should be available at least through the difficult six to nine month post-hire period, opportunities for connection with their peers should be provided, and organizations should strive to ensure clinical units with healthy work environments.


Perturbations of heart development and function in cardiomyocytes from human embryonic stem cells with trisomy 21.
Congenital heart defects (CHD) occur in approximately 50% of patients with Down syndrome (DS); the mechanisms for this occurrence however remain unknown. In order to understand how these defects evolve in early development in DS, we focused on the earliest stages of cardiogenesis to ascertain perturbations in development leading to CHD. Using a trisomy 21 (T21) sibling human embryonic stem cell (hESC) model of DS, we show that T21-hESC display many significant differences in expression of genes and cell populations associated with mesodermal, and more notably, secondary heart field (SHF) development, in particular a reduced number of ISL1(+) progenitor cells. Furthermore, we provide evidence for two candidate genes located on chromosome 21, ETS2 and ERG, whose overexpression during cardiac commitment likely account for the disruption of SHF development, as revealed by downregulation or overexpression experiments. Additionally, we uncover an abnormal electrophysiological phenotype in functional T21 cardiomyocytes, a result further supported by mRNA expression data acquired using RNA-Seq. These data, in combination, revealed a cardiomyocyte-specific phenotype in T21 cardiomyocytes, likely due to the overexpression of genes such as RYR2, NCX, and L-type Ca(2+) channel. These results contribute to the understanding of the mechanisms involved in the development of CHD. Stem Cells 2015;33:1434-1446.


Understanding the structural properties of a homologous series of bis-diphenylphosphine oxides
A homologous series of bis-diphenylphosphine oxides (C6H5)2PO(CH2)(n)PO(C6H5)2 (with n = 2-8; denoted 2-8] have been investigated to explore the effects of a range of competing and cooperative intermolecular and intramolecular interactions on the structural properties in the solid state. The important factors influencing the structural properties include intramolecular aspects such as the conformation of the aliphatic chain and the intramolecular interaction between the two P=O dipoles in the molecule, and intermolecular aspects such as long-range electrostatic interactions (dominated by the arrangement of the P=O dipoles), C-H...O interactions, C-H...pi interactions and pi...pi interactions. Compounds 3 and 5 could be crystallized only as solvate co-crystals (3 water and 5 x (toluene)2], whereas the crystal structures of all the other compounds contain only the bis-diphenylphosphine oxide molecule. The crystal structures have been determined from single-crystal X-ray diffraction data, with the exception of 7 (which has been determined here from powder X-ray diffraction data) and 4 (which was known previously). The compounds with even n represent a systematic structural series, exhibiting characteristic, essentially linear P=O...P=O...P=O dipolar arrays, together with C-H...O and C-H...pi interactions. For the compounds with odd n, on the other hand, uniform structural behaviour is not observed across the series, although certain aspects of these crystal structures contribute in a general sense to our understanding of the structural properties of bis-diphenylphosphine oxides. Importantly, for the compounds with odd n, there is "frustration" with regard to the molecular conformation, as the preferred all-anti conformation of the aliphatic chain gives rise to an unfavourable parallel alignment of the two P=O dipoles within the molecule. Clearly the importance of avoiding a parallel alignment of the P=O dipoles becomes greater as n decreases. Local structural aspects (investigated by high-resolution solid-state 31P NMR spectroscopy) and thermal properties of the bis-diphenylphosphine oxide materials are also reported.


