Miracle-dz/UniFAR-FTUs huggingface dataset:
Combating multidrug-resistant Gram-negative bacterial infections

Introduction: Multidrug-resistant (MDR) bacterial infections, especially those caused by Gram-negative pathogens, have emerged as one of the world's greatest health threats. The development of novel antibiotics to treat MDR Gram-negative bacteria has, however, stagnated over the last half century. Areas covered: This review provides an overview of recent R&D activities in the search for novel antibiotics against MDR Gram-negatives. It provides emphasis in three key areas. First, the article looks at new analogs of existing antibiotic molecules such as β-lactams, tetracyclines, and aminoglycoside as well as agents against novel bacterial targets such as aminoacyl–tRNA synthetase and peptide deformylase. Second, it also examines alternative strategies to conventional approaches including cationic antimicrobial peptides, siderophores, efflux pump inhibitors, therapeutic antibodies, and renewed interest in abandoned treatments or those with limited indications. Third, the authors aim to provide an update on the current clinical development status for each drug candidate. Expert opinion: The traditional analog approach is insufficient to meet the formidable challenge brought forth by MDR superbugs. With the disappointing results of the genomics approach for delivering novel targets and drug candidates, alternative strategies to permeate the bacterial cell membrane, enhance influx, disrupt efflux, and target specific pathogens via therapeutic antibodies are attractive and promising. Coupled with incentivized business models, governmental policies, and a clarified regulatory pathway, it is hoped that the antibiotic pipeline will be filled with an effective armamentarium to safeguard global health.
Northern region asplenia register--analysis of first two years.

OBJECTIVES: To assess the feasibility of setting up a register of patients with asplenia within a defined geographical area; to ensure that guidelines on best practice were implemented; to obtain information on antibody levels to pneumococcal capsular polysaccharides and Haemophilus influenzae type b capsular polysaccharide, before and after immunisation and annually thereafter; to raise awareness of risks among clinicians and to offer advice on management. DESIGN: Prospective recruitment using multiple sources of recruitment. Annual follow up reminders sent from Registration Centre. SUBJECTS: Population of (old, pre-1995) Northern Health Region: approximately 3.1 million. MAIN OUTCOME MEASURES: Data were obtained on reasons for asplenia, duration of asplenia, use of prophylactic antibiotics, Medic-Alert bracelets, immunisations, antibody levels, death. RESULTS: The register was initiated at the beginning of April 1995 and ran to the end of March 1997. After two years of operation, 1111 cases had been registered but the response from some health districts was poor. Major primary causes of asplenia were trauma (264), other surgical (198), lymphoproliferative disease (154), and idiopathic thrombocytopenic purpura (147). There were 664 patients on prophylactic antibiotics, of whom 498 were on continuous antibiotics. Only 18 had any type of warning bracelet. Antibody measurements were carried out at least once on 75% of patients; 306 patients had satisfactory antibody levels on first blood sample in year 1, rising to 405 in year 2; 43 patients failed to make any antibody response to Pneumovax despite multiple immunisations, and three patients failed to respond to Hib vaccine. Sixteen patients with satisfactory antibody levels in year 1 had low levels in year 2 requiring vaccine boosters. Sixteen deaths were reported, two of which were directly attributable to overwhelming sepsis. CONCLUSIONS: Registration has been successful and has raised awareness of the management of asplenia. Compliance with antibiotic prophylaxis and immunisation was initially poor. A potential high risk group of vaccine non-responders has been identified and poor persistence of pneumococcal antibodies has been identified which is likely to alter approaches to immunisation in asplenic patients.
Neurons of the Lateral Preoptic Area/Rostral Anterior Hypothalamic Area Are Required for Photoperiodic Inhibition of Estrous Cyclicity in Sheep1

