Miracle-dz/UniFAR-FTUs huggingface dataset:
Physicochemical and biological aspects of macrophage‐mediated drug targeting in anti‐microbial therapy

Macrophages are important drug targets as they mediate a wide variety of infectious diseases. Visceral leishmaniasis (VL), schistosomiasis, brucellosis, and salmonellosis are some of the well‐known infectious diseases in which macrophages play a prominent pathophysiological role. For instance, VL parasites exclusively house in the macrophages of liver and spleen. They are resistant to lysosomal degradation by unknown mechanisms, they survive and thrive safely within macrophages, they multiply, and they ultimately affect visceral organs, leading to severe pathological and sometimes even fatal conditions. The majority of routinely used drugs administered in free form distribute all over the body via systemic circulation, leading to relatively low therapeutic activity and a certain degree of toxicity. Unlike for nonmicrobial diseases, targeting parasites procuring resistance and ineffective therapeutic outcome can be obviously speculated in case of infectious disease. The preferential uptake by macrophages, intended to improve the balance between efficacy and toxicity, can be achieved by the use of nanomedicines, i.e. submicron‐sized macromolecular or particulate drug delivery systems. This insight has stimulated researchers to use nanomedicines – which tend to be recognized by macrophages as ‘foreign’ and consequently are taken up by the intended target cells much more effectively than their free drug counterparts – to improve the treatment of infectious diseases. The literature reports extensively on such approaches; however, there are several constraints that limit the application of nanomedicine in macrophage‐mediated drug targeting. Here, we briefly describe the strategies that are used to achieve effective drug targeting to macrophages, using VL as a model disease, and we also put forth an understanding of the most important limiting factors. Various physicochemical and biological factors used by researchers as reported in the literature are addressed, and the most important mechanisms and modes by which macrophage‐specific drug targeting can be achieved are summarized. Based on the evidence obtained to date, it can be concluded that targeting macrophages is a valuable and validated strategy for improving the treatment of infectious diseases.
Trends in NHS primary dental care for older people in England: implications for the future.

OBJECTIVE To examine trends over time in the National Health Service (NHS) dental service provision for older people in England and consider the implications for future care. BACKGROUND The number and proportion of older people in the population nationally are increasing and their oral health needs are changing as more people retain teeth into older age. MATERIALS AND METHODS Descriptive analysis of routinely collected activity data for primary dental care in England was undertaken over the 6-year period, 1999/2000-2004/05. Data were cleaned, grouped into age bands for analysis. Activity rates per head of population were calculated for key aspects of care. Population forecasts and national survey data were used to inform future predictions of care required. RESULTS There was an increase in absolute terms of total items (14.4%) and items per capita (10.7%) between 1999/2000 and 2004/05, with a peak of 15.7 million items claimed in 2003/04. Over the 6-year period, increases per capita were seen for dental examinations (11.3%), periodontal treatments (8.9%), fillings (1.9%), crowns (14.3%) and extractions (4.9%) amongst older people as a group. In contrast, there was a marked decrease in the episodes of care involving domiciliary care (-46.4%) and upper complete dentures (-32.9%) per capita over this period, items that were most commonly provided for the oldest age-band (85 years and over). Apart from complete dentures, the demand for care is predicted to increase. CONCLUSION The volume of primary dental care provided for older people has been increasing at a rate which exceeds population growth, but remains low. Planners and commissioners should urgently review the provision of dental care of older people to ensure that their oral health needs are being met particularly in relation to dentures and domiciliary care.
Tsunamis: bridging science, engineering and society

Tsunamis are high-impact, long-duration disasters that in most cases allow for only minutes of warning before impact. Since the 2004 Boxing Day tsunami, there have been significant advancements in warning methodology, pre-disaster preparedness and basic understanding of related phenomena. Yet, the trail of destruction of the 2011 Japan tsunami, broadcast live to a stunned world audience, underscored the difficulties of implementing advances in applied hazard mitigation. We describe state of the art methodologies, standards for warnings and summarize recent advances in basic understanding, and identify cross-disciplinary challenges. The stage is set to bridge science, engineering and society to help build up coastal resilience and reduce losses.
Do patients use decision and communication aids as prompted when meeting with breast cancer specialists?

