Self-imaging of gratings with rough strips.
We analyze the self-imaging process produced by a transmission grating whose strips present two different roughness levels. This kind of grating periodically modulates the transmitted light owing only to the different microtopographic properties of the strips. In spite of the fact that the grating is not purely periodic, it produces a kind of self-image at Talbot distances. These self-images gradually appear as light propagates, but they are not present just after the grating, as occurs in amplitude or phase gratings. There exists a distance from the grating, which depends on the stochastic properties of roughness, from which the contrast of the self-images becomes stable. Important cases are analyzed in detail, such as low- and high-roughness limits. We assume for the calculations that the grating can be used in a mobile system. Simulations using the Rayleigh-Sommerfeld regime have been performed, which confirm the validity of the theoretical approach proposed in this work.


Comorbidity Clusters and Healthcare Use in Individuals With COPD.
Individuals who share the same comorbidity profile are usually similar with regard to their disease severity, use of health care, and clinical outcomes. The identification of comorbidity clusters therefore bears prognostic information. The objective of this study was to identify and characterize comorbidity clusters in individuals with COPD in Denmark. Data from the Danish national registers were used. The study population included all individuals ≥16 y old who lived in the Danish Capital Region on January 1, 2012, and were diagnosed with COPD (N = 70,274). Comorbid chronic conditions were identified using diagnostic algorithms. A 2-step cluster analysis was performed. 81% of subjects with COPD had chronic comorbidities; the most common was hypertension (47.6%), and the least common was anxiety (0.1%). Three comorbidity clusters were identified. Cluster 1 contained 16% of the studied individuals with COPD, with all having heart disease in addition to the remaining comorbidities. Cluster 2 contained 30% of the studied individuals with COPD, of whom approximately 1 in 3 suffered from allergies, while the rest had no comorbidities. Cluster 3 contained 54% of the studied individuals with COPD, where all comorbidities but heart disease were represented. Cluster 1 contained the highest proportion of individuals over the age of 65 y, as well as the individuals with the lowest education. After adjusting for sociodemographic characteristics, individuals in Cluster 1 had the highest rates of hospitalizations and bed days. The presence of heart disease in individuals with COPD is a strong prognostic factor for socioeconomic and health vulnerability.


Sialyl Lewisx-dependent binding of human monocyte-derived dendritic cells to selectins.
The limited efficacy of monocyte-derived dendritic cell (mo-DC)-based vaccines is primarily attributed to the reduced mo-DC migratory capacity. One undefined aspect is the initial binding of mo-DCs to endothelial cells and vascular selectins. In this study, we investigated the role and modulation of the selectin binding determinant sialyl Lewis(x) (sLe(x)) in selectin-dependent mo-DC binding. Our data reveal that sLe(x) is required for maximal binding of mo-DCs to tumor necrosis factor (TNF)-α-activated endothelial cells under static conditions, as evidenced by the use of sialidase. Sialidase treatment also abrogated mo-DC cell tethering to immobilized, purified P-, L-, or E-selectin under flow. The requirement of sLe(x)-dependent binding of mo-DC to selectins was further substantiated by using sLe(x) free sugar and anti-sLe(x) antibody, which significantly suppressed mo-DC-selectin binding. P-selectin glycoprotein ligand-1 is required for mo-DC binding to both P- and L-selectin, but it is dispensable for E-selectin recognition. Interestingly, the extent of mo-DC tethering was maximal on P-selectin, followed by E- and L- selectin. Accordingly, L-selectin mediated faster mo-DC rolling than E- or P-selectin. Interferon (IFN)-γ induces a significant increase in mo-DC surface sLe(x) expression, which is probably due to the enhanced synthesis of C2GnT-I. These findings may contribute to improving mo-DC-based vaccination protocols.


Consequences of 1,4-Butanediol Misuse: A Review.
Gamma-hydroxybutyrate (GHB), along with its precursors, 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL), are potent central depressant agents widely illicitly used for their euphoric and relaxant effects. The article presents a review of the literature on the 1,4-BD misuse, the clinical picture of intoxication, development of addiction and delirium. The available evidence shows that 1,4-BD is a substance with its own psychoactive effects, a high addiction potential and potentially severe withdrawal symptoms.


Are body circumferences able to predict strength, muscle mass and bone characteristics in obesity? A preliminary study in women.
Measurement of body circumferences (BCs) is widely used as an anthropometric tool to assess body composition and health risk in obese individuals. In this preliminary work we evaluated the association of several BCs with Dual-energy X-ray Absorptiometry (DXA)-measured lean mass as well as leg press test scores with an aim at exploring the potential of BCs as predictor of body composition and muscle strength. A total of 34 female participants aged 47.3±7.6 y who were obese (BMI, 30.4-43.7 kg/m2) were recruited. The upper arm (relaxed), wrist, chest, waist, hip, thigh, and calf circumferences were measured. The skinfold-corrected muscle (including bone) circumferences at the arm, thigh, and calf site were also calculated. Lean mass components were measured by DXA with a Hologic QDR Explorer scanner according to the manufacturer's procedures. Lower limbs strength was assessed with the 1-Repetition Maximum leg press. Bivariate association between variables was assessed with the Spearman's correlation coefficient after the Benjamini and Hochberg False Discovery Rate procedure. Predictive equations were developed using stepwise multiple regression analysis. Several statistically significant correlations (Benjamini and Hochberg corrected P [Pc] < 0.05) were present between BCs and DXA-measured body composition variables, and leg press test scores with special regard to the chest, arm, waist, and hip circumferences. Multiple regression analysis yielded statistically significant predictive models (Pc < 0.05 for all; adjusted R2 ranging 0.123 - 0.504; standard error of the estimate ranging 4.0% - 11% of the mean measured value) for all body composition as well as leg press outcomes. The current findings show that BCs represent a simple, suitable anthropometric measurement with a potential to predict several lean mass components as well as lower limbs strength in obese females. The proposed predictors need to be validated in a larger sample of participants and in obese males.


Like a pig out of water: seaborne spread of domestic pigs in Southern Italy and Sardinia during the Bronze and Iron Ages.
Southern Italy has a long history of human occupation and passage of different cultures since the Early Holocene. Repeated, ancient introductions of pigs in several geographic areas in Europe make it difficult to understand pig translocation and domestication in Italy. The archeozoological record may provide fundamental information on this, hence shedding light on peopling and on trading among different ancient cultures in the Mediterranean. Yet, because of the scanty nature of the fossil record, ancient remains from human-associated animals are somewhat rare. Fortunately, ancient DNA analysis as applied to domestic species proved to be a powerful tool in revealing human migrations. Herein, we analyzed 80-bp fragment of mitochondrial DNA control region from 27 Sus scrofa ancient samples retrieved from Southern Italian and Sardinian archeological sites, spanning in age from the Mesolithic to the Roman period. Our results surprisingly indicate the presence of the Near Eastern haplotype Y1 on both Italy's major islands (Sardinia and Sicily) during the Bronze Age, suggesting the seaborne transportation of domestic pigs by humans at least during 1600-1300 BC. The presence of the Italian E2 clade in domestic contexts shows that the indigenous wild boar was effectively domesticated or incorporated into domestic stocks in Southern Italy during the Bronze Age, although the E2 haplotype has never been found in modern domestic breeds. Pigs belonging to the endemic E2 clade were thus traded between the Peninsula and Sardinia by the end of the second millennium BC and this genetic signature is still detected in Sardinian feral pigs.


Extracellular signal-regulated kinases 1/2 control claudin-2 expression in Madin-Darby canine kidney strain I and II cells.
The tight junction of the epithelial cell determines the characteristics of paracellular permeability across epithelium. Recent work points toward the claudin family of tight junction proteins as leading candidates for the molecular components that regulate paracellular permeability properties in epithelial tissues. Madin-Darby canine kidney (MDCK) strain I and II cells are models for the study of tight junctions and based on transepithelial electrical resistance (TER) contain "tight" and "leaky" tight junctions, respectively. Overexpression studies suggest that tight junction leakiness in these two strains of MDCK cells is conferred by expression of the tight junction protein claudin-2. Extracellular signal-regulated kinase (ERK) 1/2 activation by hepatocyte growth factor treatment of MDCK strain II cells inhibited claudin-2 expression and transiently increased TER. This process was blocked by the ERK 1/2 inhibitor U0126. Transfection of constitutively active mitogen-activated protein kinase/extracellular signal-regulated kinase kinase into MDCK strain II cells also inhibited claudin-2 expression and increased TER. MDCK strain I cells have higher levels of active ERK 1/2 than do MDCK strain II cells. U0126 treatment of MDCK strain I cells decreased active ERK 1/2 levels, induced expression of claudin-2 protein, and decreased TER by approximately 20-fold. U0126 treatment also induced claudin-2 expression and decreased TER in a high resistance mouse cortical collecting duct cell line (94D). These data show for the first time that the ERK 1/2 signaling pathway negatively controls claudin-2 expression in mammalian renal epithelial cells and provide evidence for regulation of tight junction paracellular transport by alterations in claudin composition within tight junction complexes.


Varicella Zoster Virus Encephalitis in Denmark From 2015 to 2019-A Nationwide Prospective Cohort Study.
Knowledge of the epidemiology and clinical characteristics of varicella zoster virus (VZV) encephalitis remains limited. Nationwide prospective cohort study of adults treated for microbiologically confirmed VZV encephalitis at Danish departments of infectious diseases from 2015 to 2019. Modified Poisson regression analysis was used to compute adjusted relative risks (RRs) of unfavorable outcome. We identified 92 adults (49% female) with VZV encephalitis, yielding an incidence of 5.3/1 000 000 per year (95% CI, 4.2-6.6). Median age was 75 years (IQR, 67-83) and immunocompromising conditions were frequent (39%). Predominant symptoms were confusion (76%), headache (56%), nausea (45%), gait disturbance (42%), and personality changes (41%). Cranial imaging showed cerebral vasculitis (including infarction and hemorrhage) in 14 (16%) patients and encephalitic abnormalities in 11 (13%) with predilection for the brainstem and deep brain structures. Intravenous acyclovir treatment was initiated a median (IQR) of 13.4 hours (5.2-46.3) since admission, while cranial imaging and lumbar puncture were performed after 6.3 hours (2.5-31.0) and 18.5 hours (4.9-42.0). In-hospital, 1-month, and 3-month mortalities were 4%, 9%, and 11%, respectively. Unfavorable outcome (Glasgow Outcome Score of 1-4) was found in 69% at discharge, with age (adjusted RR [aRR], 1.02; 95% CI, 1.01-1.03), vasculitis (aRR, 1.38; 95% CI, 1.02-1.86), and Glasgow Coma Scale (GCS) <15 (aRR, 1.32; 95% CI, 1.01-1.73) identified as independent risk factors. VZV encephalitis occurs primarily in elderly or immunocompromised patients with a higher incidence than previously estimated. The diagnosis is often delayed; risk factors for unfavorable outcome are age, cerebral vasculitis, and GCS <15.