Photoperiod determines the timing of reproductive activity in many species, yet the neural pathways whereby day length is transduced to a signal influencing gonadotropin-releasing hormone (GnRH) release are not fully understood. Physical lesions of the lateral preoptic area (lPOA)/rostral anterior hypothalamic area (rAHA) in female sheep extend the period of estrous cyclicity during inhibitory photoperiods. In the present study we sought to determine whether destroying only neurons and not fibers of passage in this area would lead to similar resistance to photosuppression. Additionally, neural tract-tracing was used to map connectivity between the lPOA/rAHA and other hypothalamic areas implicated in photoperiodic regulation of reproduction. Progesterone secretion was monitored in six sheep to determine estrous cycles for 90 days during a short-day (permissive) photoperiod. Three sheep then received bilateral injections of the excitotoxic glutamate analog, n-methyl-aspartic acid, directed toward the lPOA/rAHA, whereas three others served as controls. All were then exposed to a long-day (suppressive) photoperiod for 120 days. Control sheep ceased cycling at 40 ± 10 days (mean ± SEM), whereas lesioned sheep continued cycling through the end of the study. The results of the tract-tracing study revealed both afferent and efferent projections to the medial POA, retrochiasmatic area, arcuate nucleus, and premammillary region. Furthermore, close proximal associations with GnRH neurons from efferent projections were observed. We conclude that neurons located within the lPOA/rAHA are important for timing cessation of estrous cycles during photosuppression and that this area communicates directly with GnRH neurons and other hypothalamic areas involved in the photoperiodic regulation of reproduction.
Differential outcomes in patients treated with endocrine therapy for early or locally advanced breast cancer based on BRCA mutation status.

e22065 Background: Mutations in BRCA1 and BRCA2 genes lead to defects in DNA repair. Estrogen receptor modulates transcription of genes responsible for cell division, which depends on cell's ability to repair DNA for genomic integrity. Differential efficacy of endocrine therapy for breast cancer, therefore, may be possible depending on the tumor's BRCA mutation status. METHODS Through an IRB approved registry, breast cancer patients tested for BRCA1 and BRCA2 mutations and treated with endocrine therapy for hormone-receptor positive non-metastatic disease were identified. Primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS) respectively. Fisher's exact test or Wilcoxon rank sum test were used to assess differences among subgroups with respect to their characteristics. Cox proportional hazard analysis was used to identify univariate and multivariate risk factors for OS and PFS. RESULTS Of 115 breast cancer patients tested for BRCA mutations, 63 met the inclusion criteria of whom 16 patients were BRCA 1 or 2 mutation positive and 47 were negative. In the BRCA(+) group, 14 patients (87.5%) had stage I-III disease at diagnosis. In the BRCA(-) group, 5 patients (10.6%) had stage 0 disease while 41 patients (87.2%) had stage I-III disease at diagnosis. Stage at diagnosis was unavailable for 2 BRCA(+) and 1 BRCA(-) patients. Both groups were similar with respect to Her-2 expression status, history of ovarian suppression, age of diagnosis, and age of menopause. Median age was 48 yo in BRCA(+) group, 42 yo in BRCA(-), (p=0.12). Median follow up was 76.1 mos in BRCA(+) and 62.9 mos in BRCA(-) group. OS was worse in BRCA(+) group (HR 7.38, 95% [CI] 1.49-36.4 p=0.014). After adjustment for stage and history of ovarian suppression, the difference remained significant (HR 16.6, 95% [CI] 1.95-142, p=0.010). There was no difference in PFS (HR 2.02, 95% [CI] 0.82-4.96, p=0.13). CONCLUSIONS Patients with BRCA mutation, hormone-receptor positive hereditary breast cancer treated with endocrine therapy had inferior survival compared with similar patients who are BRCA mutation negative. Prospective studies to evaluate the differential effects of endocrine therapy in these populations are warranted. No significant financial relationships to disclose.
Fetal hepatic calcifications: prenatal diagnosis and outcome.

