Is there any relationship between human leucocyte antigen class II and chronic urticaria? (chronic urticaria and HLA class II).
The Human Leukocyte Antigen (HLA) typing of large groups of patients with various autoimmune diseases has demonstrated that some HLA alleles occur at higher frequencies in specific diseases than in the general population. Chronic urticaria has been shown to have an autoimmune basis by a previous study which found an association between chronic urticaria and specific HLA groups. We investigated the HLA subtypes of Turkish chronic urticaria patients. For this purpose 42 Turkish patients with chronic urticaria and 115 healthy controls were typed for HLA-DR and DQ by PCR-SSP (Polymerase Chain Reaction Sequence Specific Primers) low resolution DNA technique. We found an increased frequency of DR4 (42.9%, p=0.01) in chronic urticaria patients in comparison with that in healthy controls. This study supports the hypothesis that HLA alleles may be involved in the pathogenesis of chronic urticaria and that they appear to be directly involved in the initiation of the immune response.


Pulmonary inflammatory response to inhaled ultrafine particles is modified by age, ozone exposure, and bacterial toxin.
Epidemiological studies demonstrate associations between increasing levels of ambient particles and morbidity in the elderly with cardiopulmonary disease. Such findings have been challenged partly because particles may not act alone to cause these effects. We hypothesized that carbonaceous ambient ultrafine particles and ozone can act together to induce greater oxidative stress and inflammation in the lung than when administered alone and that these effects would be amplified in the compromised, aging lung. Two models of a compromised lung were used: endotoxin priming and old-age emphysema (TSK mice). Young (10 wk) and old (22 mo) male F344 rats and male TSK mice (14-17 mo) were exposed to ultrafine carbon particles (count median diameter 25 nm, 110 micrograms/m3) and to ozone (1 ppm) alone and in combination for 6 h. Inhalation of low-dose endotoxin (70 and 7.5 units estimated alveolar deposited dose in rats and mice, respectively) was used to model respiratory-tract infection. Cellular and biochemical lavage parameters and oxidant release from lung lavage cells were assessed 24 h after exposure. Inflammatory cell influx into the alveolar space was observed for both species and age groups: The combination of inhaled ultrafine carbon and ozone after endotoxin priming resulted in the greatest increase in lavage-fluid neutrophils. In general, the unstimulated and stimulated release of reactive oxygen species (ROS) from lavage inflammatory cells correlated well with the neutrophil response. There were significant effects of carbon particles as well as a consistent interaction between carbon and ozone as determined by analysis of variance (ANOVA). However, this interaction was in the opposite direction in young rats versus old rats and old TSK mice: Carbon and ozone interacted such that ROS activity was depressed in young rats, whereas it was enhanced in old rats and old TSK mice, indicating age-dependent functional differences in elicited pulmonary inflammatory cells. These results demonstrate that ultrafine carbonaceous particles inhaled for short periods of time can induce significant pulmonary inflammation and oxidative stress that are modified by age, copollutants, and a compromised respiratory tract.


Risk of transmission of respiratory viruses during aerosol-generating medical procedures (AGMPs) revisited in the COVID-19 pandemic: a systematic review.
In many jurisdictions healthcare workers (HCWs) are using respirators for aerosol-generating medical procedures (AGMPs) performed on adult and pediatric populations with all suspect/confirmed viral respiratory infections (VRIs). This systematic review assessed the risk of VRIs to HCWs in the presence of AGMPs, the role respirators versus medical/surgical masks have on reducing that risk, and if the risk to HCWs during AGMPs differed when caring for adult or pediatric patient populations. We searched MEDLINE, EMBASE, Cochrane Central, Cochrane SR, CINAHL, COVID-19 specific resources, and MedRxiv for English and French articles from database inception to September 9, 2021. Independent reviewers screened abstracts using pre-defined criteria, reviewed full-text articles, selected relevant studies, abstracted data, and conducted quality assessments of all studies using the ROBINS-I risk of bias tool. Disagreements were resolved by consensus. Thirty-eight studies were included; 23 studies on COVID-19, 10 on SARS, and 5 on MERS/ influenza/other respiratory viruses. Two of the 16 studies which assessed associations found that HCWs were 1.7 to 2.5 times more likely to contract COVID-19 after exposure to AGMPs vs. not exposed to AGMPs. Eight studies reported statistically significant associations for nine specific AGMPs and transmission of SARS to HCWS. Intubation was consistently associated with an increased risk of SARS. HCWs were more likely (OR 2.05, 95% CI 1.2-3.4) to contract human coronaviruses when exposed to an AGMP in one study. There were no reported associations between AGMP exposure and transmission of influenza or in a single study on MERS. There was limited evidence supporting the use of a respirator over a medical/surgical mask during an AGMP to reduce the risk of viral transmission. One study described outcomes of HCWs exposed to a pediatric patient during intubation. Exposure to an AGMP may increase the risk of transmission of COVID-19, SARS, and human coronaviruses to HCWs, however the evidence base is heterogenous and prone to confounding, particularly related to COVID-19. There continues to be a significant research gap in the epidemiology of the risk of VRIs among HCWs during AGMPs, particularly for pediatric patients. Further evidence is needed regarding what constitutes an AGMP.


Modeling Diffusive Mixing in Antisolvent Crystallization.
Diffusion controls local concentration profiles at interfaces between segregated fluid elements during mixing processes. This is important for antisolvent crystallization, where it is intuitively argued that local concentration profiles at interfaces between solution and antisolvent fluid elements can result in significant supersaturation overshoots over and above that at the final mixture composition, leading to poorly controlled nucleation. Previous work on modeling diffusive mixing in antisolvent crystallization has relied on Fickian diffusion, where concentration gradients are the driving force for diffusion. This predicts large overshoots in the supersaturation at interfaces between solution and antisolvent, as is often intuitively expected. However, chemical potential gradients provide a more physically realistic driving force for diffusion, and in highly nonideal solutions, such as those in antisolvent crystallization, this leads to nonintuitive behavior. In particular, as solute diffusion toward antisolvent is severely hindered, it can diffuse against its concentration gradient away from antisolvent. We apply thermodynamically consistent diffusion model based on the multicomponent Maxwell-Stefan formulation to examine diffusive mixing in a nonideal antisolvent crystallization system. Large supersaturation overshoots above that at the final mixture composition are not found when a thermodynamically consistent approach is used, demonstrating that these overshoots are modeling artifacts and are not expected to be present in physical systems. In addition, for certain conditions, localized liquid-liquid spinodal demixing is predicted to occur during the diffusive mixing process, even when the final mixture composition is outside the liquid-liquid phase separation region. Intermittent spinodal demixing driven by diffusive mixing may provide a novel explanation for differences of nucleation behaviors among various antisolvents.


MicroRNA expression patterns associated with hyperfunctioning and non-hyperfunctioning phenotypes in adrenocortical adenomas.
The adrenocortical adenoma (ACA) entity includes aldosterone-producing adenoma (APA), cortisol-producing adenoma (CPA), and non-hyperfunctioning adenoma (NHFA) phenotypes. While gene mutations and mRNA expression profiles have been partly characterized, less is known about the alterations involving microRNA (miRNA) expression. To characterize miRNA expression profile in relation to the subtypes of ACAs. miRNA expression profiles were determined in 26 ACAs (nine APAs, ten CPAs, and seven NHFAs) and four adrenal references using microarray-based screening. Significance analysis of microarrays (SAM) was carried out to identify differentially expressed miRNAs between ACA and adrenal cortices or between tumor subtypes. Selected differentially expressed miRNAs were validated in an extended series of 43 ACAs and ten adrenal references by quantitative RT-PCR. An hierarchical clustering revealed separate clusters for APAs and CPAs, while the NHFAs were found spread out within the APA/CPA clusters. When NHFA was excluded, the clustering analysis showed a better separation between APA and CPA. SAM analysis identified 40 over-expressed and three under-expressed miRNAs in the adenomas as compared with adrenal references. Fourteen miRNAs were common among the three ACA subtypes. Furthermore, we found specific miRNAs associated with different tumor phenotypes. The results suggest that miRNA expression profiles can distinguish different subtypes of ACA, which may contribute to a deeper understanding of ACA development and potential therapeutics.


Risk perception of COVID-19 among sub-Sahara Africans: a web-based comparative survey of local and diaspora residents.
Perceived risk towards the coronavirus pandemic is key to improved compliance with public health measures to reduce the infection rates. This study investigated how Sub-Saharan Africans (SSA) living in their respective countries and those in the diaspora perceive their risk of getting infected by the COVID-19 virus as well as the associated factors. A web-based cross-sectional survey on 1969 participants aged 18 years and above (55.1% male) was conducted between April 27th and May 17th 2020, corresponding to the mandatory lockdown in most SSA countries. The dependent variable was the perception of risk for contracting COVID-19 scores. Independent variables included demographic characteristics, and COVID-19 related knowledge and attitude scores. Univariate and multiple linear regression analyses identified the factors associated with risk perception towards COVID-19. Among the respondents, majority were living in SSA (n = 1855, 92.8%) and 143 (7.2%) in the diaspora. There was no significant difference in the mean risk perception scores between the two groups (p = 0.117), however, those aged 18-28 years had lower risk perception scores (p = 0.003) than the older respondents, while those who were employed (p = 0.040) and had higher levels of education (p < 0.001) had significantly higher risk perception scores than other respondents. After adjusting for covariates, multivariable analyses revealed that SSA residents aged 39-48 years (adjusted coefficient, β = 0.06, 95% CI [0.01, 1.19]) and health care sector workers (β = 0.61, 95% CI [0.09, 1.14]) reported a higher perceived risk of COVID-19. Knowledge and attitude scores increased as perceived risk for COVID-19 increased for both SSAs in Africa (β = 1.19, 95% CI [1.05, 1.34] for knowledge; β = 0.63, 95% CI [0.58, 0.69] for attitude) and in Diaspora (β = 1.97, 95% CI [1.16, 2.41] for knowledge; β = 0.30, 95% CI [0.02, 0.58] for attitude). There is a need to promote preventive measures focusing on increasing people's knowledge about COVID-19 and encouraging positive attitudes towards the mitigation measures such as vaccines and education. Such interventions should target the younger population, less educated and non-healthcare workers.


