Miracle-dz/UniFAR-FTUs huggingface dataset:
HIV Type-1 Transmission Dynamics in Recent Seroconverters: Relationship with Transmission of drug Resistance and Viral Diversity

Background HIV type-1 (HIV-1) has been shown to be frequently transmitted by acutely infected patients. We investigated the relationship between the dynamics of HIV-1 transmission within recently infected patients, the HIV-1 variability and the transmission of antiretroviral drug resistance. Methods We included patients infected between 1996 and 2006, with a plasma sample obtained <18 months after seroconversion and prior to antiretroviral therapy initiation. Reverse transcriptase (RT) and protease sequences were determined by direct population sequencing from plasma samples. Genotypic resistance was interpreted with the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales 2006 algorithm and International AIDS Society–USA list. Phylogenetic analysis (neighbour-joining and maximum likelihood methods) of RT sequences was used to determine the HIV-1 subtype and the interrelationship between sequences. Results Genotypic resistance was detected in 37/263 (14.1%) patients. Patients were infected by HIV-1 clade B in 222 (84%) cases and with non-B subtypes in 41 (16%). A total of 80 (30.4%) RT sequences were segregated in 24 clusters with bootstrap values >98% for 22 clusters. The frequency of grouping in clusters was higher within B sequences compared with non-B sequences (35.1% versus 4.9%; P<2.10-4). Drug-resistant isolates were retrieved in only 3 clusters, but the prevalence of resistance in clustering viruses (10/80, 12.5%) was not different than in isolated sequences. Conclusions The segregation into clusters suggested frequent forward transmission events in patients infected with HIV-1 subtype B, including the possibility of transmission of drug-resistant isolates. These findings warrant increasing prevention efforts and serological screening in the at-risk populations.
Prevention by daily soluble aspirin of colorectal adenoma recurrence: 4-year results of the APACC randomised trial

Background Aspirin inhibits colorectal carcinogenesis. In a randomised double-blind placebo-controlled trial, daily soluble aspirin significantly reduced recurrence of colorectal adenomas at 1-year follow-up. In this study the results of daily intake of low-dose aspirin on polyp recurrence at 4-year follow-up are presented. Methods 272 patients (naive for chronic aspirin use) with colorectal adenomas were randomly assigned to treatment with lysine acetylsalicylate 160 mg/day (n=73) or 300 mg/day (n=67) or placebo (n=132) for 4 years. The primary endpoints were adenoma recurrence and adenomatous polyp burden at year 4, comparing aspirin at either dose with placebo. The same endpoints were also assessed at year 1 or 4 (last colonoscopy performed for each patient). Results At the final year 4 colonoscopy the analysis included 185 patients (55 receiving aspirin 160 mg/day, 47 aspirin 300 mg/day and 83 placebo). There was no difference in the proportion of patients with at least one recurrent adenoma between patients receiving aspirin at either dose and those treated with placebo (42/102 (41%) vs 33/83 (40%); NS) or in the adenomatous polyp burden (3.1±5.8 mm vs 3.4±6.2 mm; NS). Also, the proportion of patients with at least one advanced recurrent adenoma did not differ (10/182 (10%) in the aspirin group vs 7/83 (7%) in the placebo group; NS). Conclusion Daily low-dose aspirin decreased adenoma recurrence significantly at 1 year but not at year 4. This discrepancy might be explained by a differential effect of aspirin according to the natural history of the polyp. Trial Registration Number NCT 00224679.
Priming of a Novel Subset of CD28+ Rapidly Expanding High-Avidity Effector Memory CTL by Post Maturation Electroporation-CD40L Dendritic Cells Is IL-12 Dependent1