OBJECTIVE The purpose of this study was to provide information on the causes and postnatal outcomes of fetal liver calcifications that were detected by ultrasound imaging. STUDY DESIGN Cases with fetal liver calcifications that were encountered between 1992 and 2001 were evaluated. A detailed fetal ultrasound imaging for associated abnormalities, maternal STORCH (syphilis, cytomegalovirus, herpesvirus 1 and 2, rubella, and Toxoplasma ) analysis, parvovirus serologic condition, and parental cystic fibrosis mutations analysis were performed; amniocentesis was offered in all cases. All infants who were born alive were examined and followed up. RESULTS Sixty-one pregnant women with fetal liver calcifications were identified. Forty of 61 patients had additional fetal abnormalities; 21 of 61 cases of fetal liver calcifications were isolated; 11/61 patients (18%) had abnormal karyotypes (trisomy 13, 4 patients; trisomy 21, 2 patients; trisomy 18, 1 patient; monosomy X (45,X), 1 patient; 4p-, 22q+, and 8p+, 1 patient). Ten of 11 patients with abnormal karyotypes had other abnormalities that were found on ultrasound imaging. Two patients had intrauterine infection, one patient had cytomegalovirus, and one patient had parvovirus B19 infection. Eighteen of 40 patients underwent pregnancy termination, one fetus died in utero, one newborn infant died, and two infants had neurologic sequelae. Of 21 patients with isolated liver calcifications, one fetus had parvovirus B19 infection and one infant had trisomy 21. The remainder of the infants each had a good outcome. CONCLUSION Fetal liver calcifications are relatively common. Isolated cases have a good prognosis after aneuploidy and infection have been ruled out. However, additional major abnormalities present a risk for chromosomal abnormalities, mainly trisomy 13.
Effects of docosahexaenoic Acid on the endothelial function in patients with coronary artery disease.

AIM The consumption of n-3 polyunsaturated fatty acids (PUFA), including docosahexaenoic acid DHA), reduces the incidence of cardiovascular events, and reduced serum levels of n-3 PUFA may be associated with an increased risk of cardiovascular events. However, controversy remains regarding which components of PUFA are associated with the endothelial function in patients with coronary artery disease (CAD). We therefore examined the associations between the n-3 and n-6 PUFA levels and CAD. METHODS We retrospectively reviewed 160 consecutive Japanese patients with CAD whose endothelial function was measured according to the percent change in flow-mediated dilation (FMD) and the serum levels of n-3 PUFA, including eicosapentaenoic acid (EPA) and DHA, and n-6 PUFA, including arachidonic acid (AA) and dihomo-gamma-linolenic acid (DHLA). RESULTS A single regression analysis showed no relationships between the FMD and the serum levels of PUFA, including EPA, DHA, AA and DHLA. In contrast, a multiple regression analysis showed that the DHA level was a positive (＜ 0.01) and age was a negative (P ＜ 0.001) contributor to an increased FMD; however, sex, body mass index, systolic and diastolic blood pressure, current/past smoking and the levels of HbA1c, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, EPA, AA and DHLA did not significantly affect the outcome. CONCLUSIONS The serum level of DHA is associated with the endothelial function evaluated according to the FMD in patients with CAD, thus suggesting that a low serum level of DHA may be a predictive biomarker for endothelial dysfunction.
Studying temperament via construction of the Toddler Behavior Assessment Questionnaire.

The Toddler Behavior Assessment Questionnaire (TBAQ) was constructed by an iterative process of item generation intended to ensure content validity, by repeated item analyses focused on internal consistency and discriminant properties, and by scale revision. During the construction and initial validation processes reported in this article, data from 1,012 records were utilized. Internal consistency reliability estimates typically exceeded . 80 for each scale. Evidence for convergent validity with other temperament questionnaires and for longitudinal stability was also obtained. Besides yielding a promising instrument, this assessment research has conceptual ramifications. For instance, components of negative affectivity (anger proneness and fearfulness) were independent, and item analyses suggested that shyness and other fears were independent as well. Consistent with most current views of temperament, the TBAQ temperament scales revealed some relationship and/or contextual specificity, as exemplified by the finding of only moderate parental agreement. The rank ordering on most temperament dimensions was impressively preserved from age 12 months, when the Infant Behavior Questionnaire (IBQ) was used, to age 18 months, when the TBAQ was used (especially when subtle differences between the IBQ and TBAQ were taken into account). Most of the analyses benefit from replication.
Human Papillomavirus Infection Among 2460 Men in Denmark: Prevalence in Relation to Age Using 2 Human Papillomavirus DNA Testing Methods