Blood expression profiles of fragile X premutation carriers identify candidate genes involved in neurodegenerative and infertility phenotypes.
Male premutation carriers presenting between 55 and 200 CGG repeats in the Fragile-X-associated (FMR1) gene are at risk of developing Fragile X Tremor/Ataxia Syndrome (FXTAS), and females undergo Premature Ovarian Failure (POF1). Here, we have evaluated gene expression profiles from blood in male FMR1 premutation carriers and detected a strong deregulation of genes enriched in FXTAS relevant biological pathways, including inflammation, neuronal homeostasis and viability. Gene expression profiling distinguished between control individuals, carriers with FXTAS and carriers without FXTAS, with levels of expanded FMR1 mRNA being increased in FXTAS patients. In vitro studies in a neuronal cell model indicate that expression levels of expanded FMR1 5'-UTR are relevant in modulating the transcriptome. Thus, perturbations of the transcriptome may be an interplay between the CGG expansion size and FMR1 expression levels. Several deregulated genes (DFFA, BCL2L11, BCL2L1, APP, SOD1, RNF10, HDAC5, KCNC3, ATXN7, ATXN3 and EAP1) were validated in brain samples of a FXTAS mouse model. Downregulation of EAP1, a gene involved in the female reproductive system physiology, was confirmed in female carriers. Decreased levels were detected in female carriers with POF1 compared to those without POF1, suggesting that EAP1 levels contribute to ovarian insufficiency. In summary, gene expression profiling in blood has uncovered mechanisms that may underlie different pathological aspects of the premutation. A better understanding of the transcriptome dynamics in relation with expanded FMR1 mRNA expression levels and CGG expansion size may provide mechanistic insights into the disease process and a more accurate FXTAS diagnosis to the myriad of phenotypes associated with the premutation.


Predictors of Chronic Opioid Use in Newly Diagnosed Crohn's Disease.
Patients with Crohn's disease (CD) are often prescribed opioids chronically to manage pain associated with their disease. However, little evidence exists to support this practice. Here, we examine newly diagnosed patients with CD with and without chronic opioid use (COU) and sought to identify predictors and consequences of COU. A nationally representative administrative health care claims that data set identified newly diagnosed patients with CD. Their data were examined during the periods 6 months before and 2 years after diagnosis. Multivariable logistic regression was used to assess predictors of COU at diagnosis. The final study cohort consisted of 47,164 patients with CD. Of them, 3.8% were identified with new COU. Chronic opioid users were more likely women, older, and likely who had more surgeries, endoscopies, admissions, and medication usage compared with other patients. Features detected before CD diagnosis that correlated with COU after diagnosis included previous opioid use (odds ratio [OR] = 6.6), chronic pain (OR = 1.36), arthritis (OR = 1.95), and mental disorders (OR = 1.58). Interestingly, emergency department visits before CD Dx increased the risk of COU (OR = 1.11), whereas endoscopy reduced COU risk (OR = 0.88). This study presents a nationally representative assessment of COU in newly diagnosed patients with CD. The results may be used to determine the impact of COU in this population and to alert clinicians to those patients with CD at high risk of COU. Chronic opioids are consistently associated with indicators of more severe disease; however, additional research is needed to determine whether COU drives disease severity or vice versa.


Preparation of noninfectious arbovirus antigens.
Noninfectious arbovirus antigens were prepared from borate-saline suspensions of infected suckling mouse brain buffered with tris(hydroxmethyl)aminomethane and treated with beta-propiolactone (BPL). The activity and stability of these antigens were enhanced by altering the buffering system, by passing the virus seed through a series of four or more continuous passages in the brains of suckling mice, or by a combination of these procedures. The titers of group A and B arbovirus antigens were comparable to titers of antigens extracted by the conventional sucroseacetone-BPL (SA-BPL) method. Antigens prepared from some ungrouped and Bunyamwera arboviruses by either the borate-saline-BPL or SA-BPL method produced inconsistent results and will require the development of more unique procedures to obtain suitable hemagglutinating antigens.


