The role of the black church in community medicine.
Historically, the black church has been the preserver and the perpetuator of the black ethos, the radix from which its defining values and norms have been generated, and the autonomous social institution that has provided order and meaning to the black experience in the United States. The traditional ethic of community-oriented service in the black ethos is highly compatible with the communitarian ethic of community medicine. Given this congruence and the much-documented fact that black Americans are an at-risk and under-served group regarding health status indicators and the provision of preventive health care, respectively, the black church is an extremely relevant locus for the practice of community medicine. A number of health programs based in or affiliated with the black church have operated throughout the United States, and these programs, along with the corpus of literature comprising conceptual articles favorable toward such a role for the black church, are reviewed within four areas of community medicine: primary care delivery, community mental health, health promotion and disease prevention, and health policy.


Expression of nitric oxide synthase in hypothalamic nuclei following axonal injury or colchicine treatment.
Nitric oxide (NO) has recently gained much attention due to its apparently double-edged role in neuronal injury. This study was aimed at elucidating neuronal nitric oxide synthase (nNOS) expression in the brain after two types of injury, namely axonal transection and colchicine treatment. The neurosecretory hypothalamo-pituitary pathway served as a model for the reaction of central neurons to these two types of injury. Axonal transection, i.e., pituitary stalk section, resulted in a qualitative increase in NOS content in the supraoptic and paraventricular nuclei. In these nuclei, there was also an increase in the number of NOS-expressing neurons after the operation. Surprisingly, in the periventricular nucleus, a strong decrease in the number of NOS-positive magnocellular neurons was observed in the anterior part of the nucleus. Intracerebroventricular injection of colchicine resulted in an increase in the cell count in the paraventricular nucleus, while the other nuclei remained unchanged. Our results suggest that axonal injury results in an increase in nNOS expression in the major neurosecretory nuclei, while the periventricular nucleus shows the opposite reaction. Colchicine treatment has an effect similar to that of axotomy in the major neurosecretory nuclei, suggesting that an increase in NOS expression may be induced by interrupted axonal transport. In the periventricular nucleus, the decrease in the number of NOS-containing neurons suggests differences among hypothalamic NOS-containing neuron groups in response to neuronal injury.


Indoxyl sulfate-lowering capacity of oral sorbents affects the prognosis of kidney function and oxidative stress in chronic kidney disease.
Indoxyl sulfate shows nephrotoxicity and is a stimulating factor for progression of chronic kidney disease (CKD). This study was conducted to determine (1) whether the indoxyl sulfate-lowering capacity of oral sorbents (Kremezin [AST-120], Kureha Corporation, Tokyo, Japan; Merckmezin, Merck Hoei Ltd., Osaka, Japan) affects the prognosis of kidney function in CKD, and (2) whether oral sorbents reduce the markers of oxidative stress. Rats with CKD were produced by 4/5 nephrectomy and were randomized into 3 groups: control rats, Merckmezin-treated rats, and Kremezin-treated rats. Kremezin and Merckmezin were administered to rats at a dose of 4 g/kg with powder chow for 16 weeks, whereas powder chow alone was administered to control rats. Administration of Kremezin significantly decreased serum and urine levels of indoxyl sulfate and serum creatinine and significantly increased creatinine clearance as compared with control values. The change in serum indoxyl sulfate noted from the initial to the final week showed a positive correlation with the change in serum creatinine and a negative correlation with the change in creatinine clearance. Kremezin significantly reduced urine levels of acrolein, a marker of oxidative stress, as compared with control levels. The indoxyl sulfate-lowering capacity of oral adsorbents affects the prognosis of kidney function in CKD. The more serum indoxyl sulfate is reduced, the better kidney function is preserved. Kremezin alleviates oxidative stress in the kidneys by reducing serum levels of indoxyl sulfate.


The influence of arousal and expectation on eyewitness memory in a virtual environment.
This study aimed to examine the effects of arousal and expectation on eyewitness memory. We exposed 97 participants to an immersive eyewitness experience by creating four virtual reality stimulus environments. The participants were randomly assigned to one of four conditions: arousing and expected, arousing and unexpected, nonarousing and expected, and nonarousing and unexpected. The results revealed that memory performance for an arousing encounter was significantly lower than that for a nonarousing encounter, and that memory performance for an unexpected environment was significantly lower compared with an expected one. In addition, memory performance was lowest in the condition that was both arousing and unexpected. No interaction between arousal and expectation was found.


Histological and biomechanical changes in a mouse model of venous thrombus remodeling.
Deep vein thrombosis and the risk of pulmonary embolism are significant causes of morbidity and mortality. Much remains unclear, however, about the mechanisms by which a venous thrombus initiates, progresses, or resolves. In particular, there is a pressing need to characterize the evolving mechanical properties of a venous thrombus for its mechanical integrity is fundamental to many disease sequelae. The primary goal of the present study was to initiate a correlation between evolving histological changes and biomechanical properties of venous thrombus. We employed an inferior vena cava ligation model in mice to obtain cylindrical samples of thrombus that were well suited for mechanical testing and that could be explanted at multiple times following surgery. Using uniaxial micro-mechanical testing, we collected stress-stretch data that were then fit with a microstructurally-inspired material model before submitting the samples to immunohistological examination. We found that venous thrombus underwent a radially inward directed replacement of fibrin with collagen between 2 weeks and 4 weeks of development, which was accompanied by the infiltration of inflammatory and mesenchymal cells. These histological changes correlated with a marked increase in material stiffness. We demonstrated that 2 to 4 week old venous thrombus undergoes drastic remodeling from a fibrin-dominated mesh to a collagen-dominated microstructure and that these changes are accompanied by dramatic changes in biomechanical behavior.


A neuroanatomy lab practical exam format in alignment with the universal design for learning framework.
The traditional format for neuroanatomy lab practical exams involves stations with a time limit for each station and inability to revisit stations. Timed exams have been associated with anxiety, which can lead to poor performance. In alignment with the universal design for learning (UDL), Timed Image Question and Untimed Image Question exam formats were designed to determine which format supports student success, especially for those who performed poorly in the traditional format. Only the Untimed Image Question format allowed students to revisit questions. All three formats were administered in a randomized order within a course for three cohorts of medical students. When all students' scores were analyzed together, the type of format had no effect. However, when analyses were conducted only on students who performed poorly in the traditional format, the type of format had an effect. These students increased their score, on average, by at least one grade level in the Untimed Image Question format compared to the traditional format. Students who performed well in the traditional format maintained their A, on average, in the two new formats. More students indicated Untimed Image Question as their most preferred format after experiencing all three formats. Most students associated the inability to revisit questions with high levels of anxiety. A neuroanatomy lab exam format was therefore identified as consistent with the UDL framework such that all students, regardless of test anxiety levels, can equally demonstrate what they learned. This format allowed for unlimited time per question and ability to revisit questions.


Historic DNA for taxonomy and conservation: A case-study of a century-old Hawaiian hawkmoth type (Lepidoptera: Sphingidae).
Analysing historic DNA from museum specimens offers the unique opportunity to study the molecular systematics and phylogenetics of rare and possibly extinct taxa. In the Hawaiian fauna, the hawkmoth, Hyles calida calida, occurs on several of the main islands and is quite frequent, whereas Hyles c. hawaiiensis is restricted to the Island of Hawaii where it appears to be very rare. Analysis of mitochondrial DNA sequences shows that Hyles c. hawaiiensis differs from the nominotypical subspecies by an average p-distance of 2.8%, which is of a similar order of magnitude to that found between other species of Hyles, suggesting that Hyles c. hawaiiensis should perhaps be awarded species status, although more data are required for a formal taxonomic revision. Given the rarity of this taxon, these analyses should be undertaken urgently so that conservation measures can be implemented before it becomes extinct.


A new flexible pressure sensor contributes to the early diagnosis of acute compartment syndrome.
Acute compartment syndrome (ACS) is a surgical emergency, caused by the sharp increase of interstitial pressure within a closed osteofascial compartment, which can impair local circulation and functions. A non-invasive sensor is needed of satisfactory sensitivity to continuously monitor the alterations of the ACS pressure, which could be used as a supplementary means in the early diagnosis of ACS. A prepared "pasting-type" flexible pressure sensor was used to establish an extracorporeal pig-skin model with a soft-tissue expander device to simulate compartment syndrome conditions. An acrylic panel was inserted into the pig skin, allowing the soft-tissue expander to expand in one direction, which is similar to the movements of a patient's bones in real life. The touch spot of the flexible pressure sensor was attached to the rind by medical tape, to record the internal and external pressure data. Relationships between the internal and external pressures at different thickness (0.87 mm, 3.53 mm and 3.97 mm), as well as that of the 3.97 mm thickness under various initial internal pressures (0.5 mmHg, 25 mmHg and 44 mmHg) were measured. Significant differences were observed in the range of internal pressures at various pig-skin thickness. After adding the acrylic panel, the measured ranges were significantly increased, with the lowest measurable internal pressure being 5 mmHg. Moreover, alterations in external pressure were also greater than in models without acrylic panels. The external pressure measured by the sensor was able to reflect an increase in intra-organizational pressure. This may be a new non-invasive and sustainable method for early diagnosis of ACS.


In vitro and in vivo responses to high and low doses of nitrogen-containing bisphosphonates suggest engagement of different mechanisms for inhibition of osteoclastic bone resorption.
The effects of nitrogen-containing bisphosphonates (N-BPs) on osteoclasts (Ocs) may differ with dose and regimen. N-BPs reduce Oc bone resorption by inhibiting the enzyme farnesyl diphosphate synthase (FPPS), an effect counteracted by geranylgeraniol (GGOH), which restores geranylgeranylation downstream of FPPS. We assessed GGOH effects on inhibition of bone resorption by the N-BPs alendronate (ALN), ibandronate (IBN), and zoledronate (ZOL) in an assay of rabbit Oc resorption of bovine cortical bone. GGOH blocked inhibition of resorption at low, but not high, N-BP concentrations, with a 14- to 20-fold increase in IC50 values for each N-BP. In vivo, growing male rats were administered doses calculated to mimic bioavailable exposures in daily (ALN, IBN), weekly (ALN), monthly (IBN), and yearly (ZOL) clinical regimens. Tibiae were harvested at 48 h, and metaphyses were analyzed. With lower ALN and IBN doses, Oc numbers rose by 26-48 %, morphology was normal, and there was no increase in apoptotic Ocs. In contrast, with higher IBN and ZOL doses, bone-associated Ocs were generally rounded in appearance and numbers of nuclei/Oc versus vehicle increased 42 and 31 %, respectively (P < 0.05). With ZOL, there was no rise in Oc number, but there was a 6.5-fold increase in apoptotic Ocs versus vehicle and a ≥13.5-fold increase versus lower-dose ALN or IBN (P < 0.05). With higher-dose IBN there was no rise in Oc number but 7- and 14-fold increases in Oc apoptosis versus low-dose ALN and IBN (P < 0.02). These results suggest that different mechanisms may come into play across the dosing spectrum of N-BPs.