Background It is crucial to understand the epidemiology and natural history of human papillomavirus (HPV) infection in both men and women, to prevent the increasing HPV-related disease burden in men. Data on HPV prevalence among men in the general population are limited. In this cross-sectional population-based study, we aimed to estimate genital HPV infection prevalence in Danish men using 2 different test methods. Methods Penile swab samples from 2460 male employees and conscripts at military barracks in Denmark were tested for HPV DNA with the hybrid capture 2 (HC2) method, and a polymerase chain reaction (PCR) assay, Inno-LiPA. The overall and age- and type-specific prevalence of HPV infection with 95% confidence intervals (CIs) were estimated, and the correlation between the 2 assays was assessed. Results The overall HPV prevalence was 22.2% (95% CI, 20.6–23.9) in the HC2 test and 41.8% (95% CI, 39.9–43.8) with PCR. Of the PCR-positive samples, 50.9% were negative in the HC2 test. Of 183 PCR-positive samples that could not be genotyped (HPVX), 88.0% (95% CI, 83.2–92.7) were HC2 negative. The most prevalent types were HPV-51, HPV-16, HPV-66, HPV-53, and HPV-6. The prevalence of high-risk and low-risk HPV peaked among men aged 20 to 29 years, whereas the HPVX prevalence increased with age. Conclusions Human papillomavirus is highly prevalent in the general male population of Denmark, with HPV-16 and HPV-51 being the most prevalent. Polymerase chain reaction detects twice as many positive samples as HC2 but includes HPVX, possibly representing cutaneous HPV types found on normal genital skin.
A phase I study of human cord blood-derived mesenchymal stem cell therapy in patients with peripheral arterial occlusive disease.

BACKGROUND AND OBJECTIVES Half of patients with critical limb ischemia (CLI) are ineligible for revascularization at diagnosis. The aim of this study was to assess the safety and feasibility of intramuscular human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) therapy in patients with CLI due to atherosclerosis obliterans (ASO) or thromboangiitis obliterans (TAO). METHODS AND RESULTS A total of eight patients (all male, median age 52 years, range 31∼77) with CLI were enrolled in this phase I trial. All patients were considered ineligible for further revascularization to improve CLI. We injected 1×10(7) hUCB-MSCs per single dose intramuscularly into the affected limb. The primary end points of safety were occurrence of adverse events (procedure-related complication, allergic reaction to hUCB-MSCs, graft-versus-host disease, cardiovascular and cerebrovascular events) and improvement of symptoms/clinical parameters (healing of foot ulcer, ankle-brachial index, and pain-free walking distance). Angiogenesis was measured with conventional angiography and scored by an independent reviewer. There were four adverse events in three patients. One patient, developed whole body urticaria after injection on treatment day, which disappeared after one day of antihistamine treatment. The other adverse events included diarrhea, oral ulceration, and elevation of serum creatinine level; all conditions improved without treatment. Abnormal results of laboratory parameters were not detected in any patients. Three of four ulcerations (75%) healed completely. Angiographic scores increased in three of eight patients. CONCLUSIONS This phase I study demonstrates that intramuscular hUCB-MSC injection is a safe and well tolerated treatment for patients with end-stage CLI due to ASO and TAO.
Dietary fat intake and risk of cardiovascular disease and all-cause mortality in a population at high risk of cardiovascular disease.

BACKGROUND Dietary fat quality and fat replacement are more important for cardiovascular disease (CVD) prevention than is total dietary fat intake. OBJECTIVE The aim was to evaluate the association between total fat intake and fat subtypes with the risk of CVD (myocardial infarction, stroke, or death from cardiovascular causes) and cardiovascular and all-cause death. We also examined the hypothetical effect of the isocaloric substitution of one macronutrient for another. DESIGN We prospectively studied 7038 participants at high CVD risk from the PREvención con DIeta MEDiterránea (PREDIMED) study. The trial was conducted from 2003 to 2010, but the present analysis was based on an expanded follow-up until 2012. At baseline and yearly thereafter, total and specific fat subtypes were repeatedly measured by using validated food-frequency questionnaires. Time-dependent Cox proportional hazards models were used. RESULTS After 6 y of follow-up, we documented 336 CVD cases and 414 total deaths. HRs (95% CIs) for CVD for those in the highest quintile of total fat, monounsaturated fatty acid (MUFA), and polyunsaturated fatty acid (PUFA) intake compared with those in the lowest quintile were 0.58 (0.39, 0.86), 0.50 (0.31, 0.81), and 0.68 (0.48, 0.96), respectively. In the comparison between extreme quintiles, higher saturated fatty acid (SFA) and trans-fat intakes were associated with 81% (HR: 1.81; 95% CI: 1.05, 3.13) and 67% (HR: 1.67; 95% CI: 1.09, 2.57) higher risk of CVD. Inverse associations with all-cause death were also observed for PUFA and MUFA intakes. Isocaloric replacements of SFAs with MUFAs and PUFAs or trans fat with MUFAs were associated with a lower risk of CVD. SFAs from pastries and processed foods were associated with a higher risk of CVD. CONCLUSIONS Intakes of MUFAs and PUFAs were associated with a lower risk of CVD and death, whereas SFA and trans-fat intakes were associated with a higher risk of CVD. The replacement of SFAs with MUFAs and PUFAs or of trans fat with MUFAs was inversely associated with CVD. This trial was registered at www.controlled-trials.com as ISRCTN 35739639.
Development of Methodology