Dendritic cell (DC)-based immunotherapeutics must induce robust CTL capable of killing tumor or virally infected cells in vivo. In this study, we show that RNA electroporated post maturation and coelectroporated with CD40L mRNA (post maturation electroporation (PME)-CD40L DC) generate high-avidity CTL in vitro that lyse naturally processed and presented tumor Ag. Unlike cytokine mixture-matured DC which induce predominantly nonproliferative effector memory CD45RA+ CTL, PME-CD40L DC prime a novel subset of Ag-specific CTL that can be expanded to large numbers upon sequential DC stimulation in vitro. We have defined these cells as rapidly expanding high-avidity (REHA) CTL based on: 1) the maintenance of CD28 expression, 2) production of high levels of IFN-γ and IL-2 in response to Ag, and 3) the demonstration of high-avidity TCR that exhibit strong cytolytic activity toward limiting amounts of native Ag. We demonstrate that induction of REHA CTL is dependent at least in part on the production of IL-12. Interestingly, neutralization of IL-12 did not effect cytolytic activity of REHA CTL when Ag is not limiting, but did result in lower TCR avidity of Ag-reactive CTL. These results suggest that PME-CD40L DC are uniquely capable of delivering the complex array of signals needed to generate stable CD28+ REHA CTL, which if generated in vivo may have significant clinical benefit for the treatment of infectious disease and cancer.
Escherichia coli: An unknown and infrequent cause of community acquired pneumonia

Our aim was to describe the incidence, clinical characteristics and outcome of community acquired pneumonia (CAP) caused by Escherichia coli through the analysis of a cohort of patients with this condition. This study includes all the patients who were admitted to our hospitals because of CAP caused by E. coli, diagnosed with highly reliable microbiological techniques, such as blood culture, bronchoscopic protected specimen brush (PSB) or transthoracic needle aspiration (TNA). 29 patients were enrolled, representing 0.4% of CAP cases admitted. Main symptoms were fever and dyspnoea. 18 patients were classified into class IV and class V of the Pneumonia Severity Index (PSI). Diagnosis was based on blood culture in 24 cases, PSB in 4 cases and by TNA in 1 case. Three of the patients died, the longer time evolution of the symptoms being the only factor related to higher mortality (p<0.05). Mean hospitalization time was 7.1±3.1 d, and correlated with severity at admission (r=0.43; p<0.003). This study demonstrates that CAP caused by E. coli is infrequent. It has an unspecific presentation and mortality rate is 10.3%, associated with longer time before admission to hospital.
Use of in situ hybridization to detect human papillomavirus in head and neck squamous cell carcinoma patients without a history of alcohol or tobacco use.

CONTEXT Head and neck squamous cell carcinoma is commonly associated with tobacco and alcohol use. There are, however, a group of patients without a significant history of tobacco or alcohol use, and the etiology of these tumors is incompletely understood. OBJECTIVE To examine tumors in this subpopulation for association with human papillomavirus (HPV) using newly available in situ hybridization probes. DESIGN Between October 2004 and October 2005, 22 patients who did not use alcohol or tobacco were included. Formalin-fixed, paraffin-embedded tissue sections were used to perform in situ hybridization using newly available probe sets (Ventana Medical Systems, Tucson, Ariz). The slides were examined for the presence of integrated HPV using light microscopy. Positive and negative xenograft controls were run with the assay. Results. -The mean age of the patients was 64 years. There were 14 men and 8 women. The most common anatomic sites included tongue (n = 8), tonsil (n = 7), and larynx (n = 7). All cases and controls were successfully stained. Only 2 cases were positive for high-risk HPV, and both demonstrated an integrated pattern. Both cases were tumors of the tonsil. No cases were positive for low-risk HPV. CONCLUSIONS These results demonstrate that the new probe sets for HPV can be used very efficiently in clinical pathology material of head and neck squamous cell carcinoma. Our data show that high-risk HPV is an uncommon finding in head and neck squamous cell carcinoma from patients who do not have a history of tobacco or alcohol use; low-risk HPV was not seen in any case.
Risk factors for age at onset of dementia due to Alzheimer's disease in a sample of patients with low mean schooling from São Paulo, Brazil

In view of the mild effects of pharmacological treatment for dementia due to Alzheimer's disease (AD), the search for modifiable risk factors is an important challenge. Although risk factors for AD are widely recognized, elements that influence the time of onset of the dementia syndrome have not been comprehensively reported. We aimed to investigate which risk factors might be associated with the age at onset of AD in a sample of patients with low mean schooling from São Paulo, Brazil.
An Intact TAR Element and Cytoplasmic Localization Are Necessary for Efficient Packaging of Human Immunodeficiency Virus Type 1 Genomic RNA