Hydrophobization and bioconjugation for enhanced siRNA delivery and targeting.
RNA interference (RNAi) is an evolutionarily conserved process by which double-stranded small interfering RNA (siRNA) induces sequence-specific, post-transcriptional gene silencing. Unlike other mRNA targeting strategies, RNAi takes advantage of the physiological gene silencing machinery. The potential use of siRNA as therapeutic agents has attracted great attention as a novel approach for treating severe and chronic diseases. RNAi can be achieved by either delivery of chemically synthesized siRNAs or endogenous expression of small hairpin RNA, siRNA, and microRNA (miRNA). However, the relatively high dose of siRNA required for gene silencing limits its therapeutic applications. This review discusses several strategies to improve therapeutic efficacy as well as to abrogate off-target effects and immunostimulation caused by siRNAs. There is an in-depth discussion on various issues related to the (1) mechanisms of RNAi, (2) methods of siRNA production, (3) barriers to RNAi-based therapies, (4) biodistribution, (5) design of siRNA molecules, (6) chemical modification and bioconjugation, (7) complex formation with lipids and polymers, (8) encapsulation into lipid particles, and (9) target specificity for enhanced therapeutic effectiveness.


Rescue of respiratory failure in pulmonary alveolar proteinosis due to pathogenic MARS1 variants.
Pulmonary alveolar proteinosis (PAP) is a heterogeneous condition with more than 100 different underlying disorders that need to be differentiated to target therapeutic options, which are generally limited. The clinical course of two brothers with pathogenic variants in the methionyl-tRNA synthetase (MARS)1 gene was compared to previously published patients. Functional studies in patient-derived fibroblasts were performed and therapeutic options evaluated. The younger brother was diagnosed with PAP at the age of 1 year. Exome sequencing revealed the homozygous MARS1 variant p.(Arg598Cys), leading to interstitial lung and liver disease (ILLD). At 2 years of age, following surgery hypoglycemia was detected, the pulmonary condition deteriorated, and the patient developed multiorgan failure. Six therapeutic whole lung lavages (WLL) were necessary to improve respiratory insufficiency. Methionine supplementation was started and a high protein diet ensured, leading to complete respiratory recovery. The older brother, homozygous for the same MARS1 variant, had a long-known distinct eating preference of methionine-rich food and showed a less severe clinical phenotype. Decreased aminoacylation activity confirmed the pathogenicity of p.(Arg598Cys) in vitro. In agreement with our review of currently published ILLD patients, the presence of hepatopathy, developmental delay, muscular hypotonia, and anemia support the multisystemic character of the disease. Catabolic events can provoke a severe deterioration of the pulmonary situation in ILLD with a need for repetitive WLL. Although the precise role of oral methionine supplementation and high protein intake are unknown, we observed an apparent treatment benefit, which needs to be evaluated systematically in controlled trials.


Responsive Dual-Targeting Exosome as a Drug Carrier for Combination Cancer Immunotherapy.
Recently, combination immunotherapy, which incorporates the activation of the immune system and inhibition of immune escape, has been proved to be a new powerful strategy for more efficient tumor suppression compared to monotherapy. However, the major challenge is how to integrate multiple immune drugs together and efficiently convey these drugs to tumor sites. Although a variety of nanomaterials have been exploited as carriers for targeting tumor issues and the delivery of multiple drugs, their potential toxicity, immune rejection, and stability are still controversial for clinical application. Here, we proposed endogenic exosomes as drug carriers to deliver two antibodies acting as tumor-targeting molecules and block checkpoint inhibitors with specific response to the tumor microenvironment and costimulatory molecules for further improvement of therapeutic effect. The versatile exosomes exhibit excellent biocompatibility and provide a combination immunotherapy platform with synergistic advantages of activation of immune response and inhibition of immune escape.


Brain-mind operational architectonics: At the boundary between quantum physics and Eastern metaphysics.
The Operational Architectonics (OA) of brain-mind functioning is a theory that unifies brain and mind through nested and dynamic hierarchy of electromagnetic brain fields. Recently, it has been enriched by concepts from physics like time, space, entropy, and self-organized criticality. This review paper advances OA theory further by delving into the foundations of quantum physics and Eastern metaphysics in relation to mind function. We aim to show that the brain-mind OA is the boundary between and integration point of quantum physics and Eastern metaphysics, and that it may inspire building a richer and more inclusive paradigm of the brain-mind relation, where quantum physics and Eastern metaphysics are inherently intertwined.


