Inhibition of GABAA-ρ receptors induces retina regeneration in zebrafish.
A potential treatment for retinal diseases is to induce an endogenous Müller glia (MG)-derived regenerative response to replace damaged neurons. In contrast to mammalian MG, zebrafish MG are capable of mediating spontaneous regeneration. We seek to define the mechanisms that enable retina regeneration in zebrafish in order to identify therapeutic targets to induce mammalian retina regeneration. We previously used pharmacological and genetic methods to inhibit gamma aminobutyric acid A (GABAA) receptors in undamaged zebrafish retinas and showed that such inhibition could induce initiation of retina regeneration, as measured by the dedifferentiation of MG and the appearance of MG-derived proliferating progenitor cells. Here, we show that inhibition of a pharmacologically distinct subset of GABAA receptors (GABAA-ρ) can also induce retina regeneration. Dual inhibition of both GABA receptor subtypes led to enhanced retina regeneration. Gene expression analyses indicate that inhibition of GABAA-ρ receptors induces a canonical retinal regenerative response. Our results support a model in which decreased levels of GABA, such as would occur after retinal cell death or damage, induce dedifferentiation of MG and the generation of proliferating progenitor cells during zebrafish retina regeneration. Animal experiments were approved by the Vanderbilt's Institutional Animal Care and Use Committee (Protocol M1800200) on January 29, 2019.


Foot laterality in children, adolescents, and adults.
This investigation reviewed 14 studies describing the trichotomous distribution of foot preference behaviour spanning early childhood to adult years. Findings suggest that a substantially greater percentage of children are mixed-footed in comparison to older individuals. A significant shift towards right-sidedness appears to occur sometime during late childhood, after which, behaviour remains relatively stable. The incidence of left-footedness is similar across the lifespan. In comparison to handedness, substantially more (about twice as many) young children are mixed-footed compared to mixed-handed. A similar pattern is noted during adolescence and adulthood, but the differences are smaller. Values for leftsidedness (upper and lower limbs) are comparable across the lifespan. Of the existing theoretical models, Annett's Right-shift hypothesis with additional propositions related to environmental influences (Collins, 1977; Porac, 1993; Provins, 1992) provides partial explanation for the findings.


[The senescence-accelerated oxys rats--a genetic model of premature aging and age-dependent degenerative diseases].
The genetic model of accelerated senescence and the associated diseases--the OXYS strain of rats--was created using selection and inbreeding of Wistar rats sensitive to cataractogenic effects of galactose. In the first 5 generations, the development of cataract was induced by galactose overconsumption, and after that, the rats were selected for early spontaneous cataract. Genetically linked with the latter was a set of features of accelerated senescence, which were inherited by the subsequent generations of the animals. At present, we have a 103rd generation of OXYS rats, who at young age develop retinopathy (similar to age-related macular degeneration in humans), osteoporosis, arterial hypertension, accelerated thymus involution, sarcopenia, and neurodegenerative changes in the brain (with the features characteristic of Alzheimer's disease), besides the cataract. This review discusses possible mechanisms of the accelerated senescence: the results of comparison of retinal transcriptomes between OXYS and Wistar(control) rats at different ages, studies of the markers of Alzheimer's disease in the retina and in certain brain regions, and the outcome of the efforts to develop congenic strains of animals via a transfer of several quantitative trait loci (QTLs) of chromosome 1 from OXYS to WAG rats that are associated with the signs of accelerated senescence. The uniqueness of OXYS rats lies in the complex composition of manifestations of the traits; accordingly, this rat model can be used not only for studies of the mechanisms of aging and pathogenesis of the age-related diseases but also for objective evaluation of new methods of treatment and prevention.


Validity and responsiveness of the euroqol as a measure of health-related quality of life in people enrolled in an AIDS clinical trial.
Brief utility measures are needed in clinical trials in addition to existing descriptive measures of health-related quality of life (HRQOL). We examined the reliability and validity of the EuroQol (EQ-SD) and MOS-HIV and their responsiveness to HIV-related clinical events. Subjects with advanced HIV disease (CD4 < 100) were enrolled in a randomized trial for CMV prophylaxis (n = 990). The EQ-5D includes a weighted sum of five domains (EQ-5D Index) and a visual analog scale (EQ-VAS). The MOS-HIV has 10 subscales and physical (PHS) and mental health summary scores (MHS). Construct validity of the EQ-5D was tested based on hypothesized relationships to subscales of the MOS-HIV. Relative precision and responsiveness to adverse experiences and opportunistic infections (Ols) were compared for the two instruments. Mean age of the patients was 38, 94% were male, 80% white, and 7% had injected drugs. Mean baseline scores for EQ-5D Index and EQ-VAS were 0.80 and 76.0, respectively, 28 and 4% reported maximum scores. Mean MOS-HIV subscales score ranged from 55 (role) to 84 (cognitive); mean PHS and MHS were 47.4 and 49.5, respectively. Correlations between MOS-HIV subscales and EQ-5D Index ranged from 0.45 (role) to 0.63 (pain); correlations with EQ-VAS ranged from 0.33 (cognitive) to 0.66 (health perceptions). Correlations between MOS-HIV PHS and MHS with EQ-5D Index were 0.61 and 0.58; and with EQ-VAS, 0.57 and 0.60, respectively. Responsiveness to adverse experiences was highest for MOS-HIV pain and PHS (effect sizes = 0.9 and 0.4); pain had the highest relative precision (2.4) for adverse experiences: EQ-VAS had the greatest relative precision (1.6) for developing an OI. In these patients with advanced HIV disease. EQ-5D showed good construct validity, but there may be a ceiling effect for its EQ-5D Index component. EQ-5D was less responsive to adverse events than the MOS-HIV. However, the EQ-VAS was most sensitive to developing an OI and is likely to be a useful measure of HRQOL for generating QALYs in cost-utility studies involving patients with advanced HIV disease.


The endoxylanases from family 11: computer analysis of protein sequences reveals important structural and phylogenetic relationships.
Eighty-two amino acid sequences of the catalytic domains of mature endoxylanases belonging to family 11 have been aligned using the programs MATCHBOX and CLUSTAL. The sequences range in length from 175 to 233 residues. The two glutamates acting as catalytic residues are conserved in all sequences. A very good correlation is found between the presence (at position 100) of an asparagine in the so-called 'alkaline' xylanases, or an aspartic acid in those with a more acidic pH optimum. Four boxes defining segments of highest similarity were detected; they correspond to regions of defined secondary structure: B5, B6, B8 and the carboxyl end of the alpha helix, respectively. Cysteine residues are not common in these sequences (0.7% of all residues), and disulfide bridges are not important in explaining the stability of several thermophilic xylanases. The alignment allows the classification of the enzymes in groups according to sequence similarity. Fungal and bacterial enzymes were found to form mostly separate clusters of higher similarity.


Derivation and applications of human hepatocyte-like cells.
Human hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) promise a valuable source of cells with human genetic background, physiologically relevant liver functions, and unlimited supply. With over 10 years' efforts in this field, great achievements have been made. HLCs have been successfully derived and applied in disease modeling, toxicity testing and drug discovery. Large cohorts of induced pluripotent stem cells-derived HLCs have been recently applied in studying population genetics and functional outputs of common genetic variants in vitro. This has offered a new paradigm for genome-wide association studies and possibly in vitro pharmacogenomics in the nearly future. However, HLCs have not yet been successfully applied in bioartificial liver devices and have only displayed limited success in cell transplantation. HLCs still have an immature hepatocyte phenotype and exist as a population with great heterogeneity, and HLCs derived from different hPSC lines display variable differentiation efficiency. Therefore, continuous improvement to the quality of HLCs, deeper investigation of relevant biological processes, and proper adaptation of recent advances in cell culture platforms, genome editing technology, and bioengineering systems are required before HLCs can fulfill the needs in basic and translational research. In this review, we summarize the discoveries, achievements, and challenges in the derivation and applications of HLCs.


Vaccine improves survival in monkey tests.
A vaccine tested at the U.S. NIAID clearly improved the survival of monkeys, a benefit not predicted by T-cell and viral load tests. It was predicted by measurements of memory T cells in the first few months of infection--giving important insights into how HIV disease develops, and how to test HIV vaccines early so that only the best candidates will go into large human trials.


Diet-induced pre-diabetes slows cardiac conductance and promotes arrhythmogenesis.
Type 2 diabetes is associated with abnormal electrical conduction and sudden cardiac death, but the pathogenic mechanism remains unknown. This study describes electrophysiological alterations in a diet-induced pre-diabetic rat model and examines the underlying mechanism. Sprague-Dawley rats were fed either high-fat diet and fructose water or normal chow and water for 6 weeks. The electrophysiological properties of the whole heart was analyzed by in vivo surface ECG recordings, as wells as ex vivo in Langendorff perfused hearts during baseline, ischemia and reperfussion. Conduction velocity was examined in isolated tissue strips. Ion channel and gap junction conductances were analyzed by patch-clamp studies in isolated cardiomyocytes. Fibrosis was examined by Masson's Trichrome staining and thin-layer chromatography was used to analyze cardiac lipid content. Connexin43 (Cx43) expression and distribution was examined by western blotting and immunofluorescence respectively. Following 6 weeks of feeding, fructose-fat fed rats (FFFRs) showed QRS prolongation compared to controls (16.1 ± 0.51 (n = 6) vs. 14.7 ± 0.32 ms (n = 4), p < 0.05). Conduction velocity was slowed in FFFRs vs. controls (0.62 ± 0.02 (n = 13) vs. 0.79 ± 0.06 m/s (n = 11), p < 0.05) and Langendorff perfused FFFR hearts were more prone to ventricular fibrillation during reperfusion following ischemia (p < 0.05). The patch-clamp studies revealed no changes in Na(+) or K(+) currents, cell capacitance or gap junctional coupling. Cx43 expression was also unaltered in FFFRs, but immunofluorescence demonstrated an increased fraction of Cx43 localized at the intercalated discs in FFFRs compared to controls (78 ± 3.3 (n = 5) vs. 60 ± 4.2 % (n = 6), p < 0.01). No fibrosis was detected but FFFRs showed a significant increase in cardiac triglyceride content (1.93 ± 0.19 (n = 12) vs. 0.77 ± 0.13 nmol/mg (n = 12), p < 0.0001). Six weeks on a high fructose-fat diet cause electrophysiological changes, which leads to QRS prolongation, decreased conduction velocity and increased arrhythmogenesis during reperfusion. These alterations are not explained by altered gap junctional coupling, Na(+), or K(+) currents, differences in cell size or fibrosis.


