Hemodynamic effects of N-acetylamrinone in a porcine model of group B streptococcal sepsis.
High plasma concentrations of N-acetylamrinone, a primary metabolite of amrinone, are measured in some children during prolonged amrinone infusion. The purpose of this investigation was to determine if N-acetylamrinone has direct hemodynamic effects independent of amrinone. Twenty neonatal piglets received an infusion of 6 x 10(9) colony-forming units/kg of group B Streptococcus to induce sepsis. Subsequently, they were divided into 1 of 3 groups and received a 1-hr infusion of either normal saline (N = 4); 8 mg/kg amrinone, followed by 20 micrograms/kg/min (N = 9); or 8 mg/kg N-acetylamrinone, followed by 20 micrograms/kg/min (N = 7). Hemodynamic measurements and arterial/venous blood-gas determinations were obtained every 30 min during the study. Systemic vascular resistance and pulmonary vascular resistance were calculated. One milliliter of blood was obtained every 30 min during drug administration to determine plasma amrinone and N-acetylamrinone concentrations. The mean amrinone plasma concentrations measured at 30 and 60 min during the infusion time in the group receiving amrinone were 8.8 +/- 1.1 and 6.9 +/- 0.7 micrograms/ml, respectively. These animals experienced a significant decrease in mean pulmonary artery pressure and pulmonary vascular resistance, compared with saline controls after a 30-min infusion of amrinone. The mean N-acetylamrinone plasma concentrations measured at 30 and 60 min during the N-acetylamrinone infusion were 7.3 +/- 0.8 and 5.7 +/- 0.6 micrograms/ml, respectively. There was no difference between any hemodynamic parameter measured in these animals, compared with saline controls at any time during the infusion. We conclude that amrinone, but not N-acetylamrinone, causes pulmonary vasodilation in a porcine model of sepsis and that the parent drug is the sole active component in amrinone.


Value in Single-level Lumbar Discectomy: Surgical Disposable Item Cost and Relationship to Patient-reported Outcomes.
This is a retrospective study. Compare improvements in health status measures (HSMs) and surgical costs to determine whether use of more costly items has any relationship to clinical outcome and value in lumbar disc surgery. Association between cost, outcomes, and value in spine surgery, including lumbar discectomy is poorly understood. Outcomes were calculated as difference in mean HSM scores between preoperative and postoperative timeframes. Prospective validated patient-reported HSMs studied were EuroQol quality of life index score (EQ-5D), Pain Disability Questionnaire (PDQ), and Patient Health Questionnaire (PHQ-9). Surgical costs consisted of disposable items and implants used in operating room. We retrospectively identified all adult patients at Cleveland Clinic main campus between October 2009 and August 2013 who underwent lumbar discectomy (652) using administrative billing data, Current Procedural Terminology (CPT) code 63030. HSMs were obtained from Cleveland Clinic Knowledge Program Data Registry. In total, 67% of operations performed in the outpatient or ambulatory setting, 33% in the inpatient setting. Among 9 surgeons who performed >10 lumbar discectomies, there were 72.4 operations per surgeon, on average. Mean surgical costs of each surgeon differed (P<0.0001). In a multivariable regression, only the surgeon and surgery type (outpatient or inpatient) were statistically correlated with surgical costs (P<0.0001 and 0.046, respectively). Changes in EQ-5D, PDQ, and PHQ-9 were not correlated with surgical costs (P=0.76, 0.07, 0.76, respectively). In multivariable regression, only surgical cost was significantly correlated to mean difference in PDQ (P=0.030). More costly surgeries resulted in worse PDQ outcomes. Mean surgical costs varied statistically among 9 surgeons; costs were not shown to be positively correlated with patient outcomes. Performing an operation using more costly disposable supplies/implants does not seem to improve patient outcomes and should be considered when constructing preference cards and during an operation.


Emergency department thoracotomy (EDT). A 26-month experience using an "agonal" protocol.
EDT can be successfully performed with the proper system in place. This includes an established thoracotomy protocol, a well-integrated EMS system, and an in-house team. Time seems to be critical, and the time between injury and EDT may be the single most important factor affecting survival other than the mechanism of injury. Cardiac penetrations, especially stab wounds, were found to have a 93 per cent survival while subdiaphragmatic penetrations had only one survivor from a group of 18 patients (5.5%). The high rate of salvage in the heart wound group probably reflects the speed of prehospital transport, though all other major series have found this group to gain the maximum benefit. No patient was successfully resuscitated from blunt injury with EDT. Three additional patients had "signs of life" restored (one pediatric blunt; two subdiaphragmatic gunshot wounds) but died of coagulopathies shortly thereafter. The experience with air ambulance patients was far too small to allow any conclusions or observations. It is felt that as the use and application of helicopters to EMS situations becomes widespread, more patients will be arriving at trauma centers with no vital signs and massive blunt injury but only moments from the accident. This special group of "dying" patients will require intense scrutiny and possibly new and inventive approaches for any hopeful salvage. Emergency thoracotomy will, no doubt, have a place as part of this. The development of a simple working protocol is of extreme importance. The protocol should be one that will allow maximum selection of patients who can benefit and elimination of those patients where EDT would be useless. The primary benefactor for EDT remains the patient sustaining a stab wound to the heart who arrives at the center shortly after injury. In other areas, such as abdominal exsanguination or severe blunt injury, further study is needed to determine what factors, prehospital and resuscitative, will improve outcome.


Determination of alpha-tocopherol in infant foods by liquid chromatography combined with atmospheric pressure chemical ionisation mass spectrometry.
A novel, sensitive and specific method for the quantification of alpha-tocopherol in two infant foods (milk and cereals) using liquid chromatography on-line with positive atmospheric pressure chemical ionisation mass spectrometry detection (LC/APCI-MS) has been developed. The samples were first saponified in order to eliminate fats and to transform tocopherol esters into free tocopherol, followed up by a liquid-liquid extraction of the analyte in petroleum benzine/diisopropyl ether (75:25, v/v) prior to injection onto the LC system. For the quantification, deuterium-labelled tocopherol was used as internal standard and the samples were monitored in selected ion monitoring (SIM) mode. Calibration curves between 1-40 microg/mL of alpha-tocopherol showed a good linear correlation (r(2) = 0.99994), and the detection limit was determined to be 2.5 ng/mL. The within-day and between-day precision were determined for several dietetic infant formulae and certified reference samples, and found to be below 3.5%. The accuracy determined on a Nestlé reference sample (milk powder) was calculated to be 115.2 +/- 1.2%, which confirms the robustness of the proposed method. This study shows that single quadrupole LC/MS can be applied for the quantification of vitamins in food and the method offers better sensitivity and selectivity than traditional method such as LC-UV. This would simplify the preparation of the food samples and consequently enhance the vitamin analysis throughput in the food area.


Abnormal discourse in semantic dementia: a data-driven approach.
Structural and content-related deficits occur in connected discourse of patients with semantic dementia (SD). We used principal components analysis (PCA) to characterise the sources of variation in word usage during picture description by controls and SD patients. This data-driven approach allowed: comparison of the distance between individuals in the two-dimensional space; correlational analyses between principal component (PC) values and performance on other tests; identification of words whose variance contributed most to the definition of the PCs.Transcripts of Cookie Theft picture descriptions from 21 patients with SD and 21 controls were used to generate frequencies of all word types (n = 557) across participants. Frequency values of words with ≥10 occurrences (n= 81) were entered into a PCA. Values of emergent dimensions were correlated with performance on tests of single word meaning. The first PC accounted for 59% of the variance, the second for a further 10%. Patients and controls showed good separation within the resulting space. Factor loading scores indicated that control performance was characterised by function (factor 1) and content (factor 2) word usage, while patients showed a greater tendency to use pronouns, deictic and generic words. Knowledge of single word meaning correlated with factor 1 but not with factor 2. Differences in word usage can differentiate connected speech of SD patients from controls using a rapid, automated, data-driven algorithm. The distinction between groups, loadings on the two components, and their differential correlations with semantic tasks raise the possibility of independent differences in syntax and lexical content.


Development of a Risk Score for Extraintestinal Manifestations of Coeliac Disease.
The aim of this study was to identify indicators of coeliac disease (CD) in an Australian cohort, beyond the known gastrointestinal symptoms. Individuals were recruited from the general population and at the 2014 Gluten Free Expo in Sydney and in Melbourne, Australia. Data on their current health status including medical history, diagnosis for CD, and family history were collected. Multivariable logistic regression was used to identify independent predictors of CD. A weighted risk score system was then generated for the independent predictors, and a risk score was calculated for each individual. A total of 301 individuals were included in the study. We found an association between CD and having a family history of CD (odds ratio [OR] 7.6, 95%confidence interval [CI] 3.7-15.6), an autoimmune disorder (OR 2.1, 95%CI 1.1-4.1), anemia (OR 5.8, 95%CI 2.8-11.9), lactose intolerance (OR 4.5, 95%CI 1.2-17.7), and depression (OR 4.8, 95%CI 1.9-11.6). Risk score analysis found individuals in the medium (OR 4.8, 95%CI 2.5 to 9.3) and high-risk (OR 36.6, 95%CI 16.4 to 81.6) groups were significantly more likely to report having CD compared with those in the low-risk group. This study identifies a set of factors more commonly observed in individuals with CD, beyond the traditional gastrointestinal complaints. These include a family history of CD, the presence of another autoimmune disorder, anemia, lactose intolerance, and depression. A risk score was developed (Coeliac Risk COMPARE) which scores individuals based on the presence or absence of these additional symptoms and provides an additional screening tool when assessing whether the patient requires follow-up testing for CD.


Attenuated psychosis syndrome: benefits of explicit recognition.
Given the unique characteristics of people who meet criteria for attenuated psychosis syndrome (APS) and the growing literature on the clinical benefits of providing services to individuals who meet these criteria, the APS diagnosis serves an important, and previously missing, role in psychiatry. The promotion of the APS diagnosis should help reduce the over-diagnosis and over-treatment of individuals with prodromal psychotic conditions and it should also encourage expanded training about attenuated psychosis among clinicians who primarily provide services to youth (a primary group who are diagnosed with APS). Only some of the individuals with APS subsequently develop psychosis, but all have existing clinical needs - regardless of subsequent conversion. The formal recognition of APS in DSM-5 will facilitate the research needed to identify and meet those needs.