GABA(A) receptor alpha4 subunit in DBA/2J and C57BL/6J mice.
GABA(A) receptors are chloride channels in the brain activated by binding of gamma-aminobutyric acid (GABA). Several important classes of drugs, including alcohol and certain antiepileptic drugs, modulate the actions of GABA. We report the sequence and expression of alpha4 subunits of GABA(A) receptors in two inbred strains of mice, DBA/2J and C57BL/6J, which differ in susceptibility to seizures and to behavioral effects of alcohol. We find no differences between the two strains in cDNA sequence, or in levels of alpha4 mRNA in whole brains of the two strains at 21 days of age, when DBA/2J are most susceptible to audiogenic seizures. We also describe the pattern of developmental expression and brain regional distribution of this subunit in mice, finding the highest developmental expression at about 14 days of age in whole brains, and the highest regional levels in hippocampus and basal forebrain (including thalamus) in adults.


Ameliorating effect of pomegranate juice consumption on carbon tetrachloride-induced sperm damages, lipid peroxidation, and testicular apoptosis.
The aim of this study was to investigate whether pomegranate juice (PJ) consumption has an ameliorating effect on carbon tetrachloride (CCl4)-induced sperm damages and testicular apoptosis associated with the oxidative stress in male rats. The study comprised of four groups (groups 1-4). Group 1 received olive oil + distilled water daily; group 2 was treated with 5 ml/kg PJ + olive oil daily; group 3 was treated with 0.25 ml/kg CCl4 dissolved in olive oil, weekly + distilled water daily; and group 4 received weekly CCl4 + daily PJ. All administrations were performed by gavage and maintained for 10 weeks. CCl4 administration caused significant decreases in body and reproductive organ weights, sperm motility, concentration and testicular catalase activity, significant increases in malondialdehyde (MDA) level, and abnormal sperm rate and apoptotic index along with some histopathological damages when compared with the control group. However, significant ameliorations were observed in absolute weights of testis and epididymis, all sperm quality parameters, MDA level, apoptotic index, and testicular histopathological structure following the administration of CCl4 together with PJ when compared with group given CCl4 only. In conclusion, PJ consumption ameliorates the CCl4-induced damages in male reproductive organs and cells by decreasing the lipid peroxidation.


Remarkable effect of alkalis on the chemoselective hydrogenation of functionalized nitroarenes over high-loading Pt/FeO x catalysts.
The chemoselective hydrogenation of substituted nitroarenes to form the corresponding functionalized anilines is an important type of reaction in fine chemistry, and the chemoselectivity is critically dependent on the rational design of the catalysts. This reaction has rarely been accomplished over high-loading Pt catalysts due to the formation of Pt crystals. Here, for the first time, we report that alkali metals (Li+, Na+, K+, etc.) can transform the non-selective high loading Pt/FeO x catalyst to a highly chemoselective one. The best result was obtained over a 5% Na-2.16% Pt/FeO x catalyst, which enhanced the chemoselectivity from 66.4% to 97.4% while the activity remained almost unchanged for the probe reaction of 3-nitrostyrene hydrogenation to 3-aminostyrene. Using aberration-corrected HAADF-STEM, in situ XAS, 57 and Fe Mössbauer and DRIFT spectroscopy, the active site of a Pt-O-Na-O-Fe-like species was proposed, which ensures that the Pt centers are isolated and positively charged for the preferential adsorption of the -NO2 group.


