Concurrent validity of neuropsychiatric subgroups on caregiver burden in Alzheimer disease patients.
In a previously published study, the authors conceptualized neuropsychiatric symptoms in Alzheimer disease (AD) patients as distinct symptom profiles with differential outcomes. In the present study, our aim was to further examine the validation of the classification by considering its concurrent validity on caregiver burden. As described previously, neuropsychiatric symptoms, as assessed by the Neuropsychiatric Inventory, in 122 patients with AD were categorized, using cluster analysis. The presence as well as the severity and frequency of symptoms were both used in the classification. After the classification, group differences in caregiver burden, as measured by Screen for Caregiver Burden, were tested using analysis of covariance. The effects of important covariates, such as functional impairment, comorbid medical conditions, parkinsonism, age, and cognitive functioning, were examined. Based on the presence of symptoms, subgroups differed in the level of caregiver distress in that caregivers of the "minimally symptomatic" and the "affective/apathetic" subgroups experienced less distress than the caregivers of the "highly symptomatic" subgroup. Based on the severity and frequency of symptoms, subgroups differed in such a way that caregivers of the "minimally symptomatic" and the "predominantly apathetic" subgroups endorsed less distress than the caregivers of the "affective" and the "highly symptomatic" subgroups. Neuropsychiatric subgroups were able to differentially predict caregiver burden. The findings appear to lend further support to the validity of classifying neuropsychiatric symptoms in AD patients using cluster analysis.


Dalhousie Pictorial Scales Measuring Dyspnea and Perceived Exertion during Exercise for Children and Adolescents.
Alternative scales to measure dyspnea and perceived exertion have been sought due to concerns regarding understanding and validity of any Borg scale in pediatric populations. To demonstrate content validity of Dalhousie Dyspnea and Perceived Exertion Scales developed for children and adolescents. We obtained ratings for dyspnea and perceived exertion using both Borg CR-10 and Dalhousie Scales during incremental cycle exercise in 100 children and adolescents, healthy or with respiratory disease. Content validity was determined by correlating perceived leg exertion rating versus heart rate or %peak work capacity and dyspnea rating versus ventilation expressed as %peak ventilation. The stimulus-perceptual response was modeled as a quadratic function with a delay term. Reproducibility, cross-modality usage, and language effects were assessed in a small group of Italian children during treadmill exercise. Pictorial ratings of dyspnea and perceived exertion measured by both scale ratings rose as expected with increasing exercise intensity in children and adolescents, demonstrating excellent correlation between perceived leg exertion versus exercise intensity and dyspnea rating versus ventilation (median Spearman ρ ≥ 0.9) with either scale. There were no systematic differences in dyspnea or perceived exertion ratings between children with or without respiratory disease. Understandability and reproducibility of the Dalhousie scales was affirmed in Italian-speaking subjects performing treadmill exercise. Dalhousie Dyspnea and Perceived Exertion Scales offer an alternative to the Borg scale for use during exercise in pediatric subjects. Children and adolescents exhibit large variation in patterns of ratings of dyspnea and perceived exertion in incremental exercise.


Serum IgE levels are increased in patients with generalized pustular psoriasis.
Psoriasis is characterized by a T-helper (Th)1/Th17 immune response, and an increase in IgE levels is a prototypical marker of Th2 immunity. The aim of this retrospective case-control study was to analyse serum total IgE levels in generalized pustular psoriasis (GPP), a rare and severe variant of psoriasis. The levels of IgE in patients with GPP and patients with psoriasis vulgaris (PV) were compared with those of healthy controls. IgE levels were also compared with the levels of C-reactive protein (CRP), an indicator of systemic inflammation. The percentage of patients with GPP who had increased IgE levels was significantly higher than that of patients with PV and of healthy controls. The mean levels of IgE were also higher in the GPP group. The IgE levels in patients with GPP had a significant positive correlation with CRP levels. We hypothesize that serum IgE level is a general indicator for increased inflammation in GPP and PV.


Evaluation of some vitamin B-complex nutriture in Ile-Ife and environs (Nigeria).
A nutritional survey was conducted in two rural areas and in the urban city of Ile-Ife (Nigeria) to determine the nutritional status of the population with respect to thiamin, riboflavin and niacin intake. On basis of socio-economic groupings, most subjects in the rural areas were found to fall under relatively low to middle income, whereas in the urban areas the subjects were more evenly distributed between low and high income. Both the rural and urban communities were found to be deficient in thiamin intake but the intakes of riboflavin and niacin were adequate and they met the daily vitamin recommended intake. A small but insignificant difference was found between male and female vitamin intake in both the urban and the rural areas. In the overall, vitamin nutriture was found to be superior in the urban areas compared with the rural areas. Lack of education and proper environmental sanitation are contributing factors in this apparent deficiency.


The effect of biological effective dose on time to symptom progression in metastatic renal cell carcinoma.
Renal cell carcinoma is commonly thought to be a radioresistant malignancy. Retrospective studies report conflicting results on the effect of radiotherapy dose escalation on response and time to progression in symptomatic metastatic disease; studies using the linear quadratic model have used alpha/beta ratios that are inappropriate for slow growing tumours. We aim to describe our experience with palliative radiotherapy in this context, relating Biological Effective Dose to outcome. From December 1995 to April 2001, 143 independent palliative radiotherapy treatments were delivered to 78 patients in a single institution. Retrospective data was obtained on the radiotherapy schedule used, symptom response and time to symptom progression. The biological effective dose (BED) was calculated using alpha/beta ratios of 3 and 7 Gy (BED3 and BED7). The Log-Rank test was used to assess any differences in time to progression, and the Cox Proportional Hazards analysis to determine prognostic factors of time to progression. Overall symptomatic response rate was 73%, with most responses being partial (67%). Forty-three (38%) patients had symptomatic progression after a median follow-up of 425 days. BED (BED3 or BED7) was not significantly different across response types (complete, partial or no response; P=0.90 and 0.88, respectively) and was not predictive for time to symptomatic progression (P=0.99 for BED3 and P=0.70 for BED7). Patients with bone metastases received less total dose (P=0.001), less BED (BED3, P=0.0013, and BED7, P=0.0005) and had a significantly longer time to progression than other sites of metastases (hazard ratio (HR) 0.4; 95% confidence interval (CI) 0.2-0.7; P=0.004). Initial treatment with interferon-alpha alone in patients presenting with metastatic disease, before palliative radiotherapy, was also associated with a shorter time to symptom progression (HR 4.6; 95% CI 1.5-14.1; P=0.007). On removal of these criteria, brain metastases became a significant predictor of progression time, with an HR of 2.5 (95% CI 1.0-5.9; P=0.05), showing an increased risk of progression with brain metastases compared with metastases elsewhere. Time from primary diagnosis to development of metastatic disease was not predictive of time to symptom progression (P=0.29). Despite the widespread assumption that renal cell carcinoma is radioresistant, retrospective assessment showed high response rates to palliative radiotherapy. On the basis of our data, higher BED does not seem to be a predictor of response or of duration of response in the palliative treatment of renal cell carcinoma. Palliation of bone pain seems to be particularly durable compared with the palliation of symptoms at other sites of metastases. A trend for shorter duration of palliative effect of whole-brain radiotherapy was noted.


An 11-year review of levetiracetam ingestions in children less than 6 years of age.
Levetiracetam is a new anticonvulsant, which works to block high-voltage-activated Ca(++) channels in children, for partial-onset seizures. Reports of clinical experience with pediatric ingestions are minimal. The purpose of this study was to characterize the toxicity of accidental levetiracetam exposures in children less than 6 years of age. This was an 11-year retrospective observational case series of pediatric (< 6 years old) levetiracetam ingestions reported to a Poison Control System from 2002 to 2013. Case narratives were individually reviewed to collect desired information on exposure and clinical course. Inclusion criteria were levetiracetam as a single ingested medication, age less than 6 years, treatment in a health care facility, and followed to a known outcome. Eighty-two cases met inclusion criteria with 55% female patients and overall median age of 2.0 years (range: 1-60 months). The levetiracetam dose ingested was reported in 69 (84.1%) cases, with exact dose (median dose, 45.0 mg/kg; range, 10.5-1429 mg/kg) reported in 33 cases (40.2%). Of these, twenty-nine cases (88%) involved the oral solution formulation and 28 cases (85%) had unintentional therapeutic error as the cause of the exposure. No dose-response relationship was demonstrated; however, the odds of a levetiracetam-naive patient, (median dose, 26.9 mg/kg; N = 15) with an unintentional exposure, developing drowsiness or ataxia was 6 times that of a patient who was not naïve to levetiracetam (median dose, 70.1 mg/kg; N = 20) (Odds ratio [OR], 6.0; 95% confidence interval [CI], 1.03-35.91).Of the 82 cases, 17 (20.7%) developed untoward clinical effects of drowsiness and/or ataxia. Eighty patients (97.6%) were treated and discharged from the emergency department, and two patients (2.4%) were admitted. The two patients admitted included a two-month old who was accidentally given a dose 10 times that of her usual dose and a 3-year old who was lethargic on arrival to the hospital after ingestion of an unknown dose. Of all patients, 66 patients (80.5%) had no effect from the drug exposure. The medical outcome was considered to be minor in 15 cases (18.3%), and moderate in 1 case (1.2%). There were no cases with major outcomes and no deaths. Pediatric levetiracetam exposures were associated with few transient clinical effects. Poison Control Centers may wish to consider acuity of ingestion when developing send-in protocols.


Anorectal emergencies: WSES-AAST guidelines.
Anorectal emergencies comprise a wide variety of diseases that share common symptoms, i.e., anorectal pain or bleeding and might require immediate management. While most of the underlying conditions do not need inpatient management, some of them could be life-threatening and need prompt recognition and treatment. It is well known that an incorrect diagnosis is frequent for anorectal diseases and that a delayed diagnosis is related to an impaired outcome. This paper aims to improve the knowledge and the awareness on this specific topic and to provide a useful tool for every physician dealing with anorectal emergencies.The present guidelines have been developed according to the GRADE methodology. To create these guidelines, a panel of experts was designed and charged by the boards of the World Society of Emergency Surgery (WSES) and American Association for the Surgery of Trauma (AAST) to perform a systematic review of the available literature and to provide evidence-based statements with immediate practical application. All the statements were presented and discussed during the WSES-AAST-WJES Consensus Conference on Anorectal Emergencies, and for each statement, a consensus among the WSES-AAST panel of experts was reached. We structured our work into seven main topics to cover the entire management of patients with anorectal emergencies and to provide an up-to-date, easy-to-use tool that can help physicians and surgeons during the decision-making process.