Immune Response to Native Lipoproteins Induces Visceral Obesity and Aortic Wall Injury in Rats: The Role of Testosterone.
The underlying mechanism of atherosclerosis and visceral obesity remains unknown.The purpose of this study was to test the hypothesis that atherosclerosis and visceral obesity are caused by an immune response to native plasma lipoproteins, and the atherogenic and adipogenic effects of the antibodies to native lipoproteins stem from the androgen deficiency that is created. Wistar rats were immunized with native human (nh) low-density (LDL) or high-density lipoproteins (HDL). Visceral fat, aortic wall structure, and testosterone levels were studied. Immunization with nhLDL or nhHDL induced in rats increased visceral abdominal fat and perivascular adipose tissue volume, the appearance of epicardial fat, and atherosclerosis-like changes in the aortic wall: accumulation of leucocytes, destruction of the intima, and disruption of the media structure. Immunized rats produced antibodies to native plasma lipoproteins, while there was no difference between immunized and adjuvant-injected rats with regard to the level of antibodies to oxidized LDL. The immune response to nhHDL caused testosterone disturbances, but it is not associated with visceral obesity and atherosclerosis. The immune response to native lipoproteins is atherogenic and adipogenic and testosterone is not involved in the atherogenic and adipogenic effects of antibodies to lipoproteins.


Analysis of DNA polymorphism (RAPD-PCR) and reciprocal effects of geese crossbreeds.
Commercial geese breeding in Poland is based on two strains of White Italian geese (W11 and W33). The crossbreeds W33 (paternal line) and W11 (maternal line) are distributed in Poland under the commercial brand of White Kołuda goose. However, there are several breeds which are covered by the animal genetic resources conservation program and kept as conservative flocks. These breeds proved invaluable to commercial geese breeding to stabilize body weight, improve muscling and decrease the amount of fat in the carcass of the crossbreeds. Therefore, this study analyzed the reciprocal crossbreeds of White Kołuda geese with the individuals from conservative flocks. DNA polymorphism (RAPD-PCR) of the crossbreeds as well as the phenotypic effect of crossbreeding was evaluated. PCR amplification of five RAPD markers resulted in obtaining 14.25 band/crossbreed group. The genetic similarity of the crossbreeds expressed as band sharing frequency (BS) ranged from 0.44 to 0.97. The direction of crossing of the W33 goose with one of the individuals from the conservative flock strongly affected the genetic similarity estimates. The body weight in the 17th or 24th week of life and the percentage of leg muscle weight in the 24th week of life differed significantly depending on the crossbreed genotype. A similar relationship was demonstrated for egg fertilization and number of nestlings per goose. As the lines were differentiated only by origin of the Z chromosome, the background of the differences in genetic polymorphism and the phenotypic records is hypothesized as (i) the linkage of some production traits with sex chromosomes; (ii) the impact of selection on W33 individuals resulting in lower performance of geese with a W33-derived Z chromosome; (iii) genetic imprinting displayed as the effect of either maternal or paternal origin of the Z chromosome.


Helicobacter pylori: a clinician's view.
Helicobacter pylori infection has been linked with a number of gastrointestinal diseases, such as peptic ulcer disease, gastric mucosa-associated lymphoid tissue lymphoma and gastric cancer. This article reviews some of the evidence for these associations, and discusses the latest recommended indications for eradication therapy.


Structural MRI substrates of cognitive impairment in neuromyelitis optica.
To identify the clinical and structural MRI markers for predicting cognitive impairment (CI) in patients with neuromyelitis optica (NMO). Fifty-four patients with NMO and 27 healthy controls underwent extensive neuropsychological testing and multimodal 3.0T MRI. The patient group was classified as CI or cognitively preserved (CP), using a criterion of ≤1.5 SD on at least 2 cognitive domains. MRI measurements included white matter (WM) lesion volume, gray matter (GM), WM, and deep GM (DGM) volume, cortical thickness, and the severity and extent of WM tract diffusion metric alterations based on fractional anisotropy and mean, axial, and radial diffusivity. Groups were compared using a multivariate general linear model, and clinical and MRI measurements were related to average cognition z scores by partial correlations and a stepwise linear regression model. Twenty-six patients with NMO (48.2%) were classified as CI and showed WM tract diffusion abnormalities, particularly increased radial diffusivity, and GM especially DGM atrophy compared with healthy controls. Patients classified as CP also showed alterations of WM tract diffusion but without significant GM atrophy. Compared with the CP group, patients with CI demonstrated a lower level of education and decreased hippocampal volume. In the whole patient group, average cognition z scores were best predicted by the level of education and hippocampal volume (R(2) = 0.46, p < 0.001). In patients with NMO, WM tract integrity disruption was identified in both CP and CI groups. GM atrophy, particularly in the DGM, was only found in the CI group. Hippocampal volume is the main MRI predictor of cognition in NMO.


Mapping resistance to powdery mildew in barley reveals a large-effect nonhost resistance QTL.
Resistance factors against non-adapted powdery mildews were mapped in barley. Some QTLs seem effective only to non-adapted mildews, while others also play a role in defense against the adapted form. The durability and effectiveness of nonhost resistance suggests promising practical applications for crop breeding, relying upon elucidation of key aspects of this type of resistance. We investigated which genetic factors determine the nonhost status of barley (Hordeum vulgare L.) to powdery mildews (Blumeria graminis). We set out to verify whether genes involved in nonhost resistance have a wide effectiveness spectrum, and whether nonhost resistance genes confer resistance to the barley adapted powdery mildew. Two barley lines, SusBgtSC and SusBgtDC, with some susceptibility to the wheat powdery mildew B. graminis f.sp. tritici (Bgt) were crossed with cv Vada to generate two mapping populations. Each population was assessed for level of infection against four B. graminis ff.spp, and QTL mapping analyses were performed. Our results demonstrate polygenic inheritance for nonhost resistance, with some QTLs effective only to non-adapted mildews, while others play a role against adapted and non-adapted forms. Histology analyses of nonhost interaction show that most penetration attempts are stopped in association with papillae, and also suggest independent layers of defence at haustorium establishment and conidiophore formation. Nonhost resistance of barley to powdery mildew relies mostly on non-hypersensitive mechanisms. A large-effect nonhost resistance QTL mapped to a 1.4 cM interval is suitable for map-based cloning.


Single implants and buccal bone grafts in the anterior maxilla: measurements of buccal crestal contours in a 6-year prospective clinical study.
Patients provided with buccal bone grafts seem to lose a substantial part of the graft in the short term. To measure long-term changes in buccal and proximal tissue volumes after local bone grafting and single implant treatment. Eight of 10 originally treated male patients were followed up for 6 years after treatment with buccal bone grafts in the central incisor region. After a healing time of 6 months, a two-stage implant surgery procedure was performed followed by single crown placement. Clinical photographs and impressions were taken prior to the surgical interventions and after crown placement and at first and fifth annual checkups. The photographs were analyzed with regard to papilla regeneration by means of a clinical papilla index. The models were used to measure the clinical length of teeth and tooth movements adjacent to the implants. Changes in buccal crest volume during the study period were measured by means of optical scanning of obtained study models. Papillae volume increased significantly (p<.05) during the first year, thereafter showing a slow further increase during the 4 following years. Three of the patients (38%) presented small movements of their adjacent central incisor in a vertical or palatal direction of less than 1 mm during the follow-up period. All patients showed resorption during the first year after grafting (p<.01), in which three patients (38%) had lost basically all of increased volume at second surgery. After abutment or crown placement, all patients showed an increased volume (p<.01), followed by an average reduction during the first year, reaching a significant level in the apical part of the crest (p<.05). Thereafter, a relatively stable average situation was observed during the following 4 years, with individual variations, however. Local bone grafting seems to create sufficient bone volume for implant placement after 6 months, but individual variations in resorption pattern make the grafting procedure unpredictable for long-term prognosis. Instead, the abutment and the crown seem to play a more important role for building up and maintaining the buccal contour in the coronal part of the crest long term.


Ultrasonographic "triangular cord": the most definitive finding for noninvasive diagnosis of extrahepatic biliary atresia.
Early diagnosis of extrahepatic biliary atresia (EHBA) is very important for a successful bile drainage procedure. An urgent and extensive investigation is warranted to make a differential diagnosis of EHBA from other cholestatic disease, especially neonatal hepatitis (NH). The diagnosis may be made by laparotomy with cholangiogram and liver biopsy but these procedure are invasive. Because a cone-shaped fibrous tissue was always found at the porta hepatis during Kasai's procedure and that type of fibrous tissue has never been seen in other types of cholestatic jaundice, the authors have used ultrasonography (US) to detect fibrous remnants at the porta hepatis in infants clinically suspected of having EHBA and identified a triangular- or tubular-shaped echogenic density in the bifurcation of the portal vein at the porta hepatis in EHBA and called it an ultrasonographic "triangular cord (TC)". The authors determined that the presence of TC denoted the EHBA. On the other hand, nonvisualization of TC was interpreted as consistent with NH. In the present study, the authors reviewed ultrasonographic examination and hepatobiliary scintigraphy in a series of 41 infants suspected of having EHBA or NH. The TC was identified in thirteen infants. In twelve of thirteen infants with TC found by US, the diagnosis of EHBA was confirmed at the time of Kasai's Roux-en-Y hepatoportojejunostomy operation. The remaining one died at 15 months of age without having treatment. TC was not visualized in 28 infants. Twenty-seven of 28 infants with absent TC improved clinically through medical treatment for NH. The other, diagnosed to have NH by needle and wedge liver biopsies, eventually showed a TC on follow-up US examination performed 40 days after the initial examinations. Moreover, follow-up percutaneous liver biopsy specimen showed typical findings of biliary atresia with bile duct proliferation and portal fibrosis. The patient underwent a Kasai hepatoportoenterostomy. On review of the hepatobiliary scintigraphy, all 13 infants with TC had no intestinal excretion of isotope. Thirteen of 28 infants (46%) without TC also had no intestinal excretion of isotope in the 24hour follow-up but all of them were confirmed to have NH by percutaneous liver biopsy and their subsequent clinical course confirmed NH with the detection of bile in their stool except one. On the basis of these results, the authors conclude that ultrasonographic TC is a very specific finding representing the fibrous cone at the porta hepatis and is a quick, simple, and definitive tool in the noninvasive diagnosis of EHBA. If TC is visualized, no further studies are necessary and exploratory-laparotomy can be done. If TC is not visualized, hepatobiliary scintigraphy is recommended to demonstrate bile duct patency. Percutaneous liver biopsy is only required if neither TC nor intestinal excretion of isotope is seen. However, early exploration or close US follow-up study is recommended in any patient suspected of having EHBA clinically, even if liver biopsy confirms the presence of NH.