Detection of 7-Dehydrocholesterol and Vitamin D3 Derivatives in Honey.
20(S)-Hydroxyvitamin D3 (20(OH)D3) is an endogenous metabolite produced by the action of CYP11A1 on the side chain of vitamin D3 (D3). 20(OH)D3 can be further hydroxylated by CYP11A1, CYP27A1, CYP24A1 and/or CYP27B1 to several hydroxyderivatives. CYP11A1 also hydroxylates D3 to 22-monohydroxyvitamin D3 (22(OH)D3), which is detectable in the epidermis. 20-Hydroxy-7-dehydrocholesterol (20(OH)-7DHC) has been detected in the human epidermis and can be phototransformed into 20(OH)D3 following the absorption of ultraviolet B (UVB) energy by the B-ring. 20(OH)D3 and its hydroxyderivatives have anti-inflammatory, pro-differentiation and anti-proliferative effects, comparable to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Since cytochromes P450 with 20- or 25-hydroxylase activity are found in insects participating in ecdysone synthesis from 7-dehydrocholesterol (7DHC), we tested whether D3-hydroxyderivatives are present in honey, implying their production in bees. Honey was collected during summer in the Birmingham area of Alabama or purchased commercially and extracted and analyzed using LC-MS. We detected a clear peak of m/z = 423.324 [M + Na]+ for 20(OH)D3 corresponding to a concentration in honey of 256 ng/g. We also detected peaks of m/z = 383.331 [M + H - H2O]+ for 20(OH)-7DHC and 25(OH)D3 with retention times corresponding to the standards. We further detected species with m/z = 407.329 [M + Na]+ corresponding to the RT of 7DHC, D3 and lumisterol3 (L3). Similarly, peaks with m/z = 399.326 [M + H - H2O]+ were detected at the RT of 1,25(OH)2D3 and 1,20-dihydroxyvitamin D3 (1,20(OH)2D3). Species corresponding to 20-monohydroxylumisterol3 (20(OH)L3), 22-monohydroxyvitamin D3 (22(OH)D3), 20,23-dihydroxyvitamin D3 (20,23(OH)2D3), 20,24/25/26-dihydroxyvitamin D3 (20,24/25/26(OH)2D3) and 1,20,23/24/25/26-trihydroxyvitamin D3 (1,20,23/24/25/26(OH)3D3) were not detectable above the background. In conclusion, the presence of 7DHC and D3 and of species corresponding to 20(OH)-7DHC, 20(OH)D3, 1,20(OH)2D3, 25(OH)D3 and 1,25(OH)2D3 in honey implies their production in bees, although the precise biochemistry and photochemistry of these processes remain to be defined.


MRI in pregnant patients with suspected abdominal and pelvic cancer: a practical guide for radiologists.
The incidence of abdominal and pelvic cancer in pregnancy is low, but it is rising as the population of pregnant women gets older. Depending on disease stage, gestational age and patient's preference, active surveillance as well as surgery and chemotherapy are feasible options during pregnancy. Correct diagnosis and staging of the tumor is crucial for choosing the best therapeutic approach. Moreover, a reproducible modality to assess the treatment response is requested. Magnetic resonance imaging (MRI) is commonly used with good results for the local staging and treatment response evaluation of most abdominal and pelvic cancers in nonpregnant patients, and it is considered relatively safe during pregnancy. The purpose of this article is to analyze the most relevant topics regarding the use of MRI in pregnant women with abdominal and pelvic cancer. We discuss MRI safety during pregnancy, including the use of gadolinium-based contrast agents (GBCAs), how to prepare the patient for the exam and MRI technique. This will be followed by a brief review on the most common malignancies diagnosed during pregnancy and their MRI appearance.


[Pathomorphological changes in the lung in acute posthemorrhagic anemia].
Lung tissue was histologically studied in 30 cadavers of those who had died from acute hemorrhage. When death occurred, several minutes after blood were marked by emphysema without alveolar edema and lymph-macrophageal infiltration of interalveolar septa whereas 1.5-2 hours after blood loss, emphysematous changes in lung tissues were accompanied with significant lymph-macrophageal infiltration of interalveolar septa and intraalveolar edema and with the signs of micro disseminated intravascular coagulation in the lung. Desquamation and necrotic changes of alveocytes were observed. At death, 24 hours or more following blood loss, there was, along with alveocytic necrotic changes in lung tissue, type 2 pneumocytic proliferation, as well as alveolar hemorrhages, vascular thrombosis in the microcirculatory bed, fibrin lumps and threads in the alveolar lumen.


Consumers in control. How the Net will reshape health care.
Two trends are converging upon the health care landscape. And the collision of these two forces may change the health care system forever. Consumerism, a trend challenging every industry throughout the nation, is magnified in health care by simple demographics. The baby boomers, the most demanding consumers history has ever known, are entering the age of high health care use en masse. They will not be denied. Meanwhile, the development of the Internet--combined with the explosion in its use--has created a medium that has the force to change industries.


Effects of mevinphos (Phosdrin) on unit discharge patterns in avian hippocampus.
Low doses of the acetylcholinesterase inhibitors, mevinphos and physostigmine, reduce hippocampal inhibitory phenomena, measured in terms of the duration of the poststimulus inhibitory pause seen in individual hippocampal neurones in the pigeon. The cholinergic antagonist, atropine, increased hippocampal inhibition. At near threshold doses, mevinphos could, in part, reverse atropine effects. At higher doses, mevinphos synergized with atropine. In the discussion, it is suggested that any organophosphate or carbamate pesticide and its antidote, atropine, may alter "attention" or "short-term memory" through effects on hippocampus at doses too low to induce grossly detectable peripheral symptomatology. Extreme caution in the use or handling of these compounds by aerial applicators is urged. Since the effects of atropine and mevinphos can synergize, the use of atropine to permit poisoned applicators to resume activity is questioned.


A new rat model of glaucoma induced by intracameral injection of silicone oil and electrocoagulation of limbal vessels.
A satisfied glaucoma model is absent now. The aim of this study was to evaluate the effect of a combination of intracameral injection of silicone oil and electrocoagulation of corneal limbal vessels and episcleral veins in the rats to establish glaucoma model. Operation was performed in each of the left eyes of 90 adult male rats. Right eyes were used as controls. Measurement of intraocular pressure (IOP) was performed with an applanation tonometer (Tono-Pen). Retinal ganglion cells (RGCs) were retrogradely labeled by applying FluoroGold onto the bilateral superior colliculus. During the follow-up (24 weeks), the IOP of the study eyes was significantly higher (P < 0.05) than the control eyes (at final examination, IOP of control eyes was (13.4 ± 1.0) mmHg and IOP of study eyes was (16.1 ± 1.8) mmHg). Correspondingly, at 24 weeks after operation, the RGCs density of the study eyes (2286.11 ± 290.45/mm(2)) was significantly lower than the control eyes (2626.46 ± 164.85/mm(2), P < 0.01). In the operated eyes, histological examination showed excavation of optic disc and increased neuroglial cells in the optic nerve, reduced thickness of retina and diminution of retinal ganglion cells, and atrophy of ciliary body and iris. Notably, the anterior chamber angle of the operated eye remained open. A combination of intracameral injection of silicone oil and electrocoagulation of corneal limbal vessels and episcleral veins may establish a reliable glaucoma model for further research.


LDL-containing immune complexes in the DCCT/EDIC cohort: associations with lipoprotein subclasses.
Immune complexes containing modified LDL (LDL-IC) and NMR-determined Total LDL particle concentrations are significantly associated with intima-media thickness (IMT). We analyzed the associations between concentrations of NMR-determined lipoprotein subclasses and LDL-IC in the DCCT/EDIC cohort. LDL-IC concentrations in women and men of the DCCT/EDIC cohort did not differ significantly and were positively associated with Total LDL particle concentrations in men and women (r=0.34, r=0.32, respectively; P<.01) and with Small LDL concentration (r=0.22, r=0.13, respectively; P<.01). In women, Large LDL concentrations were also associated with LDL-IC (r=0.20, P<.01) while in men, the association was more modest (r=0.11, P<.05). Thus, both Small and Large LDL are associated with LDL-IC formation. Based on the results from statistical mediation analyses, we concluded that plasma concentrations of LDL-IC may provide a physiological link between the statistically significant association of Total LDL particle concentration with carotid artery IMT in subjects with Type 1 diabetes. Furthermore, after adjusting for conventional risk factors, there was a decrease in LDL-IC concentration even in the presence of high Total LDL particle concentrations in those women with high concentrations of Large HDL, but the association was not evident in men. This suggests that the associations between Large HDL and Total LDL particle concentrations, and their associations with LDL-IC levels, differ by gender and suggest that LDL-IC partially mediate the contribution of Total LDL particle concentration to increased carotid IMT in diabetic men.


Interleukin-6 induces hepcidin expression through STAT3.
Iron homeostasis is maintained through meticulous regulation of circulating hepcidin levels. Hepcidin levels that are inappropriately low or high result in iron overload or iron deficiency, respectively. Although hypoxia, erythroid demand, iron, and inflammation are all known to influence hepcidin expression, the mechanisms responsible are not well defined. In this report we show that the inflammatory cytokine interleukin-6 (IL-6) directly regulates hepcidin through induction and subsequent promoter binding of signal transducer and activator of transcription 3 (STAT3). STAT3 is necessary and sufficient for the IL-6 responsiveness of the hepcidin promoter. Our findings provide a mechanism by which hepcidin can be regulated by inflammation or, in the absence of inflammatory stimuli, by alternative mechanisms leading to STAT3 activation.


A self-healable and tough nanocomposite hydrogel crosslinked by novel ultrasmall aluminum hydroxide nanoparticles.
Self-healing hydrogels like tissues or organs which are repaired automatically in response to damage show great promise. However, it remains a challenge to develop novel functional nanoparticles as crosslinkers to prepare tough and self-healing nanocomposite hydrogels. Here, we report the preparation of water-soluble ultrasmall aluminum hydroxide nanoparticles with a diameter of 2-3 nm through a simple sol-gel method. Furthermore, a tough nanocomposite hydrogel is prepared by the in situ copolymerization of acylamide and 2-acrylamido-2-methyl propane sulfonic acid in the presence of aluminum hydroxide nanoparticles. The resulting hydrogels exhibit high compressive strength of 18.9 MPa and an elongation at break of ∼2100%. Importantly, the Al-NC gel displayed a high self-healing efficiency of 86% without any external stimulus at room temperature. Moreover, we found an interesting multi-hierarchical porous morphology of the Al-NC gel depending on the contents of the aluminum hydroxide nanoparticles. The tough nanocomposite hydrogel might provide a novel promising avenue for designing advanced self-healable soft materials for various biomedical applications.


Pathogenesis and management of ureteric injuries.
The injured ureter presents a formidable urological problem, both in diagnosis and management. Injury by external trauma is uncommon but ureteric injury remains the ever-present nightmare of abdominal and pelvic surgeons. The pathogenesis of trauma to the ureter is outlined and current concepts of surgical management are reviewed. This study presents our 7-year experience (1978-1984 inclusive) with 72 ureteric injuries. The series outlines the importance of early diagnosis and prompt definitive repair in providing the best result with the least morbidity.