Limosilactobacillus fermentum ING8, a Potential Multifunctional Non-Starter Strain with Relevant Technological Properties and Antimicrobial Activity.
Lactic acid bacteria (LAB) have gained particular attention among different exopolysaccharide-producing microorganisms due to their safety status and effects on human health and food production. Exopolysaccharide-producing LAB play a crucial role in different ways, such as improving texture, mouthfeel, controlling viscosity, and for low-calorie food production. In this study, we isolated a multifunctional strain with good exopolysaccharide production properties. Limosilactobacillus fermentum ING8 was isolated from an Indian traditional fermented milk (Dahi) and evaluated for its safety, enzymatic activity, NaCl resistance and temperature tolerance, milk coagulation, and storage stability. Finally, the complete genome of this strain was sequenced and subjected to safety in silico evaluation and genomic analysis. The results revealed that L. fermentum ING8 possesses relevant technological properties, such as exopolysaccharide production, antimicrobial activity, and galactose utilization. Besides, this strain showed very high stability to storage conditions at refrigeration temperature. In addition, the genomic analysis did not evidence any possible deleterious elements, such as acquired antibiotic resistance genes, virulence genes, or hemolysis-related genes. However, all structural genes related to the galactose operon and EPS production were detected. Therefore, L. fermentum ING8 can be considered a promising multifunctional bacterium to be proposed as non-starter in different types of dairy productions.


Correlation between CCR7 expression and lymph node metastatic potential of human tongue carcinoma.
Metastasis is an important cause of cancer-related mortality. In this study, we investigated the role of CCR7 in the lymph node metastasis of tongue carcinoma. Immunohistochemistry and Western blot revealed the expression of CCR7 in tongue SCC tissues and cell lines. In addition, we examined the expression of CCL21, a ligand of CCR7, in normal and diseased lymph nodes using immunohistochemistry and/or real-time PCR. The CCR7 expression was significantly correlated with cervical lymph node metastasis, tumor staging, and histological grade (P = 0.015, 0.040, and 0.015, respectively). The multivariate analysis showed that regional lymph node metastasis, the expression of CCR7, and LVD were the independent poor prognostic factors. Knockdown of CCR7 gene resulted in a significant inhibition of migration and invasion of SCC4 cells in vitro without affecting the proliferation and apoptosis of tumor cells. Also, CCR7 knockdown obviously inhibited cervical lymph node metastasis in an animal tumor model. Our study indicated that CCR7 may play an important role in progression of tongue SCC and could be a promising target for tongue SCC therapy.


Early psychosocial intervention does not delay institutionalization in persons with mild Alzheimer disease and has impact on neither disease progression nor caregivers' well-being: ALSOVA 3-year follow-up.
Early diagnosis, initiation of Alzheimer's disease (AD) therapy and programs that support care of persons with AD at home are recommended. The objective of this study was to assess the effect of early psychosocial intervention on delaying the institutionalization of persons with AD. We also assessed the influence of intervention on AD progression, behavioral symptoms, and health-related quality of life (HRQoL) in persons with AD and caregivers. Kuopio ALSOVA study, a prospective, randomized intervention study with a 3-year follow-up, was carried out at memory clinics. Home-dwelling persons with very mild or mild AD (n = 236) and AD-targeted therapy and their family caregivers (n = 236) were randomized to the intervention or control group (1:2). Psychosocial intervention including education, counseling, and social support was given during the first 2 years (16 days). The primary outcome was the cumulative risk (controlled for death) of institutionalization over 36 months. Secondary outcomes were adjusted mean changes from baseline in disease severity, cognition, daily activities, behavior, and HRQoL for persons with AD; and change in psychological distress, depression, and HRQoL for caregivers. No differences were found in nursing home placement after the 36-month follow-up between intervention and control groups. No beneficial effects of the intervention were found on the secondary outcomes. The psychosocial intervention did not delay nursing home placement in persons with AD and had no effect on patient well-being, disease progression, or AD-related symptoms or caregiver well-being. Instead of automatically providing psychosocial intervention courses, individualized support programs may be more effective.


Requirements of Kettin, a giant muscle protein highly conserved in overall structure in evolution, for normal muscle function, viability, and flight activity of Drosophila.
Kettin is a giant muscle protein originally identified in insect flight muscle Z-discs. Here, we determined the entire nucleotide sequence of Drosophila melanogaster kettin, deduced the amino acid sequence of its protein product (540 kD) along with that of the Caenorhabditis elegans counterpart, and found that the overall primary structure of Kettin has been highly conserved in evolution. The main body of Drosophila Kettin consists of 35 immunoglobulin C2 domains separated by spacers. The central two thirds of spacers are constant in length and share in common two conserved motifs, putative actin binding sites. Neither fibronectin type III nor kinase domains were found. Kettin is present at the Z-disc in several muscle types. Genetic analysis showed that kettin is essential for the formation and maintenance of normal sarcomere structure of muscles and muscle tendons. Accordingly, embryos lacking kettin activity cannot hatch nor can adult flies heterozygous for the kettin mutation fly.


Nurse burnout: work related and demographic factors as culprits.
This study was an examination of the combined ability of perceived work environment, demographic, and work-related variables to predict burnout among 314 nurses at a large metropolitan hospital. The three dimensions of burnout measured were emotional exhaustion, depersonalization, and personal accomplishment. High work pressure and low work involvement and supervisor support predicted emotional exhaustion. Task orientation, work pressure, work involvement, and age predicted both depersonalization and personal accomplishment. Burnout among nurses on each of the three work shifts also was examined. Results are discussed from the perspective of how to decrease or to prevent burnout among nurses.


Do traits separated by metamorphosis evolve independently? Concepts and methods.
Despite the ubiquity of complex life cycles, we know little of the evolutionary constraints exerted by metamorphosis. Here, we present pitfalls and methods to answer whether animals with a complex life cycle can independently adapt to the environments encountered at each life stage, with a specific focus on the microevolution of quantitative characters. We first discuss challenges associated with study traits and populations. We further emphasize the benefits of using a combination of approaches. We then develop how multivariate methods can limit several issues by revealing genetic patterns that are invisible when only considering trait-by-trait genetic correlations. Finally, we detail how Lande's work on sexual dimorphism can be applied in measuring G matrices across life stages. The methods and tools described here will contribute towards building a predictive framework for trait evolution across life stages.


Strabismus surgery in patients with myasthenia.
The efficacy of eye muscle surgery for strabismus in patients with myasthenia is not well-documented in the literature. We reviewed the results of strabismus surgery in six patients with the confirmed diagnosis of myasthenia. Patients selected for surgery had angles of deviation that were stable for at least 5 months preoperatively. Patient age ranged from 4 to 62 years. All patients were exotropic. The four adults had moderate limitation of adduction. Surgery included horizontal rectus muscle recession and/or resection in all cases. Three cases involved additional surgery of the vertical rectus or superior oblique muscles. The mean postoperative follow up was 44 months with a minimum of 7 months. Three adults and one child achieved stable satisfactory alignment after one procedure. One child required three procedures to achieve satisfactory alignment. The results suggest that surgery is a viable option in the management of strabismus in selected patients with myasthenia.


A new endoscopic drainage technique for pancreatic abscesses.
Acute pancreatitis sometimes leads to pancreatic abscess with a high mortality rate when appropriate drainage is not applied. Pancreatic pseudocysts are also major complications of pancreatitis, which usually need to be treated only when they are symptomatic; they sometimes lead to disseminated intravascular coagulopathy or intraabdominal bleeding if they maturate. Conventional pancreatic drainage operations have sometimes been so invasive that they cannot be applied for severe cases with renal failure and disseminated intravascular coagulopathy. To avoid the risks of conventional drainage operations for pancreatic abscesses, a low invasive and effective percutaneous drainage technique guided by a laparoscope was developed and employed to a high-risk patient with post-pancreatitic pancreatic abscess. After the operation, leukocytosis and high fever improved dramatically. One year after discharge from the hospital, no recurrence of abscesses or leukocytosis have been found. Thus, this technique should be considered as a first option for the pancreatic drainage operation.


Inflammatory myofibroblastic tumor of the kidney in patient with nephron-sparing surgery. Case report and review of the literature.
According to the WHO classification, mesenchymal tumors of the kidney are divided into mesenchymal tumors occurring mainly in adults and children. Accumulating evidence suggests that renal mesenchymal tumors represent a group of histologically heterogeneous diseases. We are reporting the case of a 58-year-old man with a history of nephron-sparing surgery due to renal cell carcinoma in 2014 in his left kidney. He was urgently admitted to the hospital due to left-sided nephrotoxic and anuria. Computed tomography (CT) imaging was performed and revealed irregular tumor mass. He underwent left-sided nephrectomy. Microscopic appearance and immunoprofile allowed to diagnose the tumor as an inflammatory myofibroblastic tumor (IMT) of the kidney. According to the 2016 World Health Organization (WHO) classification of tumors of the urinary system and male genital organs, IMT is a benign mesenchymal tumor with malignant potential. Typical locations are the liver and biliary tract, lung, and gastrointestinal tract. In the urogenital system, IMT occurs mainly in the bladder. So far, 48 cases have been reported in the kidney.


Nrf2 activation in the human brain after stroke due to supratentorial intracerebral haemorrhage: a case-control study.
Pharmacological activation of the antioxidative transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) improves outcomes in experimental models of intracerebral haemorrhage (ICH). However, the Nrf2 pathway has not been previously studied in humans after ICH. Our study aims to address this gap. We selected cases with fatal ICH from a prospective community-based inception cohort study and age-matched and sex-matched controls who died suddenly of non-neurological disease. We used immunohistochemistry to quantify Nrf2 (% total area stained overall and % of nuclei stained) and CD68 expression in controls and perihaematomal, ipsilateral and contralateral brain tissue from cases. We measured downstream haem oxygenase-1 (HMOX1) and NAD(P)H dehydrogenase quinone 1 [NQO1] expression using RNA in situ hybridisation. 26 ICH cases (median age: 82 (IQR 76-86); 13 (50%) male) and eight controls (median age: 79 (IQR 77-80); 3 (37.5%) male) were included. We found no significant differences in overall % of Nrf2 staining between ICH cases and controls. However, the mean % of nuclei staining for Nrf2 seemed higher in perihaematomal compared with contralateral regions, although this was only statistically significant >60 days after ICH (25% (95% CI 17% to 33%) vs 14% (95% CI 11% to 17%), p=0.029). The percentage of perihaematomal tissue staining for CD68 was higher >60 days after ICH (6.75%, 95% CI 2.78% to 10.73%) compared with contralateral tissue (1.45%, 95% CI 0.93% to 1.96%, p=0.027) and controls (1.08%, 95% CI 0.20% to 1.97%, p=0.0008). RNA in situ hybridisation suggested increased abundance of HMOX1 and NQO1 transcripts in perihaematomal versus distant ipsilateral brain tissue obtained <7 days from onset of ICH. We found evidence of Nrf2 activation in human brain tissue after ICH. Pharmacological augmentation of Nrf2 activation after ICH might be a promising therapeutic approach.