Cerebral blood flow and oxygen uptake in endotoxic shock. An experimental study in dogs.
Cerebral blood flow (CBF), cerebral oxygen uptake (CMRO2) and central haemodynamics in anaesthetized dogs with controlled ventilation were studied at intervals for 2 h following an intravenous injection of E. coli endotoxin, 1.0-1.5 mg/kg. CBF showed a 30% decrease within 15 min after the endotoxin administration, while the arterial blood pressure was still not markedly depressed. Autoregulation to arterial blood pressure changes was maintained during endotoxinaemia and the cerebrovascular reaction to changes in arterial carbon dioxide tension (PaCO2) depressed. Normocapnic animals (PaCO2) greater than or equal to 4.0 kPa) showed an increase in CMRO2 of over 40%, that was obvious 1 h after the administration of endotoxin. The intracranial pressure was decreased with 5 min of the administration of endotoxin irrespective of the prevailing arterial blood pressure. Thereafter, it was raised above the control level. Two hours after endotoxin increased protein concentrations in cerebrospinal fluid were seen, results compatible with blood-brain barrier damage and penetration of other substances; e.g. monoamines released during endotoxinaemia could thus be expected to have a direct influence on both cerebral blood flow and metabolism.


A new species of terrestrial frog of the genus Noblella Barbour, 1930 (Amphibia: Strabomantidae) from the Llanganates-Sangay Ecological Corridor, Tungurahua, Ecuador.
We describe a new species of terrestrial frog of the genus Noblella from the eastern versants of the Ecuadorian Andes in the upper Pastaza watershed. Noblella naturetrekii sp. n. differs from its Ecuadorian congeners by the presence of a differentiated tympanic membrane and a weakly defined tympanic annulus, and eyelids with rounded tubercles. In addition, the new species is characterized by its blackish-dark brown ventral coloration scattered with little white dots and the absence of papillae at the tip of the fingers and toes. We provide a detailed description of the call and osteology of the new species. Finally, we present the most complete phylogeny of the genus, which confirms that Noblella is a non-monophyletic group.


Multiple cutaneous metastases: a rare and late sequelae of lacrimal gland adenoid cystic carcinoma.
Primary cutaneous adenoid cystic carcinoma (ACC) is an uncommon malignancy with approximately 60 cases reported in the literature. Metastatic ACC to the skin is even less frequent with eight previously published cases, including only one arising from the lacrimal gland. We report a case of a 61-year-old male, who developed multiple cutaneous metastases to the scalp and back from a lacrimal gland ACC 21 years after the initial diagnosis. Initially, in the absence of the past clinical history, the cutaneous lesions were interpreted as primary ACC of the skin. Histopathologically, the metastatic lesions were poorly circumscribed dermal and subcutaneous nodules that were composed of islands of basaloid epithelial cells with ducts and cribriform pattern, mucinous stroma and prominent perineural invasion. Histomorphologically, the cutaneous tumors were similar to the primary ACC. The cutaneous metastases were preceded by tumor dissemination to the lung and other visceral organs, and ultimately led to patient's demise. This report illustrates the importance of juditious clinico-pathologic correlation and raises awareness regarding prolonged latency of cutaneous metastases in patients with visceral ACC.


Childhood cross-gender behavior of homosexual females in Brazil, Peru, the Philippines, and the United States.
Heterosexual and homosexual females were interviewed with regard to childhood cross-gender behavior in Brazil, Peru, the Philippines, and the United States. Nine items were used to examine childhood behavior differences between heterosexual and homosexual females. Six of these items (playing with boys' toys, playing with girls' toys, dressing up in men's clothes, dressing up in women's clothes, paying attention to women's fashions, and being considered a tomboy) revealed statistically significant differences between the heterosexual and homosexual females. These differences demonstrated significant cross-cultural consistency, despite cultural variations among the societies examined. Rejection of certain gender-typical activities and interests, as well as involvement in cross-gendered activities and interests, seem to be consistent precursors of adult sexual orientation regardless of the cultural context in which these behaviors emerge.


[The principles of radiological quality assessment of water resources].
In the paper the main approaches to radiation safety of water objects have been analyzed. It is shown that radiation safety requirements for drinking water, fixed in the Rules and Regulations on radiation safety, do not ensure radiation safety of water objects used for the complex national economy needs. Application of the conservatism principle (choosing of the worst variant) for radiation safety ensuring is considered and proved. On the base of this principle the model is developed comparing the anthropocentric (sanitary--hygienic) with ecological (biota) principles for ensuring safety of water objects. It is proved, that the application of the Water Radiation Safety Rules currently in force, based on the norms of dose quotas, reserved for regulation of nuclear power plants and industry impact, ensures safety of the water ecological systems.


Intervertebral disk width in dogs with and without clinical signs of disk associated cervical spondylomyelopathy.
Disk-associated cervical spondylomyelopathy (DA-CSM) is a multifactorial neurological disorder in which progressive caudal cervical spinal cord compression is mainly caused by one or more intervertebral disk protrusions. The Doberman pinscher breed seems predisposed for this condition. The underlying cause and pathophysiology of DA-CSM are currently unknown. Recently, wider intervertebral disks have been put forward as a risk factor for development of clinically relevant DA-CSM. However, little is known about other factors affecting intervertebral disk width. Therefore the aim of this study was to assess the association between intervertebral disk width, measured on magnetic resonance imaging (MRI), and clinical status, age, gender and intervertebral disk location in dogs with and without clinical signs of DA-CSM. Doberman pinschers with clinical signs of DA-CSM (N=17),clinically normal Doberman pinschers (N=20), and clinically normal English Foxhounds (N=17), underwent MRI of the cervical vertebral column. On sagittal T2-weighted images, intervertebral disk width was measured from C2-C3 to C6-C7. Intra -and interobserver agreement were assessed on a subset of 20 of the 54 imaging studies. Intervertebral disk width was not significantly different between Doberman pinschers with clinical signs of DA-CSM, clinically normal Doberman pinschers or clinically normal English Foxhounds (p=0.43). Intervertebral disk width was positively associated with increasing age (p=0.029). Each monthly increase in age resulted in an increase of disk width by 0.0057 mm. Intervertebral disk width was not significantly affected by gender (p=0.056), but was significantly influenced by intervertebral disk location (p <0.0001). The assessed measurements were associated with a good intra -and interobserver agreement. The present study does not provide evidence that wider intervertebral disks are associated with clinical status in dogs with and without DA-CSM. Instead, it seems that cervical intervertebral disk width in dogs is positively associated with increase in age.


Rb inhibits the intrinsic kinase activity of TATA-binding protein-associated factor TAFII250.
The retinoblastoma tumor suppressor protein, Rb, interacts directly with the largest TATA-binding protein-associated factor, TAFII250, through multiple regions in each protein. To define the potential role(s) of this interaction, we examined whether Rb could regulate the intrinsic, bipartite kinase activity of TAFII250. Here, we report that Rb is able to inhibit the kinase activity of immunopurified and gel-purified recombinant TAFII250. Rb inhibits the autophosphorylation of TAFII250 as well as its phosphorylation of the RAP74 subunit of TFIIF in a dose-responsive manner. Inhibition of TAFII250 kinase activity involves the Rb pocket (amino acids 379 to 928) but not its amino terminus. In addition, Rb appears to specifically inhibit the amino-terminal kinase domain of TAFII250 through a direct protein-protein interaction. We further demonstrate that two different tumor-derived Rb pocket mutants, C706F and Deltaex22, are functionally defective for kinase inhibition, even though they are able to bind the amino terminus of TAFII250. Our results suggest a novel mechanism of transcriptional regulation by Rb, involving direct interaction with TAFII250 and inhibition of its ability to phosphorylate itself, RAP74, and possibly other targets.


Serial changes in sarcoplasmic reticulum gene expression in volume-overloaded cardiac hypertrophy in the rat: effect of an angiotensin II receptor antagonist.
This study was designed to clarify whether gene expression in the cardiac sarcoplasmic reticulum [sarcoplasmic reticulum Ca2+-ATPase (SERCA), phospholamban, ryanodine receptor and calsequestrin] changes in accordance with left ventricular functional alterations in the volume-overloaded heart. Further, the effect of the angiotensin II type 1 receptor antagonist, TCV-116, on the expression of these genes was also evaluated. Left ventricular fractional shortening was significantly increased at 7 days, had returned to control levels at 21 days, and had significantly decreased at 35 days after the shunt operation, compared with sham-operated rats. The level of SERCA mRNA was significantly decreased at both 21 days and 35 days after the shunt operation. The levels of ryanodine receptor and phospholamban mRNAs were significantly decreased at 35 days in shunt-operated rats. The decrease in the SERCA mRNA level preceded the development of cardiac dysfunction. The levels of SERCA and ryanodine receptor mRNAs were correlated positively with left ventricular fractional shortening (r=0.73, P<0.0001 and r=0.61, P<0.01 respectively). Attenuation of the decrease in left ventricular fractional shortening occurred on treatment with TCV-116. After the treatment with TCV-116, the levels of SERCA and phospholamban mRNAs were restored to the respective values in sham-operated rats. Ryanodine receptor mRNA levels remained unchanged after treatment with TCV-116. These results indicate that the down-regulation of SERCA and ryanodine receptor mRNA levels may be related to cardiac dysfunction in the volume-overloaded heart. In addition, treatment with an angiotensin II receptor antagonist may restore the altered sarcoplasmic reticulum mRNA levels to control levels, and this may result in attenuation of the functional impairment in the volume-overloaded heart.


[Real problems of conducting social-hygienic monitoring on railroads].
Sociohygienic monitoring on the railway transport, which is a branch part of the state sociohygienic monitoring system, includes observation, analysis, assessment, and prediction of the health status and habitat of railway workers and population to be served, as well as the establishment of associations of the health status with environmental factors. Standard legal, scientific-and-methodological, and organizational bases have been set up for branch monitoring. The basic parameters and the procedure for interaction of branch and territorial entities have been defined.


A luminescence-based assay for monitoring changes in alpha-synuclein aggregation in living cells.
Parkinson's disease is characterized by the accumulation of protein aggregates in the brain, termed Lewy bodies. Lewy bodies are predominantly composed of α-synuclein and mutations that increase the aggregation potential of α-synuclein have been associated with early on-set disease. Assays capable of reporting on the solubility of α-synuclein in living cells could provide a means to interrogate the influence of mutations on aggregation as well as identify small molecules capable of modulating the aggregation of α-synuclein. Herein, we repurpose our previously reported self-assembling NanoLuc luciferase fragments to engineer a platform for detecting α-synuclein solubility in living cells. This new assay is capable of reporting on changes in α-synuclein solubility caused by disease-relevant mutations as well as inhibitors of aggregation. In the long term, this new assay platform provides a means to investigate the influence of mutations on α-synuclein solubility as well as identify potential tool compounds capable of modulating α-synuclein aggregation.


