Personality and health literacy among community-dwelling older adults living in Japan.
Previous studies have demonstrated that health behaviours may be one of the major mechanisms underlying the relationship between personality and health outcomes. Such health behaviours may be established by consciousness toward one's health that include health literacy. Thus, this study aimed to explore the relationship between health literacy and its correlates, including personality, among community-dwelling older adults. This was a cross-sectional study with 683 older individuals (aged 60-84 years; 326 men and 357 women). A questionnaire was used to assess health literacy, personality, socioeconomic status, health status, and lifestyles. Health literacy was measured using the Communicative and Critical Health Literacy Scale, which is a self-report questionnaire comprising five items assessing degrees of health literacy. The Big Five personality traits were measured using the Japanese version of the Ten-Item Personality Inventory. Other variables were measured as factors associated with health literacy, including age, gender, education, subjective economic status, social isolation, chronic diseases, functional capacity, smoking and drinking. Multiple regression analysis showed that education (β = 0.10), subjective economic status (β = -0.09), social isolation (β = -0.08), functional dependence (β = -0.22), neuroticism, (β = -0.08), extraversion (β = 0.10), openness (β = 0.17), and conscientiousness (β = 0.09) were independently and significantly associated with health literacy (coefficient of determination = 0.28). This study found significant and independent associations of personality, socioeconomic status, and health status with health literacy. These results may help facilitate the development of efficient strategies to improve health status by promoting health literacy in community-dwelling older adults.


Unilateral pseudogynecomastia: an occupational hazard in manual metal-pressing factories?
Five cases of unilateral occupation-related pseudogynecomastia are presented. All the patients in these cases worked in the same metal-pressing factory. One patient with grade 4 unilateral gynecomastia in the right breast presented to the authors' outpatient department asking persistently for surgery. He also reported that all his male colleagues working in the same business (a total of 5) had different degrees of unilateral gynecomastia. Their line of work involved holding a long round rod under the axilla and then pressing the distal end of it firmly against a spinning metal plate. The patient underwent a superior pedicle breast reduction, with 1,800 ml of tissue removed from his right breast. Unfortunately, the patient experienced partial nipple loss. However, he was satisfied with the final result, and good symmetry was achieved. All five patients who worked in the same metal-pressing factory presented with unilateral gynecomastia and were examined in our department. Their average age was 51.4 years. All the patients had normal hormonal and biochemical status, and the results of screening for toxins and heavy metal exposure were negative. All the patients were heavy smokers. At examination, none of the patients had nipple discharge or retraction, skin changes, galactorrhea, or lymphadenopathy. Examination showed one patient with grade 4, three patients had grade 2, and one patient with grade 1 unilateral gynecomastia. The authors believe that gynecomastia may be considered an occupational risk in analogous metal-pressing factories because all the workers in this factory presented with some degree of unilateral gynecomastia. However, they emphasize that this may simply be an observational phenomenon without a true cause and effect relationship.


Absence of ecotropic or recombinant murine leukaemia virus in preleukaemic and leukaemic X-irradiated NZB mice.
NZB mice X-irradiated with a single dose of 630 R when they were 1-month old developed a high incidence of histologically defined lymphocytic leukaemia 8--25 weeks later. We have screened for murine leukaemia viruses (MuLV) in the lymphoid tissues of 8 of these leukaemic mice, and in 8 "preleukaemic", apparently healthy NZBs killed 1 month post irradiation. Xenotropic, but not ecotropic or recombinant MuLV, was detected by in vitro co-cultivation of bone marrow, spleen and thymus with selectively permissive cell lines, followed by the immunofluorescence test for MuLV gs antigen, and the XC test. Our results are not consistent, therefore, with the concept that the factor causing the leukaemias was an oncogenic virus activated by X-irradiation.


Massive retrograde acute type B aortic dissection in a postpartum woman with a family history of Marfan syndrome.
Acute aortic dissection is rare but potentially catastrophic complication of pregnancy. Aortic root enlargement, congenital bicuspid aortic valve disease, and Marfan syndrome have been identified as critical risk factors for peripartum aortic dissection. Most of the aortic dissections reported to date involve the ascending aorta and occur before delivery, but only a few cases of postpartum aortic dissection have been described. In this report, we discuss the management of a multigravid parturient with an extensive family history of Marfan syndrome who developed a massive retrograde type B aortic dissection 7 days after a normal spontaneous vaginal delivery.


Quantitative analysis of synaptic input to gonadotropin-releasing hormone neurons in normal mice and hpg mice with preoptic area grafts.
Mutant hypogonadal (hpg) mice with a truncated gene for the precursor to gonadotropin-releasing hormone (GnRH) show certain aspects of recovery of reproductive function after receiving grafts of normal preoptic area into the third ventricle. We have previously shown that GnRH neurons from within the grafts can innervate the appropriate neural-hemal target in the host. To determine if in turn these exogenously derived neurons receive a synaptic input comparable to the GnRH neurons in the normal animal we have now carried out a quantitative ultrastructural analysis to compare the synaptic input to GnRH neurons in the normal preoptic area and in the grafts. In almost all cases GnRH cells or dendrites in normal brains and within the grafts received a synaptic input. In normal animals, input to GnRH dendritic profiles was significantly greater (P less than 0.001) than to the somatic plasma membrane and this trend was also observed within the grafts though the difference was not statistically significant. In addition, no statistically significant difference was found between the input to GnRH structures within the grafts and in normal preoptic area. However, a substantial variability in input among grafted animals was evident which was not observed in normal animals. The sources of variability within the grafts are discussed and we suggest that the deficiencies and differences that exist in regulation of gonadotropin secretion among grafted hpg animals may be reflected in aberrant synaptic input.