Use of a novel rapid and resource-efficient cassette dosing approach to determine the pharmacokinetics and CNS distribution of small molecule 7-transmembrane receptor allosteric modulators in rat.
Approaches to efficiently and accurately define the pharmacokinetics (PK) of large sets of small molecules in rodents have been previously described. Likewise, a variety of methods for determining brain tissue distribution (BTD) have been reported for use in the discovery of therapeutics targeting the central nervous system (CNS). Herein we describe a novel cassette approach to efficiently obtain concurrent PK and BTD data from a dose of up to five compounds in one rat over 24 h. In conjunction with fraction unbound (fu) data obtained in plasma and brain homogenate, this approach serves as an efficient means to determine compound unbound brain:unbound plasma partition coefficients (K p,uu), thereby providing insight to compounds bearing poor permeability and/or active transporter activity impacting their permeation of the blood-brain barrier (BBB). This integrated approach was utilized in a lead optimization effort towards the discovery of CNS-penetrant allosteric modulators of a seven-transmembrane (7TM) receptor target. Rat PK and brain distribution was rapidly obtained for 70 compounds and correlated to data obtained from in vitro assessments. Two compounds that were evaluated in cassette and discrete studies, displayed agreement in PK (compound 1: cassette CLp = 1.6 mL min(-1) kg(-1), discrete CLp = 1.6 mL min(-1) kg(-1); compound 2: cassette CLp = 11 mL min(-1) kg(-1), discrete CLp = 8.1 mL min(-1) kg(-1)) and BTD (compound 1: cassette K p = 0.11, discrete K p = 0.09; compound 2: cassette K p < 0.05, discrete K p = 0.04). The resulting data were used to guide medicinal chemistry efforts and to enable the progression of optimized compounds to in vivo pharmacodynamic assessments.


Electron microscopical evidence for a direct contact between nerve fibres and mast cells.
A subungual solitary glomus tumour was examined by both light and electron microscopy. By light microscopy, typical tumour tissue was seen, surrounded by connective tissue. By electron microscopy, a very close morphological relationship was noted between non-myelinated nerve fibres and mast cells. These mast cells could be divided into two groups: the mast cells of the first group contain numerous mature granules and show few lamellopodia. The distance to the nerve fibre bundles ranged between 2000 and 20 nm. In the second group, the mast cells always showed direct contact with nerve fibers. They had many lamellopodia and contained almost exclusively immature granules. In some cases, invaginations of lamellopodia and broader cytoplasmatic processes into the view that mast cells may play an important part in the function of neurons.


Nanocarriers Assisted siRNA Gene Therapy for the Management of Cardiovascular Disorders.
Cardiovascular diseases (CVDs), primarily myocardial infarction (MI), atherosclerosis, hypertension and congestive heart failure symbolize the foremost cause of death in almost all parts of the world. Besides the traditional therapeutic approaches for the management of CVDs, newer innovative strategies are also emerging on the horizon. Recently, gene silencing via small interfering RNA (siRNA) is one of the hot topics amongst various strategies involved in the management of CVDs. The siRNA mechanism involves natural catalytic processes to silence pathological genes that are overexpressed in a particular disease. Also the versatility of gene expression by siRNA deciphers a prospective tactic to down-regulate diseases associated gene, protein or receptor existing on a specific disease target. This article reviews the application of siRNA against CVDs with special emphasis on gene targets in combination with delivery systems such as cationic hydrogels, polyplexes, peptides, liposomes and dendrimers.


Insights into the growing popularity of artificial intelligence in ophthalmology.
Artificial intelligence (AI) in healthcare is the use of computer-algorithms in analyzing complex medical data to detect associations and provide diagnostic support outputs. AI and deep learning (DL) find obvious applications in fields like ophthalmology wherein huge amount of image-based data need to be analyzed; however, the outcomes related to image recognition are reasonably well-defined. AI and DL have found important roles in ophthalmology in early screening and detection of conditions such as diabetic retinopathy (DR), age-related macular degeneration (ARMD), retinopathy of prematurity (ROP), glaucoma, and other ocular disorders, being successful inroads as far as early screening and diagnosis are concerned and appear promising with advantages of high-screening accuracy, consistency, and scalability. AI algorithms need equally skilled manpower, trained optometrists/ophthalmologists (annotators) to provide accurate ground truth for training the images. The basis of diagnoses made by AI algorithms is mechanical, and some amount of human intervention is necessary for further interpretations. This review was conducted after tracing the history of AI in ophthalmology across multiple research databases and aims to summarise the journey of AI in ophthalmology so far, making a close observation of most of the crucial studies conducted. This article further aims to highlight the potential impact of AI in ophthalmology, the pitfalls, and how to optimally use it to the maximum benefits of the ophthalmologists, the healthcare systems and the patients, alike.


Clinical and histological observations of continuously formed bilateral mandibular deciduous central incisor roots after traumatic coronal destruction.
We encountered a rare case of continuously forming bilateral mandibular deciduous central incisor roots after traumatic coronal destruction. The patient, 3 year 3 month old boy, had sustained an external injury which had caused the crowns of hist bilateral deciduous central incisors to fall out when he was 12 months old. Oral examination revealed two small, hard tissues resembling tooth structures on the alveolar ridge in the area of the lost mandibular central incisors. X-ray examination revealed them to be deciduous central incisor roots. We observed the extracted roots histologically and found that the lesion of the crown fracture and pulpal exposure on these roots was completely covered by newly formed irregular dentin and cementoid tissues. In this case, the causes of the continuous root formation were considered to be that the pulp tissues of traumatized teeth were able survive, so the injured lesion was quickly healed and covered with gingival tissue. The vital pulp produced the reparative hard tissue, sealing the site of pulpal exposure and continuing root formation after the trauma.


Inducible clindamycin and methicillin resistant Staphylococcus aureus in a tertiary care hospital, Kathmandu, Nepal.
Staphylococcus aureus, an important nosocomial pathogen, is frequently associated with infections in human. The management of the infections by it especially methicillin resistant ones is often difficult because methicillin resistant S. aureus is usually resistant to multiple antibiotics. Macrolide-lincosamide streptogramin B family of antibiotics is commonly used to treat such infections as an alternative to vancomycin. This study was conducted over the period of one and half year from November 2013-April 2015 in Microbiology laboratory of Nepal Medical College and Teaching Hospital, Kathmandu, Nepal to find the incidence of different phenotypes of MLSB resistance among S. aureus from clinical samples and their association with methicillin resistance. Two hundred seventy isolates of S. aureus were included in the study. Methicillin resistance was detected by cefoxitin disc diffusion method and inducible clindamycin resistance by erythromycin and clindamycin disc approximation test (D-test). Of the 270 clinical isolates of S. aureus, 25.1% (68/270) were MRSA. Erythromycin and clindamycin resistance was seen in 54.4% (147/270) and 41.8% (113/270) isolates respectively. Resistance to erythromycin and clindamycin were higher in MRSA as compared to MSSA (erythromycin-resistance: 88.2% Vs 39.1% and clindamycin-resistance: 79.4% Vs 41.8%). The overall prevalence of iMLSB and cMLSB phenotype was 11.48% (31/270) and 29.25% (79/270) respectively. Both iMLSB and cMLSB phenotypes predominated in MRSA strains. Detection rate of MRSA in our study shows the necessity to improve in healthcare practices and to formulate new policy for the control of MRSA infections. Clindamycin resistance in the form of iMLSB and cMLSB especially among MRSA emphasizes the need of D-test to be performed routinely in our set up while using clindamycin as an alternative choice to anti-staphylococcal antibiotics like vancomycin and linezolid in the treatment of staphylococcal infections.


An enantioselective approach to the preparation of chiral sulfones by Ir-catalyzed asymmetric hydrogenation.
Several chiral sulfonyl compounds were prepared using the iridium catalyzed asymmetric hydrogenation reaction. Vinylic, allylic and homoallylic sulfone substitutions were investigated, and high enantioselectivity is maintained regardless of the location of the olefin with respect to the sulfone. Impressive stereoselectivity was obtained for dialkyl substitutions, which typically are challenging substrates in the hydrogenation. As expected, the more bulky Z-substrates were hydrogenated slower than the corresponding E isomers, and in slightly lower enantioselectivity.


Correction factor in Orbscan II in the assessment of corneal pachymetry.
Comparison of corneal pachymetry assessment with ultrasound and Orbscan II using acoustic factor and subtraction methods. Ultrasound and Orbscan pachymetry for all patients with LASIK performed between July 2002 and May 2003 were retrospectively analyzed. Comparison between the 2 preoperative measurements was analyzed. Using a custom acoustic factor of 0.93, there was no significant difference between the overall ultrasound and Orbscan pachymetry (P = 0.696). However, there was underestimation in thick corneas and overestimation in thin corneas. Using the subtraction method as the correcting technique, the magnitude of over- and underestimation was reduced. The current correction method by means of acoustic factor may result in error in assessing extremes of corneal thickness. Alternative approaches such as the subtraction method can be considered to achieve more accurate results.


[Therapeutic use of anti-TNF-alpha agents in spondyloarthropathies].
CLASSICAL DATA: Spondyloarthropathies regroup several rheumatological entities (ankylosing spondylitis, reactive arthritis, psoriatic rheumatism, entero-colopathic disease rheumatism, undifferentiated spondyloarthropathies ) with validated diagnosis criteria. Drug therapy is based upon NSAIDs (non-steroidal antiinflammatories). Refractory forms may lead to severe functional impairment, raising the need of more effective treatments. IN FAVOUR OF ANTI-TNF-ALPHA AGENTS: Several arguments (TNF-alpha serum levels, elevated levels of mRNA, TNF messengers, in sacro iliac biopsies, efficacy of anti TNF-alpha agents in Crohn's disease ) justify the use of anti-TNF-alpha agents in the treatment of spondyloarthropathies. Two biologic agents have been assessed in these circumstances: a monoclonal antibody (Infliximab) and a soluble form of the TNF receptor (Etanercept). EFFICACY AND SAFETY: Results of open and controlled studies, although on small series, demonstrated the significant efficacy of anti-TNF-alpha agents on the various clinical, biological, functional and quality of life parameters, and confirmed by imaging (MRI ). Tolerance is fair, but two cases of diffuse tuberculosis have been reported with Infliximab. THERAPEUTIC PROGRESS: Even if additional studies are required to answer some questions (long term efficacy and safety, treatment modalities), anti TNF agents appear as a therapeutic progress in refractory spondyloarthropathies, for which few validated options have existed up till now.