Eosinophilic ileocolitis by Enterobius vermicularis: a description of two rare cases.
Human enterobiasis is usually mild. Occasionally, however, an "ectopic" disease may occur with a more severe course. Two rare cases of eosinophilic ileocolitis due to Enterobius vermicularis infection are reported here. Case n degree 1 was 46 years old, presenting with fever and bloody diarrhoea. Blood eosinophilia was present. Stool microscopy demonstrated red blood cells and leukocytes. A 2 mm long worm with bilateral cervical wings was found in wet-mount preparations of faecal samples. The Scotch tape test was positive for Enterobius vermicularis eggs. Colon biopsy specimens showed massive eosinophilic infiltration and a typical pinworm section overlying the infiltrated mucosa. Case n degree 2 was a 24-year-old, anti-HIV negative homosexual, presenting with watery diarrhoea. Tests for malabsorption were negative. Three mm long adult male E. vermicularis were found on stool microscopy. Biopsy specimens from the colon showed eosinophilic infiltration. In both cases a 200 mg/day course of oral mebendazole eliminated the symptoms within 3 days. In these two cases the clinical presentation of enterobiasis was atypical. A common finding was the eosinophilic infiltration of bowel mucosa, although it is still uncertain whether the worm per se may induce mast cell degranulation and eosinophil activation. Nevertheless, the possibility of Enterobius vermicularis infection should be considered in the presence of eosinophilic ileocolitis.


A study on longitudinal relationship between ultrafine dust and the prevalence of depression.
Recently, the fine dust problem caused by rapid industrialization and science and technological development has emerged as a severe social issue worldwide. This also increases the interest in its effect on human life. In particular, there is a growing concern about the harm of fine dust in Korea. This study is based on the PM 2.5 data from 2017 to 2021 provided by Air Korea to estimate changes in ultrafine dust. In addition, the data from the Community Health Survey provided by the Korea Centers for Disease Control and Prevention (KCDC) from 2017 to 2021 were used to examine the effect between the change in ultra-fine dust and the prevalence of depression. A total of 229 local governments were included in the analysis. The Latent Growth Modeling was carried out to estimate the change in ultra-fine dust and the prevalence of depressions and verify the relationship between ultra-fine dust and the prevalence of depression. The analysis result revealed that the ultra-fine dust concentration continued to decrease from 2017 to 2021. However, the depression prevalence increased from an average of 2.60% in 2017 to an average of 3.12% in 2021, suggesting the need for adequate and sufficient welfare policies for depression treatment. As a result of estimating the initial value and change rate of ultra-fine dust and depression prevalence, the higher the initial value of ultra-fine dust, the greater the decrease in ultra-fine dust. In terms of depression, the lower the initial value of the prevalence of depression, the larger the increase in depression prevalence. This study is significant in that it revealed the strong association of the longitudinal relationship between ultra-fine dust and depression, one of the biggest issues in Korea, by utilizing large-scale longitudinal data.


Mechanical properties of the myotomal musculo-skeletal system of rainbow trout, Salmo gairdneri.
Net forces and velocities resulting from in situ contractions of the myotomal musculature on one side of the body were measured at the hypural bones. Forces, velocities and power were determined with the body bent into a range of postures typical of those observed during fast-start swimming. For trout averaging 0.178 m in length and 0.0605 kg in body mass, the muscle system exerts a maximum normal force of 2.2N at the base of the caudal fin. This force is equivalent to 11.8 kN m-2 based on the mean cross-sectional area of the myotomal muscle. The maximum velocity was 1.11 m s-1, and the maximum mechanical power output, 0.64 W, or 42.4 W kg-1 muscle. Based on estimates of swimming resistance, these results would suggest acceleration rates of 7.5 to 16.5 m s-2, similar to averages observed during fast-starts. Maximum sprint speeds would range from 6.5 to 17.8 body lengths s-1, spanning the range of maximum speeds reported in the literature. It is suggested that maximum speed is limited by interactions between muscle contraction frequency and endurance. Losses in the mechanical linkages between muscle fibres and propulsive surfaces were estimated at about 50% for power with possibly greater losses in force transmission. Maximum force and power did not vary over the range of postures tested, supporting Alexander's (1969) suggestions that white muscle should contract over a small portion of the resting length of the fibres.


Percutaneous versus surgical insertion of PD catheters in dialysis patients: a meta-analysis.
Several small studies have suggested that the percutaneous method of peritoneal dialysis (PD) catheter insertion is effective and has a lower complication rate than surgical techniques (open, laparoscopic or peritoneoscopic), although no randomized, controlled study has compared these methods. Our objective was to compare percutaneous PD catheter insertion vs surgical placement in terms of 1-year catheter survival, catheter dysfunction, fluid leak and incidence of peritonitis. We searched Medline for English-language literature from 1966 through June 2014, along with national conference proceedings and reference lists of all included publications to identify relevant studies. Inclusion criteria were having a measure of catheter survival at 1 year, catheter dysfunction, peritonitis rate per patient-month or fluid leak as outcomes. Studies were excluded if they were not in English or if they included pediatric patients. Random effects models were used to derive the pooled risk ratios, differences in patency and their variations. Thirteen studies with a total of 2,681 subjects met the inclusion criteria. There was no significant difference in 1-year catheter survival in percutaneous vs surgical PD catheter placement (relative risk [RR] = 0.81; 95% confidence interval [CI]: 0.59-1.11, p = 0.19). Catheter dysfunction also did not differ significantly between the groups (pooled odds ratio [OR] = 0.86; 95% CI: 0.57-1.29, p = 0.46). The prevalence of peritoneal fluid leak also was similar for percutaneous and surgical groups (OR = 1.10; 95% CI: 0.58-2.09, p = 0.77). However, there was a significant lower incidence of peritonitis among those with percutaneous placement (incidence rate ratio [IRR] = 0.77; 95% CI: 0.62-0.96, p = 0.02). Significant heterogeneity was detected across studies (I2 = 78.4%, p<0.0001). Our results suggest that there is no significant difference in catheter survival between percutaneous and surgical placement of PD catheters. Whether there are significant benefits from percutaneous placement in terms of peritonitis rates requires further robust studies. These findings have significant implications for future design of clinical trials in the placement of PD catheters and the delivery of dialysis-related services.


Factors associated with emergency department use for mental health reasons among low, moderate and high users.
This study identified factors associated with frequency of emergency department (ED) use for mental health (MH) reasons in Quebec during 2015-2016. Participants (n = 115,066) were categorized as: 1) low (1 visit/year; 76%); 2) moderate (2 visits/year; 14%); and 3) high (3+ visits/year; 10%) ED users. Independent variables included predisposing, enabling and needs factors based on the Andersen Behavioral Model. Variables significantly associated with frequency of ED use were entered into a multinomial logistic regression. Patients with mental illness (MI), especially substance-related disorders (SRD) and schizophrenia spectrum disorders; bipolar, depressive, anxiety or personality disorders; and those with severe chronic physical illness (needs factors) were more likely to use ED for MH reasons, as were male participants 18-64 years old, and those living in metropolitan areas with high social or material deprivation (predisposing factors). Regarding enabling factors, consultations with outpatient psychiatrists and not seeing a general practitioner (GP) in the year prior to ED visit were associated with high ED use. The severity of MI/SRD contributed most to frequent ED use, while social and material deprivation in metropolitan areas, and intensity of medical care also influenced ED use for MH reasons.


Endoscopic Nd:YAG laser treatment of rectosigmoid cancer.
Forty nine patients with rectosigmoid carcinoma considered unsuitable for surgery underwent endoscopic Nd:YAG laser treatment for palliation of symptoms and tumour eradication, if feasible. Altogether 25 (51%) of the lesions had distal margins less than 7 cm from the anus and 36 (73%) extended above the peritoneal reflection. In seven patients with tumours less than 3 cm in diameter, symptomatic improvement was achieved in all (mean follow up 16 months) and complete tumour eradication in three. In the remaining 42 patients with larger tumours (34 greater than 2/3 circumferential, mean length 5.5 cm), symptomatic improvement was achieved with repeated treatments (average 3.4) in 31 (74%) over a mean follow up of 19 weeks. Of the parameters assessed, only circumferential tumour extent proved significant in predicting functional outcome after treatment. All treatment failures (eight initial, three late) occurred in patients with extensive tumours, and only seven of these patients were considered fit for colostomy. Bowel perforation occurred in two patients (5%) but there was no treatment-related mortality. Mean stay in hospital for all laser treatments was nine days (30% were outpatient attendances). These results suggest that laser therapy may be the palliative treatment of choice in patients with rectal carcinoma unsuitable for surgery.


The patient panel conference experience: what patients can teach our residents about competency issues.
In 2007, the Scott & White/Texas A&M HSC College of Medicine began requiring all internal medicine residents to attend quarterly patient panel conferences, during which former Scott & White patients speak frankly about their inpatient and outpatient experiences. The main purpose of this mixed-methods pilot study was to determine whether residents' competency education could be enhanced via the conferences. Of the 54 internal medicine residents in the residency program, 31, 39, and 41 participated in three patient panel conferences, respectively, between December 2007 and August 2008. Each resident completed an assessment that included a reflection on his or her own practice and the identification of competency issues highlighted by patients' oral narratives. Content analyses of responses to open-ended questions were performed. Consensus on themes was reached. Descriptive statistics were run on quantitative data. Six themes were identified: improve communication with patients/families, improve patient care, improve professional behaviors, empathize with patients/families, display sensitivity to patients'/families' needs/concerns, and recognize system issues. When asked if the conference highlighted competency problems, residents answered "agree" or "strongly agree" as follows: 82% for professionalism, 82.9% for systems-based practice, 85.2% for interpersonal and communication skills, and 84.4% for patient care. The majority were able to provide examples of competency issues. The patient panel conference experience was a powerful mechanism for enhancing competency education. The conferences were an effective means of presenting real-life examples of systems issues in the context of a hospital system.