Universal newborn screening for congenital cytomegalovirus infection: feasibility and relevance in a French type-III maternity cohort.
Evaluation of relevance and feasibility of universal newborn congenital cytomegalovirus infection (cCMVI) screening in saliva. Retrospective, population-based cohort study. Clamart, France, 2016-2020. All neonates born consecutively in our level III maternity unit. CMV PCR in saliva for all neonates at birth, and, if positive, CMV PCR in urine to confirm or exclude cCMVI. Prospective and retrospective characterisation of maternal infections. ROC curve analysis to assess saliva PCR performances. Acceptability of screening among staff members evaluated by a survey. Number of cCMVI neonates; number of expected and unexpected cCMVI. Among 15 341 tested neonates, 63 had cCMVI (birth prevalence of 0.4%, 95% CI 0.3-0.5). In 50% of cases, maternal infection was a non-primary infection (NPI) during pregnancy. cCMVI was expected or suspected (maternal primary infection [PI], antenatal or neonatal signs) in 24/63 neonates (38%), and unexpected in 39/63 neonates (62%). The best CMV saliva threshold to predict cCMVI was 356 (2.55 log) copies/ml [95% CI 2.52 log-3.18 log], with an area under the ROC curve of 0.97. Over 90% of the 72 surveyed staff members reported that the screening was easy and quick. No parent refused the screening. Universal screening for cCMVI with CMV PCR on saliva samples is feasible and highly acceptable to parents and healthcare providers. Over half (62%) of the cases had no prenatal/neonatal signs of cCMVI or a maternal history of CMV infection during pregnancy and would probably not have been diagnosed without universal screening. In 62% of congenital cytomegalovirus infection cases, only universal neonatal screening in saliva can detect infection.


Exposure to road traffic noise and behavioral problems in Chinese schoolchildren: A cross-sectional study.
Transportation noise is second only to air pollution as an environmental contributor to adverse health outcomes in Western countries. However, no studies investigated the association between road traffic noise and behavioral problems among schoolchildren in China. To investigate the association between exposure to road traffic noise at home and behavioral problems in Chinese schoolchildren. From January to June 2017, we screened 3236 children aged 7-13 years in Guangzhou (Guangdong, China) from the first investigation of an ongoing school-based cohort study with complete information on behavioral problems and residential geolocation. Residential road traffic noise exposure levels were assessed using a validated modeling method in different periods of the day, including daytime (Lday), nighttime (Lnight), and weighted 24-hr (Ldn). The annual mean concentration of nitrogen dioxide was also modeled in our study. Behavioral problems were assessed by the parent-rated Strengths and Difficulties Questionnaire (SDQ). Generalized linear mixed models were utilized to estimate the associations between road traffic noise and behavioral problems. In the main adjusted model, a 10-dB increase in Ldn was associated with 0.33 (95% CI: 0.08, 0.59), 0.08 (95% CI: -0.01, 0.17), and 0.09 (95% CI: 0.01, 0.16) increases in three subscales score for total difficulties score, emotional problems, and conduct problems, respectively. The same increase in Ldn was also associated with the abnormal total difficulties score (OR = 1.25, 95%CI: 1.01, 1.55), emotional problems (OR = 1.19, 95%CI: 0.98, 1.44), and conduct problems (OR = 1.28, 95%CI:1.02, 1.63). Externalising behavior appears more susceptible to traffic noise than internalising behavior. NO2 had a small impact on the associations between Ldn and behavioral problems. Our estimates were generally robust in several sensitivity analyses. Residential road traffic noise exposure might be related to increased behavioral problems in Chinese schoolchildren, such as emotional symptoms and conduct problems.


Visualization of maturation of the corpus callosum during childhood and adolescence using T2 relaxometry.
Previous studies have shown that maturation of the white matter in terms of its relative signal intensity changes on MRI is almost complete at 2-3 years of age. We hypothesized that quantitative analysis may show maturation of the white matter during childhood and adolescence. In the present study we performed multi-echo T2 relaxometry in 33 healthy subjects (girls, 15; boys, 18) aged 3-15 years. T2 relaxation times of the genu and splenium were measured. In healthy subjects, the T2 relaxation times were significantly correlated with age in both girls (r=0.611, p=.016) and boys (r=0.721, p=.001) in the splenium, but not in the genu (p>.05). To further confirm genu-to-splenium signal intensity ratio changes, a total of 389 brain MRIs were retrospectively selected from the patients who had normal results (189 girls/women, 200 boys/men; age range, 3-20 years). The genu-to-splenium signal intensity ratio was obtained from the T2-weighted images. In patients with normal MRI, the genu-to-splenium signal intensity ratio was significantly decreased with age (p<.001) by 16 years. The T2 relaxation times gradually increase in the splenium during childhood and adolescence, suggestive of maturation.


MCRS1 associates with cytoplasmic dynein and mediates pericentrosomal material recruitment.
MCRS1 is involved in multiple cellular activities, including mitotic spindle assembly, mTOR signaling and tumorigenesis. Although MCRS1 has been reported to bind to the dynein regulator NDE1, a functional interaction between MCRS1 and cytoplasmic dynein remains unaddressed. Here, we demonstrate that MCRS1 is required for dynein-dependent cargo transport to the centrosome and also plays a role in primary cilium formation. MCRS1 localized to centriolar satellites. Knockdown of MCRS1 resulted in a dispersion of centriolar satellites whose establishment depends on cytoplasmic dynein. By contrast, NDE1 was not necessary for the proper distribution of centriolar satellites, indicating a functional distinction between MCRS1 and NDE1. Unlike NDE1, MCRS1 played a positive role for the initiation of ciliogenesis, possibly through its interaction with TTBK2. Zebrafish with homozygous mcrs1 mutants exhibited a reduction in the size of the brain and the eye due to excessive apoptosis. In addition, mcrs1 mutants failed to develop distinct layers in the retina, and showed a defect in melatonin-induced aggregation of melanosomes in melanophores. These phenotypes are reminiscent of zebrafish dynein mutants. Reduced ciliogenesis was also apparent in the olfactory placode of mcrs1 mutants. Collectively, our findings identify MCRS1 as a dynein-interacting protein critical for centriolar satellite formation and ciliogenesis.