Personal computers, medical slide files, and retrieval. An organized approach.
This discussion provides an organized, rational approach to filing, storage, and retrieval of a large medical photographic slide collection. Advantages of this approach include: minimal slide storage space, simple filing, rapid retrieval based on descriptive "key words" utilizing database software, inexpensive and readily available technology for users of personal computers, and reliable tracking of slides.


Frame semantics-based study of verbs across medical genres.
The field of medicine gathers actors with different levels of expertise. These actors must interact, although their mutual understanding is not always completely successful. We propose to study corpora (with high and low levels of expertise) in order to observe their specificities. More specifically, we perform a contrastive analysis of verbs, and of the syntactic and semantic features of their participants, based on the Frame Semantics framework and the methodology implemented in FrameNet. In order to achieve this, we use an existing medical terminology to automatically annotate the semantics classes of participants of verbs, which we assume are indicative of semantics roles. Our results indicate that verbs show similar or very close semantics in some contexts, while in other contexts they behave differently. These results are important for studying the understanding of medical information by patients and for improving the communication between patients and medical doctors.


Sodium, bicarbonate, and chloride absorption by the proximal tubule.
Proximal tubules are lined with epithelial cells that contain Na-K-ATPase in their basolateral cell membrane. The luminal cell membrane contains transport proteins that couple movement of many solutes to the active transport of sodium. The cells are connected by low-resistance junctional complexes that permit passive movement of solutes via a paracellular shunt pathway. Acidification is mediated by a Na/H antiporter localized specifically in the luminal membrane and a chloride-independent, voltage-dependent bicarbonate exit process in the basolateral membrane. The rate of acidification is controlled by the pH of the luminal and peritubular fluids. Reabsorption of NaCl from the high-chloride, low-bicarbonate fluid in the late proximal tubule is approximately 40% passive and 60% active. In proximal straight tubules the active component is entirely by simple rheogenic sodium transport, with chloride absorption driven through the paracellular shunt pathway by the lumen-negative PD. In convoluted tubules the active component is primarily neutral, with both sodium and chloride transported in approximately equivalent amounts through the cell. The mechanisms for neutral NaCl transport across the luminal membrane and for chloride exit across the basolateral membrane are unknown. A reduction in peritubular Starling forces (hydraulic and oncotic pressures) suppresses net proximal reabsorption by two mechanisms: 1) increased paracellular permeability with modest backleak of solutes (bicarbonate, glucose, amino acids) whose luminal concentration falls below their plasma level, and 2) specific inhibition of active neutral transcellular transport of NaCl by reduced peritubular protein concentration by some mechanism other than inhibition of Na-K-ATPase.


Invisible cloak design with controlled constitutive parameters and arbitrary shaped boundaries through Helmholtz's equation: comment.
In a recent paper, Chen et al. [Opt. Express 17, 3581 (2009)] develop an approach to design invisible cloaks with controllable constitutive parameters by adjusting the constant k in the Helmholtz's equation. In this comment, we discuss the limitation of the free parameter k in designing cloaks. It is found that the real constant k can be chosen only as limited values in order to avoid the singular material parameters.


Bone marrow stem cells for the treatment of ischemic heart disease: a clinical trial review.
Cardiovascular disease continues to represent a significant and growing source of morbidity and mortality despite advances in traditional treatments. As a result, increasing interest and research in regenerative therapies has emerged in recent years. Among them, cell therapy represents an area of significant potential. An expanding clinical literature now exists involving the use of bone marrow-derived stem cells in the treatment of ischemic heart disease. These early studies appear to provide promising results in patient populations that include those with refractory angina, ischemic cardiomyopathy with left ventricular dysfunction, and end-stage heart failure. This review serves to provide a comprehensive examination of these clinical trials focused on several components including cell preparation, cell delivery, safety, and efficacy of these trials.


Personal Neoantigen Cancer Vaccines: A Road Not Fully Paved.
Personal neoantigen-based cancer vaccines are designed to target antigens arising from tumor-specific mutations within individual cancers and present a tremendous opportunity to capitalize on their favorable and intrinsic properties of escape from central tolerance and exquisite tumor specificity. With the endpoint of creating an optimal T-cell army to attack a tumor, neoantigen-based vaccines have demonstrated the ability to coax naïve T-cell recruits against epitopes that do not induce spontaneous immunity to raise long-lasting T-cell responses against multiple tumor-specific epitopes and subsequently to extend the breadth of responses, as immunity begets immunity via epitope spreading. Importantly, on both preclinical and clinical fronts, the association of T-cell responses to neoantigens and favorable outcomes has been demonstrated time and time again. We recognize, however, that the path forward remains long and winding and requires the field to address several key challenges, particularly overcoming evolved tumor escape mechanisms and optimizing vaccine-induced immunity. Some challenges stem from gaps in science that enable in silico prediction of antigen presentation and recognition by T-cell receptors, whereas others stem from the logistical obstacles and cost of personalization. Nevertheless, with perseverance and innovative solutions, we have little doubt that the ability of neoantigen vaccination to induce potent cancer-specific T cells will fundamentally succeed in enabling greater effectiveness of a broad array of immunotherapies. We provide our perspective on the progress and the remaining challenges to realizing the opportunity of personal neoantigen cancer vaccines.


Superacid-doped polybenzimidazole-decorated carbon nanotubes: a novel high-performance proton exchange nanocomposite membrane.
Here we demonstrate design and electrochemical characterization of novel proton exchange membranes based on Nafion and superacid-doped polymer coated carbon nanotubes (CNTs). Polybenzimidazole-decorated CNT (PBI-CNT), a high-performance proton exchange nanostructure, was doped using phosphotungstic acid (PWA) as a super proton conductor. The engineered nanohybrid structure was shown to retain water molecules and provide high proton conduction at low humidity and elevated temperatures. The developed complex nanomaterial was then incorporated into the Nafion matrix to fabricate nanocomposite membranes. The acid-base interactions between imidazole groups of PBI and sulfonate groups of Nafion facilitate proton conductivity, especially at elevated temperatures. The improved characteristics of the membranes at the nanoscale result in enhanced fuel cell power generation capacity (386 mW cm(-2)) at elevated temperatures and low humidity (40% R.H.), which was found to be considerably higher than the commercial Nafion®117 membrane (73 mW cm(-2)).


Possible Quick-Clay Motion in Turbidity Currents.
Sensitive clay masses that lie dormant for years but, as the result of a sudden shock, become turbulent, flowing mud, have been called quick clays. Such masses may move in quantity over almost flat terrain, and they exhibit the power to transport buildings and other heavy objects considerable distances. On theoretical grounds it is proposed that one of the elements in the flowage of turbidity currents on the ocean floor may be comparable to quick-clay flowage on land. Both types of flowage cover considerable areas, may move on a comparatively flat base, exhibit fairly rapid motion, involve masses of colloidal-size clay and detritus, exhibit powerful transporting power, involve porous material of high water content, and are initiated by some form of trigger action. While experimental data are inadequate for proof, the parallelism in these two forms of erosional movement warrants the suggestion that the mobile mechanisms responsible for mass transport may be similar in the two cases.


The effect of substance P on the regional lymph node antibody response to antigenic stimulation in capsaicin-pretreated rats.
The undecapeptide substance P (SP) contained in primary afferent nerves is thought to mediate that part of the neurogenic inflammatory response consisting of vasodilation and plasma extravasation. This response is diminished in rats pretreated as neonates with the neurotoxin capsaicin. It is not known whether primary afferent nerves influence cellular responses of the immune response to antigenic stimulation. Using 6- to 12-wk-old Sprague-Dawley rats pretreated as neonates with capsaicin, we examined the regional lymph node response to a s.c. antigenic stimulus of sheep red blood cells. The number of cells secreting antigen-specific antibody in these animals was reduced by more than 80% using direct and indirect plaque assay methods. The reduced antibody response in capsaicin-pretreated animals was reversed by a s.c. infusion of SP given over a 4-hr period at the injection site immediately after antigen stimulation. This response had a threshold at approximately 1.0 X 10(-5) M SP. SP1-7 (1.0 X 10(-5) M) was without effect but an infusion of SP5-11 (1.0 X 10(-5) M) reversed the effects of capsaicin treatment indicating a carboxyl-terminal effect of SP. The results suggest that the reduced response of capsaicin-treated animals to an antigenic stimulus is due to an effect of capsaicin on the SP-containing primary afferent nerves rather than a toxic effect of capsaicin on the immune system.


Skin circulation of the frog, Rana catesbeiana: distribution and dynamics.
The volume and distribution of blood flow to the skin of the bullfrog, Rana catesbeiana, from both the pulmocutaneous and systemic arterial sources were measured. Radioactively labelled microspheres (35 +/- 5 micron) were used to map the regional distribution of each of these sources and to measure the systemic blood flow to the skin during air breathing and diving. Cutaneous artery blood flow was measured with an ultrasonic (Doppler) flowmeter. The systemic supply to the skin perfuses predominantly the limbs, while the largest cutaneous artery supply is to the back and flanks of the animal. All regions received blood from both sources. The cutaneous artery blood flow decreased during diving to approximately one-third of the pre-dive level. This decrease, however, was offset by an approximately equivalent increase in systemic blood flow to the skin during diving. These data should reconcile the decrease in pulmocutaneous blood flow and the important function of the skin as a gas exchanger during diving.


Genetic switch to hypervirulence reduces colonization phenotypes of the globally disseminated group A streptococcus M1T1 clone.
The recent resurgence of invasive group A streptococcal disease has been paralleled by the emergence of the M1T1 clone. Recently, invasive disease initiation has been linked to mutations in the covR/S 2-component regulator. We investigated whether a fitness cost is associated with the covS mutation that counterbalances hypervirulence. Wild-type M1T1 group A Streptococcus and an isogenic covS-mutant strain derived from animal passage were compared for adherence to human laryngeal epithelial cells, human keratinocytes, or fibronectin; biofilm formation; and binding to intact mouse skin. Targeted mutagenesis of capsule expression of both strains was performed for analysis of its unique contribution to the observed phenotypes. The covS-mutant bacteria showed reduced capacity to bind to epithelial cell layers as a consequence of increased capsule expression. The covS-mutant strain also had reduced capacity to bind fibronectin and to form biofilms on plastic and epithelial cell layers. A defect in skin adherence of the covS-mutant strain was demonstrated in a murine model. Reduced colonization capacity provides a potential explanation for why the covS mutation, which confers hypervirulence, has not become fixed in the globally disseminated M1T1 group A Streptococcus clone, but rather may arise anew under innate immune selection in individual patients.