Identification of carbonylated lipids from different phospholipid classes by shotgun and LC-MS lipidomics.
Oxidized lipids play a significant role in the pathogenesis of numerous oxidative stress-related human disorders, such as atherosclerosis, obesity, inflammation, and autoimmune diseases. Lipid peroxidation, induced by reactive oxygen and nitrogen species, yields a high variety of modified lipids. Among them, carbonylated lipid peroxidation products (oxoLPP), formed by oxidation of the fatty acid moiety yielding aldehydes or ketones (carbonyl groups), are electrophilic compounds that are able to modify nucleophilic substrates like proteins, nucleic acid, and aminophospholipids. Some carbonylated phosphatidylcholines possess even pro-inflammatory activities. However, little is known about oxoLPP derived from other phospholipid (PL) classes. Here, we present a new analytical strategy based on the mass spectrometry (MS) of PL-oxoLPP derivatized with 7-(diethylamino)coumarin-3-carbohydrazide (CHH). Shotgun MS revealed many oxoLPP derived from in vitro oxidized glycerophosphatidylglycerols (PG, 31), glycerophosphatidylcholine (PC, 23), glycerophosphatidylethanolamine (PE, 34), glycerophosphatidylserines (PS, 7), glycerophosphatidic acids (PA, 17), and phosphatidylinositiolphosphates (PIP, 6) vesicles. This data were used to optimize LipidXplorer-assisted identification, and a python-based post-processing script was developed to increase both throughput and accuracy. When applied to full lipid extracts from rat primary cardiomyocytes treated with peroxynitrite donor SIN-1, ten PL-bound oxoLPP were unambiguously identified by LC-MS, including two PC-, two PE-, one PG-, two PS-, and three PA-derived species. Some of the well-known carbonylated PC were detected, while most PL-oxoLPP were shown for the first time.


A critical role for citrate metabolism in LPS signalling.
Macrophage activation is a key event in the inflammatory process, since these cells produce a range of pro-inflammatory molecules, including ROS (reactive oxygen species), prostaglandins, cytokines and nitric oxide. These factors promote inflammation by causing vasodilation and recruitment of neutrophils, monocytes and lymphocytes, which ultimately clear infection and repair damaged tissue. One of the most potent macrophage activators is the Gram-negative-derived bacterial cell wall component LPS (lipopolysaccharide). LPS is sensed by TLR4 (Toll-like receptor 4) and triggers highly complex signalling pathways that culminate in activation of transcription factors such as NF-κB (nuclear factor κB), which in turn increases transcription of genes encoding proteins such as COX2 (cyclo-oxygenase 2, a key enzyme in prostaglandin biosynthesis), nitric oxide synthase and cytokines such as TNF (tumour necrosis factor). Recently, a role for metabolic pathways in the regulation of LPS signalling has become a focus of research in inflammation. A notable example is LPS promoting the so-called Warburg effect - aerobic glycolysis. This allows for an up-regulation in ATP production, and also for the production of biosynthetic intermediates to meet the demands of the activated macrophages. In this issue of the Biochemical Journal, Infantino et al. add a new finding to the role of metabolism in LPS action. They demonstrate a requirement for the mitochondrial citrate carrier in the induction of ROS, nitric oxide and prostaglandins by LPS. The knockdown of the carrier with siRNA (small interfering RNA), or the use of an inhibitor BTA (benzene-1,2,3-tricarboxylate), abolishes these responses. Although no mechanism is provided, the authors speculate that acetyl-CoA is synthesized from citrate in the cytosol. The acetyl-CoA generated could be required for phospholipid biosynthesis, the phospholipids being the source of arachidonic acid for prostaglandin production. Another product of citrate metabolism, oxaloacetate, will indirectly generate nitric oxide and ROS. This finding places citrate, transported from the mitochondria, as a key player in LPS signalling, at least for ROS, nitric oxide and prostaglandin production. This somewhat unexpected role for citrate in LPS action adds to a growing literature on the role for metabolism in the regulation of signalling in inflammation.


On the variation of interaural time differences with frequency.
Interaural time difference (ITD) is a major cue to sound localization in humans and animals. For a given subject and position in space, ITD depends on frequency. This variation is analyzed here using a head related transfer functions (HRTFs) database collected from the literature and comprising human HRTFs from 130 subjects and animal HRTFs from six specimens of different species. For humans, the ITD is found to vary with frequency in a way that shows consistent differences with respect to a spherical head model. Maximal ITD values were found to be about 800 μs in low frequencies and 600 μs in high frequencies. The ITD variation with frequency (up to 200 μs for some positions) occurs within the frequency range where ITD is used to judge the lateral position of a sound source. In addition, ITD varies substantially within the bandwidth of a single auditory filter, leading to systematic differences between envelope and fine-structure ITDs. Because the frequency-dependent pattern of ITD does not display spherical symmetries, it potentially provides cues to elevation and resolves front/back confusion. The fact that the relation between position and ITDs strongly depends on the sound's spectrum in turn suggests that humans and animals make use of this relationship for the localization of sounds.


[Squamous cell carcinoma in situ of the cervix and placental site nodule: Case report].
An asymptomatic 24-year-old woman underwent a colposcopy, cervical biopsy, and subsequently, a conization for a cervical squamous cell carcinoma in situ with glandular extension. Simultaneously, an endometrial biopsy was carried out in which, incidentally, a placental site nodule was diagnosed, a rare non-neoplastic lesion originating in the intermediate trophoblast. Given the coexistence of these two entities, it was necessary to make a differential diagnosis between them and also with other pathologies of the trophoblast such as an exaggerated placental site, placental site trophoblastic tumor, and epithelioid trophoblastic tumor.


Higher Handgrip Strength Is Linked to Better Cognitive Performance in Chinese Adults with Hypertension.
There is growing evidence that in adults, higher levels of handgrip strength (HGS) are linked to better cognitive performance. However, the relationship between HGS and cognitive performance has not been sufficiently investigated in special cohorts, such as individuals with hypertension who have an intrinsically higher risk of cognitive decline. Thus, the purpose of this study was to examine the relationship between HGS and cognitive performance in adults with hypertension using data from the Global Ageing and Adult Health Survey (SAGE). A total of 4486 Chinese adults with hypertension from the SAGE were included in this study. Absolute handgrip strength (aHGS in kilograms) was measured using a handheld electronic dynamometer, and cognitive performance was assessed in the domains of short-term memory, delayed memory, and language ability. Multiple linear regression models were fitted to examine the association between relative handgrip strength (rHGS; aHGS divided by body mass index) and measures of cognitive performance. Overall, higher levels of rHGS were associated with higher scores in short-term memory (β = 0.20) and language (β = 0.63) compared with the lowest tertiles of rHGS. In male participants, higher HGS was associated with higher scores in short-term memory (β = 0.31), language (β = 0.64), and delayed memory (β = 0.22). There were no associations between rHGS and cognitive performance measures in females. We observed that a higher level of rHGS was associated with better cognitive performance among hypertensive male individuals. Further studies are needed to investigate the neurobiological mechanisms, including sex-specific differences driving the relationship between measures of HGS and cognitive performance in individuals with hypertension.


Design, synthesis and perception of fluorescently labeled isoprenoid cytokinins.
Isoprenoid cytokinins play a number of crucial roles in the regulation of plant growth and development. To study cytokinin receptor properties in plants, we designed and prepared fluorescent derivatives of 6-[(3-methylbut-2-en-1-yl)amino]purine (N6-isopentenyladenine, iP) with several fluorescent labels attached to the C2 or N9 atom of the purine moiety via a 2- or 6-carbon linker. The fluorescent labels included dansyl (DS), fluorescein (FC), 7-nitrobenzofurazan (NBD), rhodamine B (RhoB), coumarin (Cou), 7-(diethylamino)coumarin (DEAC) and cyanine 5 dye (Cy5). All prepared compounds were screened for affinity for the Arabidopsis thaliana cytokinin receptor (CRE1/AHK4). Although the attachment of the fluorescent labels to iP via the linkers mostly disrupted binding to the receptor, several fluorescent derivatives interacted well. For this reason, three derivatives, two rhodamine B and one 4-chloro-7-nitrobenzofurazan labeled iP were tested for their interaction with CRE1/AHK4 and Zea mays cytokinin receptors in detail. We further showed that the three derivatives were able to activate transcription of cytokinin response regulator ARR5 in Arabidopsis seedlings. The activity of fluorescently labeled cytokinins was compared with corresponding 6-dimethylaminopurine fluorescently labeled negative controls. Selected rhodamine B C2-labeled compounds 17, 18 and 4-chloro-7-nitrobenzofurazan N9-labeled compound 28 and their respective negative controls (19, 20 and 29, respectively) were used for in planta staining experiments in Arabidopsis thaliana cell suspension culture using live cell confocal microscopy.


Medical home capabilities of primary care practices that serve sociodemographically vulnerable neighborhoods.
Under current medical home proposals, primary care practices using specific structural capabilities will receive enhanced payments. Some practices disproportionately serve sociodemographically vulnerable neighborhoods. If these practices lack medical home capabilities, their ineligibility for enhanced payments could worsen disparities in care. Via survey, 308 Massachusetts primary care practices reported their use of 13 structural capabilities commonly included in medical home proposals. Using geocoded US Census data, we constructed racial/ethnic minority and economic disadvantage indices to describe the neighborhood served by each practice. We compared the structural capabilities of "disproportionate-share" practices (those in the most sociodemographically vulnerable quintile on each index) and others. Racial/ethnic disproportionate-share practices were more likely than others to have staff assisting patient self-management (69% vs 55%; P = .003), on-site language interpreters (54% vs 26%; P < .001), multilingual clinicians (80% vs 51%; P < .001), and multifunctional electronic health records (48% vs 29%; P = .01). Similarly, economic disproportionate-share practices were more likely than others to have physician awareness of patient experience ratings (73% vs 65%; P = .03), on-site language interpreters (56% vs 25%; P < .001), multilingual clinicians (78% vs 51%; P < .001), and multifunctional electronic health records (40% vs 31%; P = .03). Disproportionate-share practices were larger than others. After adjustment for practice size, only language capabilities continued to have statistically significant relationships with disproportionate-share status. Contrary to expectations, primary care practices serving sociodemographically vulnerable neighborhoods were more likely than other practices to have structural capabilities commonly included in medical home proposals. Payments tied to these capabilities may aid practices serving vulnerable populations.