Inhaled pan-phosphodiesterase inhibitors ameliorate ovalbumin-induced airway inflammation and remodeling in murine model of allergic asthma.
Asthma is a heterogeneous, chronic respiratory disease characterized by airway inflammation and remodeling. Phosphodiesterase (PDE) inhibitors represent one of the intensively studied groups of potential anti-asthmatic agents due to their affecting both airway inflammation and remodeling. However, the effect of inhaled pan-PDE inhibitors on allergen induced asthma has not been reported to date. In this study we investigated the impact of two, representative strong pan-PDE inhibitors from the group of 7,8-disubstituted derivatives of 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione: compound 38 and 145, on airway inflammation and remodeling in murine model of ovalbumin (OVA)-challenged allergic asthma. Female Balb/c mice were sensitized and challenged with OVA, 38 and 145 were administrated by inhalation, before each OVA challenge. The inhaled pan-PDE inhibitors markedly reduced the OVA-induced airway inflammatory cell infiltration, eosinophil recruitment, Th2 cytokine level in bronchoalveolar lavage fluid, as well as both, total and OVA-specific IgE levels in plasma. In addition, inhaled 38 and 145 decreased many typical features of airway remodeling, including goblet cell metaplasia, mucus hypersecretion, collagen overproduction and deposition, as well as Tgfb1, VEGF, and α-SMA expression in airways of allergen challenged mice. We also demonstrated that both 38 and 145 alleviate airway inflammation and remodelling by inhibition of the TGF-β/Smad signaling pathway activated in OVA-challenged mice. Taken together, these results suggest that the investigated pan-PDE inhibitors administered by inhalation are dual acting agents targeting both airway inflammation and remodeling in OVA-challenged allergic asthma and may represent promising, anti-asthmatic drug candidates.


Cervical cancer screening service utilization and associated factors among HIV positive women attending adult ART clinic in public health facilities, Hawassa town, Ethiopia: a cross-sectional study.
In Ethiopia, cervical cancer is a public health concern, as it is the second most cause of cancer deaths among reproductive age women and it affects the country's most vulnerable groups like; rural, poor, and HIV-positive women. Despite the strong evidence that cervical cancer screening results in decreased mortality from this disease, its utilization remains low. An institution-based cross-sectional study was conducted from March 2 to April 1/2019 to assess the level and factors affecting utilization of cervical cancer screening among HIV positive women in Hawassa town. Quantitative data collection methods were used. Data were gathered using a structured and pretested questionnaire. Epi-Info version 7 and SPSS version 23 were used for data entry and analysis respectively. Statistically significant association of variables was determined based on Adjusted Odds ratio with its 95% confidence interval and p-value of ≤0.05. Of the 342 women interviewed, 40.1% (95% CI: 35.00, 45.33%) of them were screened. Having a post primary education (AOR = 5.1, 95% CI: 1.8, 14.5), less than 500 cell/mm3 CD4 count (AOR = 2.7, 95% CI: 1.2, 5.9); duration since HIV diagnosis (AOR = 4.2, 95% CI: 2.1, 8.5), partner support (AOR = 4.7, 95% CI: 2.3, 9.4), having knowledge about risk factors (AOR = 2.9 (95% CI: 1.2, 6.9) and having favorable attitude towards cervical cancer and its screening (AOR = 3.7 (95% CI: 1.8, 7.5) were associated with cervical cancer screening utilization. The study revealed utilization of cervical cancer screening service was low among HIV positive women. Educational status, duration of HIV diagnosis, partner support, knowledge status about risk factor, CD4 count and attitude towards cervical cancer and its screening were associated with cervical cancer screening utilization. Health care workers need to provide intensive counseling services for all ART care attendants to increase utilization.


Antimicrobial properties of allium species.
The antimicrobial activity of Allium species has long been recognized, with allicin, other thiosulfinates, and their transformation products having antimicrobial activity. Alliums are inhibitory against all tested microorganisms such as bacteria, fungi, viruses, and parasites. Alliums inhibit multi-drug-resistant microorganisms and often work synergistically with common antimicrobials. Allium-derived antimicrobial compounds inhibit microorganisms by reacting with the sulfhydryl (SH) groups of cellular proteins. It used to be thought that allicin reacts only with cysteine and not with non-SH amino acids, but evidence has accumulated that allicin and other thiosulfinates also react with non-SH amino acids.


Computational enrichment of physicochemical data for the development of a ζ-potential read-across predictive model with Isalos Analytics Platform.
The physicochemical characterisation data from a library of 69 engineered nanomaterials (ENMs) has been exploited in silico following enrichment with a set of molecular descriptors that can be easily acquired or calculated using atomic periodicity and other fundamental atomic parameters. Based on the extended set of twenty descriptors, a robust and validated nanoinformatics model has been proposed to predict the ENM ζ-potential. The five critical parameters selected as the most significant for the model development included the ENM size and coating as well as three molecular descriptors, metal ionic radius (rion), the sum of metal electronegativity divided by the number of oxygen atoms present in a particular metal oxide (Σχ/nO) and the absolute electronegativity (χabs), each of which is thoroughly discussed to interpret their influence on ζ-potential values. The model was developed using the Isalos Analytics Platform and is available to the community as a web service through the Horizon 2020 (H2020) NanoCommons Transnational Access services and the H2020 NanoSoveIT Integrated Approach to Testing and Assessment (IATA).