Analysing the generality of spatially predictive mosquito habitat models.
The increasing spread of multi-drug resistant malaria in African highlands has highlighted the importance of malaria suppression through vector control. Its historical success has meant that larval control has been proposed as part of an integrated malaria vector control program. Due to high operation costs, larval control activities would benefit greatly if the locations of mosquito habitats could be identified quickly and easily, allowing for focal habitat source suppression. Several mosquito habitat models have been developed to predict the location of mosquito habitats. However, to what extent these models can be generalised across time and space to predict the distribution of dynamic mosquito habitats remains largely unexplored. This study used mosquito habitat data collected in six different time periods and four different modelling approaches to establish 24 mosquito habitat models. We systematically tested the generality of these 24 mosquito habitat models. We found that although habitat--environment relationships change temporally, a modest level of performance was attained when validating the models using data collected from different time periods. We also describe flexible approaches to the predictive modelling of mosquito habitats, that provide novel modelling architecture for future research efforts.


Seagrass Halodule wrightii as a new habitat for the amphioxus Branchiostoma californiense (Cephalochordata, Branchiostomidae) in the southern Gulf of California, Mexico.
The first record of the amphioxus Branchiostoma californiense on seagrass patches of Halodule wrightii in the Gulf of California is reported. Sixty individuals (19 males, 18 females, and 23 undifferentiated) were collected in May 2017 at Bahía Balandra, Gulf of California, from subtidal seagrass patches at a depth of 0.5 m at low tide. The length and weight ranged from 15.88-28.44 mm and from 0.01-0.11 g for females and 11.7-27.9 mm and 0.01-0.09 g for males, respectively. The minimum size of sexually mature individuals was 11.70 mm for males and 15.88 mm for females; 62% of the specimens were sexually mature. Analysis of the total length-weight relationship suggested an allometric growth pattern among females, males and undifferentiated individuals, whereas an analysis of the entire sample suggested an isometric growth pattern. Typical and additional morphological characters were used to identify the amphioxi. High morphological variability between individuals was found, suggesting the presence of several morphotypes. Branchiostoma californiense had been previously reported as exclusively associated with bare sandy areas, but our study shows that this species can also be found in seagrass patches, using them as breeding and feeding grounds. Thus, seagrass patches are evidenced as suitable habitats for amphioxus.


Preoperative factors associated with postoperative hypocalcemia in dogs with primary hyperparathyroidism that underwent parathyroidectomy: 62 cases (2004-2009).
To identify preoperative variables associated with postoperative hypocalcemia in dogs with primary hyperparathyroidism undergoing parathyroidectomy. Retrospective case series. 62 dogs. Medical records of dogs undergoing parathyroidectomy for treatment of primary hyperparathyroidism between January 2004 and January 2009 at 4 institutions were reviewed; data regarding various preoperative variables and postoperative serum total and ionized calcium concentrations were recorded. Preoperative ultrasonographic and surgical findings were compared regarding laterality (right, left, or bilateral) of parathyroid gland lesions. Data were analyzed via ANOVA, simple linear regression, and multiple linear regression to identify associations between preoperative variables and postoperative serum total and ionized calcium nadir concentrations. Preoperative variables significantly associated with low postoperative serum total calcium nadir concentrations included old age, history of weakness, lack of gastrointestinal tract signs, high serum parathyroid hormone concentration, and low serum calcium-phosphorus concentration product value. Preoperative variables significantly associated with low postoperative serum ionized calcium nadir concentrations included sexually intact status, low body weight, high serum urea nitrogen concentration, and lack of polyuria and polydipsia in the history. Age, body weight, serum calcium-phosphorus concentration product, and serum concentrations of parathyroid hormone and urea nitrogen were included in the final multiple linear regression model for prediction of postoperative serum calcium concentrations. Ultrasonography was performed in 58 dogs; results for 44 (75.9%) dogs agreed with surgical findings regarding laterality of parathyroid gland lesions. Prediction of postoperative hypocalcemia in dogs in this study with primary hyperparathyroidism that underwent parathyroidectomy was difficult and depended on multiple (history, physical examination, and clinicopathologic) factors.


Endoplasmic reticulum stress and lipid metabolism: mechanisms and therapeutic potential.
The endoplasmic reticulum (ER) plays a crucial role in protein folding, assembly, and secretion. Disruption of ER homeostasis may lead to accumulation of misfolded or unfolded proteins in the ER lumen, a condition referred to as ER stress. In response to ER stress, a signal transduction pathway known as the unfolded protein response (UPR) is activated. UPR activation allows the cell to cope with an increased protein-folding demand on the ER. Recent studies have shown that ER stress/UPR activation plays a critical role in lipid metabolism and homeostasis. ER-stress-dependent dysregulation of lipid metabolism may lead to dyslipidemia, insulin resistance, cardiovascular disease, type 2 diabetes, and obesity. In this paper, we examine recent findings illustrating the important role ER stress/UPR signalling pathways play in regulation of lipid metabolism, and how they may lead to dysregulation of lipid homeostasis.


The effect of vitamin A deficiency on hepatic, renal and pulmonary glutathione S-transferase activities in the rat.
Feeding male weanling rats on a vitamin A-deficient diet for 6 weeks resulted in significant increases (44-57%) in glutathione S-aryl-, S-aralkyl- S-alkyl- and S-epoxidetransferase activities in the liver cytosol. Only the S-aralkyl- (27%) and S-alkyltransferase (14%) activities were significantly increased in the kidney as a result of deficiency. There was no effect on any of the pulmonary glutathione S-transferase activities. The increases in hepatic transferase activities were due primarily to increases (25-96%) in the apparent Vmax. There were no changes in the apparant Km of any of the four drug substrates employed. With 3,4-dichloronitrobenzene as the second substrate, the apparent Km for glutathione was increased by over 2-fold in vitamin A-deficient livers as compared with controls. The relationship between these results and enhanced susceptibility to chemical carcinogens in vitamin A deficiency is briefly discussed, and comparison is made between the effects of this nutritional state and pretreatment with drug inducers on the glutathione S-transferases.


A simple method to enrich an Agrobacterium-transformed population for plants containing only T-DNA sequences.
A simple modification to standard binary vector design has been utilized to enrich an Agrobacterium-transformed population for plants containing only T-DNA sequences. A lethal gene was incorporated into the non-T-DNA portion of a binary vector, along with a screenable marker. The resulting class of vectors is designated as NTL T-DNA vectors (non-T-DNA lethal gene-containing T-DNA vectors). The lethal gene used here is a CaMV 35S-barnase gene with an intron in the coding sequence (barnase-INT); the screenable marker is a pMAS-luciferase gene with an intron in the coding sequence (LUC-int). To evaluate the utility of this vector design, tobacco plants were transformed with either the NTL T-DNA vector or a control vector from which most of the barnase-INT gene was deleted. Populations of 50 transgenic plants were scored for LUC expression. The results indicated a dramatic reduction in the presence of non-T-DNA sequences in the transgenic population using the NTL T-DNA vector. Only one transgenic plant was found to be LUC+ using the NTL vector, compared with 42 of 50 plants using the control vector. Importantly, the efficiency with which transformed tobacco plants was obtained was reduced by no more than 30%. The reduction in LUC+ transgenics was partially reversed when a barstar-expressing tobacco line was transformed, indicating that barnase expression was responsible for the reduced frequency of incorporating non-T-DNA sequences. Similar transformation results were obtained with tomato and grape. The incorporation of a barnase-INT gene outside the left border appears to provide a generally applicable tool for enriching an Agrobacterium-transformed population for plants containing only T-DNA sequences.


Sigma receptors as potential therapeutic targets for neuroprotection.
Sigma receptors comprise a unique family of proteins that have been implicated in the pathophysiology and treatment of many central nervous system disorders, consistent with their high level of expression in the brain and spinal cord. Mounting evidence indicate that targeting sigma receptors may be particularly beneficial in a number of neurodegenerative conditions including Alzheimer׳s disease, Parkinson׳s disease, stroke, methamphetamine neurotoxicity, Huntington׳s disease, amyotrophic lateral sclerosis, and retinal degeneration. In this perspective, a brief overview is given on sigma receptors, followed by a focus on common mechanisms of neurodegeneration that appear amenable to modulation by sigma receptor ligands to convey neuroprotective effects and/or restorative functions. Within each of the major mechanisms discussed herein, the neuroprotective effects of sigma ligands are summarized, and when known, the specific sigma receptor subtype(s) involved are identified. Together, the literature suggests sigma receptors may provide a novel target for combatting neurodegenerative diseases through both neuronal and glial mechanisms.


A semi-mechanistic model to predict the effects of liver cirrhosis on drug clearance.
Liver cirrhosis is characterized by a decrease in functional hepatocytes, lowered circulating levels of plasma proteins and alterations in blood flow due to the development of portacaval shunts. Depending on the interplay between these parameters and the characteristics of an administered drug, varying degrees of impaired systemic clearance and first-pass metabolism are anticipated. The Simcyp Population-based ADME Simulator has already been used successfully to incorporate genetic, physiological and demographic attributes of certain subgroups within healthy populations into in vitro-in vivo extrapolation (IVIVE) of xenobiotic clearance. The objective of this study was to extend population models to predict systemic and oral drug clearance in relation to the severity of liver cirrhosis. Information on demographics, changes in hepatic blood flow, cytochrome P450 enzymes, liver size, plasma protein binding and renal function was incorporated into three separate population libraries. The latter corresponded to Child-Pugh scores A (mild), B (moderate) and C (severe) liver cirrhosis. These libraries, together with mechanistic IVIVE within the Simcyp Simulator, were used to predict the clearance of intravenous and oral midazolam, oral caffeine, intravenous and oral theophylline, intravenous and oral metoprolol, oral nifedipine, oral quinidine, oral diclofenac, oral sildenafil, and intravenous and oral omeprazole. The simulated patients matched the clinical studies as closely as possible with regard to demographics and Child-Pugh scores. Predicted clearance values in both healthy control and liver cirrhosis populations were compared with observed values, as were the fold increases in clearance values between these populations. There was good agreement (lack of statistically significant difference, two-tailed paired t-test) between observed and predicted clearance ratios, with the exception of those for two studies of intravenous omeprazole. Predicted clearance ratios were within 0.8- to 1.25-fold of observed ratios in 65% of cases (range 0.34- to 2.5-fold). The various drugs that were studied showed different changes in clearance in relation to disease severity, and a 'one size fits all' solution does not exist without considering the multiple sources of the changes. Predictions of the effects of liver cirrhosis on drug clearance are of potential value in the design of clinical studies during drug development and, clinically, in the assessment of likely dosage adjustment.