Phylogenetic Analysis of Core Melanin Synthesis Genes Provides Novel Insights Into the Molecular Basis of Albinism in Fish.
Melanin is the most prevalent pigment in animals. Its synthesis involves a series of functional genes. Particularly, teleosts have more copies of these genes related to the melanin synthesis than tetrapods. Despite the increasing number of available vertebrate genomes, a few systematically genomic studies were reported to identify and compare these core genes for the melanin synthesis. Here, we performed a comparative genomic analysis on several core genes, including tyrosinase genes (tyr, tyrp1, and tyrp2), premelanosome protein (pmel), microphthalmia-associated transcription factor (mitf), and solute carrier family 24 member 5 (slc24a5), based on 90 representative vertebrate genomes. Gene number and mutation identification suggest that loss-of-function mutations in these core genes may interact to generate an albinism phenotype. We found nonsense mutations in tyrp1a and pmelb of an albino golden-line barbel fish, in pmelb of an albino deep-sea snailfish (Pseudoliparis swirei), in slc24a5 of cave-restricted Mexican tetra (Astyanax mexicanus, cavefish population), and in mitf of a transparent icefish (Protosalanx hyalocranius). Convergent evolution may explain this phenomenon since nonsense mutations in these core genes for melanin synthesis have been identified across diverse albino fishes. These newly identified nonsense mutations and gene loss will provide molecular guidance for ornamental fish breeding, further enhancing our in-depth understanding of human skin coloration.


Mucosal melanoma: pathogenesis, clinical behavior, and management.
Mucosal melanoma represents a rare subtype of melanoma with distinct biological, clinical, and management considerations. Knowledge regarding optimal treatment strategies for mucosal melanoma is limited and based primarily upon small case series and single-institution, retrospective analyses. Surgery remains the standard of care for loco-regional management, but the common presence of multifocal disease and the high rate of distant recurrence should be considered before pursuing aggressive surgical interventions associated with inherent significant morbidity. The role of sentinel lymph node biopsy and lymph node dissection remains unclear. Radiotherapy has not been shown to improve overall survival but may reduce the rate of local recurrence. Significant advances in the treatment of metastatic disease have been made with novel immunotherapeutic agents, the discovery of KIT and BRAF mutations and the development of targeted agents that inhibit these oncogenic pathways.


A new species of the toothed toad Oreolalax (Anura, Megophryidae) from Sichuan Province, China.
The toad genus Oreolalax is widely distributed in southwest China and northern Vietnam. A new species of the genus is described from Sichuan Province, China. Phylogenetic analyses based on the mitochondrial 12S rRNA and 16S rRNA gene sequences supported the new species as an independent clade clustered into the clade also containing O. nanjiangensis and O. chuanbeiensis. The new species can be distinguished from its congeners by a combination of the following characters: body size moderate (SVL 51.2-64.2 mm in males); head broad; tympanum hidden; interorbital region with dark triangular pattern; belly with marbling; male lacking spines on lip margin; spiny patches on chest small with thick sparse spines in male; nuptial spines thick and sparse; tibio-tarsal articulation reaching beyond nostril when leg stretched forward; toe webbing at base.


Fast fluid-attenuated inversion-recovery MR of intracranial infections.
To assess the usefulness of fast fluid-attenuated inversion-recovery (FLAIR) MR sequences in the diagnosis of intracranial infectious diseases. We compared fast FLAIR images with conventional spin-echo images (T1- and T2-weighted) obtained in 20 patients with infectious diseases (six with encephalitis, five with brain abscesses, three with meningitis, two with meningoencephalitis, two with Creutzfeldt-Jakob disease, one with epidural empyema, and one with cysticercosis). Two neuroradiologists independently reviewed the FLAIR images and compared them with the conventional spin-echo images, obtaining agreement in all patients. FLAIR images of diagnostic quality were obtained in 18 patients. In two patients, FLAIR images were degraded by motion. Lesions in the patients with encephalitis and meningoencephalitis were better delineated on FLAIR images than on spin-echo images. FLAIR images clearly depicted lesions in the basal ganglia in both patients with Creutzfeldt-Jakob disease. In patients with brain abscess, meningitis, cysticercosis, and epidural empyema, FLAIR images provided no more information than conventional spin-echo images, and the lesions were seen better on postcontrast T1-weighted spin-echo images. Fast FLAIR images showed pathologic changes in intracranial infectious diseases better than or as well as conventional T2- and proton density-weighted spin-echo sequences. However, postcontrast T1-weighted spin-echo sequences resulted in better visibility of abscess, meningitis, cysticercosis, and epidural empyema than did FLAIR images.


The proteasome inhibitor MG132 protects against acute pancreatitis.
The cell-permeant MG132 tripeptide (Z-Leu-Leu-Leu-aldehyde) is a peptide aldehyde proteasome inhibitor that also inhibits other proteases, including calpains and cathepsins. By blocking the proteasome, this tripeptide has been shown to induce the expression of cell-protective heat shock proteins (HSPs) in vitro. Effects of MG132 were studied in an in vivo model of acute pancreatitis. Pancreatitis was induced in male Wistar rats by injecting 2 x 100 microug/kg cholecystokinin octapeptide intraperitoneally (ip) at an interval of 1 h. Pretreating the animals with 10 mg/kg MG132 ip before the induction of pancreatitis significantly inhibited IkappaB degradation and subsequent activation of nuclear factor-kappaB (NF-kappaB). MG132 also increased HSP72 expression. Induction of HSP72 and inhibition of NF-kappaB improved parameters of acute pancreatitis. Thus MG132 significantly decreased serum amylase, pancreatic weight/body weight ratio, pancreatic myeloperoxidase activity, proinflammatory cytokine concentrations, and the expression of pancreatitis-associated protein. Parameters of oxidative stress (GSH, MDA, SOD, etc.) were improved in both the serum and the pancreas. Histopathological examinations revealed that pancreatic specimens of animals pretreated with the peptide demonstrated milder edema, cellular damage, and inflammatory activity. Our findings show that simultaneous inhibition of calpains, cathepsins, and the proteasome with MG132 prevents the onset of acute pancreatitis.


Properties of GABAergic neurons in the rostral solitary tract nucleus in mice.
The rostral nucleus of the solitary tract (rNST) plays a pivotal role in taste processing. The rNST contains projection neurons and interneurons that differ in morphology and intrinsic membrane properties. Although characteristics of the projection neurons have been detailed, similar information is lacking on the interneurons. We determined the intrinsic properties of the rNST GABAergic interneurons using a transgenic mouse model that expresses enhanced green fluorescent protein under the control of a GAD67 promoter. Glutamic acid decarboxylase-green fluorescent protein (GAD67-GFP) neurons were distributed throughout the rNST but were concentrated in the ventral subdivision with minimal interaction with the terminal field of the afferent input. Furthermore, the density of the GAD67-GFP neurons decreased in more rostral areas of rNST. In whole cell recordings, GAD67-GFP neurons responded with either an initial burst (73%), tonic (18%), or irregular (9%) discharge pattern of action potentials (APs) in response to membrane depolarization. These three groups also differed in passive and AP characteristics. Initial burst neurons had small ovoid or fusiform cell bodies, whereas tonic firing neurons had large multipolar or fusiform cell bodies. Irregular firing neurons had larger spherical soma. Some of the initial burst and tonic firing neurons were also spontaneously active. The GAD67-GFP neurons could also be categorized in subgroups based on colocalization with somatostatin and parvalbumin immunolabeling. Initial burst neurons would transmit the early dynamic portion of the encoded sensory stimuli, whereas tonic firing neurons could respond to both dynamic and static components of the sensory input, suggesting different roles for GAD67-GFP neurons in taste processing.


The rat follistatin gene is highly expressed in decidual tissue.
Follistatin was originally described as an ovarian polypeptide hormone able to suppress pituitary follicle-stimulating hormone (FSH) secretion in in vitro systems. We have isolated rat ovarian follistatin cDNA clones and used these to investigate the possibility that decidual tissue expresses the follistatin gene. We found that the follistatin gene is highly expressed during early pregnancy in tissue derived from the site of blastocyst implantation. Follistatin mRNA was observed in tissue obtained from the implantation site at days 6, 8 and 10 of gestation, but was not found in the placenta at later stages of gestation. This same pattern of follistatin expression was observed in pseudopregnant animals in which decidualization had been artificially induced, indicating that decidual tissue is the primary source of follistatin mRNA. In situ hybridization was used to examine follistatin gene expression in decidua in greater detail. The mRNA is preferentially found in antimesometrial tissue, and is strictly confined to the endometrial-derived decidual cells. These results suggest that follistatin might function as an important endocrine hormone during implantation of the fetus, perhaps by acting to appropriately modulate maternal FSH secretion during early pregnancy.


Intimate Partner Violence Experienced by Physicians: A Review.
Physicians play a significant role in screening for domestic violence. However, little information is available about the prevalence of physicians who experience intimate partner violence (IPV) or the implications for their clinical practice. National surveys indicate a potential prevalence of 16% for sexual abuse and 32% for abuse by an intimate partner. This extrapolates to more than 395,000 potential physician victims, the majority of which are women. We conducted a systematic review of IPV and physician victims from 1990 to 2014 that included peer-reviewed journals, trade books, and dissertations that referenced physician victims. We identified 17 publications; nine quantitative studies, four first-person accounts, one qualitative study, and a qualitative dissertation that included two physician subjects. Two case studies of victimized physicians were identified in trade books. Quantitative results noted that women reported higher prevalence for all experiences of violence [childhood exposure (6%-32%), adult IPV exposure (7%-24%)] than men (6%-10%). This review highlights the need for improved understanding of physician experience with IPV, and development of physician-sensitive resources and treatment approaches. Contributions and limitations are provided for each publication. IPV exposure impacts clinical practice, including reticence to consistently screen patients. Lower reported prevalence may be related to extreme stigma among physicians that may prevent their reporting and help seeking, but more research is needed. We provide recommendations for clinical practice, education, and future research.