Analysis of red blood cell use in elective surgeries over 12 years in Korea.
Red blood cell (RBC) transfusion is a lifesaving process for patients with perioperative bleeding, but transfusion can cause adverse events. Effective utilization and management of blood products as a limited resource is essential when considering cost-efficiency and patient safety. We analyzed the number of RBC units used during the hospitalization of patients who had undergone surgical procedures from 2002 to 2013 using National Health Insurance Service-National Sample Cohort data, which include a total of 487,238 cases for 206 selected operations. RBC units were used in 39,637 (8.1%) cases. A total of 60,815 RBC units were transfused with a mean of 0.13 units per patient overall and a mean of 1.53 units per case receiving RBC transfusion. In addition, 56.7% of the RBC units were transfused for females, and 60.1% of RBC units were transfused into patients aged 60 or older. RBC units were used most often in orthopedic surgeries (33.8%), followed by general surgeries (12.0%) and vascular surgeries (11.8%). The number of operations performed in the cohort increased from 27,690 in 2002 to 49,473 in 2013, and the mean number of RBC units used per operation also increased from 0.08 units in 2002 to 0.15 units in 2013. Continuous management for blood preparation and transfusion is needed for efficient utilization of blood. Periodic investigation on the use of blood products through nationwide studies could suggest data applicable to blood product preparation for various elective surgical operations.


Feline parathyroid hormone: validation of hormonal assays and dynamics of secretion.
Validated assays for quantification of intact parathyroid hormone (I-PTH) are no longer available. Moreover, the third-generation PTH assay that only detects the whole PTH molecule (W-PTH) has never been tested in cats. The work presented here is aimed to validate a commercially available assay for measurement of I-PTH and W-PTH in cats and to study the dynamics of PTH secretion in healthy cats. Our results show that both assays are reliable for the measurement of feline PTH. In healthy adult cats W-PTH concentration (15.1 ± 1.6 pg/mL) was greater (P < 0.001) than I-PTH concentration (9.1 ± 0.7 pg/mL). The dynamics of PTH secretion in response to changes in extracellular calcium (Ca(2+)) were investigated in 13 cats by studying PTH-Ca(2+) curves. PTH-Ca(2+) curves were obtained by intravenous infusion of disodium ethylenediaminetetraacetic acid and CaCl(2). PTH was measured using both I-PTH and W-PTH assays. During hypocalcemia a sigmoidal curve that was similar when measured with I-PTH or W-PTH was obtained. The maximal PTH concentration in response to hypocalcemia was greater with W-PTH (179.6 ± 41.9 pg/mL) than with I-PTH (67.6 ± 10.5 pg/mL; P = 0.01). However, hypercalcemia resulted in an equivalent PTH inhibition, with both assays yielding PTH concentrations as follows: W-PTH = 4.0 ± 0.4 pg/mL and I-PTH = 4.9 ± 0.3 pg/mL (NS). Parameters of the feline PTH-Ca(2+) curve are similar to what has been previously reported in dogs.


Genotoxic effect of Bothrops snake venoms and isolated toxins on human lymphocyte DNA.
In the present study, micronucleus with cytokinesis blocking and comet assays were used to evaluate the genotoxic potential of Bothrops jararacussu, Bothrops atrox, Bothrops moojeni, Bothrops alternatus (Rhinocerophis alternatus) and Bothrops brazili snake venoms, and also of some isolated toxins (MjTX-I, BthTX-I and II myotoxins, BjussuMP-II metalloprotease, and BatxLAAO l-amino acid oxidase) on human lymphocytes. Significant DNA damages were observed, indicating genotoxic potential after exposure of the lymphocytes to the toxins BthTX-I, II and BatxLAAO compared to untreated and Cisplatin-treated controls, which were able to induce greater formation of micronuclei. B. brazili, B. jararacussu and B. atrox crude venoms also presented genotoxic potential, and the latter two induced DNA breakage 5 times more often than in normal environmental conditions (control without treatment). B. jararacussu venom and its isolated toxins, as well as an LAAO from B. atrox, were able to cause lymphocyte DNA breakage in the comet test with more than 85% damage levels. The DNA damage evaluation allows a widening of the toxic-pharmacological characterization of snake venoms and their toxins and also contributes to the understanding of the mechanisms of action of these molecules in several human pathologies.


High-molecular weight dextran in human infertility surgery.
The use of intraperitoneal 32% high-molecular weight dextran 70 (Hyskon, Pharmacia Inc.) has been reported to reduce the incidence of surgical adhesions in several species. The present study was undertaken to determine the effect of 32% dextran 70 in human females who underwent major abdominal infertility operations. Adhesions were quantitated by means of standardized objective criteria in 44 women in a prospective, randomized, double-blind study, and reevaluated at second-look laparoscopy approximately 6 weeks later. The mean change in the adhesion score for all patients in the 32% dextran 70 group (n = 23) was -2.57 units (i.e., clinically "improved") versus +2.41 units (i.e., clinically "worsened") in the control group (n = 21), p = 0.016. For the subgroup of patients who underwent lysis of adhesions, the 32% dextran 70 group (n = 17) improved significantly, whereas the control group (n = 12) tended not to improve with careful technique alone (-4.2 units versus +0.3 unit, p less than 0.05). These data indicate that 32% dextran 70 not only significantly reduces the formation of adhesions overall in human infertility operations, but also is highly effective in reducing the reformation of adhesions after lysis.