Effectiveness of group acceptance and commitment therapy in treating depression for acute stroke patients.
To date, the effectiveness of acceptance and commitment therapy (ACT) for acute stroke patients has not been well recognized. The study aimed to discover the effectiveness of group-based ACT in treating depression for acute stroke patients. We conducted a randomized controlled trial with 140 acute stroke patients with depression. The ACT intervention comprised seven sessions, of 45-60 min over 4 weeks. Data were collected pre- and post-intervention and at 3-month follow-up, assessing depression, health-related quality of life (HRQoL), psychological flexibility, cognitive fusion, sleep quality, and confidence. Overall, 99.3% of the included patients were assessed as having mild depression. The ACT intervention significantly reduced depression in acute stroke patients in comparison with the control group post-intervention and at 3 months (partial η 2 = . 306 $\eta^{2}=.306$ ). Additionally ACT significantly improved HRQoL-mental component summary, sleep quality, psychological flexibility, cognitive fusion, and confidence compared with control group. ACT is effective in treating acute stroke patients with depression, and the efficacy was maintained at 3-month follow-up.


Male partner testing and sexual behaviour following provision of multiple HIV self-tests to Kenyan women at higher risk of HIV infection in a cluster randomized trial.
Without significant increases in uptake of HIV testing among men, it will be difficult to reduce HIV incidence to disease elimination levels. Secondary distribution of HIV self-tests by women to their male partners is a promising approach for increasing male testing that is being implemented in several countries. Here, we examine male partner and couples testing outcomes and sexual decision making associated with this approach in a cluster randomized trial. We examined data from women at higher risk of HIV participating in the intervention arm of an ongoing pair-matched cluster randomized trial in Kenya. HIV-negative women ≥18 years who self-reported ≥2 partners in the past month were eligible. Participants received self-tests at enrolment and three-monthly intervals. They were encouraged to offer tests to sexual partners with whom they anticipated condomless sex. At six months, we collected data on self-test distribution, male partner and couples testing, and testing and sexual behaviour in the three most recent transactional sex encounters. We used descriptive analyses and generalized estimating equation models to understand how sexual behaviour was influenced by self-test distribution. From January 2018 to April 2019, 921/1057 (87%) participants completed six-month follow-up. Average age was 28 years, 65% were married, and 72% reported income through sex work. Participants received 7283 self-tests over six months, a median of eight per participant. Participants offered a median three self-tests to sexual partners. Of participants with a primary partner, 94% offered them a self-test. Of these, 97% accepted the test. When accepted, couples testing was reported among 91% of participants. Among 1954 transactional sex encounters, 64% included an offer to self-test. When offered self-tests were accepted by 93% of partners, and 84% who accepted conducted couples testing. Compared to partners with an HIV-negative result, condom use was higher when men had a reactive result (56.3% vs. 89.7%, p < 0.01), were not offered a self-test (56.3% vs. 62.0%, p = 0.02), or refused to self-test (56.3% vs. 78.3, p < 0.01). Providing women with multiple self-tests facilitated male partner and couples testing, and led to safer sexual behaviour. These findings suggest secondary distribution is a promising approach for reaching men and has HIV prevention potential. Clinical Trial Number: NCT03135067.


Susceptibility weighted imaging: neuropsychologic outcome and pediatric head injury.
Traumatic brain injury is among the most frequent pediatric neurologic disorders in the United States, affecting multiple aspects of neuropsychologic functioning. This study assessed the efficacy of susceptibility weighted imaging as a predictor of long-term neuropsychologic functioning after pediatric brain injury compared with magnetic resonance spectroscopic imaging. Susceptibility weighted imaging is a relatively new method that is considered superior to traditional magnetic resonance imaging sequences for detecting hemorrhagic diffuse axonal injury. In this study, imaging and spectroscopy were acquired 6 +/- 4 days after injury. Measures of neuropsychologic functioning were administered to 18 children and adolescents 1-4 years post injury. Negative correlations between lesion number and volume with neuropsychologic functioning were demonstrated. Lesion volume explained over 32% of the variance in cognitive performance, explaining at least an additional 20% beyond injury severity and age at injury alone and 19% beyond magnetic resonance spectroscopic metabolite variables. Exploratory analyses resulted in notable trends, with lesions in deeper brain regions more strongly associated with poorer neuropsychologic performance. Improved detection of the extent of diffuse axonal injury following a brain injury will allow for a better understanding of its association with long-term outcome, which in turn can improve prognostic efficacy for effective treatment planning.


Postsynaptic cell type and synaptic distance do not determine efficiency of monosynaptic rabies virus spread measured at synaptic resolution.
Retrograde monosynaptic tracing using glycoprotein-deleted rabies virus is an important component of the toolkit for investigation of neural circuit structure and connectivity. It allows for the identification of first-order presynaptic connections to cell populations of interest across both the central and peripheral nervous system, helping to decipher the complex connectivity patterns of neural networks that give rise to brain function. Despite its utility, the factors that influence the probability of transsynaptic rabies spread are not well understood. While it is well established that expression levels of rabies glycoprotein used to trans-complement G-deleted rabies can result in large changes in numbers of inputs labeled per starter cell (convergence index [CI]), it is not known how typical values of CI relate to the proportions of synaptic contacts or input neurons labeled. And it is not known whether inputs to different cell types, or synaptic contacts that are more proximal or distal to the cell body, are labeled with different probabilities. Here, we use a new rabies virus construct that allows for the simultaneous labeling of pre- and postsynaptic specializations to quantify the proportion of synaptic contacts labeled in mouse primary visual cortex. We demonstrate that with typical conditions about 40% of first-order presynaptic excitatory synapses to cortical excitatory and inhibitory neurons are labeled. We show that using matched tracing conditions there are similar proportions of labeled contacts onto L4 excitatory pyramidal, somatostatin (Sst) inhibitory, and vasoactive intestinal peptide (Vip) starter cell types. Furthermore, we find no difference in the proportions of labeled excitatory contacts onto postsynaptic sites at different subcellular locations.


The Putative Use of Lithium in Alzheimer's Disease.
Alzheimer`s disease is a progressive neurodegenerative illness characterized by the invariant existence of β-amyloid plaques and neurofibrillary tangles. Presently approved pharmaceutical approaches offer only marginal efficacy and as yet there is no effective treatment which reverses or arrests the disease. Thus far, drugs targeting any single aspect of disease pathology have proved to be a failure or at best provided very slight clinical benefit. The consistent failure of drugs targeting aspects of the Aβ cascade has questioned the causal role of this pathway. There is a growing appreciation that the pathogenesis of the illness is multifactorial with Amyloid Beta, Phosphorylated Tau (ptau), inflammation, mitochondrial dysfunction, calcium dyshomeostasis, heavy metal imbalances, and GSK-3 interact in a highly complex manner to provoke a selfsustaining spiraling cascade of pathology, driving disease progression. In the light of such complex pathology, the failure of drugs aimed a targeting single molecules is not surprising as such approaches are usually ineffective against other complex diseases with a multifactorial pathogenesis. Combination therapies or multi target drugs might be more effective in controlling such illnesses. The putative neuroprotective effects of Lithium are achieved via the positive modulation of numerous homeostatic mechanisms regulating autophagy, oxidative stress, inflammation, and mitochondrial dysfunction likely achieved by inhibiting GSK-3 and inositol-145 triphosphate. Data regarding efficacy in human trials and animal models of AD are mixed, but recent data using "microdose" lithium in mild cognitive impairment is encouraging, hence lithium could be a putative multi target treatment in these patients. However, additional well designed long-term trials are needed to confirm its efficacy and safety, given that long term use is necessary to achieve reasonable therapeutic benefit.


Safety and Efficacy of Rapid Methadone Titration for Opioid Use Disorder in an Inpatient Setting: A Retrospective Cohort Study.
Inpatient guidelines for methadone titration do not exist, whereas outpatient guidelines lack flexibility and do not consider individual opioid tolerance. The evaluation of rapid, adaptable titration protocols may allow more patient-centered and effective treatment for opioid use disorder in the fentanyl era. This study performed a retrospective chart review of patients 18 years or older with opioid use disorder who were initiated on methadone at a single academic urban hospital using a rapid divided dose protocol between November 2019 and November 2020. The primary outcome was adverse events associated with methadone, specifically opioid toxicity or sedation requiring increased medical observation or intervention. The secondary outcome was total daily dose of methadone received on day 7 of titration. Ninety-eight patients were included for a total of 168 visits. Sixty-five (66%) were male, with a median age of 38 years (interquartile range, 31-42 years). Sedation occurred in 2 patients (1%), who required either naloxone administration or transfer to an intensive care unit for monitoring. Of the 135 visits where patients received at least 7 days of methadone, the mean dose on day 1 was 41 mg (SD, 9.6 mg) and on day 7 was 65 mg (SD, 20.9 mg). In this inpatient cohort, rapid methadone titration was well tolerated and resulted in patients reaching higher doses of methadone than would be possible with a standard schedule, with few adverse events. Given the known effective dose range, this approach may result in shorter time to clinical stabilization and suggests that alternative methadone titration schedules may be safe and effective in appropriately selected patients.