Racial and Ethnic Disparities in Breastfeeding Continuation Among U.S. Hispanic Mothers: Identification of Mechanisms.
Objective: We examined the extent to which social, maternal, and infant factors and Theory of Planned Behavior (TPB) domains-attitudes, perceived control, and subjective norms-mediate the relationship between maternal race and ethnicity and birth country, and breastfeeding continuation. Materials and Methods: A nationally representative cohort of 2,810 mothers with self-reported race, ethnicity, and birth country was used. Main outcomes included any and exclusive breastfeeding at 2-6 months of infant age. A conceptual framework with the aforementioned mediators of interest was developed. Logistic regression was used to examine main associations, and structural equation modeling was used to identify the extent to which proposed mediators explained the relationship between independent and dependent variables. Results: One thousand two hundred twenty-one mothers were U.S.-born non-Hispanic white (NHW), 432 U.S.-born Hispanic, 329 Mexico-born Hispanic, 107 Central- or South America-born Hispanic, 33 Caribbean-born Hispanic, and 688 U.S.-born non-Hispanic black (NHB). No differences in breastfeeding continuation among U.S.-born NHW and U.S.-born Hispanic mothers were found. In contrast, compared with U.S.-born NHW mothers, Mexico-born (odds ratio [OR] 1.99, 95% confidence interval [CI] 1.46-2.72) and Central- or South America-born (OR 3.42, 95% CI 1.89-6.17) Hispanic mothers had higher odds, and Caribbean-born Hispanic mothers had lower odds (OR 0.45, 95% CI 0.26-0.76) of any breastfeeding. These relationships were mediated by attitudes and subjective norms. Conclusions: Breastfeeding continuation among U.S. Hispanic mothers varied by birth country, highlighting the heterogeneity of breastfeeding populations of Hispanic mothers in the United States. Tailored interventions should strengthen policies supportive of positive attitudes toward and subjective norms around breastfeeding.


Distribution of NADPH-diaphorase and nitric oxide synthase in the trigeminal ganglion and mesencephalic trigeminal nucleus of the cat. A histochemical and immunohistochemical study.
The trigeminal ganglion (TrG) and mesencephalic trigeminal nucleus (MTN) neurons are involved in the transmission of orofacial sensory information. The presence of nitric oxide (NO), a putative neurotransmitter substance in the nervous system, was examined in the cat TrG and MTN using nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry and nitric oxide synthase (NOS) immunohistochemistry. In the TrG, where the majority of the trigeminal primary afferent perikarya are located, most of the intensely NADPH-d/ NOS-stained cells were small in size and distributed randomly throughout the ganglion. The medium-sized neurons were moderately stained. A plexus of pericellular varicose arborizations around large unstained ganglion cells and densely stained fibers in-between could also be observed. In the caudal part of the MTN, both NADPH-d activity and NOS immunoreactivity was present in MTN neurons. In addition, a few scattered NADPH-d/NOS-containing neurons were found in the mesencephalic-pontine junction part of the nucleus. In contrast, only nerve fibers and their terminals were present at a more rostral level in the mid- and rostral MTN. MTN neuronal perikarya were enveloped in fine basket-like NADPH-d/ NOS-positive networks. Differential expression patterns of NOS and its marker NADPH-d suggest that trigeminal sensory information processing in the cat MTN is controlled by nitrergic input through different mechanisms. We introduce the concept that NO can act as a neurotransmitter in mediating nociceptive and proprioceptive information from periodontal mechanoreceptors but may also participate in modulating the activity of jaw-closing muscle afferent MTN neurons.


Mitochondrial activity after cold preservation of pancreatic islet cells treated with pefloxacin (PFX).
Mitochondrial energetic and oxidative dysfunctions caused by free radical production trigger release of proinflammatory cytokines involved in organ rejection. The aim of this study was to investigate the role of a fluoroquinolone drug, pefloxacin (PFX) and those of various cold preservation solutions on pancreatic beta cell viability. Our data clearly demonstrate that islet cell viability, as determined by glucose-stimulated insulin secretion, is directly correlated with reduced expression of microsomal cytochrome P-450IIIA. Moreover, IL-2, a known mediator of apoptosis was found to be downregulated, whereas TNF-alpha had been upregulated for the first 18 hours after pefloxacin administration. These results demonstrate that pefloxacin downregulates the expression of cytochrome P-450IIIA isozyme and regulates the production of TNF-alpha and IL-2. Thus, we postulate that the presence of pefloxacin in the pancreatic islet cells before organ preservation facilitates increased cell viability.


Comparative study of trauma-related phenomena in subjects with pseudoseizures and subjects with epilepsy.
The purpose of this study was to examine potential differences in measures of trauma-related phenomena between subjects with pseudoseizures and subjects with intractable epilepsy. Thirty-one adult subjects with pseudoseizures and 32 subjects with intractable epilepsy (confirmed by video-EEG) were recruited from the epilepsy unit of a tertiary care hospital. Each participant completed the Impact of Event Scale, the Davidson Trauma Scale, the Mississippi Scale for Combat-Related Posttraumatic Stress Disorder (PTSD), the Dissociative Experience Scale, and the Pittsburgh Sleep Quality Index, as well as demographic, seizure history, and family functioning measures. Subjects with pseudoseizures had significantly higher mean scores on the Davidson Trauma Scale, Mississippi Scale for Combat-Related PTSD, Impact of Event Scale, and Pittsburgh Sleep Quality Index than subjects with epilepsy. In addition, a significantly higher percentage of subjects with pseudoseizures had scores above the clinical cutoff level of 30 on the Dissociative Experience Scale. Subjects with pseudoseizures exhibited trauma-related profiles that differed significantly from those of epileptic comparison subjects and closely resembled those of individuals with a history of traumatic experiences. Interventions aimed at trauma-related issues may be beneficial for patients with pseudoseizures.


Somatic Superenhancer Duplications and Hotspot Mutations Lead to Oncogenic Activation of the KLF5 Transcription Factor.
The Krüppel-like family of transcription factors plays critical roles in human development and is associated with cancer pathogenesis. Krüppel-like factor 5 gene (KLF5) has been shown to promote cancer cell proliferation and tumorigenesis and to be genomically amplified in cancer cells. We recently reported that the KLF5 gene is also subject to other types of somatic coding and noncoding genomic alterations in diverse cancer types. Here, we show that these alterations activate KLF5 by three distinct mechanisms: (i) Focal amplification of superenhancers activates KLF5 expression in squamous cell carcinomas; (ii) Missense mutations disrupt KLF5-FBXW7 interactions to increase KLF5 protein stability in colorectal cancer; (iii) Cancer type-specific hotspot mutations within a zinc-finger DNA binding domain of KLF5 change its DNA binding specificity and reshape cellular transcription. Utilizing data from CRISPR/Cas9 gene knockout screening, we reveal that cancer cells with KLF5 overexpression are dependent on KLF5 for their proliferation, suggesting KLF5 as a putative therapeutic target.Significance: Our observations, together with previous studies that identified oncogenic properties of KLF5, establish the importance of KLF5 activation in human cancers, delineate the varied genomic mechanisms underlying this occurrence, and nominate KLF5 as a putative target for therapeutic intervention in cancer. Cancer Discov; 8(1); 108-25. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1.


Dynamics of major histocompatibility complex class I association with the human peptide-loading complex.
Although the human peptide-loading complex (PLC) is required for optimal major histocompatibility complex class I (MHC I) antigen presentation, its composition is still incompletely understood. The ratio of the transporter associated with antigen processing (TAP) and MHC I to tapasin, which is responsible for MHC I recruitment and peptide binding optimization, is particularly critical for modeling of the PLC. Here, we characterized the stoichiometry of the human PLC using both biophysical and biochemical approaches. By means of single-molecule pulldown (SiMPull), we determined a TAP/tapasin ratio of 1:2, consistent with previous studies of insect-cell microsomes, rat-human chimeric cells, and HeLa cells expressing truncated TAP subunits. We also report that the tapasin/MHC I ratio varies, with the PLC population comprising both 2:1 and 2:2 complexes, based on mutational and co-precipitation studies. The MHC I-saturated PLC may be particularly prevalent among peptide-selective alleles, such as HLA-C4. Additionally, MHC I association with the PLC increases when its peptide supply is reduced by inhibiting the proteasome or by blocking TAP-mediated peptide transport using viral inhibitors. Taken together, our results indicate that the composition of the human PLC varies under normal conditions and dynamically adapts to alterations in peptide supply that may arise during viral infection. These findings improve our understanding of the quality control of MHC I peptide loading and may aid the structural and functional modeling of the human PLC.


Gating of epidermal plasmodesmata is restricted to the leading edge of expanding infection sites of tobacco mosaic virus (TMV).
Plasmodesmatal gating in epidermal cells of Nicotiana tabacum was examined in expanding infection sites of tobacco mosaic virus (TMV) expressing a fusion between the viral movement protein and the green fluorescent protein (MP-GFP). The infection sites were circular in profile and within 3 days post-inoculation had developed a brightly fluorescent leading edge, giving them a characteristic 'halo' shape. Co-localization of MP-GFP with callose demonstrated that nearly all epidermal cell plasmodesmata were targeted with MP-GFP. The fusion protein was located in the centre of the plasmodesmal pore, between paired callose platelets. Increase in plasmodesmatal size exclusion limit, as determined by the passage of microinjected 10 kDa Texas Red dextran, was restricted predominantly to cells within the fluorescent halo, and was virtually absent from cells in the centre of the expanding infection site. The plasmodesmata of these cells, however, remained fluorescently labelled with MP-GFP. Injections outside the fluorescent infection site failed to show movement of dextran, while dextran injected into cells at the leading edge moved inwards towards the centre of the lesion but not outwards into cells lacking GFP. Leaf incisions through cells ahead of the infection front halted the advance of the virus, indicating that virus replication was absent in non-fluorescent cells outside the infection site. The data provide the first demonstration that within an expanding infection site plasmodesmatal gating is under temporal control.


Q&A: Ray DuBois on Screening, Early Detection.
Raymond DuBois, MD, PhD, director of the Medical University of South Carolina's Hollings Cancer Center in Charleston, discusses cancer screening and the importance of increasing access to screening among economically disadvantaged people. He also offers thoughts on developing a pan-cancer blood test using circulating tumor DNA to aid in cancer detection.


[Kidney function disorders in "uncomplicated" skeletal trauma in children].
The renal function was studied in 198 children with non-complicated skeletal trauma (fraction of the femur, vertebral column and others). The renal function was found to be disturbed in 34,3% of the cases. The suitable treatment results in normal functioning of the kidneys within the 2nd week after trauma.