[Vulvar neoplasms and preoperative lymphography].
20 patients with histologically verified carcinoma of the vulva fulfilled the following conditions: general operability, preoperative lymphography, radical vulvectomy with inguinal lymph node resection and histological examination of all lymph nodes. It was studied how far the preoperative lymphography plays a role for the strategy of operative treatment of carcinoma of the vulva and eventually in the limitation of risks of operative treatment. A survey of the lymphatic drainage of the vulva underlines the importance of the knowledge of the lymphatic pathways for the operation and for the lymphography as performed in this hospital since 1972. The results suggest that lymphography shows an unacceptable high number of false-negative results in cases of metastatic involvement of the inguinal nodes (7 out of 10 cases), whereas it is reliable for the judgment of the iliac and paraaortal nodes. For this reason the resection of the inguinal nodes remains a necessary part of radical vulvectomy. The additional removal of intrapelvic lymph nodes has been restricted to patients with lymphographic signs of positive nodes. In our opinion preoperative lymphography is of considerable value to minimize the operative risk for patients with carcinoma of the vulva by means of a more precise preoperative diagnosis, stage-oriented therapy and postoperative control.


Modulation of factors affecting optic nerve head astrocyte migration.
The authors investigated the role of myosin light chain kinase (MYLK) and transforming growth factor beta (TGFbeta) receptor pathways in optic nerve head (ONH) astrocyte migration. They further investigated how the expression of these genes is altered by elevated hydrostatic pressure (HP). PCR was used to determine the isoforms of MYLK expressed in ONH astrocytes. siRNAs against MYLK (all isoforms) and TGFbeta receptor 2 (TGFBR2) were prepared and tested for effects on the migration of cultured ONH astrocytes. Finally, the effects of elevated HP (24-96 hours) on the expression of MYLK isoforms and selected TGFbeta pathway components were measured. Multiple isoforms of MYLK are present in ONH astrocytes from Caucasian (CA) and African American (AA) donors. Both populations express the short form (MYLK-130) and the long form (MYLK-210) of MYLK and a splicing variant within MYLK-210. MYLK-directed siRNA decreased MYLK expression and cell migration compared with control siRNA. siRNA directed against TGFbeta receptor 2 also decreased cell migration compared with control and decreased extracellular matrix genes regulated by TGFbeta signaling. Elevated HP increased the expression of MYLK-130 and MYLK-210 in both populations of astrocytes. However, TGFbeta2 was uniquely upregulated by exposure to elevated HP in CA compared with AA astrocytes. Differential expression of TGFbeta pathway genes and MYLK isoforms observed in populations of glaucomatous astrocytes applies to the elevated HP model system. MYLK may be a new target for intervention in glaucoma to alter reactive astrocyte migration in the ONH.


Forkhead transcription factor FKH-8 cooperates with RFX in the direct regulation of sensory cilia in Caenorhabditis elegans.
Cilia, either motile or non-motile (a.k.a primary or sensory), are complex evolutionarily conserved eukaryotic structures composed of hundreds of proteins required for their assembly, structure and function that are collectively known as the ciliome. Ciliome gene mutations underlie a group of pleiotropic genetic diseases known as ciliopathies. Proper cilium function requires the tight coregulation of ciliome gene transcription, which is only fragmentarily understood. RFX transcription factors (TF) have an evolutionarily conserved role in the direct activation of ciliome genes both in motile and non-motile cilia cell-types. In vertebrates, FoxJ1 and FoxN4 Forkhead (FKH) TFs work with RFX in the direct activation of ciliome genes, exclusively in motile cilia cell-types. No additional TFs have been described to act together with RFX in primary cilia cell-types in any organism. Here we describe FKH-8, a FKH TF, as a direct regulator of the sensory ciliome genes in Caenorhabditis elegans. FKH-8 is expressed in all ciliated neurons in C. elegans, binds the regulatory regions of ciliome genes, regulates ciliome gene expression, cilium morphology and a wide range of behaviors mediated by sensory ciliated neurons. FKH-8 and DAF-19 (C. elegans RFX) physically interact and synergistically regulate ciliome gene expression. C. elegans FKH-8 function can be replaced by mouse FOXJ1 and FOXN4 but not by other members of other mouse FKH subfamilies. In conclusion, RFX and FKH TF families act jointly as direct regulators of ciliome genes also in sensory ciliated cell types suggesting that this regulatory logic could be an ancient trait predating functional cilia sub-specialization.


The Microbiome and Irritable Bowel Syndrome - A Review on the Pathophysiology, Current Research and Future Therapy.
Irritable bowel syndrome (IBS) is a functional disorder which affects a large proportion of the population globally. The precise etiology of IBS is still unknown, although consensus understanding proposes IBS to be of multifactorial origin with yet undefined subtypes. Genetic and epigenetic factors, stress-related nervous and endocrine systems, immune dysregulation and the brain-gut axis seem to be contributing factors that predispose individuals to IBS. In addition to food hypersensitivity, toxins and adverse life events, chronic infections and dysbiotic gut microbiota have been suggested to trigger IBS symptoms in tandem with the predisposing factors. This review will summarize the pathophysiology of IBS and the role of gut microbiota in relation to IBS. Current methodologies for microbiome studies in IBS such as genome sequencing, metagenomics, culturomics and animal models will be discussed. The myriad of therapy options such as immunoglobulins (immune-based therapy), probiotics and prebiotics, dietary modifications including FODMAP restriction diet and gluten-free diet, as well as fecal transplantation will be reviewed. Finally this review will highlight future directions in IBS therapy research, including identification of new molecular targets, application of 3-D gut model, gut-on-a-chip and personalized therapy.


Gall bladder cancer and the role of dietary and lifestyle factors: a case-control study in a North Indian population.
Most patients with gall bladder cancer (GBC) present in the advanced stage with a poor response to therapy. Prevention or early detection is the best way to prevent death, but this requires identification of susceptible subgroups. Keeping this in mind, this study was carried out to evaluate the association between selected demographic, lifestyle, and dietary factors and GBC. A hospital-based case-control study was carried out at the All India Institute of Medical Sciences (New Delhi, India). Cases were defined as newly registered confirmed primary GBC patients. Controls were defined as healthy relatives of patients other than that of GBC. Data were collected from February 2008 to October 2009 using a semistructured interview schedule from both cases and controls. Analysis was carried out using SPSS version 15 and Epi-Info version 6. Factors found to be significant in the bivariate analysis were entered in a multivariate logistic regression analysis. A total of 122 cases and 122 controls were included in the study. There was no significant difference in age (P=0.06) and sex (P=0.66) between the cases and the controls. In the bivariate analysis, factors found to be significantly associated with GBC were illiteracy [odds ratio (OR) 8.00, P=0.000], lower socioeconomic status (OR 2.45, P=0.000), parity more than 3 (OR 9.06, P=0.000), age at first pregnancy less than 20 years (OR 2.03, P=0.018), and the use of nonliquefied petroleum gas cooking fuel (OR 4.17, P=0.000). Higher vitamin C intake had a protective effect (OR 0.33, P=0.004). In the multivariate analysis, education, intake of vitamin C, parity, and type of fuel used were significant factors. The risk factors for GBC that have been identified in the present study delineate a high-risk population group that can be targeted for preventive measures including improvement in socioeconomic status, education and lifestyle, and dietary intervention, and avoidance of the use of nonliquefied petroleum gas as cooking fuel.


Non-Ischemic Cerebral Energy Dysfunction at the Early Brain Injury Phase following Aneurysmal Subarachnoid Hemorrhage.
The pathophysiology of early brain injury following aneurysmal subarachnoid hemorrhage (SAH) is still not completely understood. Using brain perfusion CT (PCT) and cerebral microdialysis (CMD), we examined whether non-ischemic cerebral energy dysfunction may be a pathogenic determinant of EBI. A total of 21 PCTs were performed (a median of 41 h from ictus onset) among a cohort of 18 comatose mechanically ventilated SAH patients (mean age 58 years, median admission WFNS score 4) who underwent CMD and brain tissue PO2 (PbtO2) monitoring. Cerebral energy dysfunction was defined as CMD episodes with lactate/pyruvate ratio (LPR) >40 and/or lactate >4 mmol/L. PCT-derived global CBF was categorized as oligemic (CBF < 28 mL/100 g/min), normal (CBF 28-65 mL/100 g/min), or hyperemic (CBF 69-85 mL/100 g/min), and was matched to CMD/PbtO2 data. Global CBF (57 ± 14 mL/100 g/min) and PbtO2 (25 ± 9 mm Hg) were within normal ranges. Episodes with cerebral energy dysfunction (n = 103 h of CMD samples, average duration 7.4 h) were frequent (66% of CMD samples) and were associated with normal or hyperemic CBF. CMD abnormalities were more pronounced in conditions of hyperemic vs. normal CBF (LPR 54 ± 12 vs. 42 ± 7, glycerol 157 ± 76 vs. 95 ± 41 µmol/L; both p < 0.01). Elevated brain LPR correlated with higher CBF (r = 0.47, p < 0.0001). Cerebral energy dysfunction is frequent at the early phase following poor-grade SAH and is associated with normal or hyperemic brain perfusion. Our data support the notion that mechanisms alternative to ischemia/hypoxia are implicated in the pathogenesis of early brain injury after SAH.


HER-2 and TOP2A coamplification in urinary bladder cancer.
HER-2/NEU is one of the most frequently amplified oncogenes and a potential therapeutic target in bladder cancer. In breast cancer, the adjacent TOP2A gene, the molecular target for several anticancer drugs, is frequently coamplified together with HER-2. To study the amplification and expression of TOP2A and HER-2 and associations with tumor phenotype and clinical outcome in bladder cancer, a tissue microarray containing 2,317 bladder tumor samples was analyzed by FISH and immunohistochemistry. Overall amplification frequencies were 6.3% for HER-2 and 1.5% for TOP2A. Amplifications were most frequently seen in advanced-stage (pT2-4) tumors (HER-2 13.8%, TOP2A 3.4%). Of HER-2-amplified tumors, 56% also had alterations of TOP2A, including 14.7% coamplifications, 33.3% gains and 8% deletions. Only 17.6% of TOP2A amplifications occurred independently of HER-2 alterations. Both HER-2 and TOP2A amplifications were significantly associated with advanced tumor stage (HER-2 p < 0.0001, TOP2A p = 0.0218), high grade (p < 0.0001 for both) and protein overexpression (p < 0.0001 for both). TOP2A amplification and overexpression were linked to shortened survival in muscle-invasive tumors (p = 0.0042 and 0.0077, respectively). In summary, our data suggest that HER-2 amplifications are frequently linked to alterations of the TOP2A gene in bladder cancer. The anatomy of the 17q12-q21 amplicon may be important for response to therapies targeting HER-2 or TOP2A.