Key proteins in the polyamine-trypanothione pathway as drug targets against Trypanosoma cruzi.
In trypanosomatids, redox homeostasis is centered on trypanothione (N(1),N(8)-bis(glutathionyl)spermidine, T(SH)2), a low molecular weight thiol that is distinctive for this taxonomic family and not present in the mammalian host. Thus, the study of the metabolism of T(SH)2 is interesting as a potential therapeutic target. In this review, we summarize the existing evidence about the metabolism of thiols in Trypanosoma cruzi, focused on those proteins that can be considered the best candidates for selective therapy. Herein, we examine the biosynthetic pathway of T(SH)2, identifying three key points that are susceptible to attack pharmacologically: the activity of the trypanothione reductase (TR), the function of glutamate-cysteine ligase (GCL) and polyamine transport in T. cruzi. TR has been widely studied and is a good example for the development of the medicinal chemistry of antichagasic compounds. Conversely, GCL and the polyamine uptake system are high flow points in the reductive metabolism of the parasite. However, very little is known at the molecular level about these two systems. Therefore, their potential as targets for drug development is discussed, and it is suggested that research should focus on the production of alternative drugs for Chagas' disease treatment.


Comparison of Goldmann applanation tonometer, Tono-Pen and noncontact tonometer in children.
To evaluate the agreement of Goldmann applanation tonometer (GAT) with Tono-Pen and noncontact tonometer (NCT) for measurement of intraocular pressure (IOP) in pediatric age group and to evaluate the correlation between central corneal thickness (CCT) and IOP measured with the tonometers used. IOP was measured in 200 eyes in a group of Indian children, aged between 8 and 18 years using three different tonometers: NCT, the Tono-Pen and GAT. All IOP readings were made in the office settings by the same examiner. Readings obtained were compared between the instruments and with the CCT for each tonometer. Tonometer inter-method agreement was assessed by the Bland-Altmann method. The relations of CCT with absolute IOP values and inter-tonometer differences were analyzed by linear regression. The mean age was 13.37 ΁ 3.51 years. The mean IOP values recorded with NCT; Tono-Pen and GAT were 14.38, 15.63, and 12.44 mmHg, respectively. Both Tono-Pen and NCT recorded statistically higher IOP values than the GAT (P = 0.00) regardless of the CCT. The percentage increase of IOP measured over GAT was 15.66% for NCT and 25.70% for Tono-Pen which was also statistically significant. A correlation was found between CCT and IOP values obtained with all the three tonometers. IOP measurements on children vary significantly between instruments and correlations are affected by the corneal thickness. Further studies on children are needed to determine which instrument is most appropriate and to derive a normative IOP scale for the growing eye.


Chronic kidney disease and cognitive impairment in menopausal women.
Although end-stage renal disease has been associated with cognitive impairment, the relation between lesser degrees of chronic kidney disease (CKD) and cognitive impairment is less well understood. Data for 1,015 women enrolled at 10 of the 20 Heart Estrogen/Progestin Replacement Study clinical sites were analyzed. All participants were younger than 80 years and had established coronary artery disease at study entry. Participants underwent 6 standard tests of cognitive function evaluating various domains. Unadjusted, residual age- and race-adjusted, and multivariable-adjusted linear and logistic regression models were used. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease regression equation. In addition to analyses across the spectrum of GFRs, CKD was categorized as mild (estimated GFR [eGFR], 45 to 60 mL/min/1.73 m2), moderate (eGFR, 30 to 44 mL/min/1.73 m2), and severe (eGFR, <30 mL/min/1.73 m2) according to a modification of recently established classification guidelines. Mean eGFR was 57 +/- 14 mL/min/1.73 m2. In multivariable analyses, eGFR was associated significantly with impairment in global cognition, executive function, language, and memory (approximately 15% to 25% increase in risk for dysfunction/10-mL/min/1.73 m2 decrement in eGFR). Associations among eGFR and cognitive function were independent of residual effects of age and race (2 key determinants of GFR) and the contributions of education, lifestyle factors, stroke, diabetes, and other laboratory variables. CKD is associated with cognitive impairment in menopausal women with coronary artery disease.


Investigating the Added Value of the EQ-5D-5L With Two Bolt-On Items in Patients With Hemophilia.
Objective: This study examined the impact of adding two condition-specific bolt-on items to the EQ-5D-5L and assessed their psychometric properties in patients with hemophilia. Methods: The data were obtained from a nationwide cross-sectional online survey of patients with hemophilia in China. Self-reported and proxy-reported data were analyzed separately. Ceiling effect, informativity, and discriminatory power of the EQ-5D-5L with two bolt-on items, dignity (DG), and bleeding (BL), were examined. Spearman's rank correlation (rho) was used to assess the associations of the EQ-5D-5L and two bolt-on items with the Hemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) and SF-12. Multiple regression analysis was performed to evaluate the explained variance of the EQ-5D-5L and bolt-on items in predicting EQ-VAS scores. Results: A total of 895 patients and 222 caregivers completed the questionnaire. The ceiling effect decreased from 1.9 to 0.6% and 5.9 to 0.9% when using the EQ-5D-5L and the EQ-5D-5L with two bolt-on items among participants with both self- and proxy-completed questionnaires. Both DG and BL were strongly correlated with Haem-A-QoL sum score [rho: DG = 0.64 (patient) vs. 0.66(proxy); BL = 0.49 (patient) vs. 0.31 (proxy)], SF-12 mental component [rho: DG = -0.36 (patient) vs. -0.41 (proxy); BL = -0.53 (patient) vs. -0.57(proxy)], and SF-12 physical component [rho: DG = -0.61 (patient) vs. -0.61 (proxy); BL = -0.35 (patient) vs. -0.39 (proxy)]. Known-group comparisons confirmed that the two bolt-on items had satisfactory discriminatory power. Multiple regression analysis indicated that adding two bolt-on items significantly increased the ability to predict EQ-VAS scores. The adjusted R 2 increased by 8.2 and 8.8% for reports completed by the patients or patients' proxy respondents, respectively. Conclusion: Adding the DG and BL bolt-on items can increase performance on the EQ-5D-5L in patients with hemophilia. A future valuation study will be carried out.


One-stage simple mastectomy with immediate reconstruction for high-risk patients. An improved technique: the biologic basis for ductal-glandular mastectomy.
The heterogeneity of human breast carcinoma appears to be a cumulative interrelationship of genetic and environmental factors that may be identifiable with a high risk for carcinogenesis. Until breast cancer prevention is realized, one-stage total ductal-glandular mastectomy with immediate reconstruction may be offered as an alternative to simple mastectomy for women at high risk for developing cancer. This technique affords the complete extirpation of breast tissue at a deep plane with flaps that are identical in thickness to those elevated in classic mastectomies for invasive cancer. Breast reconstruction with submuscular prostheses in a one-stage procedure gives an aesthetically acceptable result. The role of ductal-glandular mastectomy as prophylaxis for invasive carcinoma warrants future prospective trials.


[Maternity in adolescents in the districts and neighborhoods of Barcelona: its association with the socioeconomic level and the prevalence of low weight at birth. The Working Group of Maternal-Child Health of the Municipal Institute of Health of Barcelona].
To describe the distribution of birth rates and low birth weight among teenagers from the health districts and neighbourhoods of Barcelona and their association with social and economic level. Environmental study. City of Barcelona. The birth rates for under-20 year olds resident in Barcelona for the periods 1980-1982, 1987-1992 and 1990-1992 were calculated. The index of family economic capacity (IFEC) was used as a social and economic indicator. The coefficient of Spearman was used as a correlative measurement. Between the periods 1980-1982 and 1990-1992, a 65% drop in the adolescent birth rate was observed. The correlation of birth rates with the IFEC for the district fell from -0.91 to -0.69 in the same period. Adolescent birth rates have very uneven geographical distribution, which correlates with the distribution of income. The percentage of low weight at birth is higher in the poorest districts, but the association with IFEC is much weaker.


Various pAQU plasmids possibly contribute to disseminate tetracycline resistance gene tet(M) among marine bacterial community.
Emergence of antibiotic-resistant bacteria in the aquaculture environment is a significant problem for disease control of cultured fish as well as in human public health. Conjugative mobile genetic elements (MGEs) are involved in dissemination of antibiotic resistance genes (ARGs) among marine bacteria. In the present study, we first designed a PCR targeting traI gene encoding essential relaxase for conjugation. By this new PCR, we demonstrated that five of 83 strains isolated from a coastal aquaculture site had traI-positive MGEs. While one of the five strains that belonged to Shewanella sp. was shown to have an integrative conjugative element of the SXT/R391 family (ICEVchMex-like), the MGEs of the other four strains of Vibrio spp. were shown to have the backbone structure similar to that of previously described in pAQU1. The backbone structure shared by the pAQU1-like plasmids in the four strains corresponded to a ~100-kbp highly conserved region required for replication, partition and conjugative transfer, suggesting that these plasmids constituted "pAQU group." The pAQU group plasmids were shown to be capable of conjugative transfer of tet(M) and other ARGs from the Vibrio strains to E. coli. The pAQU group plasmid in one of the examined strains was designated as pAQU2, and its complete nucleotide sequence was determined and compared with that of pAQU1. The results revealed that pAQU2 contained fewer ARGs than pAQU1 did, and most of the ARGs in both of these plasmids were located in the similar region where multiple transposases were found, suggesting that the ARGs were introduced by several events of DNA transposition into an ancestral plasmid followed by drug selection in the aquaculture site. The results of the present study indicate that the "pAQU group" plasmids may play an important role in dissemination of ARGs in the marine environment.


Metabolic effects of the incretin mimetic exenatide in the treatment of type 2 diabetes.
Interventional studies have demonstrated the impact of hyperglycemia on the development of vascular complications associated with type 2 diabetes, which underscores the importance of safely lowering glucose to as near-normal as possible. Among the current challenges to reducing the risk of vascular disease associated with diabetes is the management of body weight in a predominantly overweight patient population, and in which weight gain is likely with many current therapies. Exenatide is the first in a new class of agents termed incretin mimetics, which replicate several glucoregulatory effects of the endogenous incretin hormone, glucagon-like peptide-1 (GLP-1). Currently approved in the US as an injectable adjunct to metformin and/or sulfonylurea therapy, exenatide improves glycemic control through multiple mechanisms of action including: glucose-dependent enhancement of insulin secretion that potentially reduces the risk of hypoglycemia compared with insulin secretagogues; restoration of first-phase insulin secretion typically deficient in patients with type 2 diabetes; suppression of inappropriately elevated glucagon secretion to reduce postprandial hepatic output; and slowing the rate of gastric emptying to regulate glucose appearance into the circulation. Clinical trials in patients with type 2 diabetes treated with subcutaneous exenatide twice daily demonstrated sustained improvements in glycemic control, evidenced by reductions in postprandial and fasting glycemia and glycosylated hemoglobin (HbA(1c)) levels. Notably, improvements in glycemic control with exenatide were coupled with progressive reductions in body weight, which represents a distinct therapeutic benefit for patients with type 2 diabetes. Acute effects of exenatide on beta-cell responsiveness along with significant reductions in body weight in patients with type 2 diabetes may have a positive impact on disease progression and potentially decrease the risk of associated long-term complications.