Medical education and population health-A framework in the design of a new undergraduate program.
Health sciences curricular planners are challenged to add new content to established education programs. There is increasing pressure for content in public health, health systems, global health, and planetary health. These important areas often compete for curricular time. What is needed is a convergence model that builds a common framework within which students can integrate areas and better align this knowledge to the individual client or patient who they have responsibility to support. A population health framework is proposed for health sciences education programs that supports a common conceptual understanding of population health. The framework links five thematic areas that have influence on health and wellbeing and a sixth element that defines the range of methodologies essential to understanding health and wellbeing, from the individual to the population. The five areas providing convergence are: (1) the biopsychosocial development of the individual, (2) the socioeconomic factors that influence health and wellbeing, (3) the physical natural and built environment including climate, (4) the continuum of public health and health care systems, and (5) the nation state and global relationships. Using this framework, students are encouraged to think and understand individual health and wellbeing in context to the population and to utilize the appropriate methodological tools to explore these relationships. Planning for a new undergraduate medicine program illustrates the curricular elements that will be used to support student learning with foundation knowledge applied and tracked throughout the program. The proposed framework has application across health sciences disciplines and serves to build a common understanding that supports cross professional communication and collaboration.


A Novel Method for Automated Crystal Visualization and Quantification in Murine Folic Acid-Induced Acute Kidney Injury.
Folic acid-induced acute kidney injury (FA-AKI) is an increasingly prevalent rodent disease model involving the injection of a high dose of FA that culminates in renal FA crystal deposition and injury. However, the literature characterizing the FA-AKI model is sparse and dated in part due to the absence of a well-described methodology for the visualization and quantification of renal FA crystals. Using widely available materials and tools, we developed a straightforward and crystal-preserving histological protocol that can be coupled with automated imaging for renal FA crystal visualization and generated an automated macro for downstream crystal content quantification. The applicability of the method was demonstrated by characterizing the model in male and female C57BL6/JRj mice after 3 and 30 hours of FA treatment. Kidneys from both sexes and timepoints showed a bimodal distribution of FA crystal deposition in the cortical and medullary regions while, compared to males, females exhibited higher renal FA crystal content at the 30 hours timepoint accompanied by greater kidney weight and higher plasma urea. Despite comparable plasma phosphate concentrations, FA-AKI resulted in a substantially more elevated plasma intact fibroblast growth factor 23 (iFGF23) in females, reflected by a similar pattern in osseous Fgf23 mRNA expression. Therefore, the presented method constitutes a valuable tool for the quantification of renal FA crystals which can aid the mechanistic characterization of the FA-AKI model and serves as a means to control for confounding changes in FA crystallization when using the model for investigating early and prophylactic AKI therapeutic interventions.


Therapeutic reactive oxygen generation.
An increase of the intracellular reactive oxygen species (ROS) concentration leads to the development of oxidative stress and, thus, to the damage of cell components. The cause-and-effect relations between these processes have not been fully established yet. The ability of photo excited supramolecular composites containing fullerenes C60 immobilized at nanosilica particles to generate reactive oxygen species (ROS) in cells of two types (rat thymocytes, and transformed cells of ascite Erlich carcinoma, EAC, and leucosis L1210) is demonstrated. The damaging effect of photo excited C60-composites are shown, which appeared to be selective and manifested in transformed cells, but not in thymocytes. It has been shown that after the irradiation of aqueous solutions or cell suspensions in the presence of fullerene C60, the generation of reactive oxygen species is observed. It has been shown that the influence of photo excited fullerene C60 on metabolic processes depends on the composition of C60-containing complex and on the type of the cells. The damaging effects of photo excited fullerene C60-containing composites were demonstrated to be selective. The data presented suggest that the application of fullerene C60-containing composites for the selective activation of ROS-dependent death program in certain types of tumor cells is very promising.


Gut metagenomic and short chain fatty acids signature in hypertension: a cross-sectional study.
Hypertension is an independent and preventable risk factor for the development of cardiovascular diseases, however, little is known about the impact of gut microbiota composition in its development. We carried out comprehensive gut microbiota analysis and targeted metabolomics in a cross-sectional study of 29 non-treated hypertensive (HT) and 32 normotensive (NT) subjects. We determined fecal microbiota composition by 16S rRNA gene sequencing and bacterial functions by metagenomic analysis. The microbial metabolites analysed were short chain fatty acids (SCFA) both in plasma and feces, and trimethylamine N-oxide (TMAO) in plasma. The overall bacterial composition and diversity of bacterial community in the two groups were not significantly different. However, Ruminococcaceae NK4A214, Ruminococcaceae_UCG-010, Christensenellaceae_R-7, Faecalibacterium prausnitzii and Roseburia hominis were found to be significantly enriched in NT group, whereas, Bacteroides coprocola, Bacteroides plebeius and genera of Lachnospiraceae were increased in HT patients. We found a positive correlation between the HT-associated species and systolic and diastolic blood pressure after adjusted for measured confounders. SCFA showed antagonistic results in plasma and feces, detecting in HT subjects significant higher levels in feces and lower levels in plasma, which could indicate a less efficient SCFA absorption. Overall, our results present a disease classifier based on microbiota and bacterial metabolites to discriminate HT individuals from NT controls in a first disease grade prior to drug treatment.


Prevalence of Incidentally Detected Spondylolysis in Children.
To assess the prevalence of incidentally detected lumbar spondylolysis in children. We retrospectively reviewed the data of 809 patients under the age of 11 years (mean age, 7.0 ± 2.7 years; boys:girls = 479:330) who underwent abdominal and pelvic CT between March 2014 and December 2018. We recorded the presence, level, and laterality (unilateral or bilateral) of spondylolysis. Patients were divided into two groups based on the presence of spondylolysis: the spondylolysis (SP) and non-SP groups. In total, 21 cases of spondylolysis were detected in 20 patients (20/809, 2.5%). The mean age of the SP group was higher than that of the non-SP group (7.8 ± 1.8 vs. 6.9 ± 2.7 years, p > 0.05). The prevalence of spondylolysis in boys was higher than that in girls (15/479 [3.1%] vs. 5/330 [1.5%], p > 0.05). The prevalence of spondylolysis in school-age children (6-10 year olds) was higher than that in preschool-age children (0-5 year olds) (17/538 [3.2%] vs. 3/271 [1.1%], p > 0.05). L5 was the most common level of spondylolysis (76.2%); one 8-year-old boy had twolevel spondylolysis. One case of isthmic spondylolisthesis was detected in a 10-year-old boy (1/809, 0.1%). There were 11 unilateral spondylolysis cases (11/21, 52.4%). In our study, the prevalence of spondylolysis in children under the age of 11 was 2.5%. The prevalence was higher in boys than in girls and in school-age than in preschool-age children, despite the lack of any statistically significant differences.


Curricular aspects of the Fogarty bioethics international training programs.
The curriculum design, faculty characteristics, and experience of implementing masters' level international research ethics training programs supported by the Fogarty International Center was investigated. Multiple pedagogical approaches were employed to adapt to the learning needs of the trainees. While no generally agreed set of core competencies exists for advanced research ethics training, more than 75% of the curricula examined included international issues in research ethics, responsible conduct of research, human rights, philosophical foundations of research ethics, and research regulation and ethical review process. Common skills taught included critical thinking, research methodology and statistics, writing, and presentation proficiency. Curricula also addressed the cultural, social, and religious context of the trainees related to research ethics. Programs surveyed noted trainee interest in Western concepts of research ethics and the value of the transnational exchange of ideas. Similar faculty expertise profiles existed in all programs. Approximately 40% of faculty were female. Collaboration between faculty from low- and middleincome countries (LMICs) and high-income countries (HICs) occurred in most programs and at least 50% of HIC faculty had previous LMIC experience. This paper is part of a collection of papers analyzing the Fogarty International Research Ethics Education and Curriculum Development program.


Kuhnian theory-choice and virtue convergence: Facing the base rate fallacy.
Perhaps the strongest argument for scientific realism, the no-miracles-argument, has been said to commit the so-called base rate fallacy. The apparent elusiveness of the base rate of true theories has even been said to undermine the rationality of the entire realism debate. On the basis of the Kuhnian picture of theory choice, I confront this challenge by arguing that a theory is likely to be true if it possesses multiple theoretical virtues and is embraced by numerous scientists-even when the base rate converges to zero.


Single-Occupancy Patient Rooms: A Systematic Review of the Literature Since 2006.
Our review evaluated both the effects of single-occupancy patient rooms (SPRs) on patient outcomes for hospitalized adults and user opinion related to SPRs. In 2006, a requirement for SPRs in hospitals was instituted in the United States. This systematic literature review evaluates research published since that time to evaluate the impact of SPRs. The review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Databases searched included MEDLINE, CINAHL, and Scopus. Supplemental searches were performed. We included studies reporting patient outcomes or user opinion related to SPRs. Appraisal was conducted using a dual appraisal system of evidence levels and methodological quality. Forty-three studies qualified for appraisal. Three were excluded due to methodological quality (no appraisal score). One study was appraised for three individual outcomes (i.e., falls, infections, and user opinion). Eleven studies with low methodological quality scores were not included in the narrative synthesis. Overall, 87% of studies reported advantages associated with SPRs (some a combination of advantages and disadvantages or a combination of advantages and neutral results). Outcomes with the best evidence of benefit include communication, infection control, noise reduction/perceived sleep quality, and preference/perception. SPRs seem to result in more advantages than disadvantages. However, healthcare is a complex adaptive system, and decisions for 100% SPRs should be reviewed alongside related issues, such as necessary workflow modifications, unit configuration and other room layout decisions, patient populations, staffing models, and inherent trade-offs (e.g., the advantages of privacy compared to disadvantage of isolation).


Characterization of the Whole-Genome Sequence of a Beak and Feather Disease Virus Isolate from a Mallee Ringneck Parrot (Barnardius zonarius barnardi).
The complete genome sequence of beak and feather disease virus (BFDV) from a wild Australian Mallee ringneck parrot (Barnardius zonarius barnardi) was characterized. The genome consists of 1,995 nucleotides and encodes two major proteins in opposing directions. This is the first evidence of BFDV infectivity and the first complete genome sequence for this novel host.