New perspectives in advanced genitourinary malignancies.
The management of advanced genitourinary malignancies has undergone a major transformation with the advent of novel drugs and targeted therapies in recent years. Assessment of the treatment risks and benefits is required for each patient and therefore better knowledge of the different clinical and molecular aspects of these diseases is warranted. The results of further studies and biomarker validations are expected to provide more treatment options and improve outcomes in the future management of genitourinary malignancies.


Reaction dynamics of Al + CO2 → AlO + CO studied by a crossed-beam velocity map imaging technique.
The oxidation reaction of a gas-phase aluminum atom by a carbon dioxide molecule was studied by employing a crossed-beam technique at two collision energies: 27.9 and 52.8 kJ/mol. A (1 + 1) resonance-enhanced multiphoton ionization via the D2Σ+-X2Σ+ transition of AlO was applied to ionize the product. For several rotational levels of AlO in the vibrational ground state, time-sliced ion images were measured for the first time, and the angular-kinetic energy distributions were determined. All angular distributions showed forward and backward peaks; the forward peaks were more pronounced than the backward ones at the two collision energies. The product kinetic energy showed rather narrow distributions whose peaks appeared at near to the highest limit estimated from the available energies. The rotational distributions of the counter product CO, derived from the kinetic energy distributions, suggested that only a limited number of rotational states were formed and that a small amount of energies go into this mode. These results suggested that the reaction proceeds via a short-lived intermediate in which the O-C-O keeps a nearly linear structure.


Descriptive Epidemiology of Musculoskeletal Injuries in the Army 101st Airborne (Air Assault) Division.
The purpose of this study was to describe the epidemiology of musculoskeletal injuries among Soldiers of the 101st Airborne (Air Assault) Division. A total of 451 subjects (age: 27.6 ± 6.2 years, gender: males 395/451 = 87.6%) volunteered. Musculoskeletal injury data were extracted from subjects' medical charts and injuries that occurred during 1 year were described. Injury frequency, injury anatomic location and sublocation, injury cause, activity when injury occurred, and injury type were described. Injury frequency was 29.5 injuries per 100 subjects per year. Most injures affected the lower extremity (60.2% of injuries) and common anatomic sublocations for injuries were the ankle (17.3%) and knee (15.0%). Frequent causes of injuries were running (13.5%) and direct trauma (9.0%). Physical training was associated with 29.3% of the injuries. A majority of injuries were classified as pain/spasm/ache (29.3%), without further elucidation of pathology. Other frequent injury types were sprain (21.8%) and strain (14.3%). The descriptive epidemiology of musculoskeletal injuries in this population underscores the need to explore the modifiable risk factors of potentially preventable lower extremity injuries associated with physical training and running. There is scope for the development of an optimized and targeted physical training program for injury prevention in this population.


Thyroid metastases from renal cell carcinoma: review of the literature.
The thyroid gland is a rare site of clinically detectable tumor metastasis and kidneys are frequently the site of the parent malignancy. In the present review on thyroid metastases from renal cell carcinoma, cases were searched on PubMed by entering the strings: "renal carcinoma [or "hypernephroma"] AND thyroid metastasis/metastases". Thus, we retrieved a total of 111 cases that were published between 1964 and 2007, a total that became 113 by adding two patients observed by us. The female to male ratio was 1.35:1. The primary renal cancer was almost always unilateral (90%) (with no significant side preference) and only rarely bilateral (9% in men, 4% in women), whereas bilaterality of thyroid metastases was relatively more frequent (28%). Thyroid metastasis from renal cancer was commonly single with a unique node that appears solid and hypoechoic at ultrasonography, approximately 9 years after nephrectomy. Concordance of lateralization was insignificantly greater for the right kidney/right thyroid lobe pattern (54%) than for the left kidney/left thyroid lobe pattern (40%), regardless of gender. Finally, survival was longer for women. Thyroid metastases, even if rare in the clinical practice, must be considered in the differential diagnosis of a thyroid nodule, particularly in patients who have a history of malignancies.


Singlet fission in chiral carbon nanotubes: Density functional theory based computation.
Singlet fission (SF) process, where a singlet exciton decays into a pair of spin one exciton states which are in the total spin singlet state, is one of the possible channels for multiple exciton generation (MEG). In chiral single-wall carbon nanotubes (SWCNTs), efficient SF is present within the solar spectrum energy range which is shown by the many-body perturbation theory calculations based on the density functional theory simulations. We calculate SF exciton-to-biexciton decay rates R1→2 and biexciton-to-exciton rates R2→1 in the (6,2), (6,5), (10,5) SWCNTs, and in the (6,2) SWCNT functionalized with Cl atoms. Within the solar energy range, we predict R1→2∼1014-1015 s-1, while biexciton-to-exciton recombination is weak with R2→1∕R1→2≤10-2. SF MEG strength in pristine SWCNTs varies strongly with the excitation energy, which is due to highly non-uniform density of states at low energy. However, our results for the (6,2) SWCNT with chlorine atoms adsorbed to the surface suggest that MEG in the chiral SWCNTs can be enhanced by altering the low-energy electronic states via surface functionalization.


[Lumbosacral lipomas with spina bifida. Anatomo-clinical correlations. Therapeutic results].
From 1971 to 1982, the authors saw 41 patients who presented lumbo sacral lipomas with spina bifida; 9 remained outpatients and had regular clinical follow up; the other 32 were operated on; 1 was lost sight of, shortly after the operation. 40 patients were then regularly followed; of these, 15 (37%) developed neurological deficits (14 before and 1 long after surgery). Intraspinal lipomas were classified into 2 groups: group I (18 cases), when the lipomas displaced but did not include the lumbo sacral roots; group II (14 cases) when it included most or all of these roots. Despite an inevitably less satisfactory liberation of the spinal cord in the group II, post operative results were not significantly different in the 2 groups. Comparing the post operative results of this series to others in the literature, the authors come to the following 3 conclusions: 1) these operations are benign; 2) they are all the more effective when the neurological deficits are either recent or evolutive, and 3) they protect most of the patients from eventual neurological deterioration. Therefore the authors agree that patients with lumbo sacral lipomas should be operated on at the onset of neurological deficits but also recommend early intervention, even in the absence of any neurological disturbance.


Are individuals' nighttime sleep characteristics prior to shift-work exposure predictive for parameters of daytime sleep after commencing shift work?
This study aimed to examine prospectively whether individual nighttime sleep characteristics at baseline (prior to shift-work exposure) are related to parameters of daytime sleep after commencing shift work. A longitudinal field study was carried out with novice police officers of the Dutch Police Force. A total of 26 subjects were examined at baseline before they entered shift work and re-examined during follow-up sessions after four and twelve months of shift-work exposure. Wrist actigraphy and sleep diaries were used to study nocturnal sleep at baseline and daytime sleep after night shifts during follow-up sessions. As outcome variables, estimated total sleep time, sleep efficiency, and subjective sleep quality were analyzed. Daytime total sleep time showed a 66 min decline during the first year of shift-work exposure. Systematic inter-individual differences were observed for daytime total sleep time and subjective sleep quality (explaining 53% and 38% of the variance, respectively), suggesting potential predictability of these sleep parameters. Although no predictors were found for daytime total sleep time, the subjective quality of nighttime sleep before the onset of shift work predicted 40% of the variance in the subjective quality of daytime sleep after commencing shift work. Follow-up studies may reveal whether the subjective quality of baseline nighttime sleep also predicts long-term overall tolerance for shift work.


The influence of the dentist upon dimensional change and creep of amalgam.
A laboratory study showed insignificant effect on dimensional change was brought about by the operator's skill, packing technique employed, and alloy. However, creep was significantly affected by the operator's skill and the type of alloy.


Modulation of Neuronal Survival Factor MEF2 by Kinases in Parkinson's Disease.
Parkinson's disease (PD) is the second most common neurodegenerative disorder due to selective death of neurons in the substantia nigra pars compacta. The cause of cell death remains largely unknown. Myocyte enhancer factor 2 (MEF2) is a group of transcriptional factors required to regulate neuronal development, synaptic plasticity, as well as survival. Recent studies show that MEF2 functions are regulated in multiple subcellular organelles and suggest that dysregulation of MEF2 plays essential roles in the pathogenesis of PD. Many kinases associated with transcription, translation, protein misfolding, autophagy, and cellular energy homeostasis are involved in the neurodegenerative process. Following the first demonstration that mitogen-activated protein kinase p38 (p38 MAPK) directly phosphorylates and activates MEF2 to promote neuronal survival, several other kinase regulators of MEF2s have been identified. These include protein kinase A and extracellular signal regulated kinase 5 as positive MEF2 regulators, and cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β as negative regulators in response to diverse toxic signals relevant to PD. It is clear that MEF2 has emerged as a key point where survival and death signals converge to exert their regulatory effects, and dysregulation of MEF2 function in multiple subcellular organelles may underlie PD pathogenesis. Moreover, several other kinases such as leucine-rich repeat kinase 2 and PTEN-induced putative kinase 1 (PINK1) are of particular interest due to their potential interaction with MEF2.


Primary central nervous system lymphoma in Miyazaki, southwestern Japan, a human T-lymphotropic virus Type-1 (HTLV-1)-endemic area: clinicopathological review of 31 cases.
Primary central nervous system lymphoma (PCNSL) is a rare and aggressive brain tumor. The aim of this study was to clarify the prevalence of T-cell-type PCNSL (T-PCNSL) in a human T-lymphotropic virus type-1 (HTLV-1)-endemic area of Southwestern Japan. We retrospectively investigated 31 PCNSL cases diagnosed between 1996 and 2013 at the University of Miyazaki Hospital. These cases accounted for 4.4% of all nodal or extranodal malignant lymphomas. Histologically, most of these cases were diagnosed as diffuse large B-cell lymphoma, while only two cases were considered to be low-grade and high-grade B-cell lymphoma (not otherwise specified). No T-PCNSL was found in this series. In addition, Epstein-Barr virus-encoded RNAs were not detected by in situ hybridization in any of the cases. Overall, no T-PCNSL cases were found in 18 years in a region with a high frequency of HTLV-1 seropositivity, namely, Southwestern Japan. This suggests that PCNSL and lymphomas of other anatomical sites are biologically distinct.