This chapter may be entitled "Critical Methodology of Research Which I Gradually Acquired in My Younger Years. " Just before coming to this session of dictation I thought over the question of acquisition of my technique and found it very hard to pin down from what place, from what book or from what teacher, I acquired the methodology. It seemed to have been a long and gradual process, going back to my early teens. In my autobiographical chapters in Chinese I pointed out that in my early teens I was beginning to show a tendency to doubt, particularly on religious matters. I doubted many questions, revolted against a number of superstitions — ghosts, spirits, gods.
The relationship among serum insulin-like growth factor-I, insulin-like growth factor-I gene polymorphism, and bone mineral density in postmenopausal women in Korea.

OBJECTIVE The objective of this study was to test the hypothesis that the cytosine-adenine polymorphism in the insulin-like growth factor-I gene is associated with serum insulin-like growth factor-I levels and bone mineral density. STUDY DESIGN The insulin-like growth factor-I cytosine-adenine polymorphism was analyzed in 300 postmenopausal Korean women. Serum insulin-like growth factor-I, bone alkaline phosphatase, and carboxy-terminal cross-linking telopeptide of type I collagen were measured by immunoradiometric assay and enzyme-linked immunosorbent assay. Bone mineral density at the lumbar spine and proximal femur was determined by dual energy radiograph absorptiometry. RESULTS Serum insulin-like growth factor-I and bone mineral density levels in women who were homozygous for a 194-base pair allele were significantly higher than those levels in the 194-base pair heterozygotes or women who did not possess the 194-base pair allele. A significantly decreased prevalence of the 194/194 genotype was observed in the combined group of women with osteopenia and osteoporosis, compared with normal women. No correlation between insulin-like growth factor-I genotypes and bone turnover markers was found. CONCLUSION The insulin-like growth factor-I gene cytosine-adenine polymorphism relates with circulating insulin-like growth factor-I levels and bone mineral density at the lumbar spine and proximal femur.
Tractographical model of the cortico‐basal ganglia and corticothalamic connections

The cortico‐basal ganglia and corticothalamic projections have been extensively studied in the context of neurological and psychiatric disorders. Deep brain stimulation (DBS) is known to modulate many of these pathways to produce the desired clinical effect. The aim of this work is to describe the anatomy of the main circuits of the basal ganglia using tractography in a surgical planning station. We used imaging studies of 20 patients who underwent DBS for movement and psychiatric disorders. We segmented the putamen, caudate nucleus (CN), thalamus, and subthalamic nucleus (STN), and we also segmented the cortical areas connected with these subcortical areas. We used tractography to define the subdivisions of the basal ganglia and thalamus through the generation of fibers from the cortical areas to the subcortical structures. We were able to generate the corticostriatal and corticothalamic connections involved in the motor, associative and limbic circuits. Furthermore, we were able to reconstruct the hyperdirect pathway through the corticosubthalamic connections and we found subregions in the STN. Finally, we reconstructed the cortico‐subcortical connections of the ventral intermediate nucleus, the nucleus accumbens and the CN. We identified a feasible delineation of the basal ganglia and thalamus connections using tractography. These results could be potentially useful in DBS if the parcellations are used as targets during surgery. Clin. Anat. 29:481–492, 2016. © 2016 Wiley Periodicals, Inc.