ABSTRACT Although most reports defining the human immunodeficiency virus type 1 (HIV-1) genomic RNA packaging signal have focused on the region downstream of the major 5′ splice site, others have suggested that sequences upstream of the splice site may also play an important role. In this study we have directly examined the role played by the HIV-1 TAR region in RNA packaging. For these experiments we used a proviral expression system that is largely independent of Tat for transcriptional activation. This allowed us to create constructs that efficiently expressed RNAs carrying mutations in TAR and to determine the ability of these RNAs to be packaged. Our results indicate that loss of sequences in TAR significantly reduce the ability of a viral RNA to be packaged. The requirement for TAR sequences in RNA packaging was further examined by using a series of missense mutations positioned throughout the entire TAR structure. TAR mutations previously shown to influence Tat transactivation, such as G31U in the upper loop region or UCU to AAG in the bulge (nucleotides [nt] 22 to 24), failed to have any effect on RNA packaging. Mutations which disrupted the portion of the TAR stem immediately below the bulge also had little effect. In contrast, dramatic effects on RNA packaging were observed with constructs containing mutations in the lower portion of the TAR stem. Point mutations which altered nt 5 to 9, 10 to 15, 44 to 49, or 50 to 54 all reduced RNA packaging 11- to 25-fold. However, compensatory double mutations which restored the stem structure were able to restore packaging. These results indicate that an intact lower stem structure, rather than a specific sequence, is required for RNA packaging. Our results also showed that RNA molecules retained within the nucleus cannot be packaged, unless they are transported to the cytoplasm by either Rev/Rev response element or the Mason-Pfizer monkey virus constitutive transport element.
Donor‐ but not host‐derived interleukin‐10 contributes to the regulation of experimental graft‐versus‐host disease

IL‐10 is a key immune‐regulatory cytokine, and its gene polymorphisms correlate with severity of clinical GVHD. IL‐10 is made by a variety of donor and host cells, but the functional relevance of its source and its role in the biology of acute GVHD are not well understood. We used preclinical models to examine the relevance of IL‐10−/− in donor and host cellular subsets on the severity of GVHD. IL‐10−/− in host tissues or in the donor grafts did not alter donor Teff‐mediated severity of GVHD. Furthermore, neither host‐derived nor donor Teff‐derived IL‐10 was required for regulation of GVHD by WT CD4+CD25+ donor Tregs. By contrast, Treg‐derived IL‐10, although not obligatory, was necessary for optimal reduction of GVHD by mature donor Tregs. Importantly, IL‐10 from donor BM grafts was also critical for optimal donor Treg‐mediated suppression of GVHD. Together, these data suggest that IL‐10 does not contribute to the induction of GVHD severity by the Teffs. However, donor BM graft and Treg‐derived IL‐10 are important for donor Treg‐mediated suppression of GVHD.
A randomized prospective trial of amphotericin B lipid emulsion versus dextrose colloidal solution in critically ill patients.

BACKGROUND Amphotericin B is the agent of choice for most invasive fungal infections in critically ill patients. It is associated with at least a 50% incidence of nephrotoxicity, despite prophylactic measures such as sodium loading. Newer formulations of amphotericin B are available but are costly and have unknown bioavailability in critically ill patients. Previous trials in neutropenic and critically ill patients have demonstrated that mixing amphotericin B with 20% lipid solution (Intralipid; Clintec Nutrition, Deerfield, III) may decrease nephrotoxicity. METHODS In this randomized, prospective clinical trial, patients with positive fungal blood cultures, tracheal/sputum cultures or peritoneal cavity cultures were randomized to receive either 0.5 mg/kg per day of amphotericin B dextrose or 1.0 mg/kg per day of amphotericin B lipid emulsion. Duration of therapy was determined by the primary care team. Weekly 24-hour creatinine clearance was measured until 2 weeks after amphotericin B therapy was completed. RESULTS The two groups were similar based on age, white blood cell count, serum creatinine, and creatinine clearance at the beginning of therapy. The group receiving amphotericin B lipid emulsion had significantly less decrease in creatinine clearance compared with controls, despite receiving significantly more amphotericin B. CONCLUSION Amphotericin B lipid emulsion can be given at a higher total cumulative dose than amphotericin B dextrose with less nephrotoxicity.
A crucial role for Nox 1 in redox‐dependent regulation of Wnt‐β‐catenin signaling