Simulation of multimode optical fibers using the angular spectrum algorithm and a Fourier analysis.
Multimode optical fibers are gaining increased interest for higher data rate transmissions. In this work, we examine the propagation of beams in multimode optical fibers using the angular spectrum method for several values for the propagation constant V. We prepare a sequence of 4096 images over 200,000 steps, each representing a wavelength within the fiber. We perform a one-dimensional Fourier transform of these data and obtain the propagation constant for each transmitted mode. We then obtain the electric field profile for each transmitted mode. We find excellent agreement with weakly guided mode theory. This work represents another step in the use of this algorithm for analyzing more complicated optical fiber structures.


Anti-hypoxic effect of indomethacin and its interaction with prostacyclin.
The anti-hypoxic effect of indomethacin (1-10 mg/kg) was studied using the following experimental methods: asphyxic anoxia in cats, hypobaric and anoxic hypoxia in mice, incomplete ischemia by bilateral carotid occlusion and hemic hypoxia in rats. In hypobaric and anoxic hypoxia the interaction of indomethacin with the effect of prostacyclin (PCl2) was investigated. Indomethacin showed an anti-hypoxic effect in all the methods used: it enhanced anoxia resistance index in asphyxic anoxia and significantly increased survival of rats and mice subjected to experimental hypoxia. Indomethacin potentiated the effect of PGl2, shifting the anti-hypoxic dose-response curve of PGl2 to the left. The possible mechanism of action of indomethacin in relation to cyclo-oxygenase inhibition is discussed.


Review: Environmental impact on ocular surface disorders: Possible epigenetic mechanism modulation and potential biomarkers.
Throughout life, external and the internal environments interact in normal development and tissue homeostasis as well as in onset of disease. Epigenetic modifications occur in response to environmental changes and play a fundamental role in controlling gene expression without modification of the DNA base sequence. Aging, inflammation, drugs, infections and ultraviolet exposure may have profound effects on epigenetic modifications and trigger susceptibility to diseases. Increasing evidence has demonstrated that epigenetic mechanisms play a key role in regulating the physiopathology of the ocular surface. The evaluation of epigenetic factors in ocular disease would lead to further investigation regarding the potential use of therapeutic targets and diagnostic biomarkers. This review examines specific epigenetic and biochemical mechanisms that may occur in the ocular surface microenvironment. Potential correlation between epigenetic factors and targets should be considered in future approaches to prevention and/or treatment of specific ocular surface disorders.


Taking chances and making mistakes: non-genetic phenotypic heterogeneity and its consequences for surviving in dynamic environments.
Natural selection has shaped the strategies for survival and growth of microorganisms. The success of microorganisms depends not only on slow evolutionary tuning but also on the ability to adapt to unpredictable changes in their environment. In principle, adaptive strategies range from purely deterministic mechanisms to those that exploit the randomness intrinsic to many cellular and molecular processes. Depending on the environment and selective pressures, particular strategies can lie somewhere along this continuum. In recent years, non-genetic cell-to-cell differences have received a lot of attention, not least because of their potential impact on the ability of microbial populations to survive in dynamic environments. Using several examples, we describe the origins of spontaneous and induced mechanisms of phenotypic adaptation. We identify some of the commonalities of these examples and consider the potential role of chance and constraints in microbial phenotypic adaptation.


Defining genes using "blueprint" versus "instruction" metaphors: effects for genetic determinism, response efficacy, and perceived control.
Evidence supports mixed attributions aligned with personal and/or clinical control and gene expression for health in this era of genomic science and health care. We consider variance in these attributions and possible relationships to individual mind sets associated with essentialist beliefs that genes determine health versus threat beliefs that genes increase susceptibility for disease and severity linked to gene-environment interactions. Further, we contribute to theory and empirical research to evaluate the use of metaphors to define genes. Participants (N = 324) read a message that varied the introduction by providing a definition of genes that used either an "instruction" metaphor or a "blueprint" metaphor. The "instruction" metaphor compared to the "blueprint" metaphor promoted stronger threat perceptions, which aligned with both belief in the response efficacy of genetic research for health and perceived behavioral control linked to genes and health. The "blueprint" metaphor compared to the "instruction" metaphor promoted stronger essentialist beliefs, which aligned with more intense positive regard for the efficacy of genetic research and human health. Implications for health communicators include societal effects aligned with stigma and discrimination that such findings portend.


Dynamic trajectory of multiple single-unit activity during working memory task in rats.
Working memory plays an important role in complex cognitive tasks. A popular theoretical view is that transient properties of neuronal dynamics underlie cognitive processing. The question raised here as to how the transient dynamics evolve in working memory. To address this issue, we investigated the multiple single-unit activity dynamics in rat medial prefrontal cortex (mPFC) during a Y-maze working memory task. The approach worked by reconstructing state space from delays of the original single-unit firing rate variables, which were further analyzed using kernel principal component analysis (KPCA). Then the neural trajectories were obtained to visualize the multiple single-unit activity. Furthermore, the maximal Lyapunov exponent (MLE) was calculated to quantitatively evaluate the neural trajectories during the working memory task. The results showed that the neuronal activity produced stable and reproducible neural trajectories in the correct trials while showed irregular trajectories in the incorrect trials, which may establish a link between the neurocognitive process and behavioral performance in working memory. The MLEs significantly increased during working memory in the correctly performed trials, indicating an increased divergence of the neural trajectories. In the incorrect trials, the MLEs were nearly zero and remained unchanged during the task. Taken together, the trial-specific neural trajectory provides an effective way to track the instantaneous state of the neuronal population during the working memory task and offers valuable insights into working memory function. The MLE describes the changes of neural dynamics in working memory and may reflect different neuronal population states in working memory.


Ceramide compensation by ceramide synthases preserves retinal function and structure in a retinal dystrophy mouse model.
Increasing evidence has supported the role of ceramide as a mediator of photoreceptor dysfunction or cell death in ceramide accumulation and deficiency contexts. TLCD3B, a non-canonical ceramide synthase, was previously identified in addition to the six canonical ceramide synthases (CerSs), and the Tlcd3b-/- mouse model exhibited both retinal dysfunction and degeneration. As previous canonical CerS-deficient mouse models failed to display retinal degeneration, the mechanisms of how TLCD3B interacts with CerSs have not been investigated. Additionally, as the ceramide profile of each CerS is distinct, it is unclear whether the overall level or the homeostasis of different ceramide species plays a critical role in photoreceptor degeneration. Interactions between TLCD3B with canonical CerSs expressed in the retina were examined by subretinally injecting recombinant adeno-associated virus 8 vectors containing the Cers2 (rAAV8-CerS2), Cers4 (rAAV8-CerS4) and Cers5 (rAAV8-CerS5) genes. Injection of all three rAAV8-CerS vectors restored retinal functions as indicated by improved electroretinogram responses, but only rAAV8-CerS5 successfully retained retinal morphology in Tlcd3b-/- mice. CerSs and TLCD3B played partially redundant roles. Additionally, rather than acting as an integral entity, different ceramide species had different impacts on retinal cells, suggesting that the maintenance of the overall ceramide profile is critical for retinal function.


Structural, functional, and molecular MR imaging of the microvasculature.
Magnetic resonance imaging (MRI) is widely applied for functional imaging of the microcirculation and for functional and structural studies of the microvasculature. The interest in the capabilities of MRI in noninvasively monitoring changes in vascular structure and function expanded over the past years, with specific efforts directed toward the development of novel imaging methods for quantification of angiogenesis. Molecular imaging approaches hold promise for further expansion of the ability to characterize the microvasculature. Exciting applications for MRI are emerging in the study of the biology of microvessels and in the evaluation of potential pharmaceutical modulators of vascular function and development, and preclinical MRI tools can serve for the design of mechanism-of-action-based noninvasive clinical methods for monitoring response to therapy. The aim of this review is to provide a current snapshot of recent developments in this rapidly evolving field.


Influence of Cl- on organic anion transport in short-term cultured rat hepatocytes and isolated perfused rat liver.
Transport of 35S-labeled sulfobromophthalein [35S]BSP was studied in short-term cultured rat hepatocytes incubated in bovine serum albumin. At 37 degrees C, initial uptake of [35S]BSP was 5-10-fold that at 4 degrees C, linear for at least 15 min, saturable, inhibited by bilirubin, and reduced by greater than 70% after ATP depletion or isosmotic substitution of sucrose for NaCl in medium. Replacement of Na+ by K+ or Li+ did not alter uptake, whereas replacement of Cl- by HCO-3 or gluconate- reduced uptake by approximately 40%. Substitution of Cl- by the more permeant NO-3 enhanced initial BSP uptake by 30%. Efflux of [35S]BSP from cells to media was inhibited by 40% after ATP depletion or sucrose substitution. To confirm these results in a more physiologic system, transport of [3H]bilirubin was studied in isolated livers perfused with control medium or medium in which Cl- was replaced by gluconate-. Perfusion data analyzed by the model of Goresky, revealed 40-50% reductions in influx and efflux with gluconate- substitution. These results are consistent with existence of a Cl-/organic anion-exchange mechanism similar to that described by others in renal tubules.


Laparoscopy and laparotomy for patients with transverse colon cancer: comparative analysis of short-term surgical outcomes.
To compare the efficacy of laparoscopy versus laparotomy in the treatment of transverse colon cancer. Data from 100 patients with transverse colon cancer treated in our hospital from January 2018 to December 2020 were retrospectively analyzed in this study. According to the treatment methods, these patients were assigned into two groups: a laparotomy group (n=50) and a laparoscopy group (n=50). The intraoperative parameters, postoperative recovery, incidences of complications, postoperative pain, quality of life (QoL) score, postoperative serum inflammatory cytokine (hs-CRP, TNF-α, and IL-6) levels, and prognostic nutritional index (PNI) were analyzed and compared between the two groups. There was no significant difference in number of resected lymph nodes between the two groups. The operation time and intraoperative bleeding in the laparoscopy group were significantly less than those in the laparotomy group (P<0.05). The hospital stay, duration of gastrointestinal function recovery, and time of first postoperative flatus in the laparoscopy group were significantly shorter than those in the laparotomy group (all P<0.001). Moreover, the incidence of overall complications in the laparoscopy group was significantly lower than that in the laparotomy group (P<0.05). Compared with those in the laparotomy group, the VAS score was obviously lower and the QoL score was significantly higher in the laparoscopy group (all P<0.001). Patients in the laparoscopy group exhibited lower levels of postoperative hs-CRP, TNF-α and IL-6 in contrast to those in the laparotomy group (P<0.05). In additional, there was no significant difference in the PNI level before surgery between two groups. After surgery, the PNI level in the laparoscopy group was obviously higher than that in the laparotomy group (P<0.001). Laparoscopy is superior to laparotomy in treatment of transverse colon cancer through achieving better intraoperative outcomes, promoting postoperative recovery, reducing the incidence of complications and inflammatory reactions, alleviating postoperative pain, and improving therapeutic effects.