Our breast cancer clinic promotes patient use of decision and communication aids (DAs/CAs) through two mechanisms: coaching and prompting. From January through September 2010, we provided services to 462 of 1106 new visitors (42%). Of those 462 visitors, 267 (58%) received coaching. For the remainder (195 or 42%), the best we could do was prompt them to self‐administer the DA and CAs.
Endometrial Carcinomas With Lymph Node Involvement: Novel Histopathologic Factors for Predicting Prognosis

The purpose of this study was to evaluate the clinicopathologic prognostic factors of endometrial carcinoma with lymph node metastasis (stage IIIc) in 24 patients with endometrial carcinoma. Differences in survival rates were analyzed for each clinicopathologic factor. The ratio of lymph nodes containing metastatic tumor to dissected lymph nodes (metastatic ratio), invasion of tumor cells into perinodal fat, and the presence of desmoplasia were examined. No statistically significant differences in survival rates were observed between any of the histologic parameters of the primary tumors. Cases with a high metastatic ratio exhibited significantly lower survival rates. Cases without tumor invasion into perinodal fat had significantly longer survival compared with cases with invasion. Cases without desmoplasia in the positive lymph nodes had significantly longer survival than cases with desmoplasia. The number of positive lymph nodes, desmoplasia in the lymph nodes, and invasion into perinodal fat are the most important prognostic factors in stage IIIc endometrial carcinoma.
A double-blind randomized study on the effects of red clover isoflavones on the endometrium

ObjectiveTo assess the effects of a red clover-derived isoflavone extract on the Ki-67 proliferative marker of endometrial biopsies in 45-to 50-year-old perimenopausal women. We hypothesized that we would be able to detect a decrease in the Ki-67 proliferative index during the late follicular phase after a 3-month course of ∼50 mg red clover isoflavones. Isoflavones have been found to have some antiestrogenic effects, and an antiproliferative effect during the perimenopausal period may be especially useful owing to the excessive endometrial proliferation often characteristic of this period. DesignIn a double-blind, randomized, controlled study, 30 women between the ages of 45 and 50 years consented to an endometrial biopsy before and after a 3-month course of either placebo or active isoflavone extract. The biopsies were timed as close as possible to days 7–11 of the menstrual cycle, and simultaneous measurements of transvaginal endometrial thickness, uterine artery Doppler, hormone profiles, lipids, and bone markers were performed. ResultsOf 30 women, 2 did not return for a second biopsy, and a third had an unsuccessful second biopsy. Four subjects were excluded from the Intention to Treat analysis because they did not have a menstrual bleed within the time frame of the study (3 subjects) or were tested on day 13 instead of between days 7 and 11 of the cycle (1 subject). There was no change in the Ki-67 proliferation index after treatment in either group. Eight subjects in the placebo group and eight in the P-07 group had proliferative endometrial biopsies that were synchronized with estradiol levels at baseline and post-treatment, and analysis of these subjects revealed no detectable change in the relationship between estradiol levels and Ki-67 with treatment in either group. There was no change in fasting lipids, bone markers, uterine Doppler resistance, or pulsatility index. ConclusionIn this small pilot study, we did not find, using immunohistochemical quantification of the Ki-67 antigen, that red clover isoflavones had an antiproliferative effect in the endometrium. Small sample size, examination of a relatively short interval in the menstrual cycle, and isoflavone formulation may have contributed to our lack of findings; however, we believe that the issue of isoflavones and their possible antiproliferative effect is deserving of further study. A simpler physiological model with less hormonal variability, such as healthy, recently menopausal women on predetermined doses of estrogen, may prove to be more informative.
Investigation on antidiarrhoeal activity of Aristolochia indica Linn. Root extracts in mice.