Canonical Wnt signaling critically regulates cell fate and proliferation in developmental stages and adult tissues. Redox regulation through nucleoredoxin (NRX) has recently been identified in canonical Wnt signaling. However, the source of reactive oxygen species (ROS) affecting the redox state of NRX remains elusive. Our principal aim in this study was to investigate whether superoxide‐generating NADPH oxidase1 (Nox1) is involved in NRX‐regulated Wnt signaling in intestinal and colon epithelial cells. Here, we demonstrate that Wnt treatment of mouse intestinal cells induces production of ROS through Nox1. This Nox1 action is regulated by Rac1 GTPase through Wnt‐induced activation of the Rac1 guanine nucleotide exchange factor Vav2 by Src‐mediated tyrosine phosphorylation. Nox1‐generated ROS oxidize and inactivate NRX, thereby releasing the NRX‐dependent suppression of Wnt‐β‐catenin signaling through dissociation of NRX from Dvl. Nox1 small‐interference RNA inhibits cell response to Wnt, including stabilization of β‐catenin, expression of cyclin D1 and c‐Myc via the TCF transcription factor, and accelerated cell proliferation. Nox1 mediates Wnt‐induced cell growth in colon cancer cells with the normal Wnt pathway, but not in APC‐deficient colon cancer cells, which are constitutively active in Wnt signaling. Together, these results suggest the mediating role of Nox1 in redox‐dependent regulation of canonical Wnt‐β‐catenin signaling and provide further insight into the regulatory mechanism of the Wnt pathway. —Kajla, S. , Mondol, A. S. , Nagasawa, A. , Zhang, Y. , Kato, M. , Matsuno, K. , Yabe‐Nishimura, C. , Kamata, T. A crucial role for Nox 1 in redox‐dependent regulation of Wnt‐β‐catenin signaling. FASEB J. 26, 2049‐2059 (2012). www.fasebj. org
Etanercept: efficacy and safety for approved indications

Introduction: Etanercept is a tumor necrosis factor alpha (TNF-α) inhibitor, which is approved for the treatment of immune-mediated inflammatory conditions including rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and psoriasis (PsO). Areas covered: Clinical efficacy and safety data of etanercept for the approved indications are reviewed in this paper. Data were obtained from published clinical trials, registries, post-marketing data as well as information provided by Amgen. Expert opinion: Etanercept is a generally well-tolerated treatment for the approved inflammatory diseases. The most common adverse effect of etanercept treatment is injection site reaction, which is generally self-limiting and often does not require treatment. Etanercept may be associated with an increased risk for infection, the development of malignancy, demyelinating disease and congestive heart failure. Fewer patients withdraw from etanercept due to adverse events than with other biologics. For pediatric patients, there are more data for etanercept than other biologics, and etanercept may have lower rates for the development of malignancy.
A study of fluctuating asymmetry in hybrids of dwarf and normal lake whitefish ecotypes (Coregonus clupeaformis) from different glacial races

Fish ecotypes found in north temperate lakes are increasingly used as model organisms to explore patterns and processes of population divergence that may ultimately cause speciation. Processes involved in their reproductive isolation are, however, still poorly understood. Recent experimental studies on whitefish ecotypes from different glacial races revealed that embryonic mortality of hybrids was 2.4–4.7 times higher than for parental forms. In this study, we compared fluctuating asymmetry (FA) in morphological traits of these same hybrid and pure crosses to test the hypothesis that genetic stress observed in hybrids at embryonic stages is also manifested at later developmental stages. Twelve morphological traits were used to measure asymmetry. Variable degrees of asymmetry were observed depending on traits and crosses, however there was no significant difference in FA among crosses. These results thus provided no evidence in support of the working hypothesis and indicated that genetic stress may differ among life stages. It is more likely that high hybrid embryonic mortality acts together with ecological factors at later stages to increase further the extent of reproductive isolation between sympatric whitefish ecotypes.
Relationship of smoking and smokeless tobacco use to tooth loss in a central Indian population.