Effect of Horizontal Osteotomy Level on Complication Rates and Neurosensory Deficits After Sagittal Split Ramus Osteotomy.
Horizontal osteotomy is one of the most critical step at sagittal split ramus osteotomy (SSRO) and determination of the ideal height of this horizontal osteotomy is essential to avoid nerve and vessel injury. The aim of this study was to evaluate the level of the medial horizontal ramus cut as a risk factor for unfavorable outcomes in the SSRO. Sixty-four patients with dentofacial deformity who applied to Oral & Maxillofacial Surgery Department between August 2018 and August 2019 and undergone orthognathic surgery were evaluated. Out of 64, 49 patients had SSRO with or without maxillary surgery and genioplasty. Twenty-six patient had postoperative computed tomography scan with 6-months follow-up. Finally, 26 patient with 52 SSRO sides were included in this study. Computed tomography scans were evaluated and classification according to osteotomy levels was made. Postoperative neurosensory deficit, bleeding, and intraoperative complications such as bad split, visible damage to inferior alveolar bundle were assessed. Age, gender, neurosensory deficit, bad splits were analyzed and correlated with the level of the osteotomies. Fifteen osteotomies were above lingula, 24 between apex and base of lingula, and 14 below lingula. One bad split occurred, and no visible damage to the inferior alveolar bundle was seen. There was no significant difference between osteotomy groups in terms of visual analogue scale (VAS) scores (P > 0.05) but in all groups; women's VAS scores are statistically significantly higher than men. (P: 0.036). There is no correlation between the horizontal osteotomy level and intraoperative or postoperative complications. The low medial horizontal osteotomy can be safely performed in SSRO.


Preparation and characterization of chelating fibers based on natural wool for removal of Hg(II), Cu(II) and Co(II) metal ions from aqueous solutions.
The graft copolymerization of acrylonitrile (AN) onto natural wool fibers initiated by KMnO(4) and oxalic acid combined redox initiator system in limited aqueous medium was carried out in heterogeneous media. Moreover, modification of the grafted wool fibers was done by changing the nitrile group (-CN) into cyano-acetic acid α-amino-acrylic-hydrazide through the reaction with hydrazine hydrate followed by ethylcyanoacetate which eventually produce wool-grafted-poly(cyano-acetic acid α-amino-acrylic-hydrazide) (wool-g-PCAH) chelating fibers. The application of the modified fibers for metal ion uptake was studied using Hg(2+), Cu(2+) and Co(2+). The modified chelating fibers were characterized using FTIR spectroscopy, SEM and X-ray diffraction.


Gene expression patterns define pathways correlated with loss of differentiation in lung adenocarcinomas.
An analysis of microarray data from 86 lung adenocarcinomas reveals hundreds of genes significantly correlated with tumor cell differentiation. A bioinformatics approach of linking these genes to public information from the Locuslink and KEGG databases yields evidence for a loss of tumor cell differentiation being associated with biological processes of cell division, protein degradation, pyrimidine and purine metabolism, oxidative phosphorylation, glyoxylate and dicarboxylate metabolism, folate biosynthesis, and glutamate metabolism. The increased expression of genes involved in these processes is consistent with increased proliferation and metabolism characteristics of poorly differentiated tumors. The complete results of this analysis are available at http://dot.ped.med.umich.edu:2000/pub/diff/index.htm.


Type II collagen distribution in the ear of the guinea pig fetus.
By using monoclonal antibodies to type II collagen and immunohistochemical techniques, we studied the distribution of type II collagen in the developing guinea pig ear. Type II collagen appearance and disappearance corresponded to cartilage development and resorption. Type II collagen was identified in Meckel's and Reichert's cartilages, the cartilage plate of the auricle and external acoustic meatus, the ossicles, eustachian tube cartilage, and the otic capsule. Type II collagen also appeared with the development of structures in noncartilaginous parts including the tympanic membrane, tympanic annulus, basilar membrane, spiral limbus, spiral ligament, and osseous spiral lamina, Rosenthal's canal, the maculae of the utricle and saccule, and the semicircular canal membrane, crista ampullaris, and endolymphatic duct. Type II collagen is distributed widely in the ear after the early stages of development. Thus, type II collagen should be considered an important structural component of the ear.


Genetic diversity is related to climatic variation and vulnerability in threatened bull trout.
Understanding how climatic variation influences ecological and evolutionary processes is crucial for informed conservation decision-making. Nevertheless, few studies have measured how climatic variation influences genetic diversity within populations or how genetic diversity is distributed across space relative to future climatic stress. Here, we tested whether patterns of genetic diversity (allelic richness) were related to climatic variation and habitat features in 130 bull trout (Salvelinus confluentus) populations from 24 watersheds (i.e., ~4-7th order river subbasins) across the Columbia River Basin, USA. We then determined whether bull trout genetic diversity was related to climate vulnerability at the watershed scale, which we quantified on the basis of exposure to future climatic conditions (projected scenarios for the 2040s) and existing habitat complexity. We found a strong gradient in genetic diversity in bull trout populations across the Columbia River Basin, where populations located in the most upstream headwater areas had the greatest genetic diversity. After accounting for spatial patterns with linear mixed models, allelic richness in bull trout populations was positively related to habitat patch size and complexity, and negatively related to maximum summer temperature and the frequency of winter flooding. These relationships strongly suggest that climatic variation influences evolutionary processes in this threatened species and that genetic diversity will likely decrease due to future climate change. Vulnerability at a watershed scale was negatively correlated with average genetic diversity (r = -0.77; P < 0.001); watersheds containing populations with lower average genetic diversity generally had the lowest habitat complexity, warmest stream temperatures, and greatest frequency of winter flooding. Together, these findings have important conservation implications for bull trout and other imperiled species. Genetic diversity is already depressed where climatic vulnerability is highest; it will likely erode further in the very places where diversity may be most needed for future persistence.


[Sinus cavernous syndrome caused by isolated aspergillosis of the sphenoid sinus].
Isolated aspergillosis of the sphenoid sinus is a rare condition that is frequently diagnosed at a late stage because of its nonspecific and varying symptomatology. We report the case of a 75-year-old diabetic woman with a long history of retroorbital pain before she developed a subacute cavernous sinus syndrome. Neuroimaging including CT scan and MRI suggested a malignant tumor involving the sphenoid sinus but the diagnosis of aspergillosis was made intraoperatively and by histopathological examination. Soon after surgical drainage of the sphenoid sinus and systemic anti-fungal drug therapy, both retroorbital pain and cavernous sinus syndrome had completely resolved. This case emphasizes the fact that invasive isolated sphenoid sinus aspergillosis must be considered in the list of lesions causing sinus cavernous syndrome.


The Dynamics of Lateral Gene Transfer in Genus Leishmania - A Route for Adaptation and Species Diversification.
The genome of Leishmania major harbours a comparably high proportion of genes of prokaryote origin, acquired by lateral gene transfer (LGT). Some of these are present in closely related trypanosomatids, while some are detected in Leishmania only. We have evaluated the impact and destiny of LGT in genus Leishmania. To study the dynamics and fate of LGTs we have performed phylogenetic, as well as nucleotide and amino acid composition analyses within orthologous groups of LGTs detected in Leishmania. A set of universal trypanosomatid LGTs was added as a reference group. Both groups of LGTs have, to some extent, ameliorated to resemble the recipient genomes. However, while virtually all of the universal trypanosomatid LGTs are distributed and conserved in the entire genus Leishmania, the LGTs uniquely present in genus Leishmania are more prone to gene loss and display faster rates of evolution. Furthermore, a PCR based approach has been employed to ascertain the presence of a set of twenty LGTs uniquely present in genus Leishmania, and three universal trypanosomatid LGTs, in ten additional strains of Leishmania. Evolutionary rates and predicted expression levels of these LGTs have also been estimated. Ten of the twenty LGTs are distributed and conserved in all species investigated, while the remainder have been subjected to modifications, or undergone pseudogenization, degradation or loss in one or more species. LGTs unique to the genus Leishmania have been acquired after the divergence of Leishmania from the other trypanosomatids, and are evolving faster than their recipient genomes. This implies that LGT in genus Leishmania is a continuous and dynamic process contributing to species differentiation and speciation. This study also highlights the importance of carefully evaluating these dynamic genes, e.g. as LGTs have been suggested as potential drug targets.


Ocular findings in mycosis fungoides.
Thirty consecutive patients with biopsy-proved mycosis fungoides were examined ophthalmologically. Specific ocular changes, judged directly related to the mycosis fungoides, were found in 11 of the 30 subjects, usually in the late plaque or tumor stages of the disease. Tumors, especially involving the lids, were the most common ophthalmic finding. Keratitis, uveitis, and optic atrophy were also described. A review of the literature is given, and changes found in patients in this series correlate well with ophthalmic findings presented in diverse isolated case reports. It seems that the frequency of ophthalmic pathologic findings in mycosis fungoides is much more common than previously assumed.


The relevance of Choukroun's platelet-rich fibrin and metronidazole during complex maxillary rehabilitations using bone allograft. Part II: implant surgery, prosthodontics, and survival.
Extensive bone grafting remains a delicate procedure, due to the slow and difficult integration of the grafted material into the physiological architecture. The recent use of platelet concentrates aims to improve this process of integration by accelerating bone and mucosal healing. Choukroun's platelet-rich fibrin (PRF) is a healing biomaterial that concentrates in a single autologous fibrin membrane, most platelets, leukocytes, and cytokines from a 10-mL blood harvest, without artificial biochemical modification (no anticoagulant, no bovine thrombin). In this second part, we describe the implant and prosthetic phases of a complex maxillary rehabilitation, after preimplant bone grafting using allograft, Choukroun's PRF membranes, and metronidazole. Twenty patients were treated using this new technique and followed up during 2.1 years (1-5 years). Finally, 184 dental implants were placed, including 54 classical screw implants (3I, Palm Beach Gardens, FL) and 130 implants with microthreaded collar (46 from AstraTech, Mölndal, Sweden; 84 from Intra-Lock, Boca Raton, FL). No implant or graft was lost in this case series, confirming the validity of this reconstructive protocol. However, the number of implants used per maxillary rehabilitation was always higher with simple screw implants than with microthreaded implants, the latter presenting a stronger initial implant stability. Finally, during complex implant rehabilitations, PRF membranes are particularly helpful for periosteum healing and maturation. The thick peri-implant gingiva is related to several healing phases on a PRF membrane layer and could explain the low marginal bone loss observed in this series. Microthreaded collar and platform-switching concept even improved this result. Multiple healing on PRF membranes seems a new opportunity to improve the final esthetic result.