Shielding of augmented tendon--tendon repair.
Strength and function of autogenic and xenogenic reconstruction of digital extensor tendons was examined in an ovine model. In this study, tendon-graft junctions were formed by either suture augmented with a woven polyester tube (A), or augmented and shielded from surrounding tissues by chemically-treated bovine pericardium (S). By 12 wk, both A and S sheep had returned to full range of motion. Mechanical strength of both the autograft-host and xenograft-host repair sites was similar, with a pooled strength of 131 +/- 25 N (n = 15). Similarly, the mid-portion xenograft strengths were constant at approximately 366 +/- 97 N (n = 7). In contrast, mid-portion autograft strengths decreased from 380 +/- 110 N (N = 4) to 120 +/- 66 N (n = 4) if shielding was omitted. The loss in autograft strength was attributed to loss of function associated with adhesions. The use of the augmentation device coupled with an adhesion barrier gives higher initial reconstruction strength and improved function during the host repair period up to 12 wk.


Radiotherapy for T1 carcinoma of the glottis.
The management of patients with T1 carcinoma of the glottic larynx is controversial, because surgery and radiation therapy are reported to be effective treatments. Several studies have shown radiotherapy to be safe and effective, with a high percentage of voice preservation and minimal complications, but most Italian physicians prefer to surgically treat such patients. From 1980 to 1990, 36 patients with stage I squamous cell glottic carcinoma were treated with radiotherapy alone at the institute of Radiology of University of Rome "La Sapienza". In all patients the irradiation fields were limited to the larynx, with field size ranging from 4 x 4 cm to 7 x 7 cm. Total tumor doses ranged between 51 and 70 Gy (median 60 Gy) with a mean number of 30 fractions of 2 to 3 Gy per fraction (3 or 5 fractions per week). After a median follow-up of 98 months, we observed an overall survival rate at 5 years of 91.4% and actuarial 10-year survival of 85.7%. Local control was achieved in 97.1% of cases, with an event-free survival of 94.2% at 5 and 10 years. No major complications like necrosis or persistent edema of the larynx were observed. Minor complications like dysphonia (8%) and dysphagia (5.5%) were temporary; laryngeal function was completely preserved at the end of therapy. Final voice quality ranged from good to excellent. Our series confirms that radiation therapy has a major role in the management of early glottic cancer, with results comparable to surgical approaches and with better voice preservation.


Angular craniometry in craniocervical junction malformation.
The craniometric linear dimensions of the posterior fossa have been relatively well studied, but angular craniometry has been poorly studied and may reveal differences in the several types of craniocervical junction malformation. The objectives of this study were to evaluate craniometric angles compared with normal subjects and elucidate the main angular differences among the types of craniocervical junction malformation and the correlation between craniocervical and cervical angles. Angular craniometries were studied using primary cranial angles (basal and Boogard's) and secondary craniocervical angles (clivus canal and cervical spine lordosis). Patients with basilar invagination had significantly wider basal angles, sharper clivus canal angles, larger Boogard's angles, and greater cervical lordosis than the Chiari malformation and control groups. The Chiari malformation group does not show significant differences when compared with normal controls. Platybasia occurred only in basilar invagination and is suggested to be more prevalent in type II than in type I. Platybasic patients have a more acute clivus canal angle and show greater cervical lordosis than non-platybasics. The Chiari group does not show significant differences when compared with the control, but the basilar invagination groups had craniometric variables significantly different from normal controls. Hyperlordosis observed in the basilar inavagination group was associated with craniocervical kyphosis conditioned by acute clivus canal angles.


Soft Malleable Vesicles: versatile carriers for efficient topical delivery of fungal therapeutics.
Fungal infections have become a subject of great concern and the incidence of fungal infections is increasing, presenting an enormous challenge to healthcare professionals. Since most of the fungal infections are occurring over the skin, the treatment option of these infections always involves topical application. However, in topical delivery drug reaches into systemic circulation through different barriers of skin. Nevertheless, due to the low permeability, skin restricts the movement of many drugs. Hence, a delivery system is required, which deliver the medicament into the skin layers or through the skin and into the systemic circulation. Ethosomes or Soft malleable vesicles are the novel lipid vesicular carrier that offer improved skin permeability and efficient delivery due to their structure and composition. They contain high concentration of ethanol, which increases the fluidity of the skin. Therefore, in the present paper, we have explored the utility of ethosomal systems in the topical treatment of fungal infections. Structure, compositions types, mechanism and techniques of preparation of ethosome also discussed in the paper.


Development of pre-deployment primary healthcare training for Combat Medical Technicians.
To develop and run a primary healthcare (PHC) refresher package to address the range of clinical presentations to Combat Medical Technicians (CMTs) on deployment and improve their confidence and capability in providing PHC for Op Herrick 18, with particular regard to the first month of deployment. A regimental level, two-and-a-half day refresher package was developed following analysis of PHC conditions most likely to be seen on Op HERRICK 18. It consisted of lectures and skill stations with written and case-based assessment phases to demonstrate effective and safe use of CMT clinical protocols on simulated patients. Internal feedback assessed the CMT's subjective understanding of each individual section. A qualitative questionnaire was used to retrospectively evaluate the package after 1 month of deployment. Immediate feedback showed that the refresher training was well received. Following the first month of deployment, CMTs who had attended the PHC refresher package felt more confident in managing PHC patients and felt they had received training for the majority of PHC conditions witnessed during their deployment in comparison with CMTs who had not. By delivering a training package acceptable to the majority of medics, we have increased the confidence and capability of CMTs in delivering PHC within the context of their protocols and prepared them for their first month of deployment. It suggests that PHC delivery can be improved by such a package and consideration should be given to formalising this into a military training qualification.


Thoracic epidural analgesia as part of an enhanced recovery program in gynecologic oncology: a prospective cohort study.
To evaluate the safety and the effectiveness of thoracic epidural analgesia as part of the enhanced recovery after surgery (ERAS) multimodal analgesic protocol in patients with gynecologic oncology who have undergone laparotomy for suspected or confirmed malignancy. We conducted a prospective cohort study, following an enhanced recovery after surgery pathway, among patients who had undergone laparotomy for confirmed or suspected gynecological malignancy between January 2020 and September 2021. All patients who underwent laparotomy at the gynecologic oncology department for the aforementioned reason during that time were considered eligible. Patients (n=217) were divided into two groups: epidural (n=118) and non-epidural (n=99) group. Both groups were treated with the standard ERAS departmental analgesic protocol. The primary outcomes were length of hospital stay, complications, and readmission rates. Data from 217 patients (epidural group, n=118 vs non-epidural group, n=99) with median age of 61 years (IQR 53-68) were analyzed. The most common type of cancer was of ovarian origin (85/217, 39.2%, p=0.055) and median (Aletti) surgical complexity score was 3 (p=0.42). No differences were observed in the patients' demographics, clinical, and surgical characteristics. Primarily, median length of stay was 4 days in both groups with statistically significant lower IQR in the epidural group (3-5 vs 4-5, p=0.021). Complication rates were more common in the non-epidural group (38/99, 38.3% vs 36/118, 30.5%, p<0.001) with similar rates of grade III (p=0.51) and IV (0%) complications and readmission rates (p=0.51) between the two groups. Secondarily, the epidural group showed lower pain scores (p<0.001) on the day of surgery and in the first post-operative day (p<0.001), higher mobilization rates on the day of surgery (94.1% vs 57.6%, p<0.001), faster removal of urinary catheter (p<0.001), shorter time to flatus (p<0.001), and less nausea on the day of surgery (p<0.001). In this study we showed that thoracic epidural analgesia, when used as part of an ERAS protocol, is safe and offers more favorable pain relief along with a number of additional benefits, improving the peri-operative experience of patients with gynecologic cancer.


Mechanistic considerations for C-C bond reductive coupling at a cobalt(III) center.
The diamagnetic cobalt(III) dimethyl complex, cis,mer-(PMe(3))(3)Co(CH(3))(2)I, was found to promote selective C-C bond formation, affording ethane and triplet (PMe(3))(3)CoI. The mechanism of reductive elimination has been investigated by a series of kinetic and isotopic-labeling experiments. Ethane formation proceeds with a rate constant of 3.1(5) × 10(-5) s(-1) (50 °C) and activation parameters of ΔH(double dagger) = 31.4(8) kcal/mol and ΔS(double dagger) = 17(3) eu. Addition of free trimethylphosphine or coordinating solvent strongly inhibits reductive elimination, indicating reversible phosphine dissociation prior to C-C bond-coupling. EXSY NMR analysis established a rate constant of 9(2) s(-1) for phosphine loss from cis,mer-(PMe(3))(3)Co(CH(3))(2)I. Radical trapping, crossover, and isotope effect experiments were consistent with a proposed mechanism for ethane extrusion where formation of an unobserved five-coordinate intermediate is followed by concerted C-C bond formation. An unusual intermolecular exchange of cobalt-methyl ligands was also observed by isotopic labeling.


Studies on tissue expression of HBV in children with chronic hepatitis type B using Immunomax technique.
The study aimed at employing the Immunomax technique to detect the markers of HBV replication (HBcAg and HBV-DNA) in liver biopsy material, obtained from children with chronic hepatitis type B. In line with the currently modified classification of chronic hepatitis and with the increasing potential of antiviral therapy it seemed purposeful to supplement routine staining techniques with studies at the molecular level. Our studies demonstrated the effective detection of both the core antigen and HBV-DNA in liver tissue in children using immunocytochemical techniques and in situ hybridization, amplified with the Immunomax technique. HBcAg was detected in 26 out of 27 liver biopsies from patients with chronic hepatitis type B and with replication of the virus. HBV-DNA was detected in all study children with HBV infection and in 2 out of 5 cases of chronic hepatitis of a distinct etiology. No significant relationships could be found between the detection of tissue HBV markers on the one hand and the intensity of inflammatory lesions or severity of fibrosis on the other.