Visualization of rapid electron precipitation via chorus element wave-particle interactions.
Chorus waves, among the most intense electromagnetic emissions in the Earth's magnetosphere, magnetized planets, and laboratory plasmas, play an important role in the acceleration and loss of energetic electrons in the plasma universe through resonant interactions with electrons. However, the spatial evolution of the electron resonant interactions with electromagnetic waves remains poorly understood owing to imaging difficulties. Here we provide a compelling visualization of chorus element wave-particle interactions in the Earth's magnetosphere. Through in-situ measurements of chorus waveforms with the Arase satellite and transient auroral flashes from electron precipitation events as detected by 100-Hz video sampling from the ground, Earth's aurora becomes a display for the resonant interactions. Our observations capture an asymmetric spatial development, correlated strongly with the amplitude variation of discrete chorus elements. This finding is not theoretically predicted but helps in understanding the rapid scattering processes of energetic electrons near the Earth and other magnetized planets.


Dopaminergic structure-activity relationships of 2-aminoindans and cardiovascular action and dopaminergic activity of 4-hydroxy, 5-methyl, 2-di-n-propylaminoindan (RD-211).
Dopaminergic structure-activity relationships of 2-aminoindans were evaluated for their ability to inhibit responses to stimulation of cardioaccelerator nerves in cats. The major observations were as follows: 1) Unsubstituted di-n-propyl- and diethyl 2-aminoindan derivatives do not inhibit responses to stimulation of cardioaccelerator nerve, although previous studies identified stimulation of DA2-receptors. 2) 4-Hydroxy, 4,7-dimethoxy and 4-hydroxy, 5-CH3, -CH2OH or -H substitutions on selected indan derivatives produce dopaminergic activity in the cardioaccelerator nerve preparation. 3) 4-Hydroxy-2-di-n-propylaminoindan is stereoselective with the R-isomer being more potent than the S-isomer. One derivative, 4-hydroxy-5-methyl-di-n-propyl-2-aminoindan (RD-211) produced dose-dependent decreases in heart rate and mean arterial pressure. Larger doses also inhibited cardiac responses to stimulation of cardioaccelerator nerve in vivo and in isolated right atria of cats. All of the above responses were significantly inhibited by the dopamine-receptor antagonist sulpiride and not by the alpha 2-adrenoceptor antagonist yohimbine. RD-211 also possesses high affinity for 5-hydroxytryptamine1A receptors as revealed by radioligand binding studies. Results suggest that RD-211 stimulates dopamine DA2-receptors and may also activate 5-hydroxytryptamine1A receptors, but is inactive at alpha 2-adrenoceptors. RD-211 appears not to require metabolic activation even though it has the same chemical moiety as the aminotetralin homolog, which is a dopaminergic prodrug (5-hydroxy-6-methyl-2-di-n-propylaminotetralin).


Motor impairments in children associated with impairments of speech or language: a meta-analytic review of research literature.
We investigated the co-occurrence of motor impairments in children with speech and language impairments. Three search strategies produced 16 studies that met the inclusion criteria for the meta-analysis. These 16 studies yielded 110 effect sizes (d). Heterogeneity was evaluated by obtaining Q and I-squared values. Children with speech and language impairments made more motor errors than children without impairments, with a statistically significant large effect size (d = 1.23, p < .001). Statistically significant medium effects between groups were found in terms of motor score (d = -0.61, p < .001) and motor time (d = 0.47, p < .001). Heterogeneity was statistically significant for all three measurements of motor abilities. Deficits in specific speech and language disorders were associated with motor impairments. This finding might be important for the development of daily living and academic skills in children with speech and language impairments.


Mycamoeba gemmipara nov. gen., nov. sp., the First Cultured Member of the Environmental Dermamoebidae Clade LKM74 and its Unusual Life Cycle.
Since the first environmental DNA surveys, entire groups of sequences called "environmental clades" did not have any cultured representative. LKM74 is an amoebozoan clade affiliated to Dermamoebidae, whose presence is pervasively reported in soil and freshwater. We obtained an isolate from soil that we assigned to LKM74 by molecular phylogeny, close related to freshwater clones. We described Mycamoeba gemmipara based on observations made with light- and transmission electron microscopy. It is an extremely small amoeba with typical lingulate shape. Unlike other Dermamoebidae, it lacked ornamentation on its cell membrane, and condensed chromatin formed characteristic patterns in the nucleus. M. gemmipara displayed a unique life cycle: trophozoites formed walled coccoid stages which grew through successive buddings and developed into branched structures holding cysts. These structures, measuring hundreds of micrometres, are built as the exclusive product of osmotrophic feeding. To demonstrate that M. gemmipara is a genuine soil inhabitant, we screened its presence in an environmental soil DNA diversity survey performed on an experimental setup where pig cadavers were left to decompose in soils to follow changes in eukaryotic communities. Mycamoeba gemmipara was present in all samples, although related reads were uncommon underneath the cadaver.


Evidence for the autophagy of microinjected proteins in HeLA cells.
Rhodamine-conjugated proteins were microinjected into living HeLa cells. Fluorescence microscopy was then employed to study their segregation from the cytoplasm into lysosomes. Results obtained in this way were verified when the corresponding unconjugated proteins were localized by autoradiographic, histological, and antibody-staining methods after their microinjection. Most injected proteins were segregated into cytoplasmic granular structures during their removal from cells. As evidence that these were autophagic vacuoles, they were found to contain no detectable acid phosphatase activity upon formation, after which they moved to the juxtanuclear position of lysosomes and appeared to fuse with them. The segregation of microinjected proteins exhibited a high degree of selectivity. The half-times of placement of individual exogenous proteins into cytoplasmic granules varied from 3 h to nearly 3 days, and one protein, hemoglobin, was never observed to enter them. Furthermore, endogenous HeLa proteins in a size fraction near 200,000 daltons were segregated much more rapidly than those in a fraction near 40,000 daltons. In these studies, rapid protein segregation appeared to take place by a mechanism of exclusion of the injected protein from numerous cytoplasmic domains.


Why do people die of anaphylaxis? A clinical review.
Anaphylaxis is a source of anxiety for patients and healthcare providers. It is a medical emergency that presents with a broad array of symptoms and signs, many of which can be deceptively similar to other diseases such as myocardial infarction, asthma, or panic attacks. In addition to these diagnostic challenges, anaphylaxis presents management difficulties due to rapid onset and progression, lack of appropriate self-treatment education and implementation by patients, severity of the allergic response, exacerbating medications or concurrent disease, and unpredictability. The most common causes of anaphylaxis are food allergies, stinging insects and immunotherapy (allergy shots) but idiopathic anaphylaxis, latex allergy and drug hypersensitive all contribute to the epidemiology. Reactions to IVP and other dyes are coined anaphylactoid reactions but have identical pathophysiology and treatment, once the mast cell has been degranulated. As many antigens can be the trigger for fatal anaphylaxis, it is useful to examine the features of each etiology individually, highlighting factors common to all fatal anaphylaxis and some specific to certain etiologies. Generally what distinguishes a fatal from non fatal reaction is often just the rapidity to apply correct therapy. Prevention is clearly the key and should identify high-risk patients in an attempt to minimize the likely of a severe reaction. Although fatal anaphylaxis is rare, it is likely underreported.


Dietary habits of polar bears in Foxe Basin, Canada: possible evidence of a trophic regime shift mediated by a new top predator.
Polar bear (Ursus maritimus) subpopulations in several areas with seasonal sea ice regimes have shown declines in body condition, reproductive rates, or abundance as a result of declining sea ice habitat. In the Foxe Basin region of Nunavut, Canada, the size of the polar bear subpopulation has remained largely stable over the past 20 years, despite concurrent declines in sea ice habitat. We used fatty acid analysis to examine polar bear feeding habits in Foxe Basin and thus potentially identify ecological factors contributing to population stability. Adipose tissue samples were collected from 103 polar bears harvested during 2010-2012. Polar bear diet composition varied spatially within the region with ringed seal (Pusa hispida) comprising the primary prey in northern and southern Foxe Basin, whereas polar bears in Hudson Strait consumed equal proportions of ringed seal and harp seal (Pagophilus groenlandicus). Walrus (Odobenus rosmarus) consumption was highest in northern Foxe Basin, a trend driven by the ability of adult male bears to capture large-bodied prey. Importantly, bowhead whale (Balaena mysticetus) contributed to polar bear diets in all areas and all age and sex classes. Bowhead carcasses resulting from killer whale (Orcinus orca) predation and subsistence harvest potentially provide an important supplementary food source for polar bears during the ice-free period. Our results suggest that the increasing abundance of killer whales and bowhead whales in the region could be indirectly contributing to improved polar bear foraging success despite declining sea ice habitat. However, this indirect interaction between top predators may be temporary if continued sea ice declines eventually severely limit on-ice feeding opportunities for polar bears.


Metabolic syndrome and abdominal fat are associated with inflammation, but not with clinical outcomes, in peritoneal dialysis patients.
In the general population, metabolic syndrome (MetS) is correlated with visceral fat and a risk factor for cardiovascular disease (CVD); however, little is known about the significance of abdominal fat and its association with inflammation and medication use in peritoneal dialysis (PD) patients. We investigated the relationship of visceral fat area (VFA) with C-reactive protein (CRP) levels and medication use in PD patients and followed their clinical outcomes. In a prospective study from February 2009 to February 2012, we assessed diabetes mellitus (DM) status, clinical and PD-associated characteristics, medication use, CRP levels, components of MetS, and VFA in 183 PD patients. These patients were categorized into 3 groups based on MetS and DM status: non-MetS (group 1, n = 73), MetS (group 2, n = 65), and DM (group 3, n = 45). VFA was evaluated by computed tomography (CT) and corrected for body mass index (BMI). Patients in group 1 had smaller VFAs than patients in groups 2 and 3 (3.2 ± 1.8, 4.6 ± 1.9, and 4.9 ± 2.0 cm2/[kg/m2], respectively, P < 0.05) and lower CRP levels (0.97 ± 2.31, 1.27 ± 2.57, and 1.11 ± 1.35 mg/dL, respectively, P < 0.05). VFA increased with the number of criteria met for MetS. After adjusting for age, body weight, and sex, CRP and albumin levels functioned as independent positive predictors of VFA; on other hand, the use of renin-angiotensin system blockers was inversely correlated with VFA in PD patients without DM. In the survival analysis, DM patients (group 3) had the poorest survival among the 3 groups, but no significant differences were found between groups 1 and 2. This study showed that VFA and MetS are associated with CRP levels but cannot predict survival in PD patients without DM. The complex relationship of nutritional parameters to VFA and MetS may explain these results. The type of antihypertensive medication used was also associated with the VFA. The mechanisms behind these findings warrant further investigation.