Cost-effectiveness of thyroid function tests.
The cost-effectiveness of thyroid function tests (serum thyroxine concentration, triiodothyronine [T3]-resin uptake, free thyroxine index, serum T3, and serum thyrotropin concentration) was assessed in 135 ambulatory patients suspected of hypothyroidism or hyperthyroidism who did not have a history of thyroid disease requiring medication or thyroid surgery within the preceding two years. Of patients with five or more signs and symptoms compatible with thyroid dysfunction, 50.0% had biochemical abnormalities substantiating hypothyroidism or hyperthyroidism, while only 1.5% of patients with fewer than two signs and symptoms had either disease. The cost of thyroid function tests was twice as much per patient evaluated by residents as for those evaluated by faculty physicians. These results suggest that interventions to reduce the number and type of tests in patients without multiple signs and symptoms of thyroid disease could improve the cost-effective use of these tests.


Reversible binding of kynurenine to lens proteins: potential protection by glutathione in young lenses.
Human ultraviolet light (UV) filters, such as kynurenine (Kyn), readily deaminate to reactive unsaturated ketones that covalently modify proteins in older human lenses. The aim of this study was to examine in vitro rates of formation and decomposition of the three major Kyn-amino acid adducts and possible consequences for the lens. The t-Boc-protected Kyn-His, Kyn-Lys, and Kyn-Cys adducts and Kyn-Cys were synthesized from the corresponding amino acids and Kyn. Calf lens proteins were modified with Kyn by incubation at pH 7. Stability and competition studies of the adducts were conducted under physiological conditions. Kyn-amino acids and their decomposition products were quantified using HPLC. At physiological pH, Kyn-Cys adducts formed more rapidly than either Lys or His adducts, but they also decomposed readily. By contrast, His adducts were stable. Cysteine (Cys) residues in beta-crystallins were major sites of modification. The Kyn moiety, initially bound to Cys residues, was found to transfer to other amino acids. Glutathione promoted the breakdown of Kyn-Cys. These data may help explain why proteins in young lenses are not modified by UV filters in situ. The initial phase of the modification of proteins in the human lens by UV filters may be a dynamic process. In lenses, Cys residues of crystallins modify preferentially, but these adducts also decompose to release deaminated Kyn. This can then potentially react with other amino acids. Glutathione, which is present in high concentrations in the lenses of young people, may play a vital role in keeping proteins free from modification by intercepting reactive deaminated kynurenines formed by the spontaneous breakdown of free UV filters, promoting the decomposition of Kyn-Cys residues, and sequestering the unsaturated ketones once they are released from modified proteins.


The pharmacotherapeutic management of postoperative delirium: an expert update.
Postoperative delirium is a common sequela in older adults in the peri-operative period leading to poor outcomes with a complex pathophysiology which has led to a variety of different pharmacologic agents employed in attempts to prevent and treat this syndrome. No pharmacologic agent has been approved to treat this disorder, but this review discusses the pharmacologic strategies which have been tried based on the hypotheses of the causation of the syndrome including neurotransmitter imbalance, inflammation, and oxidative stress. Systematic reviews and meta-analyses of randomized clinical trials (RCTs) were included via search of electronic databases specifically for the terms postoperative delirium and pharmacologic treatments. With this approach, the recurrent topics of analgesia and sedation, antipsychotics, acetylcholinesterase inhibitors (AchE-Is), inflammation, and melatonin were emphasized and provided the outline for this review. Research evidence does not support any particular agent in any of the pharmacologic classes reviewed. However, there is some potential benefit with dexmedetomidine, melatonin, and the monitoring of anesthetic agents all of which need further clinical trials to validate these conclusions. Exploration of ways to improve studies and the application of novel pharmacologic agents may offer future benefit.


Lower Protein-to-Carbohydrate Ratio in Maternal Diet is Associated with Higher Childhood Systolic Blood Pressure up to Age Four Years.
The prenatal environment can influence development of offspring blood pressure (BP), which tracks into adulthood. This prospective longitudinal study investigated whether maternal pregnancy dietary intake is associated with the development of child BP up to age four years. Data are from 129 mother-child dyads enrolled in the Women and Their Children's Health study. Maternal diet was assessed using a validated 74-item food frequency questionnaire at 18 to 24 weeks and 36 to 40 weeks, with a reference period of the previous three months. Child systolic and diastolic BP were measured at 3, 6, 9, 12, 24, 36 and 48 months, using an automated BP monitor. Using mixed-model regression analyses adjusted for childhood growth indices, pregnancy intakes of percentage of energy (E%) polyunsaturated fat (β coefficient 0.73; 95% CI 0.003, 1.45; p = 0.045), E% omega-6 fatty acids (β coefficient 0.89; 95% CI 0.09, 1.69; p = 0.03) and protein-to-carbohydrate (P:C) ratio (β coefficient -14.14; 95% CI -27.68, -0.60; p = 0.04) were associated with child systolic BP trajectory up to 4 years. Child systolic BP was greatest at low proportions of dietary protein (<16% of energy) and high carbohydrate (>40% of energy) intakes. There may be an ideal maternal macronutrient ratio associated with optimal infant BP. Maternal diet, which is potentially modifiable, may play an important role in influencing offspring risk of future hypertension.


Anaplastic oligodendrogliomas: prognostic factors for tumor recurrence and survival.
Anaplastic oligodendrogliomas (AO) are uncommon primary brain tumors whose natural history, prognosis, and optimal management are not yet fully understood. However, they are associated with a better prognosis and response to multimodality therapy based on specific molecular changes. In this multicenter retrospective study, we analyzed the clinical characteristics of patients with AO to identify prognostic factors that influence time to progression (TTP) and survival. A retrospective search of the brain tumor databases of three institutions (the University of Texas M. D. Anderson Cancer Center, the University of California at San Francisco, and the University of Utah) for patients between 1977 and 1995 with histologically confirmed AO identified a cohort of 106 patients that was further analyzed in this study. Initial treatment included surgery alone (n = 12) or surgery followed by one of the following: radiotherapy (RT) alone (n = 49), chemotherapy alone (n = 4), chemotherapy followed by RT (n = 10), RT followed by chemotherapy (n = 20), and others (n = 11). The median age at diagnosis was 43 years, and the median Karnofsky performance score (KPS) was 90. The overall median survival was 7.3 years, and the 5-year survival rate was 62%. Univariate analysis of several clinical variables showed that only age (p < 0.0001) and KPS (p = 0.04) correlated significantly with survival. Fifty patients had disease progression after initial therapy. The median TTP was 48 months. Age at diagnosis was the only variable that correlated significantly with TTP. A trend towards longer survival with a greater extent of resection was evident. The relative efficacy of various treatment modalities could not be definitively determined because of the heterogeneity of the therapies used. Overall, patients with AO have a better prognosis after therapy compared with those who have other malignant gliomas.


[Neurotoxic syndrome in infectious diseases in children].
On the material of 72 children with infectious toxicoses the authors describe the encephalic syndrome as a manifestation of the neurotoxic syndrome. The neurotoxic syndrome was studied clinically and morphologically. A marked syndrome was characterized by a considerable edema of the brain and its stem and not infrequently by the vedging of the cerebellum into the great occipital orifice. Hemispheric focal symptomatology was typically associated with intracranial hemorrhage which was considered as a manifestation of the DIC syndrome. The authors believe that the neurotoxic syndrome in infectious toxicoses should be considered as general cerebral disorders of noninflammatory nature manifested in non-specific morphofunctional and metabolic disturbances.


Post-erysipela panniculitis ossificans of the lower leg treated with pentoxifylline.
We report the case of a female patient who developed a firm, wooden-like, nonpitting edema of the left lower leg after a dermo-hypodermitis. The clinical picture was accompanied by intense pain, strongly impacting the patient's quality of life. A soft-tissue ultrasound demonstrated several millimetric hyperechoic linear lesions whose histopathological examination was conclusive for panniculitis ossificans. A conservative medical management with compression stockings associated with pentoxifylline 800 mg/day was prescribed with improvement of the edema and, in particular, a good pain control. To date, after a 2-year therapy with pentoxifylline, the leg wooden-like edema has substantially improved, despite the persistence of the well-known foci of ossification, and the pain has resolved, conditioning a substantial improvement of the patient's quality of life. No side effect has been observed during the routine follow up. Although there is no unanimous opinion in the literature about the effect of pentoxifylline on bone formation and osteogenic differentiation, pentoxifylline treatment proved to be beneficial in our patient both for the heterotopic ossification process and the pain control. We collected some of the data in literature about pentoxifylline effects and advanced some hypotheses to explain our results. Finally, we suggest that an anti-inflammatory and vasodilators drug such as pentoxifylline could be a possible alternative in heterotopic ossification disorders.


Minimizing a tricky situation in breast irradiation with helical tomotherapy.
We report on a patient with breast cancer undergoing adjuvant intensity-modulated whole breast and lymph node irradiation with static angle tomotherapy (TomoDirect), who experienced a traumatic ipsilateral humeral fracture and was able to continue radiotherapy with helical tomotherapy and daily dosimetric monitoring by means of the Planned Adaptive module.


Thresholds for disease persistence in models for tick-borne infections including non-viraemic transmission, extended feeding and tick aggregation.
Lyme disease and Tick-Borne Encephalitis (TBE) are two emergent tick-borne diseases transmitted by the widely distributed European tick Ixodes ricinus. The life cycle of the vector and the number of hosts involved requires the development of complex models which consider different routes of pathogen transmission including those occurring between ticks that co-feed on the same host. Hence, we consider here a general model for tick-borne infections. We assumed ticks feed on two types of host species, one competent for viraemic transmission of infection, the second incompetent but included a third transmission route through non-viraemic transmission between ticks co-feeding on the same host. Since a blood meal lasts for several days these routes could lead to interesting nonlinearities in transmission rates, which may have important effects.We derive an explicit formula for the threshold for disease persistence in the case of viraemic transmission, also for the case of viraemic and non-viraemic transmission. From this formula, the effect of parameters on the persistence of infection can be determined. When only viraemic transmission occurs, we confirm that, while the density of the competent host has always a positive effect on infection persistence, the density of the incompetent host may have either a positive effect, by amplifying tick population, or a negative ("dilution") effect, by wasting tick bites on an incompetent host. With non-viraemic transmission, the "dilution" effect becomes less relevant. On the other hand, if the nonlinearity due to extended feeding is included, the dilution effect always occurs, but often at unrealistically high host densities. Finally, we incorporated the effects of tick aggregation on the hosts and correlation of tick stages and found that both had an important effect on infection persistence, if non-viraemic transmission occurred.