Failure of deactivation in the default mode network: a trait marker for schizophrenia?
Functional imaging studies in relatives of schizophrenic patients have had inconsistent findings, particularly with respect to altered dorsolateral prefrontal cortex activation. Some recent studies have also suggested that failure of deactivation may be seen. A total of 28 patients with schizophrenia, 28 of their siblings and 56 healthy controls underwent functional magnetic resonance imaging during performance of the n-back working memory task. An analysis of variance was fitted to individual whole-brain maps from each set of patient-relative-matched pair of controls. Clusters of significant difference among the groups were then used as regions of interest to compare mean activations and deactivations among the groups. In all, five clusters of significant differences were found. The schizophrenic patients, but not the relatives, showed reduced activation compared with the controls in the lateral frontal cortex bilaterally, the left basal ganglia and the cerebellum. In contrast, both the patients and the relatives showed significant failure of deactivation compared with the healthy controls in the medial frontal cortex, with the relatives also showing less failure than the patients. Failure of deactivation was not associated with schizotypy scores or presence of psychotic-like experiences in the relatives. Both schizophrenic patients and their relatives show altered task-related deactivation in the medial frontal cortex. This in turn suggests that default mode network dysfunction may function as a trait marker for schizophrenia.


In comparison with other abdominal imaging modalities, which radiologists interpret abdominal MRI?
To assess subspecialty mix and case volumes of general and abdominal subspecialty radiologists interpreting abdominal MRI. The 2016 CMS Physician/Supplier Procedure Summary Master File was used to obtain billed counts of radiologist-interpreted abdominal fluoroscopy, US, CT, and MRI examinations. The CMS Physician and Other Supplier Public Use File was used to assess the subspecialty mix and case volume of the radiologists interpreting those examinations. The fraction of all abdominal imaging examinations interpreted by generalists and abdominal subspecialty radiologists was 70.7% and 16.5% for fluoroscopy; 68.7% and 21.0% for US; 71.4% and 19.2% for CT; and 41.9% and 52.5% for MRI. In 2016, the fraction of general and abdominal radiologists interpreting > 50 fluoroscopy examinations on Medicare fee-for-service beneficiaries was 15.1% and 16.2%. For > 50 US examinations, the fraction was 61.5% and 60.5%; for > 50 CT examinations, 91.2% and 79.6%; and for > 50 MRI examinations, 4.0% and 28.5%. The fraction of abdominal imaging examinations interpreted overall by low-volume providers (those interpreting ≤ 50 examinations in 2016) was 59.5% for fluoroscopy, 17.5% for US, 6.3% for CT, and 50.6% for MRI. Nationally, most abdominal fluoroscopy, US, and CT examinations are interpreted by general radiologists, who have similar annual volumes of these examinations as abdominal subspecialty radiologists. In contrast, most abdominal MRI examinations are interpreted by abdominal subspecialty radiologists, who attain considerably higher volumes. These findings have implications for workforce planning and abdominal imaging fellowship design to ensure their graduates are optimally prepared to contribute to their future practices.


Targeting Regulatory T Cells for Therapy of Lupus Nephritis.
Lupus glomerulonephritis (LN) is a complex autoimmune disease characterized by circulating autoantibodies, immune-complex deposition, immune dysregulation and defects in regulatory T cell (Tregs). Treatment options rely on general immunosuppressants and steroids that have serious side effects. Approaches to target immune cells, such as B cells in particular, has had limited success and new approaches are being investigated. Defects in Tregs in the setting of autoimmunity is well known and Treg-replacement strategies are currently being explored. The aim of this minireview is to rekindle interest on Treg-targeting strategies. We discuss the existing evidences for Treg-enhancement strategies using key cytokines interleukin (IL)-2, IL-33 and IL-6 that have shown to provide remission in LN. We also discuss strategies for indirect Treg-modulation for protection from LN.


Respiratory function at different altitudes.
For the evaluation of a respiratory test at high altitude, several factors must be taken into account: the decreased barometric pressure, the decreased density of air and the degree of acclimatization which is related to the altitude and to the length of exposure. Several studies have shown a reduction in forced vital capacity (FVC) at high altitude and using simulated conditions, mainly related to an increase in pulmonary blood volume and development of interstitial edema. To assess the daily spirometric patterns during ascending to high altitudes we studied 17 healthy subjects at both Capanna Regina Margherita on the Italian Alps (4,559 m) and the Pyramid Laboratory in Nepal (5,050 m). Respiratory function tests were performed every day. Peak expiratory flow values significantly increased. The mean percent increase was 15% at 3,200 and 3,600 m and 26% at 4,559 m. FVC and MEF25 values showed a significant decrease (p < 0.005) during the first days above 3,500 m and improved only after several days spent above this altitude. For each subject the maximal reductions in FVC and maximal expiratory flow (MEF) at 25% of FVC however were found on different days. In our opinion, these data support the hypothesis that at high altitude the respiratory function can be affected by the presence of an increased pulmonary blood volume and/or the development of interstitial edema. The observed changes in forced expiration curves at high altitude seem to reflect the degree of acclimatization that is related to the individual susceptibility, to the altitude reached and to the duration of the exposure. These changes are transient and resolve after returning to sea level.


Evidence of psychosocial and behavioral effects related to the intention to quit alcohol in South Korea.
This study examined psychosocial and behavioral characteristics and factors that influenced certain subjects within a population-based sample of Korean drinkers to quit alcohol consumption (N = 8910). Explored were various factors of psychosocial behaviors such as socioeconomic reasons, health behavior, cues to action, and self-control related to the intentions of alcohol abstinence. Using path analysis, it was found that, for men, self-control (B = 0.51), health behavior (B = 0.78), and health literacy (B = 0.58) were positively associated with cues to action which in turn positively induced them to quit drinking. This pattern of results appeared to apply only to men and not to women. In conclusion, this study reveals that men who do not smoke, regularly exercise, have high self-control, and look for health information are likely to be active in acquiring cues for behavioral changes and making themselves motivated. However, conventions of alcohol consumption in the female population are more dependent on social factors in comparison to those of men.


Emerging species in pediatrics: a case of Acinetobacter johnsonii meningitis.
Among the microorganisms corresponding to the genus Acinetobacter, Acinetobacter johnsonii is a species of low epidemiological incidence compared to Acinetobacter baumannii. However, it has a comparable infectious capacity since it can be involved in severe diseases like bacteremia or meningitis. Its habitat is variable, usually found in humid tropical climates (as is the case in Colombia), soil, water, or animal reservoirs. It is still an unknown germ for most health personnel, as there are not many reported cases, and information about its microbiological and epidemiological characteristics is still scarce, making its identification and treatment difficult. We describe the case of A. johnsonii infection of the central nervous system in a 15-year-old female, as well as the diagnostic method used, the course of the disease, medical management, and clinical outcome. It is of utmost importance to report this type of microorganisms to facilitate early diagnosis and appropriate treatment. More scientific publications of this type are needed to broaden the knowledge about these microorganisms.


Machine learning modeling of Wigner intracule functionals for two electrons in one-dimension.
In principle, many-electron correlation energy can be precisely computed from a reduced Wigner distribution function (W), thanks to a universal functional transformation (F), whose formal existence is akin to that of the exchange-correlation functional in density functional theory. While the exact dependence of F on W is unknown, a few approximate parametric models have been proposed in the past. Here, for a dataset of 923 one-dimensional external potentials with two interacting electrons, we apply machine learning to model F within the kernel Ansatz. We deal with over-fitting of the kernel to a specific region of phase-space by a one-step regularization not depending on any hyperparameters. Reference correlation energies have been computed by performing exact and Hartree-Fock calculations using discrete variable representation. The resulting models require W calculated at the Hartree-Fock level as input while yielding monotonous decay in the predicted correlation energies of new molecules reaching sub-chemical accuracy with training.


Results of revision of total hip arthroplasty for alumina ceramic-on-ceramic bearing fracture.
The purpose of this study was to compare the results of revision total hip arthroplasty after fracture of primary ceramic components using different type of revision bearing surfaces. We analysed the results of 16 patients with a follow-up more than 3 years after first revision. 6 were revised to ceramic-on-ceramic (CoC) bearing, 9 to metal-on-polyethylene (MoP) and 1 to ceramic-on-cross-linked polyethylene (CoXLP) bearing. The mean follow-up was 87 months. Patients with revision to CoC had higher Harris Hip Score (HHS) of 89 points in comparison to the patients with revision to MoP with 84 points. Radiographic examinations revealed visible eccentric polyethylene wear with osteolysis in 3 out of 9 patients revised to MoP. There were no detrimental x-ray changes in patients revised to CoC components. We consider CoC as the best option at revision operation for ceramic component fracture.


ADHD candidate gene (DRD4 exon III) affects inhibitory control in a healthy sample.
Dopamine is believed to be a key neurotransmitter in the development of attention-deficit/hyperactivity disorder (ADHD). Several recent studies point to an association of the dopamine D4 receptor (DRD4) gene and this condition. More specifically, the 7 repeat variant of a variable number of tandem repeats (VNTR) polymorphism in exon III of this gene is suggested to bear a higher risk for ADHD. In the present study, we investigated the role of this polymorphism in the modulation of neurophysiological correlates of response inhibition (Go/Nogo task) in a healthy, high-functioning sample. Homozygous 7 repeat carriers showed a tendency for more accurate behavior in the Go/Nogo task compared to homozygous 4 repeat carriers. Moreover, 7 repeat carriers presented an increased nogo-related theta band response together with a reduced go-related beta decrease. These data point to improved cognitive functions and prefrontal control in the 7 repeat carriers, probably due to the D4 receptor's modulatory role in prefrontal areas. The results are discussed with respect to previous behavioral data on this polymorphism and animal studies on the impact of the D4 receptor on cognitive functions.