Comparison of acquisition parameters and breast dose in digital mammography and screen-film mammography in the American College of Radiology Imaging Network digital mammographic imaging screening trial.
The purpose of our study was to compare the technical performance of full-field digital mammography (FFDM) and screen-film mammography. The American College of Radiology Imaging Network Digital Mammographic Imaging Screening Trial enrolled 49,528 women to compare FFDM and screen-film mammography for screening. For quality assurance purposes, technical parameters including breast compression force, compressed breast thickness, mean glandular dose, and the number of additional views needed for complete breast coverage were recorded and analyzed for both FFDM and screen-film mammography on approximately 10% of study subjects at each site. Technical data were compiled on 5,102 study subjects at 33 sites. Clean data were obtained for 4,366 (88%) of those cases. Mean compression force was 10.7 dN for screen-film mammography and 10.1 dN for FFDM (5.5% difference, p < 0.001). Mean compressed breast thickness was 5.3 cm for screen-film mammography and 5.4 cm for FFDM (1.7% difference, p < 0.001). Mean glandular dose per view averaged 2.37 mGy for screen-film mammography and 1.86 mGy for FFDM, 22% lower for digital than screen-film mammography, with sizeable variations among digital manufacturers. Twelve percent of screen-film mammography cases required more than the normal four views, whereas 21% of FFDM cases required more than the four normal views to cover all breast tissue. When extra views were included, mean glandular dose per subject was 4.15 mGy for FFDM and 4.98 mGy for screen-film mammography, 17% lower for FFDM than screen-film mammography. Our results show that differences between screen-film mammography and FFDM in compression force and indicated compressed breast thickness were small. On average, FFDM had 22% lower mean glandular dose than screen-film mammography per acquired view, with sizeable variations in average FFDM doses by manufacturer.


Binding thermodynamics as a tool to investigate the mechanisms of drug-receptor interactions: thermodynamics of cytoplasmic steroid/nuclear receptors in comparison with membrane receptors.
Drug-receptor binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of receptor-recognition phenomena. The large number of membrane receptors so far studied has led to the discovery of enthalpy-entropy compensation effects in drug-receptor binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic receptors was known, this paper reports on binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear receptors, respectively, as determined by variable-temperature binding constant measurements. The binding at 25 degrees C appears enthalpy/entropy-driven (-53.0 </= DeltaG degrees </= -48.6, -34.5 </= DeltaH degrees </= -19.9 kJ/mol, 0.057 </= DeltaS degrees </= 0.111, and -2.4 </= DeltaC(p) degrees </= -1.7 kJ mol(-1) K(-1)) and is interpreted in terms of hydrophobic and hydrogen-bonded specific interactions. Results obtained for cytoplasmic receptors are extensively compared with those known for typical membrane receptors, in particular the adenosine A(1) receptor, to investigate the thermodynamic bases of drug-receptor binding from the most general point of view.


Imprint cytology of cat scratch disease. A report of eight cases.
The cytologic features of cat scratch disease (CSD) from eight cases in imprint smears are presented. All patients were clinicopathologically diagnosed with CSD as follows: 1) a history of animal exposure was recorded 2 to 4 weeks before lymphadenopathy; 2) the disease occurred in the autumn and winter months; 3) a characteristic histopathology in the biopsied lymph node specimens was observed; and 4) Warthin-Starry silver stain-positive bacteria were detected in four of the seven cases examined. The characteristic cytologic finding was the presence of confluent epithelioid cells with nearby and central scattering of neutrophils against a background of polymorphic inflammatory cells. Furthermore, a varying number of medium-sized to large lymphoid cells with an appearance suggestive of monocytoid B lymphocytes (MBLs) were noted to be associated with the epithelioid cells. These cytologic findings closely paralleled the histologic patterns of epithelioid cell granulomas, with and without MBLs, which we have previously reported are probably associated with the disease.


Rationale and design of a multicenter study of selegiline and alpha-tocopherol in the treatment of Alzheimer disease using novel clinical outcomes. Alzheimer's Disease Cooperative Study.
This report describes the rationale and design of a clinical trial using selegiline (10 mg/day) and alpha-tocopherol (2,000 IU/day) to slow the progression of dementia in Alzheimer disease (AD). This study was developed by the Alzheimer's Disease Cooperative Study (ADCS), a consortium of clinical research centers actively involved in AD research. The major goal of the consortium is to design and conduct clinical investigations leading to the development of treatments for AD. This study uses a randomized double-blind, placebo-controlled, 2 x 2 factorial, parallel group design to test two drugs for the treatment of AD. The primary outcome of the study is the time to reach any one of the following four endpoints: death, institutionalization, loss of two of three basic activities of daily living, and progression of Clinical Dementia Rating (CDR) stage from 2 to 3. Patients with moderately severe disease (CDR = 2) were enrolled and evaluated 10 times over a period of 2 years to determine if these agents reduce the time to reach any endpoint. A database from the Consortium to Establish a Registry for Alzheimer's Disease indicated adequate power analyses to observe a treatment effect on this clinically meaningful outcome measure. Recruitment and baseline characteristics of the population are provided. The rationale for the choice of a factorial design, the use of a novel, clinically meaningful endpoint, and the selection of a cohort of patients with AD of moderate severity are discussed.


[Community-acquired pneumonia: impact of the use of a therapeutic strategy based on probability of short-term mortality].
To assess the impact of the use of a therapeutic strategy based on classifying patients with community-acquired pneumonia (CAP) according to the probability of short-term mortality. During one year, all patients admitted to the Emergency Department with diagnosis of CAP were included. Clinicians were invited to treat patients according to a recently published protocol that stratifies patients into five categories (from low to high-risk mortality): patients assigned to class 1 were managed at home; patients included in classes 2 and 3 were assigned to a short-time period at emergency department before managed at home; and patients assigned to classes 4 and 5 were hospitalized. The final population analyzed included 101 patients. The rate of acceptability among clinicians was 96.7%. Patients were classified by the following terms: risk-class 1: 17 (16.8%); risk-classes 2 and 3: 40 (39.7%); risk-classes 4 and 5: 44 (43.6%). During follow-up, of the 57 non-hospitalized patients, 3 (5.2%) were subsequently admitted to hospital and 7 (12.2%) patients initially assigned to a short-time period at emergency department were hospitalized, and 1 (1.7%) of them died. By this program, the reduction of the hospitalization rate was 23.8%. A strategy of management of CAP based on a prognostic classification has a good safety and acceptability among clinicians, and reduces the rate of hospitalizations.


Sequence analysis and transcriptional regulation of the Escherichia coli grpE gene, encoding a heat shock protein.
We have sequenced the Escherichia coli grpE gene and shown that it encodes a 197-amino acid residue protein of 21,668-Mr. The predicted N-terminal amino acid sequence, as well as the overall amino acid composition agree well with that of the purified protein. From Northern analysis, we have shown that transcription of the grpE gene is under heat shock regulation, i.e., there is a rapid and transient increase in the rate of synthesis of grpE mRNA upon a shift-up in temperature. Forty-six bases upstream of the structural gene is a sequence closely related to the consensus heat shock promoter identified by Cowing et al. [Proc. Natl. Acad. Sci. U.S.A, 82, 2679-2683]. We have shown by S1 mapping and RNA sequencing that this is indeed the promoter for the grpE mRNA. It appears that all discernable transcription initiates only from this promoter, even under non-heat shock conditions.


Giant Peripheral Temporomandibular Osteoma With Immediate Reconstruction of Mandible.
Osteoma is a benign osteogenic tumor, which is characterized the slow-growing proliferation of compact or cancellous bone. The etiology of the lesion is not well established. Among the hypotheses, the following are related: a traumatic factor, infectious processes, or true neoplasm due to the origin of cartilaginous cells. It can present at any age, usually in young adult individuals, with equal prevalence in both sexes. The clinical characteristics of the peripheral osteoma are represented by slow asymptomatic growth, which leads to swelling and, thus, facial asymmetry. When it is related to the mandibular condyle, this growth can cause functional impairment, such as malocclusion, temporomandibular joint dysfunction, and even limited mouth-opening owing to ankylosis.


Health-related quality of life and multimorbidity in community-dwelling telecare-assisted elders in the Basque Country.
Multimorbidity is more common in the elderly population and negatively affects health-related quality of life (QoL). The aims of the study were to report the QoL of users of the Basque telecare public service (BTPS) and to establish its relationship with multimorbidity. The EuroQol questionnaire was administered to 1125 users of the service. Their sociodemographic and healthcare characteristics were obtained from BTPS databases and the Basque healthcare service. Multiple regression analysis was performed on the overall questionnaire index to determine the effect of chronic diseases and sociodemographic. Moreover, the effects of the different diseases on specific dimensions of the test were explored by logistic regression. Of the users interviewed, 82% were women, 88% ≥75 years and 66% lived alone. The average of chronic pathologies was higher among men (5.3 vs. 4.6), for the lower age range and among those not living alone (P<0.001). For QoL, men and people aged over 84 obtained better scores (0.64 and 0.61, respectively). Worse QoL was associated with being a woman, multimorbidity, and living with one or more people. The existence of multimorbidity meant impaired QoL of 2.6 points for each additional disease over the overall score (P<0.001). This study reveals that for the population covered by BTPS the impact of chronic pathologies, multimorbidity and their social context affects QoL very diversely. These diverse social and healthcare needs of community-dwelling elders allow the development and implementation of personalised services, such as telecare that facilitate them to remain at home.