Neurobehavioral hazard identification and characterization for caffeine.
This report evaluates the scientific literature on caffeine with respect to potential central nervous system (CNS) effects, specifically effects on sleep, anxiety, and aggression/risk-taking. Caffeine has been the subject of more scientific safety studies than any other food ingredient. It is important, therefore, to evaluate new studies in the context of this large existing body of knowledge. The safety of caffeine can best be described in a narrative form, and is not usefully expressed in terms of a "bright line" numerical value like an "acceptable daily intake" (ADI). Caffeine intake has been associated with a range of reversible physiological effects, in a few studies at levels of less than 100 mg in sensitive individuals. It is also clear that many people can tolerate much greater levels - perhaps up to 600-800 mg/day or more - without experiencing such effects. The reasons for this type of variability in response are described in this report. Based on all the available evidence, there is no reason to believe that experiencing such effects from caffeine intake has any significant or lasting effect on health. The point at which caffeine intake may cause harm to the CNS is not readily identifiable, in part because data on the effects of daily intakes greater than 600 mg is limited. Effects of caffeine on risk-taking and aggressive behavior in young people have received considerable publicity, yet are the most difficult to study because of ethical concerns and limitations in the ability to design appropriate studies. At present, the weight of available evidence does not support these concerns, yet this should not preclude ongoing careful monitoring of the scientific literature.


Evolutionary rescue and the coexistence of generalist and specialist competitors: an experimental test.
Competition for resources is thought to play a critical role in both the origins and maintenance of biodiversity. Although numerous laboratory evolution experiments have confirmed that competition can be a key driver of adaptive diversification, few have demonstrated its role in the maintenance of the resulting diversity. We investigate the conditions that favour the origin and maintenance of alternative generalist and specialist resource-use phenotypes within the same population. Previously, we confirmed that competition for hosts among φ6 bacteriophage in a mixed novel (non-permissive) and ancestral (permissive) host microcosm triggered the evolution of a generalist phenotype capable of infecting both hosts. However, because the newly evolved generalists tended to competitively exclude the ancestral specialists, coexistence between the two phenotypes was rare. Here, we show that reducing the relative abundance of the novel host slowed the increase in frequency of the generalist phenotype, allowing sufficient time for the specialist to further adapt to the ancestral host. This adaptation resulted in 'evolutionary rescue' of the specialists, preventing their competitive exclusion by the generalists. Thus, our results suggest that competition promotes both the origin and maintenance of biodiversity when it is strong enough to favour a novel resource-use phenotype, but weak enough to allow adaptation of both the novel and ancestral phenotypes to their respective niches.


Defining the peak: Point prevalence of SARS-CoV-2 using randomised sampling.
Since Queensland eased border restrictions to the rest of Australia on 13 December 2021, notified cases of Coronavirus disease 2019 (COVID-19) dramatically increased, with the SARS-CoV-2 Omicron variant now the most widespread variant of concern: 145,881 cases and 13 deaths were recorded in Queensland in the month following the opening of the border. For an effective public health response to a highly transmissible disease, it is important to know the prevalence in the community, but the exponential increase in cases meant that many with symptoms had difficulty getting tested. We implemented a surveillance program on the Gold Coast that used a modified randomised household cluster survey method to estimate the point prevalence of individuals with SARS-CoV-2 detected by polymerase chain reaction (PCR). The estimated point prevalence of SARS-CoV-2 detected by PCR on self-collected swabs was 17.2% on the first visit to households (22 January 2022). This subsequently decreased to 5.2% (5 February 2022) and finally to 1.1% (19 February 2022). Out of 1,379 specimens tested over five weeks, 63 had detected SARS-CoV-2 and 35 (55.6%) were sequenced. All were SARS-CoV-2 variant: B.1.1.529 (i.e. Omicron). This surveillance program could be scaled up or reproduced in other jurisdictions to estimate the prevalence of COVID-19 in the community. Since Queensland eased border restrictions to the rest of Australia on 13 December 2021, notified cases of Coronavirus disease 2019 (COVID-19) dramatically increased, with the SARS-CoV-2 Omicron variant now the most widespread variant of concern: 145,881 cases and 13 deaths were recorded in Queensland in the month following the opening of the border. For an effective public health response to a highly transmissible disease, it is important to know the prevalence in the community, but the exponential increase in cases meant that many with symptoms had difficulty getting tested. We implemented a surveillance program on the Gold Coast that used a modified randomised household cluster survey method to estimate the point prevalence of individuals with SARS-CoV-2 detected by polymerase chain reaction (PCR). The estimated point prevalence of SARS-CoV-2 detected by PCR on self-collected swabs was 17.2% on the first visit to households (22 January 2022). This subsequently decreased to 5.2% (5 February 2022) and finally to 1.1% (19 February 2022). Out of 1,379 specimens tested over five weeks, 63 had detected SARS-CoV-2 and 35 (55.6%) were sequenced. All were SARS-CoV-2 variant: B.1.1.529 (i.e. Omicron). This surveillance program could be scaled up or reproduced in other jurisdictions to estimate the prevalence of COVID-19 in the community.


[Lactose tolerance in children with chronic gastroduodenal zone diseases].
We determined the dependence of the frequency of lactose intolerance, particular features of the clinical presentation and laboratory showings on lactase deficiency on the basis of a complex clinical, anamnestic and laboratory study of 149 children with chronic gastroduodenal pathologies. It was established that the prevalence of lactose intolerance in children with superficial gastroduodenitis amounts to 58.8%, in children with erosive gastroduodenitis--66.7% and in children with stomach ulcers--83.3%. During the oral lactose load and a subsequent laboratory study we revealed an impairment of the hydrolytic function of small intestines accompanied by an increase of fecal excretion of carbohydrates (lactose and monosaccharides) as well as a considerable enhancement of bacterial fermentation. The detection of fecal excretion of the total glycoprotein hexoses characterizes a disorder of the morphofunctional state of the gastrointestinal tract in children with intestinal enzymopathies.


[Extracorporeal shock wave lithotripsy in urolithiasis. An update].
The author discusses the present role of extracorporeal shock wave treatment of urolithiasis. The views are based on personal experience and a review of the recent literature. Compared with the original device, second generation lithotriptors have led to almost painless treatment. They are less effective in fragmenting the stones, however, which implies a higher number of repeat treatments. The indications and contraindications for extracorporeal shock wave lithotripsy have remained unchanged over the last years. In principle, stones along the whole upper urinary tract can be treated. The ideal situation is a stone in the kidney pelvis less than 2.5 cm in diameter or an unimpacted stone in the upper or lower ureter, with normal collective system anatomy. The main determinants for treatment outcome are stone burden, number, location and chemical composition, presence of infection, intrarenal anatomy and fluid dynamics. Special situations often need additional treatment with other treatment modalities. Rest fragments, even less than 4 mm, are often of clinical significance within two years of treatment. Bioeffects of extracorporeal shock wave lithotripsy include anatomical and functional alterations. Usually they are resolved within weeks. The relationship between extracorporeal shock wave lithotripsy and new onset hypertension remains unresolved.


How NaCl and water content determine water activity during ripening of Gouda cheese, and the predicted effect on inhibition of Listeria monocytogenes.
This study describes the diffusion of NaCl and water in Gouda cheese during brining and ripening. Furthermore, we established water activity as a function of the NaCl-in-moisture content in Gouda cheese during ripening. We determined NaCl content, water content, and water activity in block-type Gouda cheeses that were brined for 3.8d and foil-ripened for a period of 26 wk, and in wheel-type Gouda cheeses that were brined for 0.33, 2.1, or 8.9d and subsequently nature-ripened for a period of 26 wk. The calculated diffusion coefficients of NaCl during brining were 3.6·10(-10) m(2)s(-1) in the block-type Gouda cheeses and 3.5·10(-10) m(2)s(-1) in the wheel-type Gouda cheeses. Immediately after brining, gradients of NaCl and water were observed throughout both types of cheese. During ripening, these gradients disappeared, except for the water gradient in nature-ripened cheeses. An empirical model was derived for Gouda cheese, in which water activity is expressed as a function of the NaCl-in-moisture content, as established for different brining times, locations and ripening times. Moreover, the effect of reduced water activity on inhibition of growth of Listeria monocytogenes in Gouda cheese was calculated. In addition to the presence of lactate and a pH of 5.2 to 5.3, the reduced water activity as seen in Gouda cheese can substantially contribute to inhibition of microbial growth and even to inactivation when cheeses are brined and ripened for extended times and subjected to nature-ripening.


D2-receptor-linked signaling pathways regulate the expression of hepatic CYP2E1.
This study investigated the role of catecholamine-related signaling pathways in the regulation of hepatic cytochrome P450 (CYP2E1). Central and peripheral catecholamine depletion with reserpine down-regulated CYP2E1. On the other hand, selective peripheral catecholamine depletion with guanethidine increased CYP2E1 apoprotein levels. Enrichment of peripheral catecholamines with adrenaline suppressed p-nitrophenol hydroxylase activity (PNP). PNP activity was also markedly suppressed by l-DOPA. Stimulation of D(2)-receptors with bromocriptine up-regulated CYP2E1, as assessed by enzyme activity and protein levels, whereas blockade of D(2)-dopaminergic receptors with sulpiride down-regulated this isozyme. These findings indicate that central and peripheral catecholamines have different effects on CYP2E1. Central catecholamines appear related to the up-regulation, whereas the role of peripheral catecholamines is clearly related to the type and location of adrenoceptors involved. D(2)-receptor-linked signaling pathways have an up-regulating effect on CYP2E1, while D(1)-receptor pathways may down-regulate this isozyme. It is worth noting that the widespread environmental pollutant benzo(alpha)pyrene (B(alpha)P) altered the modulating effect of catecholaminergic systems on CYP2E1 regulation. In particular, whereas stimulation or blockade of adrenoceptors had no effect on constitutive PNP activity, exposure to B(alpha)P modified the impact of central and peripheral catecholamines and alpha(2)-adrenoceptors on CYP2E1 expression. It appears that under the influence of B(alpha)P, alpha(2)-adrenergic receptor-linked signaling pathways increased CYP2E1 apoprotein levels. Given that a wide range of xenobiotics and clinically used drugs are activated by CYP2E1 to toxic metabolites, including the production of reactive oxygen species (ROS), it is possible that therapies challenging dopaminergic receptor- and/or alpha(2)-adrenoceptor-linked signaling pathways may alter the expression of CYP2E1, thus affecting the progress and development of several pathologies.