WebFARM: web server for finite automated restriction mapping.
Restriction endonucleases are indispensable tools in molecular biology and biotechnology. Type II restriction endonucleases are part of restriction modification systems. DNA fragment extraction and restriction mapping are the basis for several biotechnological activities. WebFARM is a server application for identifying restriction endonuclease recognition sites and to give information regarding restriction mapping for given nucleotide sequences. WebFARM analyses given nucleotide sequence and identify restriction site for selected restriction endonucleases. It will also provide frequency of restriction for each restriction endonuclease. http://webfarm.bioinfoindia.org/


Salmonella dublin infection: a rare cause of spontaneous bacterial peritonitis and chronic colitis in alcoholic liver cirrhosis.
Salmonella dublin is a veterinary pathogen which rarely causes human illness, although reported human isolates have increased over the past two decades. This serovar of salmonella is unusually invasive and life-threatening, although the clinical pattern of human infection is not well known. We describe a 51-year-old cirrhotic patient who presented with severe liver failure, chronic diarrhoea and left-sided segmental colitis. Radiological and endoscopic findings suggested Crohn's colitis. During the hospital stay he developed a spontaneous bacterial peritonitis (SBP) and S. dublin was isolated in the ascitic fluid. Our report supports the view that this salmonella serovar should be kept in mind as a rare cause of SBP in cirrhotic patients, especially in those cases with chronic colitis resembling Crohn's disease.


Patients with Cushing's syndrome are care-intensive even in the era of laparoscopic adrenalectomy.
We report outcomes from laparoscopic adrenalectomy (LA) comparing patients with Cushing's syndrome with those with other adrenal pathology with respect to length of stay (LOS), overall complications, and financial implications. We conducted a retrospective review of 80 continuous patients (103 glands) undergoing LA. The clinical diagnoses were: hypercortisolism (Cushing' syndrome; n=33), hyperaldosteronism (Conn's syndrome; n=20), phaeochromocytoma (n=16), and neoplasm (others; n=11). Advanced care in the intermediate or intensive care unit was necessary in 27 patients, most frequently in our Cushing's population (16 of 33 [48%]). Six patients sustained major complications, including death in two patients; seven patients sustained minor complications. LOS was longer for patients with Cushing's syndrome (mean, 5.5 vs. 3.3 days; P = 0.024). Financially, patients with Cushing's syndrome had statistically higher total hospital (P = 0.009), advanced care (P = 0.002), and anesthetic costs (P = 0.005). LA in patients with Cushing's syndrome is associated with longer hospitalizations, more frequent major complications, and higher advanced care requirements, especially for patients undergoing bilateral adrenalectomy. Minor complications were infrequent and median LOS was brief regardless of diagnosis. Patients with Cushing's syndrome had higher costs for overall hospital charges, advanced care, and anesthesia.


Development and Validation of a Surface Plasmon Resonance Biosensor for Specific Detection of Porcine Serum Albumin in Food.
Food allergies are a potential food safety and public health concern worldwide. To assure the safety of people who experience allergic reactions, it is necessary to establish effective and reliable methods for rapid detection of food allergens. This paper reports an innovative method for the rapid detection and analysis of porcine serum albumin (PSA), known as a major allergen in pork, based on a surface plasmon resonance (SPR) biosensor. The antibodies known to have a high bioactivity against PSA were verified by competitive indirect-ELISA and then immobilized on the SPR sensor surface, thus allowing them to capture PSA. The developed SPR demonstrated a linear range from 1.0 to 450 ng/mL for the measurement of PSA with a detection limit of 19.81 ng/mL. Within-day RSD (1.97-4.02%) and between-day RSD (1.88-4.15%) were no more than 5%. The SPR was evaluated for analysis of six commercial food samples and showed almost perfect agreement between the results obtained by ELISA test kits without significant differences (P > 0.05). Therefore, this assay permits accurate, specific, and sensitive detection of PSA in pork and pork products.


Effect of chirality and lipophilicity in the functional activity of evodiamine and its analogues at TRPV1 channels.
Evodiamine, a racemic quinazolinocarboline alkaloid isolated from the traditional Chinese medicine Evodiae fructus, has been reported to act as an agonist of the transient receptor potential vanilloid type-1 (TRPV1) cation channel both in vitro and in vivo. Evodiamine is structurally different from all known TRPV1 activators, and has significant clinical potential as a thermogenic agent. Nevertheless, the molecular bases for its actions are still poorly understood. To investigate the structure-activity relationships of evodiamine, the natural racemate was resolved, and a series of 23 synthetic analogues was prepared, using as the end point the intracellular Ca(2+) elevation in HEK-293 cells stably overexpressing either the human or the rat recombinant TRPV1. S-(+) evodiamine was more efficacious and potent than R-(-) evodiamine, and a new potent lead (Evo30) was identified, more potent than the reference TRPV1 agonist, capsaicin. In general, potency and efficacy correlated with the lipophilicity of the analogues. Like other TRPV1 agonists, several synthetic analogues could efficiently desensitize TRPV1 to activation by capsaicin. Evodiamine qualifies as structurally unique lead structure to develop new potent TRPV1 agonists/desensitizers.


Serum thiocyanate levels in smokers, passive smokers and never smokers.
To compare the serum thiocyanate levels in smokers, passive smokers and never smokers. Serum thiocyanate was analyzed on 135 self reported smokers, never smokers and passive smokers by UV-Spectrophotometry (Manual method of Bowler). The mean serum thiocyanate concentration (112 +/- 36.6 micromol/L) of smokers was significantly higher (p value < 0.001) as compared to passive (55 +/- 16.1 micromol/L) and never smokers (41 +/- 6.6 micromol/L). The serum thiocyanate of female smokers (133 + 28.7 micromol/L) was higher (p value < 0.05) than male smokers (103 +/- 36.3 miccromol/L). Serum thiocyanate showed 91% sensitivity, 80% specificity and 84% accuracy at > or = 60 micromol/L for smokers. Serum thiocyanate is significantly higher in smokers than passive and never smokers. Serum thiocyanate at > or = 60 micromol/L may be considered as cutoff value for distinguishing smokers from non-smokers for future studies.


A method to detect intercenter differences in the application of contemporary diagnostic criteria.
The use of specified diagnostic criteria is part of routine psychiatric practice and research. However, there is evidence that the same criteria may be interpreted and applied differently at different research centers. The next question is whether it is possible to detect these systematic intercenter differences in diagnostic practices. An inexpensive, nonlaborious, standardized method is needed that can easily be used at any site. In the present report, we demonstrate how self-report questionnaires can provide a method of detecting systematic differences in the application of contemporary diagnostic criteria. Sixty consecutively admitted inpatients with nonpsychotic major depressive disorder were interviewed with standardized schedules and diagnosed according to two interpretations of the Research Diagnostic Criteria (RDC) and DSM-III endogenous/melancholia criteria. The patients also completed the Inventory to Diagnose Depression, a self-report scale designed to diagnose major depression and subtype patients according to RDC and DSM-III endogenous/melancholia criteria. The interview to self-report ratio for diagnosing endogenous depression and melancholia was associated with diagnosticians' interpretation of the criteria. A broader application of the criteria resulted in a higher ratio. A paper-and-pencil questionnaire could be useful in detecting systematic interinvestigator differences in the broadness or narrowness with which criteria are applied. The advantage of a self-report scale is that it is free from systematic biases and tendencies of clinician raters. Of course, ratings on questionnaires are not free of bias; however, it is less likely that differences between samples will reflect a systematic variation in response set.


Evidence for plasma-mediated neutrophil superoxide anion production during myocardial infarction.
The participation of polymorphonuclear neutrophils (PMN) in the development of free-oxygen-mediated myocardial injury is well documented, but direct evidence that PMN-oriented stimuli released to the peripheral blood are able to stimulate PMN free oxygen radical production is missing. We have previously reported that peripheral blood plasma obtained from patients with acute myocardial infarction has chemotactic activity for neutrophils and augments PMN adherence. To investigate whether neutrophilic stimuli released to peripheral blood may induce PMN superoxide anion (O2-) production, we incubated PMN from healthy donors with plasma from patients with acute transmural infarction. PMN O2- production was measured by cytochrome c reduction. PMN O2- was higher under the influence of plasma obtained on the day of admission (24.66 +/- 12.41) and 1 day after onset of acute ischemia (22.91 +/- 10.37) as compared with those observed after incubation with saline (4.18 +/- 1.37; negative control) or zymosan-activated plasma (11.07 +/- 3.4; activated complement cascade positive control). In the following days, plasma-mediated PMN O2- decreased: 13.27 +/- 1.96; 12.37 +/- 3.54 and 8.18 +/- 1.56 after incubation with plasma obtained 2, 3 and 7 days after onset of symptoms, respectively. The results indicate an additional possibility of monitoring the inflammatory response to myocardial necrosis.


Lateral gene expression in Drosophila early embryos is supported by Grainyhead-mediated activation and tiers of dorsally-localized repression.
The general consensus in the field is that limiting amounts of the transcription factor Dorsal establish dorsal boundaries of genes expressed along the dorsal-ventral (DV) axis of early Drosophila embryos, while repressors establish ventral boundaries. Yet recent studies have provided evidence that repressors act to specify the dorsal boundary of intermediate neuroblasts defective (ind), a gene expressed in a stripe along the DV axis in lateral regions of the embryo. Here we show that a short 12 base pair sequence ("the A-box") present twice within the ind CRM is both necessary and sufficient to support transcriptional repression in dorsal regions of embryos. To identify binding factors, we conducted affinity chromatography using the A-box element and found a number of DNA-binding proteins and chromatin-associated factors using mass spectroscopy. Only Grainyhead (Grh), a CP2 transcription factor with a unique DNA-binding domain, was found to bind the A-box sequence. Our results suggest that Grh acts as an activator to support expression of ind, which was surprising as we identified this factor using an element that mediates dorsally-localized repression. Grh and Dorsal both contribute to ind transcriptional activation. However, another recent study found that the repressor Capicua (Cic) also binds to the A-box sequence. While Cic was not identified through our A-box affinity chromatography, utilization of the same site, the A-box, by both factors Grh (activator) and Cic (repressor) may also support a "switch-like" response that helps to sharpen the ind dorsal boundary. Furthermore, our results also demonstrate that TGF-β signaling acts to refine ind CRM expression in an A-box independent manner in dorsal-most regions, suggesting that tiers of repression act in dorsal regions of the embryo.


Towards an AIDS vaccine: the transmembrane envelope protein as target for broadly neutralizing antibodies.
Although the development of an effective vaccine is the main goal in the fight against AIDS, all attempts by numerous laboratories to develop a vaccine have failed so far. In addition, it is still unclear whether cytotoxic T cells or neutralizing antibodies or both should be induced. The major advantage of neutralizing antibodies is their ability to prevent infection and subsequent integration of the provirus into the cellular genome where it may persist in a form invisible to the immune system. Broadly neutralizing antibodies have been found in HIV infected individuals, including antibodies directed against a highly conserved region in the membrane proximal external region (MPER) of the transmembrane envelope (TM) protein gp41 of HIV-1. We successfully induced neutralizing antibodies against different gammaretroviruses by immunization with their respective TM proteins. These antibodies recognized epitopes not only in the MPER but also in the fusion peptide proximal region of the TM protein. In the case of feline leukaemia virus (FeLV), these antibodies protected cats from antigenemia following challenge. To understand the mechanism of neutralization, the interactions between neutralizing antibodies and their corresponding epitopes in the TM protein of gammaretroviruses and HIV-1 were analysed. These data may help to design antigens able to induce specific broadly neutralizing antibodies.