Current and future treatment modalities in schizophrenia: novel antipsychotic drugs and cognitive therapy.
In 60 years of use of antipsychotic drugs in schizophrenia, the only definite advance has been the introduction of clozapine. Some but not all other atypical or second-generation drugs may have small therapeutic advantages over conventional antipsychotics, but this remains controversial. New entrant atypicals seem unlikely to be therapeutically superior to conventional drugs, and glutamatergic drugs have yet to fulfill their theoretical promise. There is considerable current interest in novel mechanisms of antipsychotic action, but no such drugs have yet reached market authorization. A psychotherapeutic intervention, cognitive behavioral therapy has also found a place in the treatment of schizophrenia. However, the size of its effect against psychotic symptoms is small, and current evidence suggests no effect against negative symptoms or in reducing relapse.


Functional lumen imaging probe to assess geometric changes in the esophagogastric junction following endolumenal fundoplication.
The functional lumen imaging probe (FLIP) uses impedance planimetry to measure the geometry of a distensible organ. The purpose of this study was to evaluate FLIP as a method to determine structural changes at the gastroesophageal junction (GEJ) following transoral incisionless fundoplication (TIF) and compare these findings with the accepted methods of esophageal testing. Two different approaches (TIF1.0 and 2.0) using the EsophyX™ device were performed in six and five animals, respectively. Three dogs underwent a sham procedure. FLIP measurements were performed pre- and post-procedure and at 2-week follow-up. Upper endoscopy, manometry, and 48-h pH testing were also performed at each time point. FLIP was performed in ten patients before and 3 months after TIF. Following TIF procedures, there was a significant decrease in cross-sectional area (CSA) of GEJ compared to baseline; however, the CSA of both groups returned to baseline at 2-week follow-up. The FLIP results were supported with pH testing and correlated highly with both measures of GEJ structural integrity (LES and cardia circumference). Following TIF in humans, there was a decrease in GEJ distensibility compared to baseline that persisted to the 3-month evaluation. FLIP is able to measure and display changes in tissue distensibility at the GEJ, and results correlate with established methods of testing. FLIP may represent a single testing modality by which to diagnose GERD and evaluate the outcome after antireflux surgery.


Metallothionein Family Proteins as Regulators of Zinc Ions Synergistically Enhance the Anticancer Effect of Cannabidiol in Human Colorectal Cancer Cells.
Cannabidiol (CBD) is a chemical obtained from Cannabis sativa; it has therapeutic effects on anxiety and cognition and anti-inflammatory properties. Although pharmacological applications of CBD in many types of tumors have recently been reported, the mechanism of action of CBD is not yet fully understood. In this study, we perform an mRNA-seq analysis to identify the target genes of CBD after determining the cytotoxic concentrations of CBD using an MTT assay. CBD treatment regulated the expression of genes related to DNA repair and cell division, with metallothionein (MT) family genes being identified as having highly increased expression levels induced by CBD. It was also found that the expression levels of MT family genes were decreased in colorectal cancer tissues compared to those in normal tissues, indicating that the downregulation of MT family genes might be highly associated with colorectal tumor progression. A qPCR experiment revealed that the expression levels of MT family genes were increased by CBD. Moreover, MT family genes were regulated by CBD or crude extract but not by other cannabinoids, suggesting that the expression of MT family genes was specifically induced by CBD. A synergistic effect between CBD and MT gene transfection or zinc ion treatment was found. In conclusion, MT family genes as novel target genes could synergistically increase the anticancer activity of CBD by regulating the zinc ions in human colorectal cancer cells.


Phase I/II study of the antibody-drug conjugate glembatumumab vedotin in patients with locally advanced or metastatic breast cancer.
Glycoprotein NMB (gpNMB), a novel transmembrane protein overexpressed in 40% to 60% of breast cancers, promotes metastases in animal models and is a prognostic marker of a poor outcome in patients. The antibody-drug conjugate glembatumumab vedotin consists of a fully human anti-gpNMB monoclonal antibody, conjugated via a cleavable linker to monomethyl auristatin E. Glembatumumab vedotin is generally well tolerated, with observed objective responses in advanced melanoma. This is, to our knowledge, the first study of glembatumumab vedotin in breast cancer. Eligible patients had advanced/metastatic breast cancer with at least two prior chemotherapy regimens, including taxane, anthracycline, and capecitabine. A standard 3+3 dose escalation was followed by a phase II expansion. Immunohistochemistry for gpNMB was performed retrospectively for patients with available tumor tissue. Forty-two patients were enrolled. Dose-limiting toxicity (DLT) consisted of worsening neuropathy at 1.34 mg/kg. After excluding patients with baseline neuropathy more than grade 1, no DLT occurred through 1.88 mg/kg (the phase II dose). The phase II primary activity end point was met (12-week progression-free survival [PFS12] = 9 of 27 patients; 33%). Sixteen of 19 (84%) patients tested had gpNMB-positive tumors. At the phase II dose, median PFS was 9.1 weeks for all patients, 17.9 weeks for patients with triple-negative breast cancer (TNBC), and 18.0 weeks for patients with gpNMB-positive tumors. Two patients had confirmed partial responses; both had gpNMB-positive tumors and one had TNBC. Glembatumumab vedotin has an acceptable safety profile. Preliminary evidence of activity in treatment-resistant metastatic breast cancer requires confirmation, such as the phase II randomized trial (EMERGE) that also examines the relationship between activity and gpNMB distribution/intensity.


Using collocation and a hierarchical basis to solve the vibrational Schrödinger equation.
We show that it is possible to compute vibrational energy levels of polyatomic molecules with a collocation method and a basis of products of one-dimensional harmonic oscillator functions pruned so that it does not include functions for which the indices of many of the one-dimensional functions are nonzero. Functions with many nonzero indices are coupled only by terms that depend simultaneously on many coordinates, and they are typically small. The collocation equation is derived without invoking differences of interpolation operators, which simplifies implementation of the method. This, however, requires inverting a matrix whose elements are values of the pruned basis functions at the collocation points. The collocation points are the points on a Smolyak grid whose size is equal to the size of the pruned basis set. The Smolyak grid is built from symmetrized Leja points. Because both the basis and the grid are not tensor products, the inverse is not straightforward. It can be done by using so-called hierarchical 1-D basis functions. They are defined so that the matrix whose elements are the 1-D hierarchical basis functions evaluated at points is lower triangular. We test the method by applying it to compute 100 energy levels of CH2NH with an iterative eigensolver.


Silencing subtelomeric VSGs by Trypanosoma brucei RAP1 at the insect stage involves chromatin structure changes.
Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen variant surface glycoprotein (VSG) to evade mammalian host immune responses at the bloodstream form (BF) stage. Monoallelic expression of BF Expression Site (BES)-linked VSGs and silencing of metacyclic VSGs (mVSGs) in BF cells are essential for antigenic variation, whereas silencing of both BES-linked and mVSGs in the procyclic form (PF) cells is important for cell survival in the midgut of its insect vector. We have previously shown that silencing BES-linked VSGs in BF cells depends on TbRAP1. We now show that TbRAP1 silences both BES-linked and mVSGs at both BF and PF stages. The strength of TbRAP1-mediated BES-linked VSG silencing is stronger in the PF cells than that in BF cells. In addition, Formaldehyde-Assisted Isolation of Regulatory Elements analysis and MNase digestion demonstrated that depletion of TbRAP1 in PF cells led to a chromatin structure change, which is significantly stronger at the subtelomeric VSG loci than at chromosome internal loci. On the contrary, no significant chromatin structure changes were detected on depletion of TbRAP1 in BF cells. Our observations indicate that TbRAP1 helps to determine the chromatin structure at the insect stage, which likely contributes to its strong silencing effect on VSGs.


Inferior vena cava diameter and risk of acute decompensated heart failure rehospitalisations.
Inferior vena cava (IVC) diameter may be a surrogate for volume status in acute decompensated heart failure (ADHF). The utility of IVC diameter measurement is under studied. The aim of this study was to assess the relationship between IVC diameter, clinical variables and ADHF rehospitalisations. Retrospective chart review of 200 patients admitted for ADHF from 2018 to 2019 with transthoracic echocardiogram during index hospitalisation. Charts were assessed for ADHF rehospitalisation within 1 year. The median age was 64, 30.5% were female, and average left ventricular ejection fraction was 41%±20%. IVC diameter correlated to pulmonary arterial (PA) pressure (R=0.347, p<0.001) and body surface area (BSA) (R=0.424 p<0.001). IVC diameter corrected for BSA correlated to PA pressure (R=0.287, p<0.001) and log N-terminal B-type natriuretic peptide (NT-proBNP) (R=0.247, p≤0.01). Patients rehospitalised within 1 year had significantly greater mean IVC diameter compared with those not rehospitalised (p<0.001) while there was no difference in mean net weight lost during index hospitalisation or mean log NT-proBNP. Patients with IVC diameter greater than 2.07 cm had significantly increased ADHF rehospitalisation (85.6% vs 49.3%, log rank p<0.001) with HR 2.44 (95% CI 1.85 to 3.23, p<0.001). In multivariable Cox regression only IVC diameter (p<0.001), presence of tricuspid regurgitation (p=0.02) and NYHA class III/IV (p<0.001) independently predicted ADHF rehospitalisation within 1 year. IVC diameter is predictive of rehospitalisation in patients with ADHF and may identify patients in need of greater monitoring and diuresis.