Exercise echocardiography in the evaluation of severity of functional mitral regurgitation in patients with heart failure.
We present two cases with ischemic cardiomyopathy and similar functional mitral regurgitation (fMR) at rest, who represented different outcomes following mitral valve repair. In case 1, fMR was enhanced during exercise echocardiography, and his symptoms were improved following the repair and coronary artery bypass graft (CABG). In case 2, fMR did not change during exercise, and the improvement of his symptoms was small following the operation. Exercise echocardiography evidenced variability of the dynamic changes in fMR in patients with ischemic cardiomyopathy. The variability may be related to the outcome of the mitral valve repair.


Marginal fit of Zirconia posterior fixed partial dentures.
The aim of this study was to investigate the marginal fit of posterior fixed partial dentures (FPDs) made with 2 computer-aided design/computer-assisted manufacture systems--Procera Bridge Zirconia (Nobel Biocare) and Lava AllCeramic System (3M ESPE)--and to analyze the differences between abutments and between buccal and lingual surfaces. Twenty standardized specimens were prepared to receive posterior 3-unit FPDs. FPDs were fabricated according to the manufacturer's instructions. A scanning microscope (JSM-6400, JEOL) with a magnification of 1,000x was used for measurements. Three-way analysis of variance showed significant differences (P < .001) in marginal adaptation between the ceramic groups. Procera Bridge Zirconia showed the lowest discrepancies (26 +/- 19 microm). No significant differences were observed between abutments and surfaces, and no significant interaction was observed among the ceramic system, abutments, and surfaces. The accuracy of fit achieved by both zirconia systems was within the range of clinical acceptability, with Procera Bridge Zirconia showing the best marginal fit.


Attenuation of hyperalgesia in a rat model of neuropathic pain after intrathecal pre- or post-treatment with a neurokinin-1 antagonist.
Although many studies have demonstrated a role for substance P in pain, there have been conflicting reports implicating the involvement of substance P in neuropathic pain models. In this study, the non-peptide neurokinin-1 (NK-1) receptor antagonist, L-732,138 was chronically administered by intrathecal (i.t.) injection to rats with mono-neuropathy produced by sciatic nerve constriction. Rats exhibited tactile allodynia and cold hyperalgesia over a 16-day testing period. L-732,138 (5-200 nmol) administered i.t. prior to and for 3 consecutive days post-surgery attenuated the mechanical allodynia and cold hyperalgesia on days 4 and 8 post-surgery. The effects of i.t. L-732,138 were also determined in rats with established nerve injury-induced neuropathy. The NK-1 receptor antagonist was injected for 4 consecutive days starting on day 8 post-sciatic nerve injury. Administration of L-732,138 (5-200 nmol) i.t. produced both anti-allodynic and anti-hyperalgesic effects on day 12, but the effect was not permanent, as nociceptive thresholds were similar to controls by day 16. These results demonstrate that substance P is involved both in the induction and the maintenance of neuropathic pain and provides justification for the development and administration of substance P antagonists for the management of clinical neuropathic pain.


Development of a safe and effective pediatric dosing regimen for sotalol based on population pharmacokinetics and pharmacodynamics in children with supraventricular tachycardia.
The objective of this study was to develop age-specific dosage guidelines for sotalol in children with supraventricular tachycardia (SVT) based on a population pharmacokinetic covariate analysis, clinical trial simulations, and pharmacodynamics. A rapid onset of an effective and safe antiarrhythmic sotalol therapy, especially for infants and neonates, is frequently delayed because of age-dependent interpatient variability in pharmacokinetics and pharmacodynamics. Pediatric patients with SVT (mean age 3.51 years [range 0.03 to 17 years]) were analyzed after oral sotalol doses of 1.0 to 9.9 mg/kg/day using population pharmacokinetic analysis and clinical trial simulation (n = 76), pharmacokinetic/pharmacodynamic modeling for QT interval prolongation (n = 32), and for the concentration-antiarrhythmic-response relationship (n = 15). Inter-individual differences in oral clearance and volume of distribution could largely be attributed to size and weight differences, with an additional age effect on clearance in children younger than one year. Neonates showed a higher sensitivity toward QTc interval prolongation compared with older patients. In a subgroup of 15 patients, one-half of the patients converted into sinus rhythm at sotalol trough levels of 0.4 mug/ml and more than 95% at 1.0 mug/ml. Dosing recommendations derived for different age groups based on these findings were starting dose and target dose of 2 and 4 mg/kg/day for neonates, 3 and 6 mg/kg/day for infants and children <6 years, and 2 and 4 mg/kg/day for children >6 years. This study provides an example for rational drug dosage in children that copes with interpatient variability and can be easily switched to an individually guided therapy based on effective sotalol trough levels.


Ectopic hyperparathyroidism due to an auto-transplanted parathyroid gland.
Hyperparathyroidism due to the autografted parathyroid gland should be suspected in patients who undergone parathyroid auto-transplantation.


Insulin-like growth factor-1 in articular cartilage repair for osteoarthritis treatment.
Articular cartilage repair is a critical issue in osteoarthritis (OA) treatment. The insulin-like growth factor (IGF) signaling pathway has been implicated in articular cartilage repair. IGF-1 is a member of a family of growth factors that are structurally closely related to pro-insulin and can promote chondrocyte proliferation, enhance matrix production, and inhibit chondrocyte apoptosis. Here, we reviewed the role of IGF-1 in cartilage anabolism and catabolism. Moreover, we discussed the potential role of IGF-1 in OA treatment. Of note, we summarized the recent progress on IGF delivery systems. Optimization of IGF delivery systems will facilitate treatment application in cartilage repair and improve OA treatment efficacy.