BACKGROUND The present study aimed at investigating the effect of ethanolic extract (EtAI), and aqueous extract (AqAI) of Aristolochia indica Linn roots on castor oil-induced diarrhoea and study on small intestinal transit. Phytochemical analysis of extracts was performed as per standard procedure. MATERIALS AND METHODS The oral toxicity study using Swiss albino mice was performed in accordance with OECD guidelines. The EtAI and AqAI extracts of Aristolochia indica Linn were studied for antidiarrhoeal property using castor oil-induced diarrhoeal model and charcoal-induced gastrointestinal motility test in Swiss albino mice. RESULTS Among the tested doses of 200 and 400 mg/kg body weight, the extracts reduced the frequency and severity of diarrhoea in test animals throughout the study period. At the same doses, the extract delayed the intestinal transit of charcoal meal in test animals as compared to the control and the results were statistically significant. CONCLUSION Experimental findings showed that ethanol extract of Aristolochia indica Linn root possess significant antidiarrheal activity and may be a potent source of anti-diarrhoeal drug in future.
Ricin Cytotoxicity Is Sensitive to Recycling between the Endoplasmic Reticulum and the Golgi Complex (*)

Cytotoxic proteins that kill mammalian cells by catalytically inhibiting protein synthesis must enter the cytosol in order to reach their substrates. With the exception of diphtheria toxin, which enters the cytosol from acidified endosomes, the intracellular site of translocation of other toxins including ricin, Escherichia coli Shiga-like toxin-1, and Pseudomonas exotoxin A is likely to involve early compartments of the secretory pathway. We have used a molecular approach to identify the site and mechanism of toxin delivery to the cytosol by transiently expressing mutant GTPases that inhibit the assembly of biochemical complexes mediating anterograde and retrograde transport in the exocytic and endocytic pathways. The results provide evidence to suggest that receptors actively recycling between the endoplasmic reticulum and terminal Golgi compartments are essential for toxin translocation to the cytosol from the endoplasmic reticulum. The rapid kinetics of intoxication demonstrate a substantial level of bidirectional membrane flow and sorting through the early secretory pathway.
Auditory and visual distractors disrupt multisensory temporal acuity in the crossmodal temporal order judgment task

The ability to synthesize information across multiple senses is known as multisensory integration and is essential to our understanding of the world around us. Sensory stimuli that occur close in time are likely to be integrated, and the accuracy of this integration is dependent on our ability to precisely discriminate the relative timing of unisensory stimuli (crossmodal temporal acuity). Previous research has shown that multisensory integration is modulated by both bottom-up stimulus features, such as the temporal structure of unisensory stimuli, and top-down processes such as attention. However, it is currently uncertain how attention alters crossmodal temporal acuity. The present study investigated whether increasing attentional load would decrease crossmodal temporal acuity by utilizing a dual-task paradigm. In this study, participants were asked to judge the temporal order of a flash and beep presented at various temporal offsets (crossmodal temporal order judgment (CTOJ) task) while also directing their attention to a secondary distractor task in which they detected a target stimulus within a stream visual or auditory distractors. We found decreased performance on the CTOJ task as well as increases in both the positive and negative just noticeable difference with increasing load for both the auditory and visual distractor tasks. This strongly suggests that attention promotes greater crossmodal temporal acuity and that reducing the attentional capacity to process multisensory stimuli results in detriments to multisensory temporal processing. Our study is the first to demonstrate changes in multisensory temporal processing with decreased attentional capacity using a dual task paradigm and has strong implications for developmental disorders such as autism spectrum disorders and developmental dyslexia which are associated with alterations in both multisensory temporal processing and attention.
Identification of Nck Family Genes, Chromosomal Localization, Expression, and Signaling Specificity*