Sexual assault, social reactions, and physical health.
This study examined the role of postassault social reactions in the association between sexual assault and physical health in a convenience sample of 155 women completing a mail survey. Regression analysis showed that tangible aid/information support and depressive symptoms were each related to poorer perceived health, whereas other positive social reactions (e.g., emotional support/validation) were related to better health perceptions. More severe (e.g., physically violent) assaults were associated with poorer current perceptions of one's physical health. Negative social reactions (e.g., distraction/discourage talking) mediated this association, suggesting that the link between assault severity and poorer health may be due to increased negative social reactions to victims of these assaults. Implications for studying the role of social reactions in relation to health consequences of sexual assault are discussed.


Histology of the mucosa of the oesophagogastric junction and the stomach in adult Rana perezi.
The histological structure of the frog digestive mucosa changes at the oesophagogastric junction. The pseudostratified ciliated mucosal epithelium of oesophageal type changes to a simple mucus-secreting epithelium of gastric type. The glands straighten and the muscularis mucosae develops as a complete layer. The muscularis increases in thickness. Unlike the mammalian stomach, in the frog the surface of the plicae forms convoluted ridges that delimit furrow-shaped pits. Two types of gastric glands are distinguished, fundal and pyloric. The former consist of mucous, oxynticopeptic and endocrine cells. The pyloric glandular cells are mainly of mucus-secreting type with scattered endocrine cells. Scattered endocrine cells of P, D, G, A, EC, and EC-L-like types are found in the glands along the stomach. It is concluded that the mucosal structure of the anuran oesophagogastric junction and stomach is less complicated than that of mammals, including man.


Population and clonal level responses of a perennial grass following fire in the northern Chihuahuan Desert.
Relationships involving fire and perennial grasses are controversial in Chihuahuan Desert grasslands of southern New Mexico, USA. Research suggests that fire delays the resprouting of perennial grasses well after two growing seasons. However, such results are confounded by livestock grazing, soil erosion, and drought. Additionally, post-fire grass responses may depend on initial clone size. We evaluated the effects of fire, grazing, and clone size on Bouteloua eriopoda (black grama) in southern New Mexico grasslands. Four 2-ha plots were established in each of four sites. Fire and grazing were applied or not applied in 1999 such that four treatment combinations were assigned randomly to plots within each site. Within each plot, small (0-10 cm(2) basal area), medium (10-30 cm(2)), and large ( > 30 cm(2)) clones were initially mapped in five 0.91-m(2) quadrats where grass attributes and litter cover were evaluated before and at the end of two growing seasons following fire. Maximum fire temperature was also measured. At a population level, canopy and litter cover were each approximately 50% less in burned than unburned areas. However, compared to initial levels, canopy height had increased by 10% at the end of the study, regardless of fire. At a clonal level, basal cover reductions were attributed mostly to large clones that survived fire. Smaller clone densities had decreased by as much as 19% in burned compared to unburned areas, and fire reduced the basal cover of medium clones. Basal and canopy cover, recruitment, and clone basal area decreased with increased fire temperatures. Almost all responses were independent of grazing, and interactive effects of grazing and fire were not detected. Fire did not kill all perennial grass clones, regardless of size. However, rapid responses were likely influenced by above-average precipitation after fire. Future studies in desert grasslands should examine how perennial grass dynamics are affected by fire, precipitation patterns, and interactions with grazing.


Medical Management and Diagnostic Testing among Stable Angina Patients in India: The STable Angina obseRvational (STAR) Registry.
To study the practice pattern in the management of patients with stable angina (SA) in India. The Stable Angina obseRvational Registry (STAR) prospectively enrolled patients provisionally diagnosed with SA by non-interventional practicing internists in India. Patients were followed for 3 months after enrollment to assess medical treatment, diagnostic management, and interventional treatment of coronary artery disease (CAD). At the study conclusion, a statistical analysis retrospectively categorized patients not at risk of CAD by the Morise-Jalisi scale though this was not part of the study protocol. Between January and May 2012, 2079 patients were enrolled at 131 centres. Mean age was 57 ± 11 years, 62% were men, and 40% had a history of diabetes. Over 90% of patients completed follow-up visit, >85% received statins and antiplatelet medications, >70% received beta blockers, and >60% received angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers. Diagnostic testing rates were low: 93% for electrocardiogram, 44% echocardiogram, 42% chest radiography, 12% stress test, and 8% underwent noninvasive CT or invasive coronary angiography, of which, 86% had abnormal results. After the study, the Morise-Jalisi probability of CAD was intermediate in 42% and high in 51% of patients. Only 3.4% of all patients had coronary revascularization. In a large cohort of Indian patients with SA, disease severity and probability of CAD were high. Clinicians used evidence-based care for medical management, but underutilized diagnostic testing. Patients with SA in India need to be risk-stratified for probability and severity of CAD and, if indicated, receive additional diagnostic testing.


A multiplex polymerase chain reaction method for the simultaneous detection of GSTM1, GSTT1, and GSTP1 polymorphisms.
Glutathione S-transferases (GSTs) play an important role in the detoxification of a wide variety of toxicants. Among GSTs, GSTM1 and GSTT1 polymorphic deletions and the GSTP1 Ile105Val polymorphism were often studied in combination in many diseases because of their additive effects, but they were usually genotyped by two separate methods. The purpose of the present study was to develop a simple and reliable method to simultaneously detect these three polymorphisms. The three polymorphisms of 259 volunteers were genotyped using a multiplex polymerase chain reaction (PCR) method based on a tetra-primer amplification refractory mutation system-PCR (T-ARMS-PCR), and the results were validated by multiplex PCR for GSTM1 and GSTT1 polymorphisms and DNA sequencing of the GSTP1 Ile105Val polymorphism, respectively. The multiplex PCR method of GSTM1, GSTT1, and GSTP1 polymorphisms based on T-ARMS-PCR can simultaneous detect the three polymorphisms in a single PCR. The results of this method are in perfect accord with the results of the multiplex PCR method of determining GSTM1, GSTT1 polymorphisms, and DNA sequencing of GSTP1 Ile105Val polymorphism. The novel multiplex PCR method of GSTM1, GSTT1, and GSTP1 polymorphisms is simple, fast, low-cost, and reliable for the simultaneous detection of GSTM1, GSTT1, and GSTP1 Ile105Val polymorphisms.


Vitamin D status in children and adults in Sweden: dietary intake and 25-hydroxyvitamin D concentrations in children aged 10-12 years and adults aged 18-80 years.
The study aimed to estimate vitamin D intake and plasma/serum 25-hydroxyvitamin D (25(OH)D) concentrations, investigate determinants of 25(OH)D concentrations and compare two 25(OH)D assays. We conducted two nationwide cross-sectional studies in Sweden with 206 school children aged 10-12 years and 1797 adults aged 18-80 years (n 268 provided blood samples). A web-based dietary record was used to assess dietary intake. Plasma/serum 25(OH)D was analysed by liquid chromatography-mass spectrometry (LC-MS) and immunoassay in adults and LC-MS/MS in children. Most participants reported a vitamin D intake below the average requirement (AR), 16 % of children and 33 % of adults met the AR (7⋅5 μg). In adults, plasma 25(OH)D below 30 and 50 nmol/l were found in 1 and 18 % of participants during the summer period and in 9 and 40 % of participants during the winter period, respectively. In children, serum 25(OH)D below 30 and 50 nmol/l were found in 5 and 42 % of participants (samples collected March-May), respectively. Higher 25(OH)D concentrations were associated with the summer season, vacations in sunny locations (adults), and dietary intake of vitamin D and use of vitamin D supplements, while lower concentrations were associated with a higher BMI and an origin outside of Europe. Concentrations of 25(OH)D were lower using the immunoassay than with the LC-MS assay, but associations with dietary factors and seasonal variability were similar. In conclusion, vitamin D intake was lower than the AR, especially in children. The 25(OH)D concentrations were low in many participants, but few participants had a concentration below 30 nmol/l.


Caffeine intake and abstract reasoning among 1374 unselected men and women from general population. Role of the -163C>A polymorphism of CYP1A2 gene.
The possible effect of caffeine as an enhancer of cognitive performance, particularly that on abstract reasoning, has never been studied in an epidemiological setting, especially in relation to -163C>A polymorphism of CYP1A2 gene, largely controlling caffeine metabolism. Aim of this study was to ascertain whether in general population free chronic caffeine intake modifies abstract reasoning, and if this effect is influenced by the above mentioned genotype, by age, schooling, ethanol intake and smoking habits. We studied 1374 unselected men and women aged 51 ± 15 years (range 18-89) from a general population. Daily caffeine intake deriving from coffee, tea, chocolate or cola was calculated from an anamnestic questionnaire and from a 7-day dietary diary. Abstract reasoning was measured in the frame of a neuropsychological assessment as the ability to find a concept linking two words indicating objects or actions and explaining how they were connected. In age-schooling-adjusted linear regression, the higher the caffeine intake, the better the abstraction score. Abstract reasoning depended on caffeine in the -163C>A CC homozygous only (so-called slow metabolizers), where it was higher in the 3rd tertile of caffeine intake. Age and ethanol reduced while smoking and schooling enhanced this association. The interaction term between caffeine and the -163C>A polymorphism was accepted in linear regressions. Caffeine consumption resulted innocuous for the A-carriers (so-called fast metabolizers). In general population, a positive association between caffeine intake and abstract reasoning exists in the CC homozygous of the -163C>A polymorphism of CYP1A2 gene.