Immunohistochemical Examination of Trophoblast Syncytialization during Early Placentation in Sheep.
During the peri-implantation period, multinucleated syncytia are formed in the sheep placenta. For over 20 years the scientific consensus has been that during trophoblast syncytialization in sheep, binucleate trophoblast giant cells (BNCs) differentiate from mononuclear trophoblast cells, and individual BNCs fuse with individual luminal epithelial (LE) cells to form trinucleate cells. These trophoblast-LE syncytial plaques then grow through continued BNC migration and fusion. Therefore, LE cells are thought to be incorporated into syncytial plaques. However, these ideas were based on electron microscopy studies, without benefit of molecular markers for BNC and LE cells to support conclusions. The aim of this study was to observe interactions between BNCs and uterine LE cells using immunohistochemical localization for molecular markers for BNCs and uterine LE cells. We performed immunofluorescence staining, laser capture microdissection, and TUNEL staining on the uterine-placental tissues of sheep during early placentation. We observed: (1) syncytial cells containing more than two nuclei within the trophoblast cell layer; (2) depolarized LE cells that express caspase 3 and stain positively for TUNEL; (3) engulfment of caspase 3-positive LE cells by trophoblast giant cells (TGCs) and empty spaces within the LE layer at sites of implantation; (4) rapid enlargement of syncytial plaques; and (5) E-cadherin and TUNEL-positive cells within the uterine stroma underlying degenerating LE was coincident with accumulation of CD45-positive cells at these sites. These data suggest that during early placentation: (1) fusion between trophoblasts is not limited to the formation of BNCs, and the term 'trophoblast giant cell (TGC)' may be appropriate; (2) LE cells undergo apoptosis; (3) apoptotic LE cells are eliminated by TGCs; (4) fusion is not limited to the incorporation of new BNCs but involves the lateral fusion between growing syncytial plaques; and (5) TGCs carry apoptotic LE cells away from the uterine-placental interface for elimination by immune cells within the stroma. These data indicate that uterine LE cells are not incorporated into syncytial plaques, but are engulfed and eliminated, and that early placentation in sheep is more similar to early placentation in humans than is currently understood in that both develop mononucleated cytotrophoblast and multinucleated syncytiotrophoblast layers of entirely placental origin. The elimination of LE cells by sheep TGCs might provide insights into elimination and penetration of LE cells during human embryo implantation.


Molecular cloning and functional expression of KCNQ5, a potassium channel subunit that may contribute to neuronal M-current diversity.
We have isolated KCNQ5, a novel human member of the KCNQ potassium channel gene family that is differentially expressed in subregions of the brain and in skeletal muscle. When expressed in Xenopus oocytes, KCNQ5 generated voltage-dependent, slowly activating K(+)-selective currents that displayed a marked inward rectification at positive membrane voltages. KCNQ5 currents were insensitive to the K(+) channel blocker tetraethylammonium but were strongly inhibited by the selective M-current blocker linopirdine. Upon coexpression with the structurally related KCNQ3 channel subunit, current amplitudes increased 4-5-fold. Compared with homomeric KCNQ5 currents, KCNQ3/KCNQ5 currents also displayed slower activation kinetics and less inward rectification, indicating that KCNQ5 combined with KCNQ3 to form functional heteromeric channel proteins. This functional interaction between KCNQ5 and KCNQ3, a component of the M-channel, suggests that KCNQ5 may contribute to a diversity of heteromeric channels underlying native neuronal M-currents.


Deep Multi-View Feature Learning for EEG-Based Epileptic Seizure Detection.
Epilepsy is a neurological illness caused by abnormal discharge of brain neurons, where epileptic seizure can lead to life-threatening emergencies. By analyzing the encephalogram (EEG) signals of patients with epilepsy, their conditions can be monitored and seizure can be detected and intervened in time. As the identification of effective features in EEG signals is important for accurate seizure detection, this paper proposes a multi-view deep feature extraction method in attempt to achieve this goal. The method first uses fast Fourier transform (FFT) and wavelet packet decomposition (WPD) to construct the initial multi-view features. Convolutional neural network (CNN) is then used to automatically learn deep features from the initial multi-view features, which reduces the dimensionality and obtain the features with better seizure identification ability. Furthermore, the multi-view Takagi-Sugeno-Kang fuzzy system (MV-TSK-FS), an interpretable rule-based classifier, is used to construct a classification model with strong generalizability based on the deep multi-view features obtained. Experimental studies show that the classification accuracy of the proposed multi-view deep feature extraction method is at least 1% higher than that of common feature extraction methods such as principal component analysis (PCA), FFT and WPD. The classification accuracy is also at least 4% higher than the average accuracy achieved with single-view deep features.


Unstained negative image patterns. A checkpoint for quality slides.
Before stains were available, pathologists had to rely on unstained sections viewed through crude microscopes, but they still were able to make diagnoses and discoveries. Unstained sections may still be used to advantage in making diagnoses of skin lesions quickly, accurately, and easily on the basis of negative image patterns. Low-power scanning by conventional microscopy of freshly cute and mounted, still wet, paraffin sections of skin specimens enables the histotechnologist and dermatopathologist to accomplish three things: 1) to check orientation of the sections at an early stage, 2) to cut complete sections, and 3) to find the area or areas of pathology to cut. Furthermore, because diagnoses can be made from unstained sections, extra cuts for special stains may be ordered in advance of routine staining. The dermato-pathology laboratory is able, therefore, to produce slides of better quality and diagnoses more accurately and quickly.


Modification of Initial Empirical Antibiotic Prescription and its Impact on Patient Outcome: Experience of an Indian Intensive Care Unit.
Data on the overall impact of antibiotic modification following initial empiric prescription in both culture-positive and culture-negative critically ill patients are exiguous. In a retrospective analysis of "ANT-CRITIC" study, we classified ICU patients receiving empirical antibiotics who remained in the ICU for >72 hours or till availability of culture results (whichever is longer) into five groups based on culture results and antibiotic modification: negative culture, no change (group I), positive culture, no change (group II), positive culture, de-escalation (group III), positive culture, escalation (group IV) and negative culture, antibiotic modification (group V). Baseline variables and clinical outcomes were compared. Logistic regression analysis was performed to look for independent variables associated with mortality. 276 prescription episodes were analyzed. Group II was associated with worsening organ dysfunction at 72 hours, lower clinical cure rate at day 7, and higher hospital mortality. There was an independent association between group II prescription and hospital mortality [adjusted OR 2.774 (CI 1.178-6.533), p = 0.02]. Group III received longer duration of antibiotic (mean duration = 8.27 ± 4.11 days, median duration = 7 days [IQR 5-11]). Outcomes of critically ill infected patients differ significantly when they are classified based on culture result and antibiotic modification pattern. Ghosh S, Singh A, Lyall A. Modification of Initial Empirical Antibiotic Prescription and its Impact on Patient Outcome: Experience of an Indian Intensive Care Unit. Indian J Crit Care Med 2023;27(8):583-589.


Characterization of an Animal Model to Study Risk Factors and New Therapies for the Cardiorenal Syndrome, a Major Health Issue in Our Aging Population.
The cardiorenal syndrome (CRS) is a major health problem in our aging population. The term was introduced to cover disorders of the kidneys and heart, whereby dysfunction of one organ may induce dysfunction of the other. As the natural history of the CRS is mostly slow, hence difficult to explore in clinical trials, adequate animal models combining cardiovascular and renal disease are required. Therefore, we developed and characterized a usable model for CRS type 4, i.e. chronic kidney disease (CKD) causing cardiac dysfunction. CKD was induced in rats by supplementing the diet with adenine. During 8 weeks, several aspects of CRS were studied: CKD, mineral-bone disorder (MBD), cardiovascular disease, and (iron-deficiency) anemia. Hereto, the following parameters were monitored: serum creatinine, calcium, phosphate, FGF23, dynamic bone parameters, aortic Ca deposits, heart weight, serum NT-proANP, Hct, Hb, reticulocytes, spleen iron, and serum hepcidin. Animals developed a severe CKD together with a disturbed mineral balance as reflected by the increased serum creatinine and phosphorus levels and decreased serum calcium levels; and in association herewith aberrations in hormonal levels of FGF-23. In turn, the well-known and highly undesirable complications of CKD, i.e. high turnover bone disease and pathological vessel calcification were induced. Furthermore (iron-deficiency) anemia developed quickly. The animal model described in this article in many aspects mimics the human situation of the CRS type 4 and will be useful to concomitantly evaluate the effects of new treatment strategies on the various aspects of CRS.


[Imbalance of T lymphocyte subpopulations in patients with psoriasis and its immune correction].
We investigated the levels of T-lymphocytes and their subpopulations-T-helper cells (TH) and T-suppressor cells (TS)-in the peripheral blood of 57 patients suffering from various clinical forms of psoriasis. Considerable decrease of the TH/TS rate (0.2 to 1.2) was found in 29 patients (15 with vulgar, 8 with arthropatic, and 6 with exudative psoriasis). The total number of T-lymphocytes was normal in 20 of these patients. In 8 patients showing a marked disbalance of TH and TS immunomodulators, thymalin and natrii nucleinas were included in the complex schedule of antipsoriatic therapy. As a result of the immunocorrective therapy, the disbalance normalized in 6 cases accompanied by regression of the psoriatic rash. The disbalance of TH and TS in the peripheral blood of the patients has a certain pathogenic significance in the development of psoriasis, and immunocorrection becomes necessary for successful therapy in severer forms of the disease.


Detection of inhibitors of phenotypically drug-tolerant Mycobacterium tuberculosis using an in vitro bactericidal screen.
Many whole cell screens of chemical libraries currently in use are based on inhibition of bacterial growth. The goal of this study was to develop a chemical library screening model that enabled detection of compounds that are active against drug-tolerant non-growing cultures of Mycobacterium tuberculosis. An in vitro model of low metabolically active mycobacteria was established with 8 and 30 day old cultures of M. smegmatis and M. tuberculosis, respectively. Reduction of resazurin was used as a measure of viability and the assay was applied in screens of chemical libraries for bactericidal compounds. The model provided cells that were phenotypically-resilient to killing by first and second-line clinical drugs including rifampicin. Screening against chemical libraries identified proteasome inhibitors, NSC310551 and NSC321206, and a structurally-related series of thiosemicarbazones, as having potent killing activity towards aged cultures. The inhibitors were confirmed as active against virulent M. tuberculosis strains including multi- and extensively-drug resistant clinical isolates. Our library screen enabled detection of compounds with a potent level of bactericidal activity towards phenotypically drug-tolerant cultures of M. tuberculosis.