Anterior Column Realignment: Analysis of Neurological Risk and Radiographic Outcomes.
Anterior column realignment (ACR) is a less invasive alternative to 3-column osteotomy for the correction of sagittal imbalance. We hypothesized that ACR would correct sagittal imbalance with an acceptable neurological risk. To assess long-term neurological and radiographic outcomes after ACR. Patients ≥18 yr who underwent ACR from 2005 to 2013 were eligible. Standing scoliosis radiographs were studied at preoperation, postoperation (≤6 wk), and at minimum 2 yr of follow-up. Clinical/radiographic data were collected through a retrospective chart review, with thoracic 1 spino-pelvic inclination (T1SPi) used as the angular surrogate for sagittal vertical axis. A total of 26 patients had complete data, with a mean follow-up of 2.8 yr (1.8-7.4). Preoperative, sagittal parameters were lumbar lordosis (LL) of -16.1°, pelvic incidence (PI)-LL of 41.7°, T1SPi of 3.6°, and pelvis tilt (PT) of 32.4°. LL improved by 30.6° (P < .001) postoperation. Mean changes in PT (-8.3), sacral slope (8.9), T1SPi (-4.9), and PI-LL (-33.5) were all significant. The motion segment angle improved by 26.6°, from 5.2° to -21.4° (P < .001). Neurological complications occurred in 32% patients postoperation (n = 8; 1 patient with both sensory and motor). New thigh numbness/paresthesia developed in 3 (13%) patients postoperation; only 1 (4%) persisted at latest follow-up. A total of 6 (24%) patients developed a new lower extremity motor deficit postoperation, with 4 (8%) having persistent new weakness at last follow-up. Out of 8 patients with preoperative motor deficit, half saw improvement postoperation and 75% improved by last follow-up. There was net motor improvement, with 24% of patients improving and 16% having persistent new weakness at latest follow-up; 60% were unchanged. Radiographic results demonstrate that ACR is a useful tool to treat severe sagittal plane deformity.


Sheath area in Brahman and grade Brahman calves and its association with preweaning growth traits.
Data from 439 Brahman (B) and grade Brahman (GB; 7/8 Brahman or more) calves born from 1970 through 1975 at the USDA Subtropical Agricultural Research Station were used to estimate least-squares means, heritabilities and genetic correlations for sheath area and preweaning growth traits. Grade Brahman calves weighed more (P less than .01) at birth and gained more (P less than .01) preweaning than B calves, although sheath areas were not different. Males exceeded (P less than .01) heifers in all preweaning growth traits and had larger (P less than .01) sheath areas. Heritabilities were: sheath area, .45 +/- .13; birth weight, .25 +/- .13; average daily gain, .38 +/- .15 and weaning weight, .35 +/- .15. Genetic correlations between sheath area and birth weight, average daily gain and weaning weight were .23 +/- .35, .58 +/- .25 and .52 +/- .27. These results suggest selection could be effective in reducing sheath area in B and B-derivative breeds, but would be antagonistic to preweaning growth traits. Because of relatively low phenotypic correlations between sheath area and preweaning growth rate (.27) and weaning weight (.29), continued emphasis on increasing growth rate or weaning weight could generally be maintained with careful attention to avoiding large sheath areas through independent culling level or index selection procedures.


Q fever awareness in Australia: A scoping review.
To investigate the level of Q fever awareness in Australia. A scoping review was conducted by searching the electronic databases Medline, PubMed and Web of Science using keywords for Q fever, awareness, knowledge, and Australian locations. The search was initially limited to articles published in the 10 years prior to June 2022 and then extended up to and including August 2023; yielding 387 records. Fifteen articles were assessed as being eligible. These articles reported on surveys and interviews conducted with farmers, veterinary practitioners and nurses, medical practitioners, policy makers, researchers, industry representatives, animal science students, cat breeders, wildlife rehabilitators, and agriculture show attendees. Farmers were the largest group represented. Level of Q fever awareness amongst these communities, including those at high-risk, was generally low. The need for increased awareness was recognised. General practitioner awareness levels were low and recognised to be so by high-risk groups. Awareness of preventive measures including vaccination was greater among those with greater awareness and risk. With the availability of a highly effective vaccine in Austrlia, there is a need to increase Q fever knowledge and awareness among high-risk groups and primary health care practitioners. Strategies to increase awareness and knowledge of Q fever risks and prevention strategies may assist with reducing Q fever burden in Australia.


Broiler welfare trade-off: A semi-quantitative welfare assessment for optimised welfare improvement based on an expert survey.
In order to support decision making on how to most effectively improve broiler welfare an innovative expert survey was conducted based on principles derived from semantic modelling. Twenty-seven experts, mainly broiler welfare scientists (n = 20; and 7 veterinarians), responded (response rate 38%) by giving welfare scores (GWS, scale 0-10) to 14 benchmarking housing systems (HSs), and explaining these overall scores by selecting, weighing and scoring main welfare parameters, including both input and output measures. Data exploration followed by REML (Linear Mixed Model) and ALM (Automatic Linear Modelling) analyses revealed 6 clusters of HSs, sorted from high to low welfare, i.e. mean GWS (with superscripts indicating significant differences): 1. (semi-natural backyard) Flock (8.8a); 2. Nature (7.7ab), Label Rouge II (7.4ab), Free range EU (7.2ab), Better Life (7.2ab); 3. Organic EU (7.0bc), Freedom Food (6.2bc); 4. Organic US (5.8bcd), Concepts NL (5.6abcdef), GAP 2 (4.9bcd); 5. Conventional EU (3.7de), Conventional US (2.9ef), Modern cage (2.9abcdef); 6. Battery cage (1.3f). Mean weighting factors (WF, scale 0-10) of frequently (n> = 15) scored parameters were: Lameness (8.8), Health status (8.6), Litter (8.3), Density (8.2), Air quality (8.1), Breed (8.0), Enrichment (7.0) and Outdoor (6.6). These did not differ significantly, and did not have much added value in explaining GWS. Effects of Role (Scientist/Vet), Gender (M/F) and Region (EU/non-EU) did not significantly affect GWS or WF, except that women provided higher WF than men (7.2 vs 6.4, p<0.001). The contribution of welfare components to overall welfare has been quantified in two ways: a) using the beta-coefficients of statistical regression (ALM) analyses, and b) using a semantic-modelling type (weighted average) calculation of overall scores (CalcWS) from parameter level scores (PLS) and WF. GWS and CalcWS were highly correlated (R = ~0.85). CalcWS identified Lameness, Health status, Density, Breed, Air quality and Litter as main parameters contributing to welfare. ALM showed that the main parameters which significantly explained the variance in GWS based on all PLS, were the output parameter Health status (with a beta-coefficient of 0.38), and the input parameters (stocking) Density (0.42), Litter (0.14) and Enrichment (0.27). The beta-coefficients indicated how much GWS would improve from 1 unit improvement in PLS for each parameter, thus the potential impact on GWS ranged from 1.4 welfare points for Litter to 4.2 points for Density. When all parameters were included, 81% of the variance in GWS was explained (77% for inputs alone; 39% for outputs alone). From this, it appears that experts use both input and output parameters to explain overall welfare, and that both are important. The major conventional systems and modern cages for broilers received low welfare scores (2.9-3.7), well below scores that may be considered acceptable (5.5). Also, several alternatives like GAP 2 (4.9), Concepts NL (5.6), Organic US (5.8) and Freedom Food (6.2) are unacceptable, or at risk of being unacceptable due to individual variation between experts and farms. Thus, this expert survey provides a preliminary semi-quantified decision-support tool to help determine how to most effectively improve broiler welfare in a wide range of HSs.


Potential fitness trade-offs for thermal tolerance in the intertidal copepod Tigriopus californicus.
Thermal adaptation to spatially varying environmental conditions occurs in a wide range of species, but what is less clear is the nature of fitness trade-offs associated with this temperature adaptation. Here, populations of the intertidal copepod Tigriopus californicus are examined at both local and latitudinal scales to determine whether these populations have evolved differences in their survival under high temperature stress. A clear pattern of increasing high temperature stress tolerance is seen with decreasing latitude, consistent with temperature adaptation. Additionally, there is also evidence for significant variation in thermal tolerance on a smaller scale. The competitive fitness of pairs of northern and southern copepod populations were also examined under a series of lower, more moderate temperatures. These fitness assays show that the southern populations that have the best survival under extreme high temperatures have lowered competitive fitness at the lower temperatures tested, whereas the fitness of the southern populations exceeded that of the northern populations at the highest temperatures tested. Combined, these results suggest that there may be evolutionary trade-offs between performance at high and stressful temperatures and fitness at moderate temperatures in this species.


Prevalence of diagnosed depression, anxiety, and ADHD among youth with type 1 or type 2 diabetes mellitus.
We examined the prevalence of diagnosed depression, anxiety, and ADHD among youth by diabetes type, insurance type, and race/ethnicity. These mental disorders were more prevalent among youth with diabetes, particularly those with type 2 diabetes, with non-Hispanic White youth with Medicaid and diabetes having a higher prevalence than other races/ethnicities.


Comparative effectiveness research: a cornerstone of healthcare reform?
Comparative Effectiveness Research (CER) has recently emerged as a major theme in health care reform. Unfortunately, there is a widespread lack of understanding about what it will do and fear that it will do more harm than good. These concerns include threats to individual physician's autonomy and professionalism, as well as fears that care will be rationed based on such findings. In this paper, we argue that the main components of the current healthcare reform (HCR) bills, which include expanding insurance while increasing efficiencies through cost containment, should embrace CER. This type of research will provide a "safeguard" against "blind" cost-containment, so that the new financial incentives being introduced can be actualized effectively and safely. Evidence for this is provided from examples from the authors' prior and current research as well as from the literature. We also argue that the requirement for data from CER will create long-term disincentives for "me-too" drugs and devices and, therefore, become a catalyst for effective innovation.


Clinical significance of monitoring early symptom change to predict outcome.
Even with efforts to develop medication algorithms for the treatment of psychiatric illnesses, there is no single authoritative method that can be used to incorporate multiple factors in the treatment decision process. For this reason, physicians are faced with the often daunting task of sifting through the numerous treatment options for psychiatric illness to develop an approach that will prove the most successful for their patients. Investigating patient patterns of response, particularly during the acute phase of treatment, and bearing them in mind when developing treatment protocols may assist clinicians in optimally managing the degree and course of symptom response. We present here a consideration of the timing and nature of response as well as individual patient predictors, which may impact therapy decisions. Furthermore, we explore the clinical significance of integrating response patterns into the treatment approach. We believe that an analysis of response patterns, in conjunction with the use of other practice guidelines, is a viable method to more effectively navigate critical decision points in the treatment process and ultimately have a dramatic effect on patient outcome.