PURPOSE The present study was conducted to determine the patterns of tooth loss among subjects with different tobacco- related habits and compare it with non-users of tobacco. MATERIALS AND METHODS A total of 1075 patients over the age of 14 years attending the Department of Periodontics, People's College of Dental Sciences and Research Centre, Bhopal, India from May to September 2009 were included in the study. Besides name, age and gender, information regarding tobacco habits was recorded through interviews. Based on the tobacco habits, the patients were grouped into 4 categories: group 1 (non-users of tobacco), group 2 (smokers only), group 3 (smokeless tobacco users only) and group 4 (users of both smoking and smokeless tobacco). Tooth loss was determined by clinical examination of all permanent teeth excluding the third molars. Tooth loss included missing or extracted teeth as well as teeth indicated for extraction due to periodontal disease, dental caries or wasting diseases. Prevalence and mean tooth loss for whole dentition, maxillary and mandibular arches were compared between the 4 groups. The chi-square test and one-way ANOVA were used for comparing the prevalence and mean tooth loss, respectively, between different groups. RESULTS The overall prevalence and mean tooth loss, respectively, for different groups were as follows: group 1: 28.3% and 0.85; group 2: 56.1% and 1.97; group 3: 58.7% and 2.38; group 4: 56.7% and 2.48 (P < 0.001 for both prevalence and mean tooth loss). The prevalence and mean tooth loss, respectively, for the maxillary arch for the different groups were: group 1: 15.3% and 0.32; group 2: 43% and 1.24; group 3: 34.3% and 0.91; group 4: 45.4% and 1.26 (P < 0.001 for both prevalence and mean tooth loss). The prevalence and mean tooth loss, respectively, for the mandibular arch for the different groups were: group 1: 22.3% and 0.52; group 2: 33.6% and 0.73; group 3: 50.9% and 1.48; group 4: 48.5% and 1.23 (P < 0.001 for both prevalence and mean tooth loss). CONCLUSION When compared to non-users of tobacco, tooth loss was greater among subjects who consumed tobacco. In India, where consumption of tobacco in different forms is very common, public health programmes need to be implemented to increase public awareness regarding the adverse effects of tobacco on oral health.
Age at diagnosis and transmission of invasive melanoma in 23 families with cutaneous malignant melanoma/dysplastic nevi.

BACKGROUND Familial melanoma patients tend to have an earlier age at first melanoma diagnosis, thinner lesions, a different histologic distribution, and a higher frequency of multiple primary melanomas than patients with nonfamilial melanoma. Previous examination of a large melanoma kindred from Texas suggested that although cutaneous malignant melanoma (CMM) was transmitted in an autosomal dominant fashion, there were sex differences in penetrance and disease expression. PURPOSE This study further evaluated the age at diagnosis, sex difference in penetrance and disease expression, and segregation of familial CMM. METHODS We evaluated the age at diagnosis and transmission of CMM in 23 U.S. white families with CMM/dysplastic nevi who had been followed 5-17 years. We estimated the median and mean ages at diagnosis of invasive melanoma for all individuals, for men and women separately, and by generation. Using the computer program BMDP1L, we also estimated the cumulative probability of an offspring developing CMM as a function of age according to whether the mother or father had melanoma. In addition, we used a life-table approach to estimate the probability that offspring of CMM parents were affected with CMM (penetrance). RESULTS The median age at diagnosis in the 23 kindreds (n = 106) was 33 years, substantially less than that of patients with sporadic melanomas in the U.S. white population. For females, the median age at diagnosis was 29 years; for males, it was 36 years. Nine percent of the case patients developed CMM before age 20 compared with 2% in the general population. There was little difference in the transmission pattern of melanoma between males and females in the 23 families, although sons of CMM parents had a higher risk of CMM than daughters of CMM parents. This difference was, however, based on small numbers and was not statistically significant. The penetrance estimates for CMM were high. They rose rapidly from 6% at age 18 to 85% by age 48. The median age at diagnosis of invasive melanoma decreased dramatically in successive generations; the reduction was 11-16 years per generation and was statistically significant (P < .0001). CONCLUSIONS AND IMPLICATIONS Although this reduction in median age at diagnosis may result partly from increased surveillance in hereditary melanoma families and the fact that individuals in the younger generations have not yet reached the highest at-risk ages for developing melanoma, the possibility of changes in melanoma risk and risk factors, genetic and/or environmental, across generations should be considered.