Bactericidal and non-cytotoxic activity of bacteriocin produced by Lacticaseibacillus paracasei F9-02 and evaluation of its tolerance to various physico-chemical conditions.
This study aims to explore novel lactic acid bacteria (LAB) from breast-fed infants' faeces towards characterizing their antimicrobial compound, bacteriocin. The LAB, Lacticaseibacillus paracasei F9-02 showed strong antimicrobial activity against clinical pathogens. Their proteinaceous nature was confirmed as the activity was completely abolished when treated with proteinaceous enzymes and retained during neutral pH and catalase treatment. The purified bacteriocin showed antimicrobial activity at the minimum inhibitory concentration (MIC) value of 7.56 μg/ml against vancomycin-resistant Enterococcus sp. [vancomycin-resistant enterococcal (VRE)], and methicillin-resistant Staphylococcus aureus (MRSA), 15.13 μg/ml against Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella enterica subsp. enterica serotype typhi and 30.25 μg/ml against Shigella flexneri. Present study also proved the bactericidal, non-cytotoxic and non-hemolytic nature of bacteriocin. Additionally, bacteriocin retained their stability under various physico-chemical conditions, broad range of pH (2-10), temperature (40-121°C), enzymes (amylase, lipase and lysozyme), surfactants [Tween-20, 80, 100 and sodium dodecyl sulfate (SDS)], metal ions (CaCl2 , FeSO4 , ZnSO4 , MgSO4 , MnSO4 , CuCl2 ) and NaCl (2%-8%). The molecular weight of bacteriocin (~28 kDa) was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), functional and active groups were assessed by Fourier Transform-Infrared (FT-IR). To our knowledge, this is the first study reporting L. paracasei from breast-fed infants' faeces and assessing their antimicrobial compound, bacteriocin. The study results furnish the essential features to confirm the therapeutic potential of L. paracasei F9-02 bacteriocin.


Molecular and Morphological Characterization of Cysticercus tenuicollis in Red Deer (Cervus elaphus) from Turkey.
Cysticercus tenuicollis, the metacestode stage of Taenia hydatigena has a worldwide distribution and is particularly common in rural areas and developing countries. In rare cases, T. hydatigena infection may result in the death of its host due to severe damage or secondary bacterial infections. Generally, when multiple cysts are attached to the liver, it causes economic losses. The infection can be detected using morphological, histopathological and more recently, molecular investigations. In the present study, we describe molecular and morphological characterization of C. tenuicollis detected in a 3 month-old female red deer (Cervus elaphus) during necropsy. Cystic samples were stained with haematoxylin-eosin (HE) and Masson's trichrome stain for histopathological examination, and molecular characterization of the complete mitochondrial cytochrome c oxidase subunit 1 (cox1) gene region was performed. This study provides the first morphological, histopathological, and molecular data on C. tenuicollis isolated from red deer in Turkey.


Duodenal Mucosal Expression of COVID-19-Related Genes in Health, Diabetic Gastroenteropathy, and Functional Dyspepsia.
SARS-CoV-2 infects the gastrointestinal tract and may be associated with symptoms that resemble diabetic gastroparesis. Why patients with diabetes who contract COVID-19 are more likely to have severe disease is unknown. We aimed to compare the duodenal mucosal expression of SARS-CoV-2 and inflammation-related genes in diabetes gastroenteropathy (DGE), functional dyspepsia (FD), and healthy controls. Gastrointestinal transit, and duodenal mucosal mRNA expression of selected genes were compared in 21 controls, 39 DGE patients, and 37 FD patients from a tertiary referral center. Pathway analyses were performed. Patients had normal, delayed (5 FD [13%] and 13 DGE patients [33%]; P = 0.03 vs controls), or rapid (5 FD [12%] and 5 DGE [12%]) gastric emptying (GE). Compared with control participants, 100 SARS-CoV-2-related genes were increased in DGE (FDR < 0.05) vs 13 genes in FD; 71 of these 100 genes were differentially expressed in DGE vs FD but only 3 between DGE patients with normal vs delayed GE. Upregulated genes in DGE include the SARS-CoV2 viral entry genes CTSL (|Fold change [FC]|=1.16; FDR < 0.05) and CTSB (|FC|=1.24; FDR < 0.05) and selected genes involved in viral replication (eg, EIF2 pathways) and inflammation (CCR2, CXCL2, and LCN2, but not other inflammation-related pathways eg, IL-2 and IL-6 signaling). Several SARS-CoV-2-related genes were differentially expressed between DGE vs healthy controls and vs FD but not between DGE patients with normal vs delayed GE, suggesting that the differential expression is related to diabetes per se. The upregulation of CTSL and CTSB and replication genes may predispose to SARS-CoV2 infection of the gastrointestinal tract in diabetes.


Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials.
This analysis was conducted to determine the efficacy of extracted or synthesized soybean isoflavones in the alleviation of hot flashes in perimenopausal and postmenopausal women. PubMed and The Cochrane Controlled Clinical Trials Register Database were searched for relevant articles reporting double-blinded randomized controlled trials through December 14, 2010. References within identified articles, as well as peer-reviewed articles that had come to the attention of the authors through other means, were also examined for suitability. This systematic review and meta-analysis, which evaluated the effects of isoflavones on the frequency, severity, or composite score (frequency × severity) of hot flashes compared with placebo was conducted according to Cochrane Handbook guidelines. From 277 potentially relevant publications, 19 trials (reported in 20 articles) were included in the systematic review (13 included hot flash frequency; 10, severity; and 3, composite scores), and 17 trials were selected for meta-analyses to clarify the effect of soybean isoflavones on hot flash frequency (13 trials) and severity (9 trials). Meta-analysis revealed that ingestion of soy isoflavones (median, 54 mg; aglycone equivalents) for 6 weeks to 12 months significantly reduced the frequency (combined fixed-effect and random effects model) of hot flashes by 20.6% (95% CI, -28.38 to -12.86; P < 0.00001) compared with placebo (heterogeneity P = 0.0003, I = 67%; random effects model). Meta-analysis also revealed that isoflavones significantly reduced hot flash severity by 26.2% (95% CI: -42.23 to -10.15, P = 0.001) compared with placebo (heterogeneity, P < 0.00001, I = 86%; random effects model). Isoflavone supplements providing more than 18.8 mg of genistein (the median for all studies) were more than twice as potent at reducing hot flash frequency than lower genistein supplements. Soy isoflavone supplements, derived by extraction or chemical synthesis, are significantly more effective than placebo in reducing the frequency and severity of hot flashes. Additional studies are needed to further address the complex array of factors that may affect efficacy, such as dose, isoflavone form, baseline hot flash frequency, and treatment duration.


Quantitative genetics of serum sex hormone-binding globulin levels in participants in the San Antonio Family Heart Study.
Sex hormone-binding globulin (SHBG) is a steroid-binding plasma protein with a high affinity for testosterone that has been inversely associated with cardiovascular disease risk in many populations. SHBG may also act as a receptor in some tissues. Although the function of SHBG is relatively well understood, comparatively little is known about genetic factors contributing to the normal variation of serum SHBG levels. We estimated the heritability (h2) of serum SHBG levels in 717 related Mexican-Americans participating in the San Antonio Family Heart Study (SAFHS). We found a significant heritability (h2 = 0.31, P < .0001) for serum SHBG levels; age, exogenous hormones, smoking status, diabetic status, and adiposity showed significant associations (P < .05) with mean levels of SHBG. Sex was associated with mean SHBG levels but not with genetic or environmental variance in SHBG levels; heritability estimates were the same for males and females. These results indicate a significant genetic influence on SHBG in Mexican-Americans. Thus, SHBG may prove to be an important indicator of genetic risk for cardiovascular disease in this population, as well as others.


Establishment and characterization of a Fas-resistant T cell line.
Fas is a cell surface receptor that controls a signal transduction pathway leading to apoptosis. We established an antihuman Fas monoclonal antibody (mAb)-resistant variant, kit-225-FR, from the human T cell line, kit-225. Flow cytometric analysis revealed that the expression of Fas molecules on kit-225-FR was preserved. The defect in Fas molecule was not detected either by reverse transcription polymerase chain reaction (PCR) analysis of the Fas transcript or by PCR-single strand conformation polymorphism analysis of the Fas gene in kit-225-FR. Although kit-225-FR was resistant to a high concentration of anti-Fas mAb, apoptosis could be induced, as with the wild type, by exogenous C2-ceramide exposure. MORT1/FADD was expressed at wild-type level in kit-225-FR, as determined by Western blot analysis. It therefore appears that the apoptotic signal transduction in kit-225-FR is defective between FADD and the sphingomyelin-ceramide pathway. By comparing the differences from the wild-type kit-225, kit-225-FR would serve as a useful cell line for analyzing Fas-specific signal transduction pathways in detail.


[Comparative study of the acceptability of Tilade Syncroner and Tilade Standard by mildly asthmatic patients. Syncroner Trial Research Group].
An open multicenter randomized, cross over study has compared the patients acceptance and preference of nedocromil sodium delivered as metered dose inhaler (MDI) containing 112 puffs and attached to an open tube spacer, the Syncroner with the same product as MDI containing 56 puffs delivered through a standard mouthpiece adaptator. One hundred and forty four patients (67 males) suffering from moderate asthma (mean FEV1: 86%) aged 18 to 70 years received alternatively 2 puffs of 2 mg 4 times a day of nedocromil sodium either by Syncroner or by the standard adaptator for two weeks in random order. The acceptance of each device was assessed by a questionnaire after two weeks of treatment. At the end of the study, the preference was recorded globally by the mean of a visual analog scale and for each of the following criteria: tolerability, shape, efficacy, hygiene, easiness to use, cleaning, contents and confidence. After two weeks of treatment the Syncroner was as well accepted as the standard mouthpiece and even better in terms of contents, cleaning and confidence. At the end of the study, 50.4% of patients prefering the Syncroner and 49.6% the standard mouthpiece. Patients significantly favoured the Syncroner because of its contents, hygiene, and cleaning (p < 0.05 for these 3 criteria) and tolerability (p = 0.07). In conclusion, after two weeks of treatment, the Syncroner was as well accepted as the standard MDI, 50% of patients preferred the new inhalation device. Considering its interest as training aid and the better lung deposition, it can be proposed for drug delivery without risk of a rejection by patients.


Vitamin A, endocrine tissues and hormones: interplay and interactions.
Vitamin A (retinol) is a micronutrient critical for cell proliferation and differentiation. In adults, vitamin A and metabolites such as retinoic acid (RA) play major roles in vision, immune and brain functions, and tissue remodelling and metabolism. This review presents the physiological interactions of retinoids and endocrine tissues and hormonal systems. Two endocrine systems have been particularly studied. In the pituitary, retinoids targets the corticotrophs with a possible therapeutic use in corticotropinomas. In the thyroid, retinoids interfere with iodine metabolism and vitamin A deficiency aggravates thyroid dysfunction caused by iodine-deficient diets. Retinoids use in thyroid cancer appears less promising than expected. Recent and still controversial studies investigated the relations between retinoids and metabolic syndrome. Indeed, retinoids contribute to pancreatic development and modify fat and glucose metabolism. However, more detailed studies are needed before planning any therapeutic use. Finally, retinoids probably play more minor roles in adrenal and gonads development and function apart from their major effects on spermatogenesis.