Fukuyama congenital muscular dystrophy: a neuroradiologic review.
We reviewed neuroradiologic findings of Fukuyama congenital muscular dystrophy (FCMD) and correlated them with the known neuropathology. All patients showed thick and bumpy cortices with shallow sulci corresponding to polymicrogyria, and approximately half of the patients showed pachygyric cortex with smooth surface corresponding to type II lissencephaly. The two types of cortical dysplasias presented characteristic distributions: the former demonstrated frontal lobe involvement in all and parietotemporal lobe involvement in some, whereas the latter involved the temporo-occipital lobes. Most patients showed prolonged T1 and T2 signal in the white matter, which was indistinct in neonates and infrequently seen in adolescents. Cerebellar polymicrogyria depicted as disorganized cerebellar foliation accompanying cysts were found more than 90% of the patients. In conclusion, brain MRI demonstrates findings consistent with the known neuropathology of FCMD. The detection of the two types of cerebral cortical dysplasia with characteristic distribution and cerebellar abnormalities is helpful in the differential and early diagnosis.


Swine Enteric Coronaviruses (PEDV, TGEV, and PDCoV) Induce Divergent Interferon-Stimulated Gene Responses and Antigen Presentation in Porcine Intestinal Enteroids.
Swine enteric coronaviruses (SECoVs) including porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), and porcine deltacoronavirus (PDCoV), account for the majority of lethal watery diarrhea in neonatal pigs and pose significant economic and public health burdens in the world. While the three SECoVs primarily infect intestinal epithelia in vivo and cause similar clinical signs, there are evident discrepancies in their cellular tropism and pathogenicity. However, the underlying mechanisms to cause the differences remain unclear. Herein, we employed porcine enteroids that are a physiologically relevant model of the intestine to assess the host epithelial responses following infection with the three SECoVs (PEDV, TGEV, and PDCoV). Although SECoVs replicated similarly in jejunal enteroids, a parallel comparison of transcriptomics datasets uncovered that PEDV and TGEV infection induced similar transcriptional profiles and exhibited a more pronounced response with more differentially expressed genes (DEGs) in jejunal enteroids compared with PDCoV infection. Notably, TGEV and PDCoV induced high levels of type I and III IFNs and IFN-stimulated gene (ISG) responses, while PEDV displayed a delayed peak and elicited a much lesser extent of IFN responses. Furthermore, TGEV and PDCoV instead of PEDV elicited a substantial upregulation of antigen-presentation genes and T cell-recruiting chemokines in enteroids. Mechanistically, we demonstrated that IFNs treatment markedly elevated the expression of NOD-like receptor (NLR) family NLRC5 and major histocompatibility complex class I (MHC-I) molecules. Together, our results indicate unique and common viral strategies for manipulating the global IFN responses and antigen presentation utilized by SECoVs, which help us a better understanding of host-SECoVs interactions.


Absence of differentiation-related expression of keratin 10 in early stages of vulvar squamous carcinoma.
Using specific monoclonal antibodies (DE-K10 and DE-SCK respectively), the expression of some differentiation-related epidermal keratins was studied in 38 human vulvar squamous carcinomas. In the epidermis, expression of keratin 10 (K10) strictly paralleled the extent of differentiation; it was absent in the basal layer, appeared in the first suprabasal layers and increased in concentration towards the granular layer. However, K10 was rarely detected (1 case out of 12) in early stages of vulvar squamous carcinomas (tumours less than 2 cm, clinical stage I) regardless of the tumour grade. In larger and more advanced tumours (greater than 2 cm, clinical stages II and III), K10 was detected in 21 out of 26 cases. Its expression appeared to be related to maturation of malignant keratinocytes, being preferentially detected in more-differentiated parts. Occasionally however, cells that did not show histological signs of keratinisation were also K10-positive. Modified stratum corneum keratins (recognized specifically by monoclonal antibody DE-SCK) were detected in the most keratinized areas (horn pearls and their close vicinity) of some K10-positive tumours, i.e., in a pattern close to their normal expression in terminally differentiated epidermal cells. These data suggest differences in the regulation of K10 expression during the differentiation processes in the normal keratinising squamous epithelium and in squamous carcinomas. While the normal pattern of vulvar epithelial differentiation is accompanied by an increasing expression of K10, malignant keratinocytes, also when these are histologically moderately or well differentiated, cease expressing this keratin in the early stages of tumour development.


Perinatal exposure to ethanol in rats induces permanent disturbances of breathing and chemosensitivity during adulthood.
Perinatal exposure to drugs of abuse, including alcohol (ethanol), is known to impinge the development of respiratory function. However, most studies described the short-term effects of these exposures, focusing mostly on the early postnatal life. After exposure to ethanol during gestation and lactation we have previously shown that 3-4 week-old rat exhibit chronic hypoventilation and an altered response to hypoxia at the end of ethanol exposure. However, whether these deficits are reversible following ethanol withdrawal remained unknown. Here, we investigated through whole-body plethysmography the respiratory activity of 2 months-old rats exposed to ethanol from gestation to weaning followed by one month of ethanol withdrawal. After ethanol withdrawal, rats persistently exhibited a significant reduction in respiratory frequency without change in tidal volume associated to a lower arterial blood oxygen content. In addition, the response to hypoxia in these rats was reduced whereas the response to hypercapnia remained unaltered. In conclusion perinatal exposure to ethanol in rats, unlike exposure to cocaine, morphine or nicotine, is characterized by selective alterations of basal respiratory activity and chemosensitivity that persist long after withdrawal.


Comparison of Home-Based Oral Fluid Rapid HIV Self-Testing Versus Mail-in Blood Sample Collection or Medical/Community HIV Testing By Young Adult Black, Hispanic, and White MSM: Results from a Randomized Trial.
We aimed to determine in a randomized trial if young adult black, Hispanic, and white men-who-have-sex-with-men (YMSM) are more likely to complete home-based oral fluid rapid HIV self-testing than either mail-in blood sample collection or medical facility/community organization-based HIV testing. Stratified by race/ethnicity, participants were randomly assigned to use a free oral fluid rapid HIV self-test (n = 142), a free mail-in blood sample collection HIV test (n = 142), or be tested at a medical facility/community organization of their choice (n = 141). Of the 425 participants, completion of assigned test (66% oral fluid vs. 40% mail-in blood sample vs. 56% medical facility/community), willingness to refer (36% oral fluid vs. 20% mail-in blood sample vs. 26% medical facility/community), and legitimate referrals (58% oral fluid vs. 43% mail-in blood sample vs. 43% medical facility/community) were greater in the oral fluid rapid HIV self-test than the mail-in blood sample collection HIV test arm, but not the medical facility/community testing arm. There were no differences in assigned test completion by race/ethnicity. Although free home-based oral fluid rapid HIV self-testing showed moderate promise in facilitating HIV testing among black, Hispanic, and white YMSM, it did not lead to greater testing than directing these YMSM to medical facility/community HIV testing venues. ClinicalTrials.gov Identifier: NCT02369627.


[Biologic therapy in idiopathic inflammatory myopathy].
The aim of this article is to study the evidence-based knowledge related to the use of biological therapies in patients diagnosed with idiopathic inflammatory myopathy (dermatomyositis, polymyositis and inclusion body myositis). In this review the leading published studies related to the use of biological therapy in patients with myositis are analysed; mainly those with high methodological standards, that means randomized and controlled studies. Methodological drawbacks due to the rarity and heterogeneity of these complex diseases are also addressed. Up to now is not possible to ascertain the biologics as a recommended therapy in patients with myositis, at least based in the current evidence-based knowledge, although it can not be neglected as a therapeutic option in some clinical situations, taking into account the scarce of effective treatments in those patients, especially in refractory myositis. Future studies probably will help to better define the role of biological therapies in patients with idiopathic inflammatory myopathy.


Bradykinin antagonists as anti-cancer agents.
The nonapeptide bradykinin is an important growth factor for many cancers. Certain peptide and non-peptide bradykinin antagonists show remarkable anti-cancer activities in both in vitro and in vivo cancer models, especially of lung and prostate cancers. Bradykinin antagonists stimulate apoptosis in cancers by a novel "biased agonist" mechanism: they block intracellular increase of calcium concentration but stimulate the MAP kinase pathway. This unbalanced effect stimulates caspase activation. In nude mouse xenotransplants of lung and prostate cancers the antagonists inhibit angiogenesis and activation of membrane metalloproteases (MMP 2 and 9). In the xenotransplants certain bradykinin antagonists showed higher potency than standard anti-cancer drugs, without evident toxicity to the hosts. These compounds offer great promise for development of new anti-cancer drugs.


Phylogenetic and Genomic Characterization of Whole Genome Sequences of Ocular Herpes Simplex Virus Type 1 Isolates Identifies Possible Virulence Determinants in Humans.
There are limited data on the prevalence and genetic diversity of herpes simplex virus type 1 (HSV-1) virulence genes in ocular isolates. Here, we sequenced 36 HSV-1 ocular isolates, collected by the Bascom Palmer Eye Institute, a university-based eye hospital, from three different ocular anatomical sites (conjunctiva, cornea, and eyelid) and carried out a genomic and phylogenetic analyses. The PacBio Sequel II long read platform was used for genome sequencing. Phylogenetic analysis and genomic analysis were performed to help better understand genetic variability among common virulence genes in ocular herpetic disease. A phylogenetic network generated using the genome sequences of the 36 Bascom Palmer ocular isolates, plus 174 additional strains showed that ocular isolates do not group together phylogenetically. Analysis of the thymidine kinase and DNA polymerase protein sequences from the Bascom Palmer isolates showed multiple novel single nucleotide polymorphisms, but only one, BP-K14 encoded a known thymidine kinase acyclovir resistance mutation. An analysis of the multiple sequence alignment comprising the 51 total ocular isolates versus 159 nonocular strains detected several possible single nucleotide polymorphisms in HSV-1 genes that were found significantly more often in the ocular isolates. These genes included UL6, gM, VP19c, VHS, gC, VP11/12, and gG. There does not seem to be a specific genetic feature of viruses causing ocular infection. The identification of novel and common recurrent polymorphisms may help to understand the drivers of herpetic pathogenicity and specific factors that may influence the virulence of ocular disease.