Already a dozen molecules share binding to the Src homology (SH) 3 domains of human Nck, an SH3-SH3-SH3-SH2 adapter protein. We reason that there may be multiple gene members of Nck to accommodate the large binding repertoires. Here we report identification of novel human and mouse Nck genes and rename them as the Nckα and Nckβ genes (including the human Nckα, human Nckβ, mouse Nckα, and mouse Nckβ genes). Nckα and Nckβ share 68% amino acid identity, whereas the two Nckα and two Nckβ across the species show 96% identity to each other. The human Nckβ gene is mapped to 2q12, whereas the human Nckα gene has previously been mapped at 3q21. Antibodies specifically against Nckα and Nckβ detect Nckα and Nckβ with an identical molecular mass in the same cells of various origins. Ectopically expressed Nckβ, but not its SH2 domain mutant, strongly inhibits epidermal growth factor- and platelet-derived growth factor-stimulated DNA synthesis. Consistently, epidermal growth factor receptor and platelet-derived growth factor receptor preferentially interact with Nckβ over Nckα in vitro. This study indicates that Nck is a multiple gene family and that each gene may have its own signaling specificity. Because previous anti-Nck (human Nckα) antibodies cross-react with Nckβ, reassessment of those studies with specific Nck genes would be necessary.
Barriers to Care and Comorbidities along the U.S.-Mexico Border

Objective. While limited access to care is associated with adverse health conditions, little research has investigated the association between barriers to care and having multiple health conditions (comorbidities). We compared the financial, structural, and cognitive barriers to care between Mexican-American border residents with and without comorbidities. Methods. We conducted a stratified, two-stage, randomized, cross-sectional health survey in 2009–2010 among 1,002 Mexican-American households. Measures included demographic characteristics; financial, structural, and cognitive barriers to health care; and prevalence of health conditions. Results. Comorbidities, most frequently cardiovascular and metabolic conditions, were reported by 37.7% of participants. Controlling for demographics, income, and health insurance, six financial barriers, including direct measures of inability to pay for medical costs, were associated with having comorbidities (odds ratios [ORs] ranged from 1.7 to 4.1, p<0.05). The structural barrier of transportation (OR=3.65, 95% confidence interval [CI] 1.91, 6.97, p<0.001) was also associated with higher odds of comorbidities, as were cognitive barriers of difficulty understanding medical information (OR=1.71, 95% CI 1.10, 2.66, p=0.017), being confused about arrangements (OR=1.82, 95% CI 1.04, 3.21, p=0.037), and not being treated with respect in medical settings (OR=1.63, 95% CI 1.05, 2.53, p=0.028). When restricting analyses to participants with at least one health condition (comparing one condition vs. having ≥2 comorbid conditions), associations were maintained for financial and transportation barriers but not for cognitive barriers. Conclusion. A substantial proportion of adults reported comorbidities Given the greater burden of barriers to medical care among people with comorbidities, interventions addressing these barriers present an important avenue for research and practice among Mexican-American border residents.
Gay men and other men who have sex with men in West Africa: evidence from the field

This paper presents a synthesis of lessons learned from field experiences in HIV prevention, treatment and care services for men who have sex with men in the four contiguous West African countries of the Gambia, Guinea-Bissau, Guinea-Conakry and Senegal. Service provision for men who have sex with men in these countries is contextualised by the epidemiology of HIV, as well as the socio-political environment. These countries share notable commonalities in terms of social structures and culture, though past approaches to the needs of men who have sex with men have varied greatly. This synthesis includes three distinct components. The first focuses on what is known about HIV epidemiology among men who have sex with men in these countries and provides an overview of the data gaps affecting the quality of service provision. The second aspect describes the HIV prevention and treatment services currently available and how organisations and strategies have evolved in their approach to working with men who have sex with men. Finally, an examination of the political and cultural climate highlights socio-cultural factors that enable or impede HIV prevention and treatment efforts for men who have sex with men. The review concludes with a series of recommendations for impactful research, advocacy and service provision to improve the health and human rights context for men who have sex with men in West Africa.
Why Women Apologize More Than Men