Bilineal inheritance of PKD1 abnormalities mimicking autosomal recessive polycystic disease.
Dominant polycystic kidney disease is common and usually presents clinically in adulthood. Recessive polycystic kidney disease is much less common and frequently presents antenatally or in the neonatal period with severe renal involvement. These are usually thought of as clinically distinct entities but diagnostic confusion is not infrequent. We describe an infant with antenatally diagnosed massive renal enlargement and oligohydramnios with no resolvable cysts on ultrasound scanning. He underwent bilateral nephrectomy because of respiratory compromise and poor renal function but died subsequently of overwhelming sepsis. Genetic analysis revealed that he had bilineal inheritance of abnormalities of PKD1 and no demonstrable abnormalities of PKD2 or PKHD1. Biallelic inheritance of abnormalities of PKD1 may causextremely severe disease resembling autosomal recessive polycystic kidney disease (ARPKD) which can result indiagnostic confusion. Accurate diagnosis is essential forgenetic counseling [corrected].


Dual regulation by G proteins of agonist-dependent phosphorylation of muscarinic acetylcholine receptors.
Muscarinic acetylcholine receptors purified from porcine atrium were phosphorylated, depending on the presence of agonists, by a protein kinase partially purified from porcine brain, which had similar properties to the beta-adrenergic receptor kinase. GTP-binding regulatory proteins (Go) had dual effects on the phosphorylation of muscarinic receptors, i.e. stimulation at lower concentrations and inhibition at higher concentrations. The stimulatory effect was reproduced with the beta gamma subunit of Go and the inhibitory effect with the combination of the alpha and beta gamma subunits.


Chordomas: A review with emphasis on their pathophysiology, pathology, molecular biology, and genetics.
Chordomas are uncommon, bone, axial, or (rarely) extra-axial tumors that are malignant and frequently recur but less commonly metastasize. They usually affect adults, with a very small proportion being pediatric tumors. For children, such tumors present a different biology, since they are more common as scull rather than sacral tumors, with aggressive histological features, including a loss of SMARCB1/INI1 and a dismal prognosis. Histologically, chordomas, believed to derive from notochordal tissue, characteristically show physaliphorous cells in a myxoid or chondroid matrix. Dedifferentiated and poorly differentiated forms can be observed. Moreover, a grading scale for chordomas has been proposed. Cytokeratin, EMA, S100, and brachyury are expressed by most chordomas. These are chemo-resistant tumors, for which surgical resection and/or radiotherapy are the treatments of choice. In this review, the histological, immunohistochemical, molecular, and clinical data of chordomas are discussed.


Fatty acid balance regulates α-synuclein pathology.
A recent study by Tripathi et al. used a protein engineering approach to demonstrate that cellular stress caused by familial α-synuclein mutations can be alleviated by altering the monounsaturated fatty acid equilibrium in neuronal cells. This work supports the notion that metabolic perturbation of lipids may be involved in the pathogenesis of Parkinson's disease.


Improved synthesis of seven aromatic Baylis-Hillman adducts (BHA): evaluation against Artemia salina Leach. and Leishmania chagasi.
We described a very efficient procedure to prepare seven aromatic compounds (1-7), a new class of antileishmanial substances, through Baylis-Hillman reaction (BHR). With one, all the Baylis-Hillman adducts were prepared in quantitative yields by reaction of the corresponding aromatic aldehydes in acrylonitrile at 0 degrees C in only 10-40min reaction time. We present our results about the toxicities of these compounds evaluated on the microcrustaceous Artemia salina Leach. and against promastigote Leishmania chagasi. All substances evaluated in this work have showed high bioactivity. The 3-hydroxy-2-methylene-3-(4-bromopheny)propanenitrile (4) (LC(50)=30.9 microg/mL on A. salina; IC(50)=25.2 microM on L. chagasi) was the most active compound evaluated on A. salina Leach. and on promastigote L. chagasi. The 2-[hydroxy(pyridin-4-yl)methyl]acrylonitrile (7) (LC(50)=30.9 microg/mL on A. salina Leach.; IC(50)=4.8 microg/mL on L. chagasi) was also a very active substance evaluated in this work on promastigote L. chagasi.


Subjective poverty, mental health, and mortality among Chinese older people: a prospective cohort study from 2008 to 2018.
The associations of duration of subjective poverty and poverty status with mortality among older people remains inconclusive, and the underlying mechanisms of mental health on them are rarely discussed in population-based epidemiological studies. We used the data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) (2008-2018). The Cox regression model was used to estimate hazard ratio (HR) and 95% confidence intervals (CIs) for mortality. Mediation analysis was applied to assess the effect of mental health. When compared with participants without subjective poverty, those who reported subjective poverty at one time point (2008 or 2011) or two time points (2008 and 2011) had a higher risk of death, with multivariable-adjusted HR (95% CIs) of 1.08 (1.00-1.16) and 1.22 (1.06-1.39), respectively. For poverty status, the multivariable-adjusted HR (95% CIs) of mortality were 0.81 (0.66-0.98) for "just objective poverty" and 0.78 (0.62-0.98) for "neither subjective nor objective poverty" compared with participants who reported "just subjective poverty", while there was no statistically significant association between "poverty subjectively and objectively" and mortality (HR = 0.88, 95% CI 0.72-1.07). Besides, we found that the proportion mediated by mental health was 26.6%, and age was a significant effect modifier. Subjective poverty may be associated with a higher risk of death among Chinese older people. This study showed that promoting mental health alone may not substantially reduce socioeconomic inequality in health. Further explorations of measures to tackle the social determinants of health are still needed.


Effect of L-carnitine on ketone bodies, redox state and free amino acids in the liver of hyperammonemic mice.
L-Carnitine stimulates urea synthesis in mice given a LD100 of ammonium acetate. Unprotected mice show decreased levels of hepatic ketone bodies and lowered NADH/NAD+ ratio in both cytosol and mitochondria. L-Carnitine enhances markedly the production of beta-hydroxybutyrate and raises the NADH/NAD+ ratio in mitochondria. The alterations induced by ammonium acetate in the free amino acid pool are prevented by L-carnitine. The results shown in this paper indicate that L-carnitine stimulates fatty acid oxidation as well as flux through the Krebs cycle in hyperammonemic mice and that these effects may be responsible for the increase in urea synthesis in these animals.