Relationship between the para-homologous sodium channel point mutation (g --> c at nucleotide 2979) and knockdown resistance in the German cockroach using multiplex polymerase chain reaction to discern genotype.
Extensive use of pyrethroid insecticides for urban pest control has led to widespread pyrethroid resistance in the German cockroach. A mutation at nucleotide position 2979 (G to C, causing a leucine to phenylalanine change) in the S6 transmembrane segment of domain II of the para-homologous voltage-gated sodium channel has been previously identified in knockdown-resistant cockroaches and demonstrated by site-directed mutagenesis to reduce channel sensitivity to pyrethroids. In a recent survey, 83% of pyrethroid-resistant German cockroach populations were found to possess this mutation. A German cockroach strain with a low incidence of the L993F mutation was subjected to selection pressure with cypermethrin and subsequently evaluated over several generations for the knockdown resistance phenotype. Correspondingly, we determined the genotype of individual cockroaches of each population at the 2979 position of the para-homologous gene. Genotype was discerned by development of a polymerase chain reaction method that employed a mismatched primer-template set. A direct relationship was observed between mean knockdown time and the presence of the kdr mutation. Furthermore, individuals homozygous for the kdr mutation exhibited a significantly higher mean knockdown time than heterozygotes or wildtype cockroaches. This is the first report demonstrating the progressive expression of the kdr allele in response to insecticide selection pressure.


Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD.
The association between proton pump inhibitors (PPI) use and risk of acute interstitial nephritis has been described. However, whether exposure to PPI associates with incident CKD, CKD progression, or ESRD is not known. We used Department of Veterans Affairs national databases to build a primary cohort of new users of PPI (n=173,321) and new users of histamine H2-receptor antagonists (H2 blockers; n=20,270) and followed these patients over 5 years to ascertain renal outcomes. In adjusted Cox survival models, the PPI group, compared with the H2 blockers group, had an increased risk of incident eGFR<60 ml/min per 1.73 m2 and of incident CKD (hazard ratio [HR], 1.22; 95% confidence interval [95% CI], 1.18 to 1.26; and HR, 1.28; 95% CI, 1.23 to 1.34, respectively). Patients treated with PPI also had a significantly elevated risk of doubling of serum creatinine level (HR, 1.53; 95% CI, 1.42 to 1.65), of eGFR decline >30% (HR, 1.32; 95% CI, 1.28 to 1.37), and of ESRD (HR, 1.96; 95% CI, 1.21 to 3.18). Furthermore, we detected a graded association between duration of PPI exposure and risk of renal outcomes among those exposed to PPI for 31-90, 91-180, 181-360, and 361-720 days compared with those exposed for ≤30 days. Examination of risk of renal outcomes in 1:1 propensity score-matched cohorts of patients taking H2 blockers versus patients taking PPI and patients taking PPI versus controls yielded consistent results. Our results suggest that PPI exposure associates with increased risk of incident CKD, CKD progression, and ESRD.


Synuclein Family Members Prevent Membrane Damage by Counteracting α-Synuclein Aggregation.
The 140 amino acid protein α-synuclein (αS) is an intrinsically disordered protein (IDP) with various roles and locations in healthy neurons that plays a key role in Parkinson's disease (PD). Contact with biomembranes can lead to α-helical conformations, but can also act as s seeding event for aggregation and a predominant β-sheet conformation. In PD patients, αS is found to aggregate in various fibrillary structures, and the shift in aggregation and localization is associated with disease progression. Besides full-length αS, several related polypeptides are present in neurons. The role of many αS-related proteins in the aggregation of αS itself is not fully understood Two of these potential aggregation modifiers are the αS splicing variant αS Δexon3 (Δ3) and the paralog β-synuclein (βS). Here, polarized ATR-FTIR spectroscopy was used to study the membrane interaction of these proteins individually and in various combinations. The method allowed a continuous monitoring of both the lipid structure of biomimetic membranes and the aggregation state of αS and related proteins. The use of polarized light also revealed the orientation of secondary structure elements. While αS led to a destruction of the lipid membrane upon membrane-catalyzed aggregation, βS and Δ3 aggregated significantly less, and they did not harm the membrane. Moreover, the latter proteins reduced the membrane damage triggered by αS. There were no major differences in the membrane interaction for the different synuclein variants. In combination, these observations suggest that the formation of particular protein aggregates is the major driving force for αS-driven membrane damage. The misbalance of αS, βS, and Δ3 might therefore play a crucial role in neurodegenerative disease.