First report of methicillin-resistant Staphylococcus aureus Cordobes/Chilean clone involved in nosocomial infections in Brazil.
SUMMARY Methicillin-resistant Staphylococcus aureus (MRSA) commonly causes infection in hospitalized patients. Resistance is due to the acquisition of mecA gene located on the chromosomal element SCCmec and to date 12 types have been identified. Specific epidemic clones of MRSA have emerged with enhanced ability to spread within and among hospitals and to cross national boundaries. We studied 30 isolates from patients with MRSA infections at two hospitals in Porto Alegre city from April to December, 2008 and determined their SCCmec type by PCR. Representative strains were typed by PFGE. Eighteen (60%) isolates carried SCCmec type III and had PFGE profiles clonally related to the previously characterized Brazilian epidemic clone, and 11 (36·7%) isolates with pulsotypes closely related to the Cordobes/Chilean clone harboured SCCmec type I. To the best of our knowledge, this is the first report of the appearance of Cordobes/Chilean clone involved in nosocomial infection in Brazil.


[From surgical gloves to the rat. The various stages of microsurgery learning].
The paper describes the different stages of microsurgical training which should be followed in an experimental laboratory; it also stresses the main characteristics to which microsurgical trainees must pay attention without neglecting any steps, even the most banal ones, because microsurgery is a sequence of exercises and not a single one (microsuture). The rigorous and increasingly difficult step-by-step progress of the different phases allows the trainee to face the different passages with greater ability and mastery without losing that enthusiasm which is the motivating force. Obstacles and failures can be evaluated with a more critical and reflective eye. Microsurgical training foresees the gradual passage from synthetic materials, such as surgical gloves, to non-living biological structures, such as chicken legs, finishing with experimental animals such as the rat. These biological models are almost identical to human structures making the experimental stage very similar to direct clinical application. Microsurgery, nowadays, is an integral part of all surgical disciplines. A correct approach to surgery using a microscope, according to this teaching scheme, is surely of great help not only for young surgeons but for the veterans of surgery too.


Uptake, metabolism, accumulation and toxicity of cyanide in Willow trees.
Chemicals taken up into plants may be accumulated so leading to toxic effects. Uptake and phytotoxicity of free cyanide was determined with the willow-tree transpiration test. Willow sets were grown in sand and irrigated with varying levels of cyanide (CN). Toxicity was determined by measuring transpiration. At CN concentrations below 10 mg/L, no toxic effects were observed. At 20 mg/L, transpiration was reduced to approximately 50% after 96 h. With 30, 40 and 50 mg/L, the transpiration decreased with a similar rate to < 20% of the initial transpiration within 96 h. Accumulation of cyanide in plant tissue was observed at 40 and 50 mg/L. The kinetics of metabolism of cyanide by roots, stems and leaves of willows was determined by the closed-bottle metabolism test. The Michaelis-Menten parameters v(max) and K(M)(maximal metabolic velocity and half-saturation constant, respectively) were determined by nonlinear regression. Estimates of uptake and metabolism were balanced using a nonlinear mathematical model. The model predicted that at low doses (<10 mg/L), the cyanide would be rapidly metabolized. At higher doses, uptake would be faster than metabolism and consequently cyanide would accumulate in the plant tissue. This relation between external dose and internal accumulation is nonlinear and explains the toxic effects observed.


Vesicle trafficking dynamics and visualization of zones of exocytosis and endocytosis in tobacco pollen tubes.
Pollen tubes are one of the fastest growing eukaryotic cells. Rapid anisotropic growth is supported by highly active exocytosis and endocytosis at the plasma membrane, but the subcellular localization of these sites is unknown. To understand molecular processes involved in pollen tube growth, it is crucial to identify the sites of vesicle localization and trafficking. This report presents novel strategies to identify exocytic and endocytic vesicles and to visualize vesicle trafficking dynamics, using pulse-chase labelling with styryl FM dyes and refraction-free high-resolution time-lapse differential interference contrast microscopy. These experiments reveal that the apex is the site of endocytosis and membrane retrieval, while exocytosis occurs in the zone adjacent to the apical dome. Larger vesicles are internalized along the distal pollen tube. Discretely sized vesicles that differentially incorporate FM dyes accumulate in the apical, subapical, and distal regions. Previous work established that pollen tube growth is strongly correlated with hydrodynamic flux and cell volume status. In this report, it is shown that hydrodynamic flux can selectively increase exocytosis or endocytosis. Hypotonic treatment and cell swelling stimulated exocytosis and attenuated endocytosis, while hypertonic treatment and cell shrinking stimulated endocytosis and inhibited exocytosis. Manipulation of pollen tube apical volume and membrane remodelling enabled fine-mapping of plasma membrane dynamics and defined the boundary of the growth zone, which results from the orchestrated action of endocytosis at the apex and along the distal tube and exocytosis in the subapical region. This report provides crucial spatial and temporal details of vesicle trafficking and anisotropic growth.


[Hydrolysis of streptococcal polysaccharides by micromycete dextranases].
The effect of dextranase enzyme preparations obtained from Penicillium piscarium BIM G-102, Penicillium funiculosum, Aspergillus insuetus G-116 and Aspergillus ustus on polysaccharides synthesized by cariesogenic Streptococcus sanguis and Streptococcus mitis was being studied. According to the data obtained dextranases from P. piscarium, P. funiculosum and Asp. ustus can be considered as a promising anticarious agent.


Value evaluation of serum (sdLDLc*HCYc)/HDLc ratio in the stability of intracranial arterial plaques in patients with acute cerebral infarction.
We aimed to analyze the value of serum (sdLDLc*HCYc)/HDLc ratio in the stability of intracranial arterial plaques among patients with acute cerebral infarction. A retrospective analysis was conducted on 140 patients with acute cerebral infarction admitted to the neurology department and 101 healthy individuals for regular examinations in our hospital from 2013 to 2019, who were respectively allocated into the study group and the control group. Participants in both groups were measured for serum sdLDLc, HDLc, and HCYc using peroxidase method, enzyme-linked immunosorbent assay, and enzyme method, respectively. The laboratory indexes of the two groups were compared. The multivariate logistic regression analysis was done to analyze the influencing factors of the stability of intracranial artery plaque in patients with acute cerebral infarction. The value of high-density lipoprotein cholesterol (HDL-C), homocysteine, sdLDLc, (sdLDLc*HCYc)/HDLc in diagnosing the stability of intracranial artery plaque was also evaluated in patients with acute cerebral infarction. There was no distinct difference in height, hypertension, diabetes, coronary heart disease, smoking history and drinking history between the two groups (P>0.05). The study group showed statistically significant differences in age, gender, weight, and BMI (P<0.05). The current study demonstrated no statistical difference in the levels of TG, low-density lipoprotein cholesterol (LDL-C), α-lipoprotein, and HCYc between the two groups (P>0.05). However, the levels of TC, HDL-C, sdLDLc, (sdLDLc*HCYc)/HDLc in the study group were significantly different when comparing with the control group (P<0.05). No statistically significant difference was found in the levels of TG, triglycerides, LDL-C, α-lipoprotein, and HCYc among patients with different degrees of stenosis in the study group (P>0.05). The level of HDL-C was significantly lower in cases of severe stenosis compared to no stenosis, mild stenosis and moderate stenosis, with severe stenosis showing the lowest levels; mild stenosis had lower levels than no stenosis, while moderate stenosis had lower levels than both no stenosis and mild stenosis (P<0.05). The levels of sdLDLc, (sdLDLc*HCYc)/HDLc exhibited a significant increase in cases of severe stenosis as compared tono stenosis, mild stenosis, and moderate stenosis. Furthermore, the levels of sdLDLc, (sdLDLc*HCYc)/HDLc were found to be higher in moderate stenosis as compared to no stenosis and mild stenosis. Similarly, the levels of sdLDLc, (sdLDLc*HCYc)/HDLc were observed to be higher in mild stenosis than no stenosis (P<0.05).The independent variables were set as the indicators with difference in single factor comparison, including age, gender, BMI, TC, LDL-C, HDL-C, HCYc, sdLDLc, (sdLDLc*HCYc)/HDLc. The dependent variable was the stability of intracranial artery plaque in patients with acute cerebral infarction. After variable selection, the results showed that the factors influencing the stability of intracranial artery plaque in patients with acute cerebral infarction were age, BMI, (sdLDLc*HCYc)/HDLc. The degree of plaque enhancement was used as a criterion to reflect the stability of plaque. ROC curve analysis showed that (sdLDLc*HCYc)/HDLc had a higher evaluation value for the stability of intracranial artery plaque than HDL-C, homocysteine, and sdLDLc in patients with acute cerebral infarction. The serum (sdLDLc*HCYc)/HDLc ratio was found to have potential in evaluating the stability of intracranial arterial plaques in patients with acute cerebral infarction.


Utilization of phytate and nonphytate phosphorus in chicks as affected by source and amount of vitamin D3.
Commercial and laboratory-strain crossbred chicks responded (P < .01) markedly to 1alpha-hydroxycholecalciferol (1alpha-OH D3) during the 2nd and 3rd wk of life. Bone-ash responses exceeded 50% when this compound was added at 20 microg/kg to phosphorus (P)-deficient corn-soybean meal diets containing surfeit levels (25 microg/kg) of cholecalciferol (D3). Phosphorus excretion was decreased (P < .01) and, thus, retention was increased (P < .01) when 1alpha-OH D3 was supplemented. A P-deficient (.10% P) casein-amino acid purified diet, devoid of D3, was used to determine whether 15 microg/kg of D3 was sufficient to facilitate optimal absorption of the nonphytate P contained in this diet. Bone ash responded to .075% P addition (KH2PO4), and chicks fed diets with .175% nonphytate P exhibited further bone-ash responses to 15 microg/kg of D3 or 10 microg/kg 1alpha-OH D3. Higher levels of either of these D3 compounds did not produce additional responses. This suggested that 15 to 25 microg/kg of D3 in a P-deficient corn-soybean meal diet (.28% phytate P and .14% nonphytate P) is more than adequate to facilitate optimal absorption of the nonphytate P present in the diet. A P-deficient casein-dextrose diet (.13% nonphytate P and 15 microg/kg D3) was fed in the final chick assay, and chicks fed this diet did not show bone ash responses to 1alpha-OH D3 or to microbial-derived phytase (1,470 units/kg). Thus, with P-deficient corn-soybean meal diets containing at least 15 microg D3/kg, 1alpha-OH D3 supplementation markedly increased weight gain and bone ash because it increased the utilization of phytate P.