Antimicrobial susceptibility testing of six clinical isolates of Aspergillus.
Several different methods of performing susceptibility tests on six clinical isolates of Aspergillus are described. Some of the conditions that affected the level of susceptibility to drugs were: the type of media used, temperature and time of incubation, and the initial inoculum size. For amphotericin B susceptibility testing, the effectiveness of the polyene antibiotic as measured by visual growth was equivalent to the effectiveness as measured by inhibition of ribonucleic acid synthesis and dry-weight increase. For 5-fluorocytosine and rifampin, the visual-turbidity method gave minimum inhibitory concentrations that were much higher than those determined by effects on ribonucleic acid synthesis and dry weight. The reason for these discrepancies in susceptibility testing with 5-fluorocytosine and rifampin are unknown. We conclude that the most relevant test of this fungus to antifungal agents will have to be determined by the correlation of in vitro data with animal experiments and clinical results.


Systematic review: Exposure to pets and risk of asthma and asthma-like symptoms.
Studies of exposure to pets and risk of asthma have yielded conflicting results. We performed a systematic review to synthesize the evidence of the effect of exposure to pets in the home on the risk of asthma and asthma-related symptoms. We also assessed differences between the studies as sources of heterogeneity of the results. We conducted a MEDLINE search (until the end of 1999) using the following boolean search command: (asthma[all] OR wheez*[all]) AND (domestic animal*[all] OR pets[all]). The outcome was limited to either diagnosis of asthma or the symptom of wheezing. The exposure of interest was domestic animals in the home. Appropriate temporal relationship was defined as present in studies with either pet keeping within the first 2 years of life, in the past, or exposure to pets preceding the outcome. Thirty-two of the 217 retrieved articles fulfilled the eligibility criteria. Inappropriate time sequence of the exposure and outcome information was an important source of heterogeneity and an indication of potential selection bias. Therefore we analyzed studies focusing on early exposure or ensuring appropriate temporal sequence. The pooled risk estimates for both asthma (fixed-effects odds ratio, 1.11; 95% CI, 0.98-1.25; heterogeneity, P =.04; random-effects odds ratio, 1.09; 95% CI, 0.89-1.34) and wheezing (fixed-effects odds ratio, 1.19; 95% CI, 1.05-1.35; heterogeneity, P =.03; random-effects odds ratio, 1.17; 95% CI, 0.95-1.44) indicated a small effect, which was limited to studies with a median study population age of over 6 years (fixed-effects odds ratio, 1.19; 95% CI, 1.02-1.40; heterogeneity, P =.04; random-effects odds ratio, 1.15; 95% CI, 0.86-1.56; fixed-effects odds ratio, 1.29; 95% CI, 1.12-1.48; heterogeneity, P =.31). In younger children the harmful effect disappeared for wheezing (odds ratio, 0.80; 95% CI, 0.59-1.08; P =.38). Exposure to pets appears to increase the risk of asthma and wheezing in older children. The observed lower risk among exposed than among unexposed young children is consistent with a protective effect in this age group but could also be explained by selection bias.


Comparison of ligand-based and receptor-based virtual screening of HIV entry inhibitors for the CXCR4 and CCR5 receptors using 3D ligand shape matching and ligand-receptor docking.
HIV infection is initiated by fusion of the virus with the target cell through binding of the viral gp120 protein with the CD4 cell surface receptor protein and the CXCR4 or CCR5 co-receptors. There is currently considerable interest in developing novel ligands that can modulate the conformations of these co-receptors and, hence, ultimately block virus-cell fusion. This article describes a detailed comparison of the performance of receptor-based and ligand-based virtual screening approaches to find CXCR4 and CCR5 antagonists that could potentially serve as HIV entry inhibitors. Because no crystal structures for these proteins are available, homology models of CXCR4 and CCR5 have been built, using bovine rhodopsin as the template. For ligand-based virtual screening, several shape-based and property-based molecular comparison approaches have been compared, using high-affinity ligands as query molecules. These methods were compared by virtually screening a library assembled by us, consisting of 602 known CXCR4 and CCR5 inhibitors and some 4700 similar presumed inactive molecules. For each receptor, the library was queried using known binders, and the enrichment factors and diversity of the resulting virtual hit lists were analyzed. Overall, ligand-based shape-matching searches yielded higher enrichments than receptor-based docking, especially for CXCR4. The results obtained for CCR5 suggest the possibility that different active scaffolds bind in different ways within the CCR5 pocket.


Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck.
In 1992, we reported the first analysis of a randomized trial comparing alternating radiotherapy and chemotherapy with radiotherapy alone in the treatment of squamous cell carcinoma of the head and neck. The results of that 3-year analysis indicated that the combined treatment had superior efficacy. After an additional 2 years of follow-up, we again compared the efficacy of the two treatment regimens, with attention paid to differences in overall survival, progression-free survival, and locoregional relapse-free survival. One hundred fifty-seven patients with untreated, unresectable squamous cell carcinoma of the head and neck were randomly assigned to receive either chemotherapy (four courses of cisplatin [20 mg/m2] and fluorouracil [200 mg/m2], given daily for 5 consecutive days during weeks 1, 4, 7, and 10) plus radiotherapy (three courses of 20 Gy each, given in fractions of 2 Gy per day during weeks 2-3, 5-6, and 8-9) or radiotherapy alone (70 Gy total dose, given in fractions of 2 Gy per day, 5 days per week). Eighty patients received the combined therapy, and 77 were treated with radiotherapy alone. Responses, failures, and toxic effects associated with the two treatment regimens were compared. Overall survival, progression-free survival, and locoregional relapse-free survival were calculated according to the Kaplan-Meier method; the logrank test was used to compare survival parameters between the two patient groups. Reported P values are two-sided. As reported previously, toxic effects associated with the combined therapy included both chemotherapy- and radiotherapy-related effects; however, the incidence and severity of mucositis were nearly identical among patients in the two treatment arms. The combined treatment was associated with a statistically significant increase in the frequency of complete response (i.e., the disappearance of clinically detectable disease for at least 4 weeks) (43% for the combined-treatment group compared with 22% for the radiotherapy-only group; P = .037, chi-squared test). Five-year estimates of overall survival in the combined-treatment group compared with the radiotherapy-only group were 24% (95% confidence interval [CI] = 14%-40%) and 10% (95% CI = 4%-24%), respectively (P = .01, logrank test). The estimates of progression-free survival at 5 years in the combined-treatment group compared with the radiotherapy-only group were 21% (95% CI = 11%-37%) and 9% (95% CI = 3%-22%), respectively (P = .008, logrank test). Finally, the 5-year estimates of locoregional relapse-free survival were 64% (95% CI = 36%-84%) in the combined-treatment group and 32% (95% CI = 10%-65%) in the radiotherapy-only group (P = .038, logrank test). The superiority of alternating chemotherapy and radiotherapy over radiotherapy alone in treating unresectable squamous cell carcinoma of the head and neck seen at 3 years was confirmed at 5 years. However, additional trials must be conducted before considering the combined approach as standard therapy.


The association between sub-therapeutic antibiotics and Salmonella Typhimurium in market-weight swine: a systematic review and summation of evidence from 1950 to 2007.
A systematic review approach was used to evaluate the association between sub-therapeutic antibiotics in feed and Salmonella Typhimurium isolation in market-weight finisher swine raised in modern swine production systems. Fourteen challenge trials described the efficacy of different antibiotics after challenge with S. Typhimurium. The studies identified were of limited evidentiary value for the review question because they were not relevant to the review question, i.e. conducted in artificial settings on small numbers of young pigs. None of the studies reported using blinding during outcome assessment. No antibiotic regimen was evaluated more than once. The association between sub-therapeutic antibiotics and Salmonella outcomes in market-weight swine raised in modern production systems cannot be summarized using the currently available literature. Many available studies fail to report critical study design features such as blinding and/or to take into account the data generated from longitudinal studies.


Length-independent charge transport of well-separated single-crystal TiO2 long nanowire arrays.
Long, well-separated single crystal TiO2 nanowire (NW) arrays with rapid charge transport properties hold great promise in photoelectrochemical and energy storage devices. Synthesis variations to increase the NWs length generally result in the widening of the NWs and fusion at their roots which, in turn, increases the structural disorder and slows charge transport. As such, well-separated single-crystal TiO2 NW arrays with rapid charge transport properties have been limited to lengths of about 3-4 μm. In this work, by adjusting the HCl/DI-water ratio and adding specific organic ligands to the reaction solution that slow the lateral growth rate we achieve well-separated single-crystal rutile TiO2 NW arrays with a length of ∼10 μm and an aspect ratio of approximately 100. The charge transport is 100 times faster than that of nanoparticle films and remarkably exhibits length-independence, a behavior that can be attributed to the well-separated architecture. The synthesis strategy can be extended to the fabrication of other well-separated metal oxide NW arrays and represents an important tool in achieving high performance photoelectrochemical and electrical energy storage devices.


Periods of high dengue transmission defined by rainfall do not impact efficacy of dengue vaccine in regions of endemic disease.
To evaluate the association of rainy season with overall dengue disease incidence and with the efficacy of the Sanofi Pasteur recombinant, live, attenuated, tetravalent vaccine (CYD-TDV) in two randomized, controlled multicenter phase III clinical trials in Asia and Latin America. Rainy seasons were defined for each study site using climatological information from the World Meteorological Organization. The dengue attack rate in the placebo group for each study month was calculated as the number of symptomatic, virologically-confirmed dengue events in a given month divided by the number of participants at risk in the same month. Time-dependent Cox proportional hazard models were used to test whether rainy season was associated with dengue disease and whether it modified vaccine efficacy in each of the two trials and in both of the trials combined. Rainy season, country, and age were all significantly associated with dengue disease in both studies. Vaccine efficacy did not change during the rainy season in any of the analyses. Although dengue transmission and exposure are expected to increase during the rainy season, our results indicate that CYD-TDV vaccine efficacy remains constant throughout the year in endemic regions.


Parameter estimation in Bayesian high-resolution image reconstruction with multisensors.
In this paper, we consider the estimation of the unknown parameters for the problem of reconstructing a high-resolution image from multiple undersampled, shifted, degraded frames with subpixel displacement errors. We derive mathematical expressions for the iterative calculation of the maximum likelihood estimate of the unknown parameters given the low resolution observed images. These iterative procedures require the manipulation of block-semi circulant (BSC) matrices, that is, block matrices with circulant blocks. We show how these BSC matrices can be easily manipulated in order to calculate the unknown parameters. Finally the proposed method is tested on real and synthetic images.