How does the employer contribution for the federal employees health benefits program influence plan selection?
Market reform of health insurance is proposed to increase coverage and reduce growth in spending by providing an incentive to choose low-cost plans. However, having a choice of plans could result in risk segmentation. Risk-adjusted payments have been proposed to address risk segmentation but are criticized as ineffective. An alternative to risk adjustment is to subsidize premiums, as in the Federal Employees Health Benefits Program (FEHBP). Subsidizing premiums may also increase total premium spending. We find that there is little risk segmentation in the FEHBP and that reducing the premium subsidy would lower government premium spending and slightly increase risk segmentation.


Acute renal failure in Reye's syndrome.
From 1979 to 1985, 8 children with clinical and biochemical features of Reye's Syndrome developed acute renal failure. Within the same period, a total of 28 cases of Reye's Syndrome were admitted to the Paediatric Units of Singapore General Hospital. Six of them were females and 2 were males. The mean age at presentation was 28.4 months and the range was between 9 months to 47 months. Four of them died eventually. There appeared to be a correlation between the eventual outcome and severity of renal failure and neurological state of admission.


Effects of calcium on membrane potential and sodium influx in barnacle muscle fibers.
The influence of internal and external Ca2+ on membrane potential and 22Na influx were tested in internally perfused giant barnacle muscle fibers. The fibers depolarized by about 2-3 mV, and Na+ influx increased when external Ca2+ was removed. These effects were inhibited and reversed by adding 2 mM La3+ externally but not by tetrodotoxin (TTX). Ca2+ channel blockers did not prevent the depolarization. Increasing internal free Ca2+ ([Ca2+]i) from 10(-7) to 10(-5) M also stimulated Na+ influx and depolarized the fibers by a few millivolts. Neither external La3+ nor TTX prevented the effects of raising [Ca2+]i; however, internal tetrabutylammonium ions depolarized the fibers and attenuated the internal Ca2+-dependent effects. These data are consistent with the idea that removal of external Ca2+ activates a La3+-sensitive channel that is permeable to Na+; raising [Ca2+]i activates a La2+-insensitive, Na+-permeable channel that may be similar to the internal Ca2+-activated nonselective cation channels observed in cardiac muscle. The results demonstrate that all Na+ (and Ca2+) fluxes that do not contribute to Na-Ca exchange must be carefully identified before the exchange stoichiometry can be determined from Na+ and Ca2+ flux measurements.


[Pure red cell aplasia in patient affected by myelodysplastic syndrome treated with R-Epo].
Pure red cell aplasia (PRCA) is a rare condition described in patients with chronic kidney disease during alpha-Epo treatment subcutaneous administered generated by anti-R-Epo antibodies. Recently two cases of PRCA have been reported in patients affected by myelodysplastic syndrome treated with R-Epo. We described one more case of PRCA in a patient with refractory anemia treated with R-Epo.


Alternatives to In Vivo Draize Rabbit Eye and Skin Irritation Tests with a Focus on 3D Reconstructed Human Cornea-Like Epithelium and Epidermis Models.
Human eyes and skin are frequently exposed to chemicals accidentally or on purpose due to their external location. Therefore, chemicals are required to undergo the evaluation of the ocular and dermal irritancy for their safe handling and use before release into the market. Draize rabbit eye and skin irritation test developed in 1944, has been a gold standard test which was enlisted as OECD TG 404 and OECD TG 405 but it has been criticized with respect to animal welfare due to invasive and cruel procedure. To replace it, diverse alternatives have been developed: (i) For Draize eye irritation test, organotypic assay, in vitro cytotoxicity-based method, in chemico tests, in silico prediction model, and 3D reconstructed human cornea-like epithelium (RhCE); (ii) For Draize skin irritation test, in vitro cytotoxicity-based cell model, and 3D reconstructed human epidermis models (RhE). Of these, RhCE and RhE models are getting spotlight as a promising alternative with a wide applicability domain covering cosmetics and personal care products. In this review, we overviewed the current alternatives to Draize test with a focus on 3D human epithelium models to provide an insight into advancing and widening their utility.