[Fever in acute illness: beneficial or harmful?].
Fever has had a long phylogenetic history: it occurs not only in infected birds and mammals, but also in infected reptiles, amphibians, fish and even insects. When these "cold-blooded" animals are prevented from adapting their body temperature to the risen thermoregulatory set-point by behavioral means, a more severe state of disease and a higher mortality are the consequences. It seems unlikely that an energy-dependent process, such as fever, would have been retained for hundreds of millions of years, in so many groups of organisms, if it provided no selective advantage. Fever may represent a leukocyte-based amplification mechanism to affect host challenge: enhanced motility of leukocytes, enhanced lymphocyte response to mitogens, increased production of interferon, enhanced immune response to viral antigens. Evidence for a beneficial effect of fever is also supported by the results of our animal experiments. Intraperitoneal injection of a high dose of bacterial lipopolysaccharide (LPS) in rats induces a septic shock like state which is accompanied by hypothermia on the day of LPS-administration and a robust fever on the following days. Co-injection of a neutralizing synthetic form of the soluble tumor necrosis factor (TNF) type 1 receptor completely neutralizes LPS-induced bioactive TNF in the lavage of the abdominal cavity and in blood plasma. Treatment with the TNF-antagonist results in much faster recovery from the hypothermic state. The rats develop pronounced fever already on the day of injection and there is significantly less reduction in body weight and food and water intake. Similar, but less pronounced effects can be induced by treatment with inhibitors of the inducible form of nitric oxide (NO)-synthase indicating that TNF-induced detrimental effects are, in part, mediated by excessive formation of NO. These results confirm that an accelerated onset of fever or a faster recovery from hypothermia in a septic state may have rather beneficial than maladaptive effects.


ADAM17 promotes breast cancer cell malignant phenotype through EGFR-PI3K-AKT activation.
A disintegrin and metalloproteinase-17 (ADAM17) is involved in proteolytic ectodomain shedding of several membrane-bound growth factors and cytokines. The expression and activity of ADAM17 increase under some pathological conditions such as stroke and glioma. ADAM17 promotes neural progenitor cell migration and contributes to stroke-induced neurogenesis after stroke and brain tumor growth and invasion. In the present study, we sought to elucidate whether ADAM17 contributes to breast cancer progression and its mechanisms. To this end, we examined the role of ADAM17 in the proliferation, invasion and tube formation of MDA-MB-231 breast cancer cells in vitro. Stable transfection of the MDA-MB-231 cell line with either a plasmid for overexpression of human ADAM17, or a siRNA to ADAM17 was employed in this study to establish high or low ADAM17 expression in breast cancer cells, respectively. For study of mechanism, the ADAM17 inhibitor TAPI-2 and the PI3K-AKT inhibitor LY294002 were used to counteract high ADAM17 expression or the activated PI3K-AKT pathway. Proliferation of MDA-MB-231 breast cancer cells were tested by MTT, Bromodeoxyuridine incorporation assay, growth curve and sulforhodamine B assay. Matrigel invasion assays were used to assess the ability of MDA-MB-231 cells to penetrate the Extra Cellular Matrix. A Matrigel tube formation assay was performed to test capillary tube formation ability. EGFR-PI3K-Akt pathway activation in MDA-MB-231 cells under different ADAM17 expression levels were tested by western blot and ELISA. Our data show that ADAM17 promotes the MDA-MB-231 malignant phenotype by increased proliferation, invasion and angiogenesis. TGFalpha, VEGF secretion and VEGF expression was increasing by ADAM17 and counteracted by ADAM17 siRNA, TAPI-2 and LY294002 in MDA-MB-231 cells. ADAM17 activated, whereas ADAM17 siRNA, TAPI-2 and LY294002 deactivated the EGFR-PI3K-AKT signal pathway, which correlated with MDA-MB-231 cell malignant phenotype changes. This study suggests ADAM17 contributes to breast cancer progression through activation of the EGFR-PI3K-AKT signal pathway.


Seroreactivity and prevalence of syphilis in donors at a blood bank in Barranquilla, Colombia
Introduction: Syphilis is a public health concern given its high impact on morbidity and mortality. Objective: We aimed to determine the association of syphilis seroreactivity and seroprevalence with sociodemographic variables of donors at a blood bank in the district of Barranquilla, Colombia, during 2015 and 2016. Materials and methods: We conducted a descriptive cross-sectional study based on the results of the treponemal and nontreponemal tests and the sociodemographic variables of the study population. We performed a univariate analysis to determine the absolute and relative frequencies for each categorical variable. We determined the seroreactivity against Treponema pallidum and the prevalence of active syphilis infection, and we used Pearson's chi-square test to evaluate the differences between the proportions. Results: We found a seroreactivity of 1.86% in individuals with previous T. pallidum infection, and a prevalence of 0.93% in those with active T. pallidum infection. These values were higher in adult men and older adults, widowers, the unemployed, and people living in municipalities of the Department of Atlántico other than Barranquilla and its metropolitan area. The incidence of syphilis infection showed a significant association with sex and occupation. Conclusion: In comparison to the national average, syphilis seroreactivity was high among blood donors. There was an association between syphilis infection incidence and sociodemographic variables such as sex and occupation.


[Thalidomide in the treatment of chronic discoid lupus erythematosus].
Thalidomide is the second line treatment of chronic lupus erythematosus. The efficacy of this treatment, the minimal effective doses and tolerance are poorly documented in the literature. We present the data of a single-center retrospective studied among 18 patients with chronic lupus erythematosus, treated with thalidomide from 1998 to 2003. Inclusion criteria were: the presence of clinical lesions evoking the disease, confirmed by histological examination and direct immunofluorescence and treatment with thalidomide for more than 2 months. Mean age on diagnosis was of 35.8 years. Thalidomide had been initiated a mean of 10.6 years after diagnosis of chronic lupus erythematosus. In 13 out of 18 patients, thalidomide had been prescribed because of failure with prior treatments. Fifteen patients were improved by thalidomide (83.3 p. 100), with 11 (61 p. 100) complete and 4 (22 p. 100) partial remissions. Two (11 p. 100) patients were stabilized and treatment failed in one. The mean initial dose was of 100 mg/d (50-150), and maintenance dose was of around 50 mg/d (56 mg/d). The mean follow-up with thalidomide was of 19.4 months. Only one withdrawal due to side effects was reported. The most frequent side effects were: asthenia (33 p. 100), paresthesia (22 p. 100) and weight gain (16.6 p. 100). No side effects were reported in 10 out of 18 patients. This study confirms the efficacy of low dose thalidomide in the treatment of chronic lupus erythematosus. In our experience, tolerance to this treatment is good, the most frequent side effect was asthenia, but usually mild. No significant peripheral neuropathy was noted. The fear of side effects, notably neurological, should not delay initiation of thalidomide in the case of failure with current treatments.


The Photorhabdus asymbiotica virulence cassettes deliver protein effectors directly into target eukaryotic cells.
Photorhabdus is a highly effective insect pathogen and symbiont of insecticidal nematodes. To exert its potent insecticidal effects, it elaborates a myriad of toxins and small molecule effectors. Among these, the Photorhabdus Virulence Cassettes (PVCs) represent an elegant self-contained delivery mechanism for diverse protein toxins. Importantly, these self-contained nanosyringes overcome host cell membrane barriers, and act independently, at a distance from the bacteria itself. In this study, we demonstrate that Pnf, a PVC needle complex associated toxin, is a Rho-GTPase, which acts via deamidation and transglutamination to disrupt the cytoskeleton. TEM and Western blots have shown a physical association between Pnf and its cognate PVC delivery mechanism. We demonstrate that for Pnf to exert its effect, translocation across the cell membrane is absolutely essential.


Anxiety and depression in asthma.
there is growing awareness of the correlation between psychological factors, the course of asthma, and the outcomes of asthma treatment. However, the implications of this correlation are still poorly understood. Here, we review the role of anxiety and depression in asthma with a focus on recent literature. recent studies suggest an interaction between behavioral, neural, endocrine, and immune processes and suggest that psychological factors play an active role in the genesis of asthma. Notably, the role of chronic stress has been investigated, including the parental psychological state during pregnancy. There is evidence that in patients with asthma, such stress may induce hyporesponsiveness of the hypothalamus-pituitary-adrenal axis, resulting in reduced cortisol secretion. even though it is generally accepted that anxiety and depression are more common in asthmatic patients and that there is a close correlation between psychological disorders and asthma outcomes, such as poorer control of asthma symptoms, the implications and practical consequences of this link remain weak. New studies are introducing an intriguing model of the links between emotional stress, brain centers, the immune system, and the hypothalamus-pituitary-adrenal axis that is far removed from the original concept of 'asthma nervosa'.


Revisiting the novelty effect: when familiarity, not novelty, enhances memory.
Reports of superior memory for novel relative to familiar material have figured prominently in recent theories of memory. However, such novelty effects are incongruous with long-standing observations that familiar items are remembered better. In 2 experiments, we explored whether this discrepancy was explained by differences in the type of familiarity under consideration or by differences in the difficulty of discriminating targets from lures, which may lead to source confusion for familiar but not novel targets. In Experiment 1, we directly tested whether previously observed novelty effects were the result of novelty, discrimination demands, or both. We used linguistic materials (proverbs) to replicate the novelty effect but found that it occurred only when familiar items were subject to source confusion. In Experiment 2, to examine better how novelty influences episodic memory, we used experimentally familiar, pre-experimentally familiar, and novel proverbs in a paradigm designed to overcome discrimination demand confounds. Memory was better for both types of familiar proverbs. These results indicate that familiarity, not novelty, leads to better episodic memory for studied items, regardless of whether familiarity is experimentally induced or based on prior semantic knowledge. We argue that proposals that state that information is encoded better if it is novel are based on over-generalizations of effects arising from the distinctiveness of novel materials.


Over-treatment of carbapenemase-producing Enterobacteriaceae.
To describe the treatment and outcomes of patients with carbapenemase-producing Enterobacteriaceae and evaluate whether these cases represented active infection requiring antibiotic therapy or colonization. Adult inpatients with carbapenemase-producing Enterobacteriaceae were retrospectively evaluated. Cases were classified as colonization versus infection by 2 infectious diseases physicians. Multiple cultures that grew in the same patient within a 2-week period were evaluated as a single case. A total of 42 cases among 35 patients were identified. The mean age of the cohort was 67.7 ± 13.7 y, mean APACHE II score was 17.9 ± 8.6, and 77% of patients were in the intensive care unit when the carbapenem-producing Enterobacteriaceae was isolated. Klebsiella pneumoniae (84%) was the predominant organism; urine (36%), tissue/wound/drainage (25%), and blood (20%) were the most common sites of collection. Though 43% of cases were classified as colonization, 56% of these cases were treated with antibiotics. Only 1 patient characterized as colonized subsequently developed infection, 29 days later. Among infected cases, colistin (55%), meropenem (41%), aminoglycosides (32%), and tigecycline (27%) were used for treatment, and combination antimicrobial therapy was common (55%). Clinical and microbiological success was higher in patients receiving combination therapy (83% vs 60%, p = 0.35). Colistin monotherapy was only successful in urinary infections. All-cause hospital mortality was 29%. Nearly half of cases represented colonization, yet the majority were treated with broad-spectrum antibiotics. Determining infection versus colonization is a critical first step in managing patients with carbapenemase-producing Enterobacteriaceae. The risk of not treating apparent colonization appears low.