Tuning Ambipolarity of the Conjugated Polymer Channel Layers of Floating-Gate Free Transistors: From Volatile Memories to Artificial Synapses.
Three-terminal synaptic transistor has drawn significant research interests for neuromorphic computation due to its advantage of facile device integrability. Lately, bulk-heterojunction-based synaptic transistors with bipolar modulation are proposed to exempt the use of an additional floating gate. However, the actual correlation between the channel's ambipolarity, memory characteristic, and synaptic behavior for a floating-gate free transistor has not been investigated yet. Herein, by studying five diketopyrrolopyrrole-benzotriazole dual-acceptor random conjugated polymers, a clear correlation among the hole/electron ratio, the memory retention characteristic, and the synaptic behavior for the polymer channel layer in a floating-gate free transistor is described. It reveals that the polymers with balanced ambipolarity possess better charge trapping capabilities and larger memory windows; however, the high ambipolarity results in higher volatility of the memory characteristics, namely poor memory retention capability. In contrast, the polymer with a reduced ambipolarity possesses an enhanced memory retention capability despite showing a reduced memory window. It is further manifested that this enhanced charge retention capability enables the device to present artificial synaptic characteristics. The results highlight the importance of the channel's ambipolarity of floating-gate free transistors on the resultant volatile memory characteristics and synaptic behaviors.


Preferential estrogen receptor β ligands reduce Bcl-2 expression in hormone-resistant breast cancer cells to increase autophagy.
Acquired resistance to selective estrogen receptor (ER) modulators (SERM) and downregulators (SERD) is a significant clinical problem in the treatment of estrogen (E2) receptor-positive (ER(+)) breast cancers. There are two ER subtypes, ERα and ERβ, which promote and inhibit breast cancer cell proliferation, respectively. Although ER(+) breast cancers typically express a high ratio of ERα to ERβ, the acquisition of SERM resistance in vitro and in vivo is associated with increased relative expression of the ERβ. On some gene enhancers, ERβ has been shown to function in opposition to the ERα in the presence of E2. Here, we demonstrate that two different ERβ agonists, WAY-20070 and a novel "A-CD" estrogen called L17, produce a marked reduction in G(2)-M phase correlated with effects on cyclin D1 and cyclin E expression in a SERM/SERD-resistant breast cancer cell line. ERβ agonists recruited both the ERα and ERβ to the Bcl-2 E2-response element strongly reducing Bcl-2 mRNA and protein in an ERβ-dependent manner. L17 recruited RIP140 to the Bcl-2 promoter in cells overexpressing ERβ. Exposure to the ERβ ligands also resulted in increased processing of LC3-I to LC3-II, indicative of enhanced autophagic flux. The coaddition of ERβ agonist and the autophagy inhibitor chloroquine resulted in a significant accumulation of sub-G1 DNA which was completely prevented by the addition of the caspase inhibitor Z-VAD-FMK. We propose that combined therapies with an ERβ agonist and an inhibitor of autophagy may provide the basis for a novel approach to the treatment of SERM/SERD-resistant breast cancers.


The Anatomy of the Medial Patellofemoral Complex.
The term "medial patellofemoral complex" (MPFC) was proposed to describe the static medial stabilizer of the patella, typically referred to as the medial patellofemoral ligament. In light of our increasing understanding of the attachment of its fibers to the quadriceps tendon in addition to the patella, the term MPFC is used in this article. The purpose of this article is to describe and discuss the anatomy of the MPFC.


Injection of demineralized bone matrix with bone marrow concentrate improves healing in unicameral bone cyst.
Unicameral bone cysts are benign lesions that usually spontaneously regress with skeletal maturity; however, the high risk of pathologic fractures often justifies treatment that could reinforce a weakened bone cortex. Various treatments have been proposed but there is no consensus regarding the best procedure. We compared the healing rates and failures of two methods of cure based on multiple injections of corticosteroid or a single injection of demineralized bone matrix (DBM) in association with bone marrow concentrate (BMC). We retrospectively reviewed 184 patients who had one of the two treatments for unicameral bone cysts with cortical erosion. Clinical records were reviewed for treatment failures and radiographs for healing in all patients. The minimum followup was 12 months for the Steroids Group (mean, 48 months; range, 12-120 months) and 12 months for the DBM + BMC Group (mean, 20 months; range, 12-28 months). After one treatment we observed a lower healing rate of cysts treated with multiple injections of steroids compared with the healing after the first injection of DBM + BMC (21% versus 58%, respectively). At last followup, 38% healed with steroids and 71% with DBM + BMC. The rate of failure after one steroid injection was higher than after a single injection of BDM + BMC (63% versus 24%, respectively). We observed no difference in fracture rates after treatment between the two groups. A single injection of DBM added with autologous bone marrow concentrate appears to provide a higher healing rate with a lower number of failures compared with a single injection of steroids.


SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion.
Sirtuins are NAD+-dependent protein deacylases that regulate several aspects of metabolism and aging. In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control have remained enigmatic. Using a combination of phylogenetics, structural biology, and enzymology, we show that SIRT4 removes three acyl moieties from lysine residues: methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaconyl (MGc)-lysine. The metabolites leading to these post-translational modifications are intermediates in leucine oxidation, and we show a primary role for SIRT4 in controlling this pathway in mice. Furthermore, we find that dysregulated leucine metabolism in SIRT4KO mice leads to elevated basal and stimulated insulin secretion, which progressively develops into glucose intolerance and insulin resistance. These findings identify a robust enzymatic activity for SIRT4, uncover a mechanism controlling branched-chain amino acid flux, and position SIRT4 as a crucial player maintaining insulin secretion and glucose homeostasis during aging.


Differential transcriptome patterns for acute cellular rejection in recipients with recurrent hepatitis C after liver transplantation.
Histopathological evaluation of the liver via biopsy remains the standard procedure for the diagnosis of both acute cellular rejection (ACR) and recurrent hepatitis C (RHC) after liver transplantation. Nevertheless, it is often difficult to diagnose ACR in hepatitis C virus-positive recipients because of changes in common and overlapping with RHC. The aim of this study was to identify potential target genes for ACR in recipients with RHC. We analyzed 22 liver biopsy samples obtained from 21 hepatitis C virus-positive recipients. The clinicopathological diagnosis based on biopsy examination was ACR-predominant with superimposed RHC in 9 samples (ACR group) and RHC without ACR (non-ACR group) in 13. Using oligonucleotide microarrays, we compared the transcriptional changes in the 2 groups and selected 2206 genes that were significantly modulated in ACR. We analyzed the regulatory networks in ACR with Ingenuity Pathway Analysis software, and we confirmed with quantitative real-time polymerase chain reaction the reproducibility of caspase 8, apoptosis-related cysteine peptidase and bone morphogenetic protein 2 up-regulation in another group of validation samples, representing 2 genes from the core network as the target genes for ACR. Our results demonstrated novel transcriptome patterns for ACR with concurrent RHC that were distinct from those of recipients with only RHC, suggesting that gene expression profiling may be useful in the diagnosis of ACR in recipients with hepatitis C.


Design, development, and implementation of a critical pathway in simultaneous pancreas-kidney transplant recipients.
The purpose of this study was to assess the effect of implementation of a critical pathway after simultaneous pancreas-kidney transplantation on length of stay and hospital charges. Two well-matched groups were compared: 10 patients who received transplants in 1991 (before implementation of the critical pathway) and 10 patients who received transplants in 1995 (after implementation). For the initial transplant hospitalization, the critical pathway was associated with significant reductions in length of stay, total number of laboratory tests, clinical laboratory charges, and total inpatient charges with organ acquisition charges excluded. Despite the rising costs of medical care, we have designed and implemented a critical pathway for simultaneous pancreas-kidney transplantation that has stabilized hospital charges by decreasing length of stay and the number of clinical laboratory tests.


The class A scavenger receptor, macrophage receptor with collagenous structure, is the major phagocytic receptor for Clostridium sordellii expressed by human decidual macrophages.
Clostridium sordellii is an emerging pathogen associated with highly lethal female reproductive tract infections following childbirth, abortion, or cervical instrumentation. Gaps in our understanding of the pathogenesis of C. sordellii infections present major challenges to the development of better preventive and therapeutic strategies against this problem. We sought to determine the mechanisms whereby uterine decidual macrophages phagocytose this bacterium and tested the hypothesis that human decidual macrophages use class A scavenger receptors to internalize unopsonized C. sordellii. In vitro phagocytosis assays with human decidual macrophages incubated with pharmacological inhibitors of class A scavenger receptors (fucoidan, polyinosinic acid, and dextran sulfate) revealed a role for these receptors in C. sordellii phagocytosis. Soluble macrophage receptor with collagenous structure (MARCO) receptor prevented C. sordellii internalization, suggesting that MARCO is an important class A scavenger receptor in decidual macrophage phagocytosis of this microbe. Peritoneal macrophages from MARCO-deficient mice, but not wild-type or scavenger receptor AI/II-deficient mice, showed impaired C. sordellii phagocytosis. MARCO-null mice were more susceptible to death from C. sordellii uterine infection than wild-type mice and exhibited impaired clearance of this bacterium from the infected uterus. Thus, MARCO is an important phagocytic receptor used by human and mouse macrophages to clear C. sordellii from the infected uterus.


Combination of TRAIL gene therapy and chemotherapy enhances antitumor and antimetastasis effects in chemosensitive and chemoresistant breast cancers.
We recently found that breast cancer cell lines that are resistant to chemotherapy or to the recombinant TRAIL protein are susceptible to TRAIL gene therapy. However, it is unclear whether a combination of TRAIL gene therapy and chemotherapy will have enhanced antitumor activity or can be used for the treatment of metastasis. In this study, we investigated the combined effect of TRAIL gene therapy and chemotherapeutic agents, including doxorubicin, paclitaxel, vinorelbine, gemcitabine, irinotecan, and floxuridine, in different breast cancer cell lines. In all the cell lines tested, including a breast cancer cell line that is resistant to chemotherapy, the combination of TRAIL gene therapy and cytotoxic agents had either a synergistic or an additive effect. An in vivo study showed that aerosolized administration of an adenovector expressing the GFP-TRAIL fusion protein from the human telomerase reverse transcriptase promoter (designated Ad/gTRAIL) also decreased the number of lung metastases from both doxorubicin-sensitive and doxorubicin-resistant breast cancer cell lines. The combination of TRAIL gene therapy and chemotherapy resulted in a further reduction of lung metastatic nodules with minimal toxicity. These results suggest that a combination of TRAIL gene therapy and chemotherapy is effective in the treatment of metastatic diseases.