Perceptions of the risks and benefits of upper limb transplantation among individuals with upper limb amputations.
Upper limb transplantation is a life-enhancing rather than life-saving procedure. Little research has investigated how individuals with upper limb amputations perceive the benefits and risks of this complex procedure. To address this knowledge gap, the authors conducted qualitative research with individuals with upper limb amputations to understand their perspectives. Twenty-two individuals with upper limb amputations (age range, 24 to 73 years) participated in a focus group (n=5) or semistructured interview (n=17) about the benefits and risks of upper limb transplantation. Data were analyzed by means of constant comparative methods and a two-phase analysis process. Participants identified enhanced functional performance and improved appearance as the greatest potential benefits. Over half of participants indicated that function was a more important consideration than appearance. Enhanced function performance was a relative concept strongly influenced by individual expectations, which varied widely. Increased sensation, psychological well-being, and social acceptability were also described as potential benefits. Identified risks included health risks and the demands of transplantation and recovery, decreased functional performance, and uncertainty over outcomes from upper limb transplantation as an experimental procedure. Participants also expressed concerns regarding the psychological impact of negative outcomes and adverse events. Participants had a large variation in their perceived importance of the many risks and benefits of upper limb transplantation. These findings elucidate how potential upper limb transplantation candidates evaluate the benefits and risks of the procedure. The findings can also inform important issues to address and outcomes to assess in the pretransplant and posttransplant settings.


[Study of the antagonistic action of actinomycetes on anthrax bacilli].
Capacity for the growth inhibition of the highly virulent causative agent of Siberia plague was studied with respect to actinomycetous strains from soil samples of the Ukraine. It was found that on nutrient media 88.4, 88.9, 88.1 and 93.4% of the isolates inhibited the growth of Bac. anthracis, Bac. cereus, Bac. mycoides and Tsenkovsky vaccine strain respectively. Representatives of very different taxonomic groups were found among the antagonistic actinomycetes. Clearance of the soil from Siberia plague bacilli stable to the outer effect with the help of the active strain L-721 of Act. chromofuscus was observed. The effect was chown in sterilized soil, not sterile soil and soil monolith.


Three-phase capillary entry conditions in pores of noncircular cross-section.
In this work we challenge the assumption that the capillary entry pressures for displacements in three-phase flow are the same as those in two-phase flow. Using an energy balance, as derived by R.P. Mayer and R.A. Stowe (J. Colloid Interface Sci. 20 (1965) 893-911) and H.M. Princen (J. Colloid Interface Sci. 30 (1969) 69-75; 30 (1969) 359-371; 34 (1970) 171-184) for two-phase flow, we derive a general formula for determination of the capillary entry pressures for piston-like displacement of two bulk phases in a pore where a third phase may also be present. The method applies to capillaries of angular cross-section and uniform but arbitrary wettability. To use this method we have determined all possible underlying phase occupancies in cross-sections on either side of the main terminal meniscus, in particular the presence of corner arc menisci (AMs). Indeed, the capillary entry pressures for piston-like displacements depend on the pressure in the remaining third phase if the cross-sectional fluid configurations contain this phase. This dependence only vanishes when layers of the intermediate-wetting phase completely separate the wetting and the non-wetting phases. The complexity of the corresponding equations and the quantitative effects are studied using two different geometries, the equilateral triangle and the rhombus. The main difference is that the latter geometry has unequal corners, which may carry different AMs. We have carried out a limited sensitivity study with respect to the effect of wettability, the spreading coefficient of the intermediate-wetting phase, and the aspect ratio of the principal radii of the rhombus.