Comparison of salt stress resistance genes in transgenic Arabidopsis thaliana indicates that extent of transcriptomic change may not predict secondary phenotypic or fitness effects.
Engineered abiotic stress resistance is an important target for increasing agricultural productivity. There are concerns, however, regarding possible ecological impacts of transgenic crops. In contrast to the first wave of transgenic crops, many abiotic stress resistance genes can initiate complex downstream changes. Transcriptome profiling has been suggested as a comprehensive non-targeted approach to examine the secondary effects. We compared phenotypic and transcriptomic effects of constitutive expression of genes intended to confer salt stress tolerance by three different mechanisms: a transcription factor, CBF3/DREB1a; a metabolic gene, M6PR, for mannitol biosynthesis; and the Na⁺/H⁺ antiporter, SOS1. Transgenic CBF3, M6PR and SOS1 Arabidopsis thaliana were grown together in the growth chamber, greenhouse and field. In the absence of salt, M6PR and SOS1 lines performed comparably with wild type; CBF3 lines exhibited dwarfing as reported previously. All three transgenes conferred fitness advantage when subjected to 100 mm NaCl in the growth chamber. CBF3 and M6PR affected transcription of numerous abiotic stress-related genes as measured by Affymetrix microarray analysis. M6PR additionally modified expression of biotic stress and oxidative stress genes. Transcriptional effects of SOS1 in the absence of salt were smaller and primarily limited to redox-related genes. The extent of transcriptome change, however, did not correlate with the effects on growth and reproduction. Thus, the magnitude of global transcriptome differences may not predict phenotypic differences upon which environment and selection act to influence fitness. These observations have implications for interpretation of transcriptome analyses in the context of risk assessment and emphasize the importance of evaluation within a phenotypic context.


Low Plasma Omega-3 Fatty Acid Levels May Predict Inferior Prognosis in Untreated Diffuse Large B-Cell Lymphoma: A New Modifiable Dietary Biomarker?
Dietary factors that may reduce the risk of relapse or prolong remission are an area of interest for patients with cancer. There is little data on the role of omega-3 fatty acids (n-3 FA) in patients diagnosed with lymphoma. This pilot biomarker study evaluated the prognostic significance of n-3 FA levels in patients with diffuse large B-cell lymphoma (DLBCL). In this analysis, low n-3 FA may be associated with inferior event free survival at 24 months in this disease. Larger studies are needed to confirm this association and could provide the basis for prospective investigation of whether modifying n-3 levels with diet may improve outcome in lymphoma.


The afterlife of interspecific indirect genetic effects: genotype interactions alter litter quality with consequences for decomposition and nutrient dynamics.
Aboveground-belowground linkages are recognized as divers of community dynamics and ecosystem processes, but the impacts of plant-neighbor interactions on these linkages are virtually unknown. Plant-neighbor interactions are a type of interspecific indirect genetic effect (IIGE) if the focal plant's phenotype is altered by the expression of genes in a neighboring heterospecific plant, and IIGEs could persist after plant senescence to affect ecosystem processes. This perspective can provide insight into how plant-neighbor interactions affect evolution, as IIGEs are capable of altering species interactions and community composition over time. Utilizing genotypes of Solidago altissima and Solidago gigantea, we experimentally tested whether IIGEs that had affected living focal plants would affect litter decomposition rate, as well as nitrogen (N) and phosphorous (P) dynamics after the focal plant senesced. We found that species interactions affected N release and genotype interactions affected P immobilization. From a previous study we knew that neighbor genotype influenced patterns of biomass allocation for focal plants. Here we extend those previous results to show that these changes in biomass allocation altered litter quality, that then altered rates of decomposition and nutrient cycling. Our results provide insights into above- and belowground linkages by showing that, through their effects on plant litter quality (e.g., litter lignin:N), IIGEs can have afterlife effects, tying plant-neighbor interactions to ecosystem processes. This holistic approach advances our understanding of decomposition and nutrient cycling by showing that evolutionary processes (i.e., IIGEs) can influence ecosystem functioning after plant senescence. Because plant traits are determined by the combined effects of genetic and environmental influences, and because these traits are known to affect decomposition and nutrient cycling, we suggest that ecosystem processes can be described as gene-less products of genetic interactions among the species comprising ecological communities.


Evidence of under-reporting of early-onset preeclampsia using register data.
Early-onset preeclampsia, traditionally defined as presenting before 34 gestational weeks, is associated with even higher risks of perinatal death, placental abruption, and stroke, than late-onset preeclampsia. We estimated the degree of misclassification in a high-risk population of lupus pregnancies and a general population comparator when gestational age at delivery defined preeclampsia phenotype compared to first preeclampsia diagnosis. Patients with lupus and general population comparators from Sweden with ≥1 singleton pregnancy in the Medical Birth Register with a documented ICD code for preeclampsia were included (2002-2016). We used gestational age at delivery (<34 versus ≥34 weeks) to phenotype preeclampsia early- versus late-onset and then reclassified based on first preeclampsia diagnosis date in the Patient Register. We cross-tabulated the two definitions and calculated sensitivity using the visit-based definition as the reference standard for general population and lupus pregnancies, overall and among nulliparous women. 331 pregnancies were diagnosed with preeclampsia, of which 322 were in both registers. Of those, 58 were early-onset based on gestational age at delivery (n = 29 in lupus pregnancies). Overall, 9% of early-onset preeclampsia in lupus (sensitivity 91%, 95% confidence interval [CI] 75, 98) was misclassified as late-onset compared to 19% in the general population (sensitivity 81%, 95% CI 64, 92). We noted similar misclassification (4% vs 22%) among nulliparous women. In the general population, early-onset preeclampsia was more likely misclassified as late-onset than in the high-risk lupus population. Relying on gestational age at delivery to phenotype preeclampsia, this way underestimates the occurrence of early-onset preeclampsia. This also suggests that the burden of early-onset preeclampsia as a public health concern may be under-reported, although this may be more applicable to milder preeclampsia where expectant management is employed. Research of biological and maternal predictors of early-onset preeclampsia may be dealing with differentially misclassified outcomes or samples.


[Preoperative preparation for cataract operation in artificial lens implantation].
A method of producing ocular hypotony, a decrease in motility, sufficient akinesia of the facial nerve as well as deep analgesia is described. This procedure seems to be more comfortable for the patient and preferable for the surgeon because it is safe. It consists of a single retrobulbar injection using a high-capacity syringe and oculopression at a higher pressure with a special instrument over a period of 20 minutes. The advantage of this method, some theoretical information, and the author's experience with it are communicated.


Late-onset bacterial endophthalmitis following glaucoma drainage implantation.
Abstract. A clinicopathologic report of late-onset bacterial endophthalmitis 4 years after implantation of a Baerveldt drainage implant is described. An 80-yearold woman with glaucoma presented 8 years after tube shunt implantation with clinical endophthalmitis. During surgical removal of the implant, a small conjunctival buttonhole caused by the suture securing the plate to the sclera was noted to be the only entry site. Vitreous and anterior chamber taps were performed with intravitreal antibiotics. Cultures revealed Streptococcus pneumoniae infection. The pathologic analysis showed epithelialization of the conjunctival buttonhole and diffuse ocular inflammation, mucopurulent material, and fibrovascular membranes. Due to severe pain, the eye was enucleated after 1 week. [Ophthalmic Surg Lasers Imaging 2003;34:128-130.].


Synthesis and biological evaluation of selective phosphonate-bearing 1,2,3-triazole-linked sialyltransferase inhibitors.
The critical role of sialyltransferase (ST) enzymes in tumour cell growth and metastasis, as well as links to multi-drug and radiation resistance, has seen STs emerge as a target for potential antimetastatic cancer treatments. One promising class of ST inhibitors that improve upon the pharmacokinetic issues of previous inhibitors is the 1,2,3-triazole-linked transition-state analogues. Herein, we present the design and synthesis of a new generation of 1,2,3-triazole-linked sialyltransferase inhibitors, along with their biological evaluation demonstrating increased potency for phosphonate bearing compounds. The six most promising inhibitors presented in this work exhibited a greater number of binding modes for hST6Gal I over hST3Gal I, with K i ranging from 3-55 μM. This work highlights phosphonate bearing triazole-linked compounds as a promising class of synthetically accessible ST inhibitors that warrant further investigation.


Systemically administered wound-homing peptide accelerates wound healing by modulating syndecan-4 function.
CAR (CARSKNKDC) is a wound-homing peptide that recognises angiogenic neovessels. Here we discover that systemically administered CAR peptide has inherent ability to promote wound healing: wounds close and re-epithelialise faster in CAR-treated male mice. CAR promotes keratinocyte migration in vitro. The heparan sulfate proteoglycan syndecan-4 regulates cell migration and is crucial for wound healing. We report that syndecan-4 expression is restricted to epidermis and blood vessels in mice skin wounds. Syndecan-4 regulates binding and internalisation of CAR peptide and CAR-mediated cytoskeletal remodelling. CAR induces syndecan-4-dependent activation of the small GTPase ARF6, via the guanine nucleotide exchange factor cytohesin-2, and promotes syndecan-4-, ARF6- and Cytohesin-2-mediated keratinocyte migration. Finally, we show that genetic ablation of syndecan-4 in male mice eliminates CAR-induced wound re-epithelialisation following systemic administration. We propose that CAR peptide activates syndecan-4 functions to selectively promote re-epithelialisation. Thus, CAR peptide provides a therapeutic approach to enhance wound healing in mice; systemic, yet target organ- and cell-specific.


Cleavage of oxidized guanine nucleotide and ADP sugar by human NUDT5 protein.
MutT-related proteins, including Escherichia coli MutT and the human MTH1 (NUDT1), degrade 8-oxo-7, 8-dihydrodeoxyguanosine triphosphate (8-oxo-dGTP) to 8-oxo-dGMP and thereby prevent mutations caused by the misincorporation of 8-oxoguanine into DNA. The human NUDT5, which has an intrinsic activity to cleave ADP sugars to AMP and sugar phosphate, possesses the ability to degrade 8-oxo-dGDP to the monophosphate. Since 8-oxo-dGDP and 8-oxo-dGTP are interconvertible by cellular enzymes, NUDT5 has the potential to prevent errors during DNA replication. The two activities associated with NUDT5 exhibit different pH dependencies; the optimum for the cleavage of ADP ribose is pH 7-9, while that for 8-oxo-dGDPase is around pH 10. The kinetic parameters for the two types of reactions indicated that ADP ribose is a better substrate for NUDT5 compared with oxidized guanine nucleotides. The 8-oxo-dGDP cleavage was competitively inhibited by ADP ribose and its reaction product, AMP, and in reverse, the cleavage of ADP ribose was inhibited by 8-oxo-dGDP. These results imply that the two types of substrates may share the same binding site for catalysis.