Despite wide acceptance of the stereotype that women apologize more readily than men, there is little systematic evidence to support this stereotype or its supposed bases (e.g., men’s fragile egos). We designed two studies to examine whether gender differences in apology behavior exist and, if so, why. In Study 1, participants reported in daily diaries all offenses they committed or experienced and whether an apology had been offered. Women reported offering more apologies than men, but they also reported committing more offenses. There was no gender difference in the proportion of offenses that prompted apologies. This finding suggests that men apologize less frequently than women because they have a higher threshold for what constitutes offensive behavior. In Study 2, we tested this threshold hypothesis by asking participants to evaluate both imaginary and recalled offenses. As predicted, men rated the offenses as less severe than women did. These different ratings of severity predicted both judgments of whether an apology was deserved and actual apology behavior.
Intraoperative Cardiac Arrests in Adults Undergoing Noncardiac Surgery: Incidence, Risk Factors, and Survival Outcome

Background:Intraoperative cardiac arrest (ICA) is a rare but potentially catastrophic event. There is a paucity of recent epidemiological data on the incidence and risk factors for ICA. The objective of this study was to assess the incidence, risk factors, and survival outcome of ICAs in adults undergoing noncardiac surgery. Methods:The authors analyzed prospectively collected data for all noncardiac cases in the American College of Surgeons National Surgical Quality Improvement Program database from the years 2005 to 2007 (n = 362,767). Results:The incidence of ICA was 7.22 per 10,000 surgeries. After adjustment for American Society of Anesthesiologists physical status and other covariates, the odds of ICA increased progressively with the amount of transfusion (adjusted odds ratios = 2.51, 7.59, 11.40, and 29.68 for those receiving 1–3, 4–6, 7–9, and ≥ 10 units of erythrocytes, respectively). Other significant risk factors for ICA were emergency surgery (adjusted odds ratio = 2.04, 95% CI = 1.45–2.86) and being functionally dependent presurgery (adjusted odds ratio = 2.33, 95% CI = 1.69–3.22). Of the 262 patients with ICA, 116 (44.3%) died within 24 h, and 164 (62.6%) died within 30 days. Conclusions:Intraoperative blood loss as indicated by the amount of transfusion was the most important predictor of ICA. The urgency of surgery and the preoperative composite indicators of health such as American Society of Anesthesiologists status and functional status were other important risk factors. The high case fatality suggests that primary prevention might be the key to reducing mortality from ICA.
Low‐frequency power of heart rate variability is not a measure of cardiac sympathetic tone but may be a measure of modulation of cardiac autonomic outflows by baroreflexes

Power spectral analysis of heart rate variability has often been used to assess cardiac autonomic function; however, the relationship of low‐frequency (LF) power of heart rate variability to cardiac sympathetic tone has been unclear. With or without adjustment for high‐frequency (HF) power, total power or respiration, LF power seems to provide an index not of cardiac sympathetic tone but of baroreflex function. Manipulations and drugs that change LF power or LF:HF may do so not by affecting cardiac autonomic outflows directly but by affecting modulation of those outflows by baroreflexes.
Evidence for Grief as the Major Barrier Faced by Alzheimer Caregivers: A Qualitative Analysis

Feelings of loss and grief are frequent companions for current Alzheimer's family caregivers. Increased acknowledgment and understanding of caregiver grief among researchers has led to more comprehensive explorations of the multifaceted nature of caregiver grief and loss. Absent from the literature, however, is an exploration of anticipatory grief as an actual barrier to the task of caregiving. Through an analysis of 353 open-ended survey responses, the present article explores links between anticipatory grief, ambiguous loss, and principal barriers that family members face as dementia caregivers across the state of Indiana. By drawing parallels between caregiver responses and the Marwit-Meuser Caregiver Grief Inventory subscales, this article illustrates that the fundamental barrier experienced by current Alzheimer's caregivers appears to be a combination of anticipatory grief and ambiguous loss rather than hands-on care issues. The implications of this finding for future caregiver research and interventions are discussed.