A Case Report of Neonatal 2019 Coronavirus Disease in China.
In December 2019, the coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China and now has spread in many countries. Pregnant women are a population susceptible to COVID-19 and are more likely to have complications and even progress to severe illness. We report a case of neonatal COVID-19 in China with pharyngeal swabs testing positive by real-time reverse-transcription polymerase chain reaction assay 36 hours after birth. However, whether the case is a vertical transmission from mother to child remains to be confirmed.


Systematic enhancement of polymerization of recombinant sickle hemoglobin mutants: implications for transgenic mouse model for sickle cell anemia.
To provide quantitative information on the sites that promote polymerization of sickle hemoglobin (HbS) after formation of the initial hydrophobic bond involving Val-6(beta) [E6V(beta)] and also to provide hemoglobins with an enhanced polymerization that could be used in a mouse model for sickle cell anemia, we have expressed recombinant double, triple, and quadruple HbS mutants with substitutions on both the alpha- and beta-chains, E6V(beta)/E121R(beta), D75Y(alpha)/E6V(beta)/E121R(beta) and D6A(alpha)/D75Y(alpha)/E6V(beta)/E121R(beta). These recombinant hemoglobins were extensively characterized by high-performance liquid chromatography analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, isoelectric focusing, amino acid analysis, and mass spectroscopy. They retained the functional properties of the Hb tetramer and polymerized in a linear manner at progressively lower Hb concentration as a function of the degree of substitution, suggesting that these remote sites (alphaD6A, alphaD75Y, and betaE121R) on the alpha- and beta-chains exhibit additive, enhanced polymerization properties. The quadruple mutant has a polymerization concentration close to that of the purified SAD hemoglobin from transgenic mouse red blood cells consisting of HbS, Hb Antilles, and Hb D-Punjab. Normal mouse Hb increases the polymerization concentration of each mutant. Thus, the general approach of using recombinant Hbs as described here should prove useful in elucidating the quantitative aspects of the mechanism of HbS polymerization and in identifying the contribution of individual sites to the overall process. The strategy described here demonstrates the feasibility of a systematic approach to achieve future recombinant HbS mutants that could provide a new generation of the transgenic mouse model for sickle cell anemia.


Quality of diet plans for weight loss featured in women's magazines. A cross-sectional descriptive study.
Brazil has the fifth largest population of obese individuals in the world. Women's magazines publish a large number of diet plans, and therefore the objective of this study was to assess the quality of these plans. Cross-sectional descriptive study. We included the Brazilian women's magazines of highest circulation published between January and June 2014 that advertised diets for weight loss on their covers. We extracted the quantities of macro and micronutrients from each of these diet plans and compared these quantities with the World Health Organization nutritional guidelines for adult women. We also checked the total energy quantities of these plans, and any recommendations about water intake and physical activity. We identified 136 potentially eligible magazine issues; 41 were excluded and 95 issues of 6 different magazines were included in the study. We found that 83.1 % of the plans had carbohydrate and fiber levels below the recommendations. On the other hand, the protein and saturated fatty acid levels were above the recommendations in 97.8% and 95.7% of the plans, respectively; 75.7% of the diets had inadequate calcium levels and 70.5% had low iron levels. Only 30 plans specified the total daily quantity of dietary energy and in 53.3% of these, the information was inconsistent with our estimates; 20% of the plans had no recommendations on daily water intake and 37.5% did not give recommendations regarding physical activity practices. The diet plans for weight loss featured in Brazilian women's magazines are of low quality.


Etranacogene dezaparvovec for the treatment of adult patients with severe and moderately severe hemophilia B.
Etranacogene dezaparvovec is the first gene therapy approved for treatment of adults with severe and moderately severe hemophilia B. This review describes the results of the clinical trial program of AMT-060 and etranacogene dezaparvovec, outlining the pharmacokinetic, clinical efficacy and safety data. With the entry of etranacogene dezaparvovec into the market, this review summarizes the treatment landscape in hemophilia B and discusses the current unknowns in the field. Gene therapy appears to be a feasible option for adults with severe and moderately severe hemophilia B. Etranacogene dezaparvovec enables most patients to reach stable factor IX (FIX) levels after a single intravenous infusion, eliminating the need for regular prophylaxis; thus, drastically reducing treatment burden and avoiding variable bleeding risk owing to fluctuating FIX activity levels. Efficacy of etranacogene dezaparvovec has been demonstrated even in the presence of preexisting neutralizing antibodies (up to a titer of 1:678), with a relative low risk of transaminitis and its associated potential loss of transgene expression. However, long-term data are required to ascertain the durability of FIX levels achieved and safety. The cost-effectiveness and adoption of innovative payment models for reimbursement are key in choosing gene therapy over existing treatments.


Model reduction using a posteriori analysis.
Mathematical models in biology and physiology are often represented by large systems of non-linear ordinary differential equations. In many cases, an observed behaviour may be written as a linear functional of the solution of this system of equations. A technique is presented in this study for automatically identifying key terms in the system of equations that are responsible for a given linear functional of the solution. This technique is underpinned by ideas drawn from a posteriori error analysis. This concept has been used in finite element analysis to identify regions of the computational domain and components of the solution where a fine computational mesh should be used to ensure accuracy of the numerical solution. We use this concept to identify regions of the computational domain and components of the solution where accurate representation of the mathematical model is required for accuracy of the functional of interest. The technique presented is demonstrated by application to a model problem, and then to automatically deduce known results from a cell-level cardiac electrophysiology model.


Adsorption of dianionic surfactants based on amino acids at different surfaces studied by QCM-D and SPR.
The adsorption of three dicarboxylic amino acid-based surfactants, disodium N-lauroylaminomalonate, disodium N-lauroylaspartate, and disodium N-lauroylglutamate, has been studied by surface plasmon resonance (SPR) and the quartz crystal microbalance with dissipation monitoring (QCM-D). These surfactants have high cmc values, which means that the unimer concentration is high at the plateau value of adsorption. This gives rise to a considerable "bulk effect", which must be deducted from the observed value in order to obtain the true value of the adsorbed amount. In this article, we show how this can be done for the QCM-D technique. Adsorption is studied on silica, gold, gold hydrophobized by a self-assembled layer of an alkane thiol, and hydroxyapatite. Adsorption on hydroxyapatite differs very much among the three surfactants, with the aspartate derivative giving the strongest and the glutamate giving the weakest adsorption. This difference is explained as the difference in ability of the dicarboxylic amphiphiles to chelate calcium in the crystal lattice.


Stakeholder Feedback of Electronic Medication Adherence Products: Qualitative Analysis.
Medication management among older adults continues to be a challenge, and innovative electronic medication adherence products have been developed to address this need. The aim of this study is to examine user experience with electronic medication adherence products, with particular emphasis on features, usefulness, and preferences. Older adults, caregivers, and health care providers tested the usability of 22 electronic medication adherence products. After testing 5 products, participants were invited to participate in a one-on-one interview to investigate their perceptions and experiences with the features, usefulness, and preference for electronic medication adherence products tested. The interviews were audio recorded, transcribed, and analyzed using exploratory inductive coding to generate themes. The first 13 interviews were independently coded by 2 researchers. The percentage agreement and Cohen kappa after analyzing those interviews were 79% and 0.79, respectively. A single researcher analyzed the remaining interviews. Of the 37 participants, 21 (57%) were older adults, 5 (14%) were caregivers, and 11 (30%) were health care providers. The themes and subthemes generated from the qualitative analysis included product factors (subthemes: simplicity and product features, including availability and usability of alarms, portability, restricted access to medications, and storage capacity) and user factors (subthemes: sentiment, affordability, physical and cognitive capability, and technology literacy and learnability). Electronic medication adherence products have the potential to enable independent medication management in older adults. The choice of a particular product should be made after considering individual preferences for product features, affordability, and the sentiment of the users. Older adults, caregivers, and health care providers prefer electronic medication adherence products that are simple to set up and use, are portable, have easy-to-access medication compartments, are secure, and have adequate storage capacity.


Effect of ascorbate on serum lipids and urate metabolism during exhaustive training.
Physical activity is associated with beneficial changes in serum lipids, but exhaustive exercise has been suggested to increase oxidative stress. To test the effect of ascorbate (vitamin C) on serum lipids and the metabolism of urate, which is the most important intrinsic antioxidant, during exhaustive exercise, we performed a randomized, blinded, placebo-controlled study on eight male well-trained athletes. Subjects were randomly allocated to either a group given 1000 mg of ascorbate daily (n=4) or a placebo group (n=4). Fasting serum lipids and urate concentrations were measured before and after 3 weeks of training. Although serum low-density lipoprotein (LDL)-cholesterol levels decreased and high-density lipoprotein (HDL)-cholesterol levels increased significantly in the ascorbate group after the 3 weeks of training, serum LDL-cholesterol levels increased and HDL-cholesterol levels decreased significantly in the placebo group. Furthermore, serum urate levels were elevated significantly in the placebo group; however, these levels did not change in the ascorbate group. When compared with the placebo group, significantly higher serum HDL-cholesterol and lower serum LDL-cholesterol and urate levels were observed in the ascorbate group after training. In conclusion, our results suggested that ascorbate may contribute to the desirable changes in serum lipids during exhaustive training and suggest the significant association between ascorbate and urate under intense training.