Ra-223 SPECT for semi-quantitative analysis in comparison with Tc-99m HMDP SPECT: phantom study and initial clinical experience.
Image-based measurement of absorbed dose of Ra-223 dichloride may be useful in predicting therapeutic outcome in patients with castration-resistant prostate cancer (CRPC). In general, SPECT has been found to be more accurate than planar imaging in terms of lesion-based analysis. The aims of this study were to assess the feasibility and clinical usefulness of Ra-223 SPECT. The energy spectrum of Ra-223 and SPECT images of a cylindrical phantom with a hot rod were obtained to determine the collimator candidates and energy window settings suitable for clinical Ra-223 SPECT (basic study A). Another phantom with a tube-shaped chamber and two spheres simulating bowel activity and metastatic lesions in the lumbar spine was scanned with medium-energy general-purpose (MEGP) and high-energy general-purpose (HEGP) collimators (basic study B). Ten patients with CRPC underwent SPECT imaging 2 h after Ra-223 injection successively with MEGP and HEGP collimators in random order for 30 min each. Lesion detectability and semi-quantitative analyses of bone metastasis (i.e. lesion-to-background ratio (LBR)) were performed compared to Tc-99m HMDP SPECT. Basic study A revealed that an 84-keV photopeak ± 20% using the HEGP collimator offers better SPECT image quality than the other imaging conditions. Basic study B showed that uptake in one of the spheres was overestimated by overlapped activity of the tube-shaped chamber in planar imaging whereas the spheres had similar counts and significantly higher sphere-to-background ratio in SPECT. On both planar and SPECT images, HEGP gave higher image contrast than MEGP (p < 0.01). In the clinical study, Ra-223 SPECT at 84 keV ± 20% depicted more lesions with the HEGP than with the MEGP collimator (51 vs 36, p = 0.013). There was a positive correlation between LBR in Tc-99m SPECT and in Ra-223 SPECT (r = 0.67 with the MEGP and 0.69 with the HEGP collimator, p < 0.01). LBRs were significantly higher with the HEGP than with the MEGP collimator (p < 0.01). We recommended the use of the HEGP collimator at 84 keV ± 20% for Ra-223 SPECT imaging. Lesion-based semi-quantitative analysis in the human study revealed a good correlation between Ra-223 and Tc-99m HMDP SPECT in the early phase (2-3 h post injection).


Long-Term Tolerability and Safety of Pharmacological Treatment of Adult Attention-Deficit/Hyperactivity Disorder: A 6-Year Prospective Naturalistic Study.
Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder typically treated with stimulants and atomoxetine. Data on long-term tolerability and safety of such pharmacological treatment in subjects diagnosed in adulthood are limited. A cohort of adults diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria was followed-up on an average of 6 years after first evaluation. Of 168 adults, 112 (67%) who initiated medication were available for follow-up. Data were obtained from patient record data, self-report forms, and a telephone interview. Of the 112 participants assessed, 57 (51%) were still on treatment with methylphenidate (MPH) at follow-up and 55 (49%) had discontinued. The 3 leading reasons for discontinuing treatment with MPH were lack of effect (29%), elevated mood or hypomania (11%), and losing contact with the prescribing physician (9%). The most common adverse effects in subjects still on treatment with MPH were decreased appetite (28%), dry mouth (24%), anxiousness/restlessness and increased pulse frequency (19% each), decreased sexual desire (17%), and perspiration (15%). Subjects still on treatment reported increased quality of life, a higher level of functioning, and a greater understanding of their way of functioning from those being close compared with nonmedicated subjects. The high attrition rate underscores the need for further research to identify possible modes to increase retention to treatment. Those diagnosed with ADHD and on long-term treatment with stimulants experience mild and tolerable adverse effects.