Supramacromolecular organization of gold nanocrystals capped with amphiphilic hyperbranched polyethyleneimine.
The supramolecular structural aspects of hetero-assemblies constituted of gold nanoparticles capped with amphiphilic unimolecular micelles were studied using synchrotron-based small angle X-ray scattering (SAXS). Experimental results revealed that straightforward transfer of citrate-capped Au nanoparticles from an aqueous environment to a toluenic solution of amphiphilic hyperbranched polymers results in the spontaneous integration of the nanocrystals into the extended hydrophilic domains of self-assembled supramolecular structures. In this way, we were able to self-organize metal-polymer nanoarchitectures in solution displaying interesting thermoactive functions, i.e.: hybrid assemblies exhibiting negative thermal expansion coefficients. We consider that this strategy has potentiality to realize self-organized supramolecular hetero-assemblies as it provides an alternative methodology to spontaneously integrate nanoscale building blocks into preformed supramolecular objects.


Active electrolocation of polarized objects by a pulse-discharging electric fish, Gnathonemus petersii.
Weakly electric fish react to resistance and capacitance of objects that locally amplify and distort their self-generated Electric Organ Discharge (EOD) received by their skin receptors. The successive-layer structure of tissues gives certain biological materials a kind of electrical anisotropy. A polarized object, for instance, will conduct current differently in one versus the other direction. This diode-like electric anisotropy should make a significant difference to a Mormyrid who emits a directional, biphasic EOD and whose receptors are sensitive to EOD amplitude and distortion changes. The ability of Gnathonemus petersii (Mormyridae) to discriminate polarity was investigated on a virtual object by manipulating changes in a circuit comprised of diodes combined in various ways. The "novelty response," an increase in the discharge rate in response to perceived changes, was used to assess the fish's sensitivity. Indeed, G. petersii detects polarized objects and discriminates between polarity directions. However, the diode-like anisotropy entails a voltage threshold. Because voltage decreases with distance, and the EOD comprises opposite phases of different amplitudes, the active spaces of detection and discrimination are different and depend on the object orientation. Electric polarity thus extends the "palette" of dielectric properties used by this fish to evaluate object quality, direction, and distance.


CT tube current for attenuation map in a combined PET/CT system: obese patient simulated phantom study.
The CT portion of PET/CT provides attenuation correction of the PET emission scan. This study was performed to evaluate how much the CT tube current can be lowered while still providing attenuation maps on PET images. Two body phantoms (outside diameters of 300 and 500 mm) were used to investigate, and PET/CT acquisitions were performed with an Aquiduo PCA-7000B (Toshiba Medical Systems, Otawara, Japan). The CT scan was performed with the following parameters (120 kVp; 0.5-s rotation; 10, 20, 40, 80, 160, 200, 320, 460 mA). After the CT scan, PET images for (18)F-FDG (5.3 kBq/mL) were obtained for 4 min/bed position. The linear attenuation coefficients for (18)F-FDG in 300- and 500-mm phantoms, pixel values and SD of CT images, radioactivity concentration values and hot- and cold-sphere contrast on PET images in the 500-mm phantom were evaluated. In the 300-mm phantom, all eight tube currents gave average linear attenuation coefficients of approximately 0.095 cm(-1). In contrast, the average linear attenuation coefficients of the 500-mm phantom at 10, 20, and 40 mA were significantly decreased (0.081, 0.087, and 0.092 cm(-1), respectively; p < 0.05) as compared to 0.096 cm(-1) of the other tube currents. Further, CT pixel values decreased 10 and 20 mA. Thus, the background radioactivity concentration values at 10 and 20 mA were substantially underestimated to be 57 and 80%, respectively (p < 0.05); the hot-sphere contrast values at 10 and 20 mA were 0.26 and 0.29; the cold-sphere contrast values at 10, 20, and 40 mA were -0.33, -0.16, and 0.08. Although the linear attenuation coefficients in the 300-mm phantom remained the same with varying CT tube currents, the 500-mm phantom yielded significant differences in the range 10-40 mA. Therefore, the CT tube currents for attenuation correction should be adjusted over 40 mA in obese patients.


Trends of tuberculosis meningitis and associated mortality in Texas, 2010-2017, a large population-based analysis.
As the most severe form of tuberculosis (TB), TB meningitis (TBM) is still associated with high mortality even in developed countries. In certain areas of the United States (U.S.), more than 50% of the TBM patients die with TB or have neurological sequelae and complications despite the availability of advanced health care. This population-based analysis aimed to determine the risk factors and trends associated with TBM morbidity and mortality using state-wide surveillance data. De-identified surveillance data of all confirmed TB patients from the state of Texas between 01/2010 and 12/2017 reported to the National TB Surveillance System was analyzed. Spatial distribution of TBM cases was presented by Stata's Geographic Information Systems mapping. Univariate and multiple generalized linear modeling were used to identify risk factors associated with meningitis morbidity and mortality. Non-parametric testing was used to analyze morbidity and mortality trends. Among 10,103 TB patients reported in Texas between 2010 and 2017, 192 (1.9%) had TBM. During this 8-year period, the TBM proportion fluctuated between 1.5% and 2.7% with peaks in 2011 (2.7%) and 2016 (2.1%) and an overall non-significant trend (z = -1.32, p = 0.19). TBM had a higher mortality at diagnosis (8.9%), during treatment (14.1%) and overall (22.9%) compared to non-TBM (1.9%, 5.3%, and 7.2%, respectively, p<0.001). While mortality during treatment was unchanged over time in non-TBM patients (z = 0.5, p = 0.62), it consistently increased in TBM patients after 2013 (z = 3.09, p = 0.002). TBM patients had nearly five times the risk for overall death in multivariate analysis [aRR 4.91 (95% CI 3.71, 6.51), p<0.001]. TBM patients were younger, and more likely to present with miliary TB or HIV (+). Age ≥45 years, resident of a long-term care facility, IDU, diabetes, chronic kidney disease, abnormal chest radiography, positive AFB smear or culture and HIV (+) were independently associated with higher mortality. TBM remains challenging in Texas with significantly high mortality. Risk factors determined by multivariate modeling will inform health professionals and lay a foundation for the development of more effective strategies for TBM prevention and management.