The characterisation of AOP2: a gene associated with the biosynthesis of aliphatic alkenyl glucosinolates in Arabidopsis thaliana.
Glucosinolates, a group of nitrogen and sulfur containing compounds associated with plant-insect interactions, are produced by a number of important Brassicaceae crop species. In Arabidopsis the AOP2 gene plays a role in the secondary modification of aliphatic (methionine-derived) glucosinolates, namely the conversion of methylsulfinylalkyl glucosinolates to form alkenyl glucosinolates, and also influences aliphatic glucosinolate accumulation. This study characterises the primary structural variation in the coding sequences of the AOP2 gene and identifies three different AOP2 alleles based on polymorphisms in exon two. To help determine the regulatory mechanisms mediating AOP2 expression amongst accessions, AOP2 5' regulatory regions were also examined however no major differences were identified. Expression of the AOP2 gene was found to be most abundant in leaf and stem tissue and was also found to be light dependent, with a number of light regulatory elements identified in the promoter region of the gene. In addition, a study was undertaken to demonstrate that the Arabidopsis AOP2 gene product is functional in planta. The over-expression of a functional AOP2 allele was found to successfully convert the precursor methylsulfinyl alkyl glucosinolate into the alkenyl form. The expression of the AOP2 gene has been found to be influenced by light and is most highly expressed in the photosynthetic parts of the Arabidopsis plant. The level of AOP2 transcript decreases rapidly in the absence of light. AOP2 exists as at least three alleles in different Arabidopsis accessions and we have demonstrated that one of these, AOP2-2, is functionally able to convert methylsulfinyl glucosinolates into the alkenyl form. The demonstration of the in planta functionality of the Arabisopsis AOP2 gene is an important step in determining the feasibility of engineering glucosinolate profiles in food plants.


Post-transcriptional regulation of sex determination in Caenorhabditis elegans: widespread expression of the sex-determining gene fem-1 in both sexes.
The fem-1 gene of C. elegans is one of three genes required for all aspects of male development in the nematode. Current models of sex determination propose that the products of the fem genes act in a novel signal-transduction pathway and that their activity is regulated primarily at the post-translational level in somatic tissues. We analyzed the expression of fem-1 to determine whether it revealed any additional levels of regulation. Both XX hermaphrodites and XO males express fem-1 at approximately constant levels throughout development. Somatic tissues in hermaphrodites adopt female fates, but they nonetheless express fem-1 mRNA and FEM-1 protein, suggesting that the regulation of fem-1 activity is post-transcriptional and probably post-translational. A compact promoter directs functional expression of fem-1 transgenes, as assayed by their masculinizing activity in fem-1 mutants. Activity also requires any two or more introns, suggesting that splicing may enhance fem-1 expression. The minimal noncoding sequences required for activity of fem-1 transgenes suffice to direct expression of a fem-1::lacZ reporter gene in all somatic tissues in both sexes. Many fem-1 transgenes, including those that rescue male somatic development in fem-1 mutants, paradoxically feminize the germline. We suggest that they do so by interfering with the germline expression of the endogenous fem-1 gene.


Normal patterns of fetal activity in the third trimester.
The incidence and frequency of fetal respiratory movements (FRM) and fetal trunk movements (FTM) were measured in 21 normal pregnancies between 28 and 39 weeks gestation. Fetal activity was assessed with a real-time ultrasound scanner and all observed movements were punched directly onto computer tape. Recordings were made for one hour in three over a 24 hour period, providing a total of 168 hours for analysis. The overall mean percentage incidence of FRM was 31 per cent at a mean breathing rate of 43 breaths/minute. The mean percentage incidence of FRM during the day (0800-1759 hours) was 37 per cent. The overall mean percentage incidence of FTM was 18 per cent with a mean of 29 moves per 30 minute observation period. The mean percentage incidence of FTM during the day (0800-1759 hours) was 16 per cent. There was a well-defined circadian variation in fetal activity with FRM peaking between 1900 and 2200 hours, and FTM between 2200 and 0100 hours. There was considerable variation in the amount of FRM and FTM recorded from hour to hour. Total fetal activity rarely fell below 10 per cent in any one recording period and this measurement may be a more useful clinical test of fetal well-being than FRM or FTM alone.


Job characteristics and satisfaction of pharmacy technicians.
Perceptions of job characteristics and job satisfaction of central-area technicians and drug-administration technicians at The Ohio State University Hospitals were analyzed. A questionnaire was administered to 79 pharmacy drug-administration technicians; 44 central-area technicians; 10 pharmacy residents, who served as objective raters (5 in the central area and 5 in the decentral area); 13 central-area pharmacists; and 17 decentral-area pharmacists. Perceived job characteristics were measured with the Job Characteristics Inventory; job satisfaction was measured by the Minnesota Job Satisfaction Questionnaire. The two groups of technicians differed significantly in their perceptions of task identity, task significance, and dealing with others. Significantly greater autonomy in technicians' jobs was perceived to exist by pharmacists and raters in both areas than by technicians. Significantly greater task identity was perceived by the central-area technicians than by their raters, and significantly greater task importance was perceived by both groups of technicians than by their pharmacists and raters. Friendship opportunities were perceived to exist to a significantly greater degree by decentral pharmacists and raters than by the drug-administration technicians. In the institution studied, both central-area and drug-administration technicians tended to be dissatisfied with their jobs. Central-area technicians' satisfaction was influenced most by the technicians' relationships with their supervisors and the feelings of accomplishment they gained. Drug-administration technicians were most satisfied if they believed they had opportunities to use their abilities. Efforts to increase job satisfaction among pharmacy technicians should focus on increasing feedback and task identity.


Differential nuclear matrix protein expression in prostate cancers: correlation with pathologic stage.
Nuclear Matrix Proteins (NMP) have been shown to be tissue and cell-type specific. Several unique NMPs have been investigated in various cancerous tissues, including prostate, bladder and kidney, and some are presently utilized as tumor markers. This study was aimed at characterizing the differential NMP expression in the pathologically more aggressive prostate cancers. High resolution two-dimensional gel electrophoresis and silver staining was used to elucidate the NMP distribution of fresh prostate cancer nuclei, obtained from 39 radical prostatectomy specimens, surgically removed from men with clinically localized prostate cancer. Based on the final pathological grading, specimens were grouped according to predicted prognosis: poor--with seminal vesicle (SV) or lymph node (LN) involvement or established capsular penetration (ECP) with gleason score >7; intermediate--organ confined (OC) or focal capsular penetration (FCP) with gleason score 7 or ECP with gleason score 6; and good--with OC or FCP and gleason score <7. A specific charged protein (YL-1) of molecular weight 76 kD and isoelectric range 6.0-6.6 was found to be consistently present in 19 of 19 aggressive cancers. It was present only in 1 of 10 in the group with good prognosis and weakly positive in 9 of 10 in the intermediate group. Within this preliminary study, the expression of YL-1 appears to be related to aggressive prostate cancer, suggesting a potential marker of poor prognosis for clinically localized prostate cancer. Further characterization of the identity and function of this NMP is needed to fully ascertain its clinical potential.


Novel paternity testing by distinguishing parental alleles at a VNTR locus in the differentially methylated region upstream of the human H19 gene.
Conventional PCR-based genotyping is useful for forensic testing but cannot be used to determine parental origins of alleles in DNA specimens. Here we describe a novel method of combined conventional genotyping and PIA typing (parentally imprinted allele typing) at a minisatellite region upstream from the H19 locus. The PIA typing uses two sets of primers and DNA digested with methylation-sensitive Hha I enzyme. The first amplification produces only the methylated fragment of paternal H19 allele, and the second detects polymorphism in the minisatellite. Hence, this distinguishes paternal and maternal alleles by difference in the DNA methylation. Furthermore, the polymorphism in this polymorphic locus was examined using 199 unrelated Japanese and 171 unrelated Germans, their polymorphism information content being 0.671 and 0.705, respectively. Feasibility of this typing is demonstrated for six families, and the usefulness is shown by application to paternity testing.


The effect of supplementing pony diets with yeast on 2. The faecal microbiome.
There is a need to develop feeding strategies to prevent the adverse effect of concentrate feeding in high-performance horses fed energy-dense diets aiming to maintain their health and welfare. The objective of this study is to determine the effect of a VistaEQ product containing 4% live yeast Saccharomyces cerevisiae (S. cerevisiae), with activity 5 × 108 colony-forming unit/g and fed 2 g/pony per day, on faecal microbial populations when supplemented with high-starch and high-fibre diets using Illumina next generation sequencing of the V3-V4 region of the 16S ribosomal RNA gene. The four treatments were allocated to eight mature Welsh section A pony geldings enrolled in a 4-period × 8 animal crossover design. Each 19-day experimental period consisted of an 18-day adaptation phase and a single collection day, followed by a 7-day wash out period. After DNA extraction from faeces and library preparation, α-diversity and linear discriminant analysis effect size were performed using 16S metagenomics pipeline in Quantitative Insights Into Microbial Ecology (QIIME™) and Galaxy/Hutlab. Differences between the groups were considered significant when linear discriminant analysis score was >2 corresponding to P < 0.05. The present study showed that S. cerevisiae used was able to induce positive changes in the equine microbiota when supplemented to a high-fibre diet: it increased relative abundance (RA) of Lachnospiraceae and Dehalobacteriaceae family members associated with a healthy core microbiome. Yeast supplementation also increased the RA of fibrolytic bacteria (Ruminococcus) when fed with a high-fibre diet and reduced the RA of lactate producing bacteria (Streptococcus) when a high-starch diet was fed. In addition, yeast increased the RA of acetic, succinic acid producing bacterial family (Succinivibrionaceae) and butyrate producing bacterial genus (Roseburia) when fed with high-starch and high-fibre diets, respectively. VistaEQ supplementation to equine diets can be potentially used to prevent acidosis and increase fibre digestibility. It may help to meet the energy requirements of performance horses while maintaining gut health.


Clinical use of cimetidine in acute renal failure after resection of abdominal aneurysms.
Gastrointestinal bleeding and infection are leading causes of mortality in patients with acute renal failure. Cimetidine, an H2 blocker, has been reported to be useful in the treatment of duodenal ulceration in patients undergoing hemodialysis. Sequential organ failure is common in patients who have had resection of dissecting abdominal aneurysms. Because acute renal failure is included in the definition of sequential organ failure, we attempted to determine whether cimetidine could significantly reduce gastrointestinal bleeding in our series of patients who had acute renal failure after resection of dissecting abdominal aneurysms.