Probiotics and prebiotics in gastrointestinal disorders.
This review summarizes the clinical efficacy of probiotics and prebiotics in gastrointestinal disorders and examines the mechanisms of action related to their therapeutic effect. The demonstration that immune and epithelial cells can discriminate between different microbial species has extended the known mechanism(s) of action of probiotics beyond simple barrier and antimicrobial effects. It has also confirmed that probiotic bacteria modulate mucosal and systemic immune activity and epithelial function. The progressive unraveling of these mechanisms of action has led to new credence for the use of probiotics and prebiotics in clinical medicine. Level I evidence now exists for the therapeutic use of probiotics in infectious diarrhea in children, recurrent Clostridium difficile-induced infections and postoperative pouchitis. Level II evidence is emerging for the use of probiotics in other gastrointestinal infections, prevention of postoperative bacterial translocation, irritable bowel syndrome, and in both ulcerative colitis and Crohn disease. Nevertheless, one consistent feature has emerged over the past year: Not all probiotic bacteria have similar therapeutic effects. Future clinical trials will need to incorporate this fact into trial planning and design. The use of probiotics and prebiotics as therapeutic agents for gastrointestinal disorders is rapidly moving into the "mainstream." Mechanisms of action explain the therapeutic effects and randomized; controlled trials provide the necessary evidence for their incorporation into the therapeutic armamentarium.


[Glucose consumption and dehydrogenase activity of the cells of the arsenite-oxidizing bacterium Pseudomonas putida].
The rates of glucose assimilation and dehydrogenase activity were studied in Pseudomonas putida oxidizing arsenite. The rate of glucose utilization by the cells decreased in the presence of arsenites in the medium at the beginning because of the microbial adaptation to arsenite. The activity of dehydrogenase fell down when the cells were cultivated in the medium with arsenite. An inverse correlation existed between the rate of glucose assimilation and arsenite oxidation. Apparently, arsenites were oxidized under the action of metabolites produced by P. putida in the process of its heterotrophous growth.


Provider Education about Glaucoma and Glaucoma Medications during Videotaped Medical Visits.
Objective. The purpose of this study was to examine how patient, physician, and situational factors are associated with the extent to which providers educate patients about glaucoma and glaucoma medications, and which patient and provider characteristics are associated with whether providers educate patients about glaucoma and glaucoma medications. Methods. Patients with glaucoma who were newly prescribed or on glaucoma medications were recruited and a cross-sectional study was conducted at six ophthalmology clinics. Patients' visits were videotape recorded and patients were interviewed after visits. Generalized estimating equations were used to analyze the data. Results. Two hundred and seventy-nine patients participated. Providers were significantly more likely to educate patients about glaucoma and glaucoma medications if they were newly prescribed glaucoma medications. Providers were significantly less likely to educate African American patients about glaucoma. Providers were significantly less likely to educate patients of lower health literacy about glaucoma medications. Conclusion. Eye care providers did not always educate patients about glaucoma or glaucoma medications. Practice Implications. Providers should consider educating more patients about what glaucoma is and how it is treated so that glaucoma patients can better understand their disease. Even if a patient has already been educated once, it is important to reinforce what has been taught before.


Stillbirth 2010-2018: a prospective, population-based, multi-country study from the Global Network.
Stillbirth rates are high and represent a substantial proportion of the under-5 mortality in low and middle-income countries (LMIC). In LMIC, where nearly 98% of stillbirths worldwide occur, few population-based studies have documented cause of stillbirths or the trends in rate of stillbirth over time. We undertook a prospective, population-based multi-country research study of all pregnant women in defined geographic areas across 7 sites in low-resource settings (Kenya, Zambia, Democratic Republic of Congo, India, Pakistan, and Guatemala). Staff collected demographic and health care characteristics with outcomes obtained at delivery. Cause of stillbirth was assigned by algorithm. From 2010 through 2018, 573,148 women were enrolled with delivery data obtained. Of the 552,547 births that reached 500 g or 20 weeks gestation, 15,604 were stillbirths; a rate of 28.2 stillbirths per 1000 births. The stillbirth rates were 19.3 in the Guatemala site, 23.8 in the African sites, and 33.3 in the Asian sites. Specifically, stillbirth rates were highest in the Pakistan site, which also documented a substantial decrease in stillbirth rates over the study period, from 56.0 per 1000 (95% CI 51.0, 61.0) in 2010 to 44.4 per 1000 (95% CI 39.1, 49.7) in 2018. The Nagpur, India site also documented a substantial decrease in stillbirths from 32.5 (95% CI 29.0, 36.1) to 16.9 (95% CI 13.9, 19.9) per 1000 in 2018; however, other sites had only small declines in stillbirth over the same period. Women who were less educated and older as well as those with less access to antenatal care and with vaginal assisted delivery were at increased risk of stillbirth. The major fetal causes of stillbirth were birth asphyxia (44.0% of stillbirths) and infectious causes (22.2%). The maternal conditions that were observed among those with stillbirth were obstructed or prolonged labor, antepartum hemorrhage and maternal infections. Over the study period, stillbirth rates have remained relatively high across all sites. With the exceptions of the Pakistan and Nagpur sites, Global Network sites did not observe substantial changes in their stillbirth rates. Women who were less educated and had less access to antenatal and obstetric care remained at the highest burden of stillbirth. Clinicaltrials.gov (ID# NCT01073475).


Optimization of inverse treatment planning using a fuzzy weight function.
A fuzzy approach has been applied to inverse treatment planning optimization in radiation therapy. The proposed inverse-planning algorithm optimizes both the intensity-modulated beam (IMB) and the normal tissue prescription. In the IMB optimization, we developed a fast-monotonic-descent (FMD) method that has the property of fast and monotonic convergence to the minimum for a constrained quadratic objective function. In addition, a fuzzy weight function is employed to express the vague knowledge about the importance of matching the calculated dose to the prescribed dose in the normal tissue. Then, a validity function is established to optimize the normal tissue prescription. The performance of this new fuzzy prescription algorithm has been compared to that based on hard prescription methods for two treatment geometries. The FMD method presented here both provides a full-analytical solution to the optimization of intensity-modulated beams, and guarantees fast and monotonic convergence to the minimum. It has been shown that the fuzzy inverse planning technique is capable of achieving an optimal balance between the objective of matching the calculated dose to the prescribed dose for the target volume and the objective of minimizing the normal tissue dose.


Significance of T helper 17 immunity in transplantation.
The aim of this review is to provide an overview of significance of T helper 17 (Th17) immunity in acute, chronic and antibody-mediated allograft rejection. The role of Th17 immunity in development of de-novo autoimmunity following transplantation is outlined. It will also consider the impact of Th17 immunity on transplantation tolerance. Potential therapies to target Th17 immunity are discussed. Interleukin17 (IL-17) is produced by a wide variety of immune and non-immune cells in response to injury. IL-17 production by tubular epithelial cells in response to complement activation in acute antibody-mediated rejection may perpetuate immune injury. Th17-dependent de-novo autoimmunity contributes to chronic allograft rejection. Targeting IL-17 not only inhibits Th17 immunity but also attenuates Th1 immunity by affecting the initial recruitment of immune cells to sites of inflammation and modulates innate and adaptive immune responses that ultimately lead to tissue destruction. Th17 immunity is now beginning to be appreciated as a set of responses mediated not only by CD4 Th17 cells but a variety of immune cells and a plethora of cytokines that collaborate to mediate immune disorders, including transplant rejection. Development and contribution of de-novo autoimmunity to chronic rejection is increasingly appreciated. The developmental plasticity of Tregs and Th17 cells is a major hurdle to Treg-based cellular therapies for transplantation. Several biologics targeting Th17 immunity are under evaluation for autoimmune disease. It remains to be determined whether these can be used in transplantation to improve outcomes.


25-Hydroxyvitamin D Concentration and Sleep Duration and Continuity: Multi-Ethnic Study of Atherosclerosis.
To determine the associations of 25-hydroxyvitamin D (25(OH)D) concentration with sleep continuity, quality, and symptoms, and to explore race/ethnic variation. Cross-sectional study. Multi-Ethnic Study of Atherosclerosis (MESA). There were 1,721 adults. Sleep outcomes were measured by polysomnography, actigraphy, and questionnaires. Serum 25(OH)D concentration was expressed by clinical thresholds (< 20, 20-29, ≥ 30 ng/mL) and continuously. Using linear regression, we determined the associations between 25(OH)D concentration and sleep duration, efficiency, and symptoms, and assessed race/ethnic variation. Mean age was 68.2 ± 9.1 y, and 37.2% were white, 27.7% African American, 11.9% Chinese Americans, and 23.2% Hispanic. Mean 25(OH)D concentration was 25.4 ± 10.5 ng/mL. 25(OH)D deficient participants had the shortest sleep duration, lowest sleep efficiency, and highest sleepiness scores. After adjusting for demographics, obesity, and health habits, deficient individuals slept an average of 13.0 min (95% confidence interval, -22.8, -3.2) shorter than sufficient individuals. Race/ethnic-stratified analyses indicated that the strongest associations were in African Americans, in whom adjusted sleep duration was 25.6 ± 11.7 min shorter in deficient versus sufficient individuals (P = 0.04), and in Chinese Americans, adjusted apnea-hypopnea index (AHI) was 7.5 ± 3.3 events/h higher in deficient versus sufficient individuals. Overall, there were modest associations between 25-hydroxyvitamin D (25(OH)D) concentration and sleep traits. However, race-stratified analyses suggested the association between 25(OH)D concentration and sleep traits varied by race/ethnicity. Vitamin D deficiency was most strongly associated with short sleep duration in African Americans and with elevated apnea-hypopnea index in Chinese Americans, suggesting that race/ethnicity may modify these associations.


Effects of quercetin and EGCG on mitochondrial biogenesis and immunity.
To test the influence of 1000 mg of quercetin (Q) with or without 120 mg of epigallocatechin 3-gallate (EGCG), 400 mg of isoquercetin, and 400 mg of eicosapentaenoic acid and docosahexaenoic acid (Q-EGCG) on exercise performance, muscle mitochondrial biogenesis, and changes in measures of immunity and inflammation before and after a 3-d period of heavy exertion. Trained cyclists (N = 39) were randomized to placebo (P), Q, or Q-EGCG and ingested supplements in a double-blinded fashion for 2 wk before, during, and 1 wk after a 3-d period in which subjects cycled for 3 h x d(-1) at approximately 57% Wmax. Blood, saliva, and muscle biopsy samples were collected before and after 2 wk of supplementation and immediately after the exercise bout on the third day. Blood and saliva samples were also collected 14 h after exercise. Two-week supplementation resulted in a significant increase in plasma quercetin for Q and Q-EGCG and granulocyte oxidative burst activity (GOBA) in Q-EGCG. Immediately after the third exercise bout, significant decreases for C-reactive protein (CRP), and plasma interleukin 6 (IL-6) and interleukin 10 (IL-10) were measured in Q-EGCG compared with P. Granulocyte colony-stimulating factor and CRP were reduced in Q-EGCG 14 h after exercise. No group differences were measured in muscle messenger RNA expression for peroxisome proliferator-activated receptor gamma coactivator alpha, citrate synthase, or cytochrome c. Two-week supplementation with Q-EGCG was effective in augmenting GOBA andin countering inflammation after 3 d of heavy exertion in trained cyclists.