Capicua regulates follicle cell fate in the Drosophila ovary through repression of mirror.
The dorsoventral axis of the Drosophila egg is established by dorsally localized activation of the epidermal growth factor receptor (Egfr) in the ovarian follicular epithelium. Subsequent positive- and negative-feedback regulation generates two dorsolateral follicle cell primordia that will produce the eggshell appendages. A dorsal midline domain of low Egfr activity between the appendage primordia defines their dorsal boundary, but little is known about the mechanisms that establish their ventral limit. We demonstrate that the transcriptional repressor Capicua is required cell autonomously in ventral and lateral follicle cells to repress dorsal fates, and functions in this process through the repression of mirror. Interestingly, ectopic expression of mirror in the absence of capicua is observed only in the anterior half of the epithelium. We propose that Capicua regulates the pattern of follicle cell fates along the dorsoventral axis by blocking the induction of appendage determinants, such as mirror, by anterior positional cues.


The resistance index in the fetal middle cerebral artery by gestational age and ventricle size in a normal population.
To study the association between fetal middle cerebral artery flow and the lateral cerebral ventricular width throughout gestation. The study is a prospective cohort evaluation of 430 singleton male and female fetuses between 20 and 40 weeks' normal gestation. Abdominal ultrasonography and Doppler measurements were performed to measure the fetal atrial ventricular size and resistance index (RI) of the middle cerebral artery. The mean (+/- standard deviation) ventricular width was 6.2 +/- 1.2 mm. The modification in the RI of the middle cerebral artery throughout gestation showed a biphasic mode, increasing gradually to a peak at 30 weeks' gestation and decreasing progressively thereafter. No significant correlation was found between the middle cerebral artery flow and the lateral cerebral ventricular width (r =.11). In addition to the 430 cases studied, three cases of mild ventriculomegaly and three cases of hydrocephalus were evaluated. The RI of the middle cerebral artery was within the normal range in all six of these cases. Fetal middle cerebral artery blood flow is not affected by the width of the lateral ventricles, even in enlarged ventricles.


Frustrated wants and entitlements: fundamental components of CRNA job satisfaction.
A comparative study was conducted examining CRNA feelings of deprivation or resentment as they relate to their job satisfaction. Deprivation is described in Faye Crosby's Theory of Relative Deprivation (1976), which posits that six psychological preconditions (wanting, comparison other, deserving, past expectations, future expectations, and lack of self-blame) have an impact on individual perceptions and can influence job satisfaction. Relative deprivation is defined as a sense of grievance or feeling of resentment that one has been unjustly deprived of some desired thing. It is also sometimes referred to as the discrepancy between one's legitimate expectations and one's actual situation. The three hypotheses examined compare the influence of the six Crosby preconditions of relative deprivation and the three background variables of gender, education, and individual job autonomy on CRNA-felt deprivation. Results from three-way analysis of variance indicated that of the three background variables, only degree of autonomy was found to be significant in explaining felt deprivation. That is, irrespective of gender or educational level, CRNAs reporting higher degrees of job autonomy had lower feelings of deprivation or resentment about their jobs than did individuals reporting limited job autonomy. Degree of autonomy, thus being the key background determinant of CRNA-felt deprivation (F = 14.609, P < .01). Further analysis employing multiple regression revealed that when both the background and the Crosby psychological variables were examined together, the explained variance in deprivation was dramatically increased by the psychological variables far in excess of the background variables. The two psychological variables of wanting and deserving were found as most significant in explaining CRNA felt deprivation. Results indicate the importance of CRNA frustrated wants (wanting) and CRNA perceived entitlements (deserving) as key factors contributing to CRNA job satisfaction above and beyond the three background variables studied.


Otalgia with a normal ear.
Ear pain is a diagnostic problem when examination of the ear shows no pathology. Referred otalgia may be caused by neoplasms; dental abnormalities or infections; temporomandibular joint dysfunction; sinus, pharyngeal or salivary gland infections; temporal arteritis; cervical arthritis, or one of the neuralgias. Ear pain may also be psychogenic.


Critical Low Catastrophe: A Case Report of Treatment-Refractory Hypoglycemia following Overdose of Long-Acting Insulin.
Overdose of long-acting insulin can cause unpredictable hypoglycemia for prolonged periods of time. The initial treatment of hypoglycemia includes oral carbohydrate intake as able and/or parenteral dextrose infusion. Refractory hypoglycemia following these interventions presents a clinical challenge in the absence of clear guidelines for management. Octreotide has sometimes been used, but its use is generally limited to sulfonylurea overdose. In this case report, we present a case of refractory hypoglycemia following an overdose of 900 units of long-acting insulin glargine that failed to respond to usual modes of therapy mentioned above. Stress-dose corticosteroids were then initiated, followed by subsequent improvement in IV dextrose and glucagon requirements and blood glucose levels. Hence, corticosteroids may serve as an adjunctive therapy in managing hypoglycemia and can be considered earlier in the course of treatment in patients with refractory hypoglycemia to prevent volume overload, especially when large volumes of dextrose infusions are required.


Chain-length-specific anti-Candida activity of cationic lipo-oxazoles: a new class of quaternary ammonium compounds.
Candida species have become resistant to commonly used anti-fungal drugs like fluconazole and echinocandins. In our screen, a series of quaternary ammonium compounds (QACs) emerged as an alternative treatment choice for drug-resistant Candida infections. Medium alkyl chain cationic lipo-oxazoles comprising six to thirteen twin carbon chains and a quaternary ammonium unit were synthesized and evaluated for their in vitro anti-Candida and biofilm inhibition activity. SEM was performed to visualize membrane distortion.Results/Key findings. Heptyl and octyl chain analogues (5c, 6b and 6c) showed promising anti-fungal activity. Compound 5c was active against both fluconazole-sensitive and resistant clinical isolates of Candida albicans as well as non-albicans Candida strains. 5c also inhibited the adhesion of C. albicans cells to a polystyrene surface and restricted biofilm formation. SEM further confirmed Candida cell membrane distortion by 5c. A novel class of QACs, called cationic lipo-oxazoles, was tested and found to exhibit anti-fungal activity against planktonic cells as well as biofilms of Candida.


Cardiogenic shock treated with temporary mechanical circulatory support in Brazil: The effect of learning curve.
Treatment with mechanical circulatory support (MCS) has been proposed to mitigate mortality in cardiogenic shock (CS). However, there is a lack of data on MCS programs implementation and the effect of the learning curve on its outcomes in limited resources countries such as Brazil. Prospective cohort of patients with CS admitted in four tertiary-care centers treated with Impella CP or veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Clinical outcomes were peri-procedural complications, short-term mortality rate, and the centers' learning curve. The cohort was divided into two periods: from April 2017 to July 2018 (n = 24), and from August 2018 to December 2020 (n = 25). The study enrolled 49 patients [age 59 (43-63) years; 34 (70%) males]. The most common causes for CS were acute myocardial infarction in 22 (45%) and acute decompensation of chronic heart failure in 10 (20%). VA-ECMO was employed in 35 (71%) and Impella CP in 14 (29%) of patients. Overall complications occurred in 37 (76%) of patients, where major bleeding in 19 (38%) was the most common. The overall mortality rate was 61%, but it was lower in the second period (40%) in comparison to the first period (83%), p = 0.002. The learning curve analysis showed a decrease in the mortality rate after 40 consecutive cases. Implementation of a temporary MCS program for refractory CS in a limited resource country is feasible. The learning curve effect might have played a role on survival rate since high morbimortality has decreased within time reaching optimal results by the end of the study.


Tumor markers in mammary carcinoma. An evaluation of carcinoembryonic antigen, placental alkaline phosphatase, pseudouridine and CA-50.
In 104 patients with breast cancer, carcinoembryonic antigen (CEA), placental alkaline phosphatase (PLAP) and the carbohydrate antigen CA-50 were analysed in serum. Excretion of the modified nucleoside, pseudouridine, was analysed in urine. The patients were subdivided in three different clinical stages according to disease manifestations. Levels of CEA and pseudouridine correlated to clinical stage and 58 per cent of the patients with distant metastases had elevated levels of CEA, compared with 36 per cent for pseudouridine. For PLAP and CA-50, the levels did not show any clear correlation to clinical stage. Increased activity of PLAP correlated strongly to tobacco smoking. A decrease in the level of CEA was observed following radical mastectomy. Increase in CEA levels predicted relapse in 5 out of 14 patients within about 3 to 6 months. In patients with tumor manifestations, elevated CEA levels predicted an inferior prognosis compared to those with ordinary levels.


The influenza virus M2 protein cytoplasmic tail interacts with the M1 protein and influences virus assembly at the site of virus budding.
The cytoplasmic tail of the influenza A virus M2 proton-selective ion channel has been shown to be important for virus replication. Previous analysis of M2 cytoplasmic tail truncation mutants demonstrated a defect in incorporation of viral RNA (vRNA) into virions, suggesting a role for M2 in the recruitment of M1-vRNA complexes. To further characterize the effect of the M2 cytoplasmic tail mutations on virus assembly and budding, we constructed a series of alanine substitution mutants of M2 with mutations in the cytoplasmic tail, from residues 71 to 97. Mutant proteins M2-Mut1 and M2-Mut2, with mutations of residues 71 to 73 and 74 to 76, respectively, appeared to have the greatest effect on virus-like particle and virus budding, showing a defect in M1 incorporation. Mutant viruses containing M2-Mut1 and M2-Mut2 failed to replicate in multistep growth analyses on wild-type (wt) MDCK cells and were able to form plaques only on MDCK cells stably expressing wt M2 protein. Compared to wt M2 protein, M2-Mut1 and M2-Mut2 were unable to efficiently coimmunoprecipitate with M1. Furthermore, statistical analysis of planar sheets of membrane from cells infected by virus containing M2-Mut1 revealed a reduction in M1-hemagglutinin (HA) and M2-HA clustering as well as a severe loss of clustering between M1 and M2. These results suggest an essential, direct interaction between the cytoplasmic tail of M2 and M1 that promotes the recruitment of the internal viral proteins and vRNA to the plasma membrane for efficient virus assembly to occur.