Personalization algorithm for real-time activity recognition using PDA, wireless motion bands, and binary decision tree.
Inactive and sedentary lifestyle is a major problem in many industrialized countries today. Automatic recognition of type of physical activity can be used to show the user the distribution of his daily activities and to motivate him into more active lifestyle. In this study, an automatic activity-recognition system consisting of wireless motion bands and a PDA is evaluated. The system classifies raw sensor data into activity types online. It uses a decision tree classifier, which has low computational cost and low battery consumption. The classifier parameters can be personalized online by performing a short bout of an activity and by telling the system which activity is being performed. Data were collected with seven volunteers during five everyday activities: lying, sitting/standing, walking, running, and cycling. The online system can detect these activities with overall 86.6% accuracy and with 94.0% accuracy after classifier personalization.


Family practitioner committee records--a neglected resource. 1. An information service for general practitioners based on claims for fees.
Data held by a London family practitioner committee for the purpose of paying general practitioners' capitation and item of service fees were analysed every quarter for one year to provide an information service for general practices in the area. Each practice received a quarterly printout showing the age structure of its patient population, the numbers of new registrations and removals and data about items of service. These were expressed as rates which could be compared with those of the area as a whole, and with the highest and lowest rates found in individual practices. A survey at the end of the year showed that the service was welcomed and found useful by the practices. A fully computerized family practitioner committee could provide a similar service without great difficulty, and could make it more informative by linking items of service to specific age groups; data about prescribing and use of hospital and district services could also be incorporated when the relevant agencies are fully computerized too.


Categories and inheritance of resistance to Nilaparvata lugens (Hemiptera: Delphacidae) in mutants of indica rice 'IR64'.
Varietal mutants can be useful for developing durable resistance, understanding categories of resistance, and identifying candidate genes involved in defense responses. We used mutants of rice 'IR64' to isolate new sources of resistance to the planthopper Nilaparvata lugens (Stål) (Hemiptera: Delphacidae). We compared two mutants that showed a gain and loss of resistance to N. lugens, to determine the categories of resistance to this pest. Under choice tests, female planthoppers avoided settling and laid fewer eggs on the resistant mutant 'D518' than on the susceptible mutant D1131, susceptible check 'TN1', and wild-type IR64, indicating that antixenosis was the resistance category. Similarly, under no-choice conditions, planthoppers laid 29% fewer eggs in D518 than in IR64, but they oviposited more in 'D1131' and TN1. Honeydew excretion was greater on D1131 seedlings but slightly lower on D518 than on IR64. Nymphal survival and adult female weight did not differ among rice cultivars. D518 showed higher tolerance of N. lugens infestations than IR64. Genetic analysis of the F1, F2, and F3 populations derived from D518 x IR64 revealed that resistance in D518 is dominant and controlled by a single gene. Despite the variation in resistance to N. lugens, both mutants and IR64 performed similarly in the field. The mutant D518 is a new source of durable resistance to N. lugens, mainly due to enhanced antixenosis to female hoppers for settling and oviposition.


Soy isoflavones alleviate polycystic ovary syndrome in rats by regulating NF- κB signaling pathway.
Soy isoflavones have been widely used in the treatment of clinical gynecological diseases. The aim of this study was to investigate the therapeutic effect and molecular mechanism of Soy isoflavones on rats with polycystic ovary syndrome (PCOS). Sprague-Dawley rats were orally administered 1 mg/kg letrozole for 21 consecutive days to induce the PCOS rat model. After PCOS induction, Soy isoflavones (100 mg/kg) or metformin (Positive control; 500 mg/kg) was administered continuously for 28 days. Then, H&E staining was used to observe the pathological changes of ovary. The serum hormone levels and the levels of antioxidant and inflammatory cytokines in ovarian tissue were detected. Additionally, the expression of NF-κB signaling pathway protein was detected by Western blot. Our results showed that soy isoflavones treatment significantly reduced the body weight, ovarian volume and weight, and improved estrous cycle in PCOS rats. H&E staining showed that the number of cystic dilated follicles and atretic follicles in ovarian tissue diminished, showing healthy follicles and corpus luteum. In addition, soy isoflavones treatment markedly decreased serum testosterone and luteinizing hormone (LH) levels, as well as oxidative stress levels and inflammation levels, and increased estradiol (E2) and follicle stimulating hormone (FSH) levels. At the same time, Soy isoflavones treatment inhibit the phosphorylation level of NF-κB p65 and increased the IκBα expression in ovarian tissues of PCOS rats. Overall, Soy isoflavones can improve ovarian morphology and hormone disorders in PCOS rats by inhibiting the activity of NF-κB pathway and enhancing anti-inflammatory and antioxidant capacity.


Continental Drift and Speciation of the Cryptococcus neoformans and Cryptococcus gattii Species Complexes.
Genomic analysis has placed the origins of two human-pathogenic fungi, the Cryptococcus gattii species complex and the Cryptococcus neoformans species complex, in South America and Africa, respectively. Molecular clock calculations suggest that the two species separated ~80 to 100 million years ago. This time closely approximates the breakup of the supercontinent Pangea, which gave rise to South America and Africa. On the basis of the geographic distribution of these two species complexes and the coincidence of the evolutionary divergence and Pangea breakup times, we propose that a spatial separation caused by continental drift resulted in the emergence of the C. gattii and C. neoformans species complexes from a Pangean ancestor. We note that, despite the spatial and temporal separation that occurred approximately 100 million years ago, these two species complexes are morphologically similar, share virulence factors, and cause very similar diseases. Continuation of these phenotypic characteristics despite ancient separation suggests the maintenance of similar selection pressures throughout geologic ages.


Metastatic breast cancer induces an osteoblast inflammatory response.
Breast cancer preferentially metastasizes to the skeleton, a hospitable environment that attracts and allows breast cancer cells to thrive. Growth factors released as bone is degraded support tumor cell growth, and establish a cycle favoring continued bone degradation. While the osteoclasts are the direct effectors of bone degradation, we found that osteoblasts also contribute to bone loss. Osteoblasts are more than intermediaries between tumor cells and osteoclasts. We have presented evidence that osteoblasts contribute through loss of function induced by metastatic breast cancer cells. Metastatic breast cancer cells suppress osteoblast differentiation, alter morphology, and increase apoptosis. In this study we show that osteoblasts undergo an inflammatory stress response in the presence of human metastatic breast cancer cells. When conditioned medium from cancer cells was added to human osteoblasts, the osteoblasts were induced to express increased levels of IL-6, IL-8, and MCP-1; cytokines known to attract, differentiate, and activate osteoclasts. Similar findings were seen with murine osteoblasts and primary murine calvarial osteoblasts. Osteoblasts are co-opted into creating a microenvironment that exacerbates bone loss and are prevented from producing matrix proteins for mineralization. This is the first study implicating osteoblast produced IL-6, IL-8 (human; MIP-2 and KC mouse), and MCP-1 as key mediators in the osteoblast response to metastatic breast cancer cells.


Genomic DNA-based hMSH2 and hMLH1 mutation screening in 32 Eastern United States hereditary nonpolyposis colorectal cancer pedigrees.
Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant cancer syndrome characterized by early age of onset colorectal cancer (mean 45 years) as well as endometrial, urinary tract, and upper gastrointestinal adenocarcinomas. The HNPCC phenotype has been shown to segregate with germline mutations in the human homologues of the DNA mismatch repair genes MSH2, MLH1, PMS1, and PMS2. However, the majority of published DNA mismatch repair gene mutation surveys associated with HNPCC kindreds report multiple levels of preselection, including 2p and 3p chromosomal linkage analysis and the evaluation of microsatellite instability of proband colorectal cancers prior to mutation analysis. For this reason, the concise contribution of each of the known DNA mismatch repair genes to the HNPCC phenotype remains unknown. We report the results of a genomic DNA-based analysis of hMSH2 and hMLH1 germline mutations in 32 unrelated Eastern United States HNPCC kindreds. These families were selected for study on the basis of phenotype only. We identified three hMSH2 and six hMLH1 mutations in eight families, for a positive mutation rate of 25%. Two mutations were identified in one of the families. Four of the mutations detected have not been reported in the literature previously. One of the mutation-positive families is African American; the others were of European-American ancestry. These results provide a clarification of the contribution of hMSH2 and hMLH1 to the HNPCC phenotype and suggest that in the majority of Eastern United States HNPCC kindreds selected by phenotype alone, the molecular genetic basis for the disease remains unknown.


Functional analysis of a predicted flavonol synthase gene family in Arabidopsis.
The genome of Arabidopsis (Arabidopsis thaliana) contains five sequences with high similarity to FLAVONOL SYNTHASE1 (AtFLS1), a previously characterized flavonol synthase gene that plays a central role in flavonoid metabolism. This apparent redundancy suggests the possibility that Arabidopsis uses multiple isoforms of FLS with different substrate specificities to mediate the production of the flavonols, quercetin and kaempferol, in a tissue-specific and inducible manner. However, biochemical and genetic analysis of the six AtFLS sequences indicates that, although several of the members are expressed, only AtFLS1 encodes a catalytically competent protein. AtFLS1 also appears to be the only member of this group that influences flavonoid levels and the root gravitropic response in seedlings under nonstressed conditions. This study showed that the other expressed AtFLS sequences have tissue- and cell type-specific promoter activities that overlap with those of AtFLS1 and encode proteins that interact with other flavonoid enzymes in yeast two-hybrid assays. Thus, it is possible that these "pseudogenes" have alternative, noncatalytic functions that have not yet been uncovered.


Immune Checkpoint-Mediated Interactions Between Cancer and Immune Cells in Prostate Adenocarcinoma and Melanoma.
Prostate adenocarcinoma (PCa) and melanoma are paradigmatic examples of tumors that are either poorly or highly sensitive to therapies based on monoclonal antibodies directed against regulatory pathways in T lymphocytes [i.e., immune checkpoint blockade (ICB)]. Yet, approximately 40% of melanoma patients are resistant or acquire resistance to ICB. What characterize the microenvironment of PCa and ICB-resistant melanoma are a scanty cytotoxic T cell infiltrate and a strong immune suppression, respectively. Here, we compare the tumor microenvironment in these two subgroups of cancer patients, focusing on some among the most represented immune checkpoint molecules: cytotoxic T lymphocyte-associated antigen-4, programmed death-1, lymphocyte activation gene-3, and T cell immunoglobulin and mucin-domain containing-3. We also report on several examples of crosstalk between cancer and immune cells that are mediated by inhibitory immune checkpoints and identify promising strategies aimed at overcoming ICB resistance both in PCa and melanoma.