Diagnosis and management of heart failure in the elderly.
Heart failure is common in the elderly and is associated with a significant morbidity and mortality. It accounts for about 5% of adult medical admissions and the expenditure of 1% of the total National Health Service budget. Clinical presentation in old age may be with the classical symptoms of heart failure but often, due to multiple pathology and low functional ability, presentation is atypical. Both nonspecific symptoms and signs of heart failure, are often a delayed presentation in this population, make diagnosis difficult. Treatment of the failing heart in an older person is similar to the young however, diligence is required when prescribing due to age-related pharmacokinetic changes and co-existent morbidity. This may result in polypharmacy and an increase in drug interactions which themselves may have deleterious consequences. However, knowledge of the aetiology of heart failure in old age and the possible atypical presentation as well as available treatments, will result in better management and improved quality of life and reduced mortality in the elderly heart failure population.


Head and Facial Injuries in Interscholastic Women's Lacrosse.
The Purpose of this study was to determine the advisability of protective headgear for interscholastic women playing lacrosse by recording the occurrence of head and facial injuries. During this 3-year study, the head and facial region was the most frequently injured individual area (5.4/100 athletes) of all body structures. The three areas of the head and face that were injured the most were: the head (36%), the eye (23%), and the nose (18%). Being struck by an opponent's stick or the ball were the two most common mechanisms of injury, with contusions (63%), lacerations (14%), and concussions (10%) being the most frequent injuries. Athletes were most often in the act of catching the ball or being stick-checked when the injury occurred to the head and facial area. Twice as many head and facial injuries occurred during game play than practice, with on-goal and midfield play being the most hazardous situations. Over the 3-year study, 75% of the athletes who sustained a head or facial injury were incapacitated for 0 to 1 day. Due to the lack of severity of injuries, we concluded that helmets were not necessary for interscholastic women.


Cement-implant interface contamination: possible reason of inferior clinical outcomes for rough surface cemented stems.
Shape-closed cemented implants rely on a stronger bond and have displayed inferior clinical outcomes when compared to force-closed designs. Implant contamination such as saline, bone marrow and blood prior to cement application has the potential to affect the cement-implant bond. The consequences of implant contamination were investigated in this study. Fifty Titanium alloy (Ti-6Al-4V) dowels were separated into ten groups based on surface roughness and contaminant, and then cemented in polyvinyl chloride tubes. Push-out testing was performed at 1mm per minute. The roughness of the dowel surface was measured before and after the testing. The dowel surface and cement mantel were analyzed using a Scanning Electron Microscopy (SEM) to determine the distribution and characteristics of any debris and contaminants on the surface. Contaminants largely decreased stem-cement interfacial shear strength, especially for rough surfaces. Saline produced the greatest decrease, followed by blood. The effect of bone marrow was less pronounced and similar to that of oil. Increasing surface roughness increased the interfacial bonding strength, even with contaminants. There was a non-significant increase in mean bonding strength for smooth surfaces with bone marrow and oil contamination. SEM showed that contaminants influence the interfacial bond by different mechanisms. More debris was found on rough samples following testing. The results of this study underscore the importance of keeping an implant free from contamination, and suggest if contamination does occur, a saline rinse may further decrease the stability of an implant. The deleterious effects of contamination on rough surface cement bonding were considerable, and indicate that contamination at the time of surgery may, in part, contribute to inferior clinical outcomes for rough surfaced cemented stems.


Comorbidity, chemotherapy toxicity, and outcomes among older women receiving adjuvant chemotherapy for breast cancer on a clinical trial: CALGB 49907 and CALGB 361004 (alliance).
We evaluated associations among comorbidity, toxicity, time to relapse (TTR), and overall survival (OS) in older women with early-stage breast cancer receiving adjuvant chemotherapy. Cancer and Leukemia Group B 49907 (Alliance) randomly assigned women ≥ 65 years old with stages I-III breast cancer to standard adjuvant chemotherapy or capecitabine. We reviewed data from 329 women who participated in the quality of life companion study CALGB 70103 and completed the Physical Health Subscale of the Older American Resources and Services Questionnaire. This questionnaire captures data on 14 comorbid conditions and the degree to which each interferes with daily activities. A comorbidity burden score was computed by multiplying the total number of conditions by each condition's level of interference with function. Outcomes were grade 3 to 5 toxicity, TTR, and OS. Logistic regression was used to evaluate associations between comorbidity and toxicity, and Cox proportional hazards models for TTR and survival. Number of comorbidities ranged from 0 to 10 (median 2); the comorbidity burden score ranged from 0 to 25 (median 3). The most common conditions were arthritis (58%) and hypertension (55%). Comorbidity was associated with shorter OS, but not with toxicity or TTR. The hazard of death increased by 18% for each comorbidity (hazard ratio [HR] = 1.18, 95% CI = 1.06 to 1.33) after adjusting for age, tumor size, treatment, node and receptor status. Comorbidity burden score was similarly associated with OS (HR = 1.08; 95% CI, 1.03 to 1.14). Among older women enrolled onto a clinical trial, comorbidity was associated with shorter OS, but not toxicity or relapse.


Design of novel substituted phthalocyanines; synthesis and fluorescence, DFT, photovoltaic properties.
The 4-(2-[3,4-dimethoxyphenoxy] phenoxy) phthalonitrile was synthesized as the starting material of new syntheses. Zinc, copper, and cobalt phthalocyanines were achieved by reaction of starting compound with Zn(CH3COO)2, CuCl2, and CoCl2 metal salts. Basic spectroscopic methods such as nuclear magnetic resonance electronic absorption, mass and infrared spectrometry were used in the structural characterization of the compounds. Absorption, excitation, and emission measurements of the fluorescence zinc phthalocyanine compound were also investigated in THF. Then, structural, energy, and electronic properties for synthesized metallophthalocyanines were determined by quantum chemical calculations, including the DFT method. The bandgap of HOMO and LUMO was determined to be chemically active. Global reactivity (I, A, η, s, μ, χ, ω) and nonlinear properties were studied. In addition, molecular electrostatic potential (MEP) maps were drawn to identify potential reactive regions of metallophthalocyanine (M-Pc) compounds. Photovoltaic performances of phthalocyanine compounds for dye sensitive solar cells were investigated. The solar conversion efficiency of DSSC based on copper, zinc, and cobalt phthalocyanine compounds was 1.69%, 1.35%, and 1.54%, respectively. The compounds have good solubility and show nonlinear optical properties. Zinc phthalocyanine gave fluorescence emission.


Granuloma, vasculitis, and demyelination in sarcoid neuropathy.
Despite the suggestion that direct compression by granuloma and ischemia resulting from vasculitis can cause nerve fiber damage, the mechanisms underlying sarcoid neuropathy have not yet been fully clarified. We examined the clinicopathological features of sarcoid neuropathy by focusing on electrophysiological and histopathological findings of sural nerve biopsy specimens. We included 18 patients with sarcoid neuropathy who had non-caseating epithelioid cell granuloma in their sural nerve biopsy specimens. Although electrophysiological findings suggestive of axonal neuropathy were observed, particularly in the lower limbs, all but three patients showed ≥1 abnormalities in nerve conduction velocity or distal motor latency. Additionally, a conduction block was observed in 11 of the 16 patients for whom waveforms were assessed; five of them fulfilled motor nerve conduction criteria strongly supportive of demyelination as defined in the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guideline for chronic inflammatory demyelinating polyneuropathy (CIDP). In most patients, sural nerve biopsy specimens revealed a mild to moderate degree of myelinated fiber loss. Fibrinoid necrosis was observed in one patient, and electron microscopy analysis revealed demyelinated axons close to granulomas in six patients. Patients with sarcoid neuropathy may meet the EAN/PNS electrophysiological criteria for CIDP due to the frequent presence of conduction blocks. Based on our results, in addition to the ischemic damage resulting from granulomatous inflammation, demyelination may play an important role in the mechanism underlying sarcoid neuropathy.


Molecular dynamics simulations of HLA-DR4 (DRB1*0405) complexed with analogue peptide: conformational changes in the putative T-cell receptor binding regions.
The specific recognition of foreign peptide bound to the major histocompatibility complex (MHC) molecule by T-cell receptor (TCR) leads to T-cell activation. We found that analogue peptides containing single amino acid substitutions at the third amino acid position (p3), p5, p7 and p8 of the index peptide (YWALEAAAD) induced different response patterns of T cell clones specific for the index peptide in the context of the human MHC class II molecule HLA-DR4. Analogue peptides were classified into three types, agonists, antagonists or null peptides (non-agonistic and non-antagonistic peptides). A molecular basis for how these slight changes lead to such different consequences for T cells has not been described. To explore the mechanistic basis of these observations, molecular dynamics simulations at 300 K of 300 ps duration were carried out for the DR4-index peptide, DR4-agonist, and DR4-antagonist complexes. The simulations showed that the DR4-antagonist complexes were distinguished from the DR4-index peptide and DR4-agonist complexes by relatively higher deviations of C(alpha) atoms in proposed TCR-binding regions, suggesting that subtle changes of the exposed framework of the peptide binding groove by the antagonist peptides could induce the TCR antagonistic activities.


Crystal structure of the diglycidyl ether of eugenol.
The diep-oxy monomer, C13H16O4 {DGE-Eu; systematic name: 2-[3-meth-oxy-4-(oxiran-2-ylmeth-oxy)benz-yl]oxirane}, was synthesized from eugenol by a three-step reaction. It consists of a 1,2,4-tris-ubstituted benzene ring substituted by diglycidyl ether, a meth-oxy group and a methyl-oxirane group. The three-membered oxirane rings are inclined to the benzene ring by 61.0 (3) and 27.9 (3)°. The methyl-ene C atom of one of the two terminal epoxide rings is positionally disordered [refined occupancy ratio = 0.69 (1):0.31 (1)]. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds, forming layers parallel to the ab plane. The layers are linked by C-H⋯π inter-actions, forming a three-dimensional network.