Determination of ribonucleoside triphosphates and deoxyribonucleoside triphosphates in Novikoff hepatoma cells by high-performance liquid chromatography.
A rapid, specific, and sensitive method has been developed for the determination of ribonucleoside and deoxyribonucleoside triphosphates in Novikoff hepatoma cells. A simple three-step procedure was used. Extraction of the biological material with 5% cold trichloroacetic acid (TCA); elimination of TCA by ethilic ether wash and concentration of the sample by lyophilization; and separation of CTP, dCTP, ATP, dATP, UTP, dTTP, GTP, dGTP and their quantitation by anionic-exchange high-performance liquid chromatography under isocratic conditions. All the compounds were identified by comparing their retention times with those of pure compounds, by cochromatography with single pure ribonucleoside triphosphates (NTPs) or deoxyribonucleoside triphosphates (dNTPs), and by comparing the 280 nm:254 nm spectral ratios of the peaks with those of known NTP and dNTP standards. The specific activity of all the above mentioned nucleotides also was determined in Novikoff hepatoma cells labeled with [32P]orthophosphate.


Using Ga-67 scintigraphy in prostatic abscess.
The use of Ga-67 scintigraphy (Ga) in prostate inflammatory diseases may be restricted by the difficulty in distinguishing between the accumulation of Ga-67-citrate (Ga-citrate) in the lesion and feces. The diagnosis of prostatic abscess has been mainly made by other radiologic methods without scintigraphic studies and no finding of Ga has been reported. This patient demonstrated that coordinating the findings of Ga-citrate accumulation can be helpful in making a prompt diagnosis of a possibly fatal prostatic abscess, especially in those patients with poorly defined clinical symptoms and high risk factors.


Postherpetic neuralgia: the importance of preventing this intractable end-stage disorder.
An argument is presented here for postherpetic neuralgia as an intractable end-stage disorder for many patients. The exciting possibility of prevention of this disorder by early, aggressive treatment exists; however, the extent to which therapy can be effective is unknown. Early, aggressive treatment of the pain of herpes zoster is, nevertheless, urged, and the options for treatment are discussed. These options include antiviral therapy within the first 72 h, if possible, from the onset of rash or radicular pain and the use of analgesics, including opioids (if necessary), nerve blocks, and early antidepressant therapy. In addition, the extent to which vaccination of older adults will prevent postherpetic neuralgia is unknown but appears to hold promise.


The learning process in biofeedback: is it feed-forward or feedback?
Twenty participants responded to inquiries about strategies used, and thoughts during, each of three electromyograph biofeedback sessions. The purpose of the study was to learn more about what individuals report doing during biofeedback and, specifically, to determine if individuals construct a response using feedback to sense subtle differences in muscle tension (feedback processes), or select a response from an existing repertoire using feedback primarily for confirmation (feed-forward processes). Protocol analyses found considerable support for feed-forward processes and little support for feedback processes. Such results are important because early reliance on feed-forward processes may result in limited control and limited transfer.


Decreased prostatic secretory function in canine benign prostatic hyperplasia is not due to decreased levels of muscarinic cholinergic receptors.
The ejaculatory volume and the prostatic secretory capacity (ml. ejaculate per gm. prostate wet weight) were determined for a group of dogs with normal and hyperplastic prostates. The ejaculatory volume and prostatic secretory capacity in dogs with BPH were decreased by 70 per cent and 80 per cent respectively, compared to dogs with normal prostates. Radioligand receptor binding using [3H]N-methylscopolamine, a muscarinic cholinergic antagonist, was performed on a similar group of dogs with normal and hyperplastic prostates. The mean equilibrium dissociation constant for the binding of [3H]N-methylscopolamine to homogenates obtained from normal and hyperplastic prostates was 0.21 nM. and 0.19 nM. respectively, demonstrating that the affinity of the receptor binding sites was not altered by the development of BPH. The tissue density of the muscarinic cholinergic receptors (fmol. per mg. prostate wet weight) and the cellular density of these receptors (fmol. per mg. DNA) were not significantly different in normal and hyperplastic prostates. These data indicate that the dramatic reduction in prostatic secretory capacity associated with canine BPH is not related to changes in the muscarinic cholinergic receptor binding capacity.


Enzyme-based high-performance liquid chromatography supports as probes of enzyme activity and inhibition: the immobilization of trypsin and alpha-chymotrypsin on an immobilized artificial membrane high-performance liquid chromatography support.
Immobilized artificial membrane (IAM) HPLC supports have been used to immobilize the enzymes alpha-chymotrypsin and trypsin. The enzymes were trapped in hydrophobic cavities on the support and were not covalently attached to the IAM surface. The resulting IAM-enzyme supports retained the hydrolytic activity of the immobilized enzymes: the IAM-trypsin support catalyzed the hydrolysis of N alpha-benzoyl-DL-arginine-p-nitroanilide (BAPNA), and the IAM-alpha-chymotrypsin support (IAM-ACHT) catalyzed the hydrolysis of a number of substrates, including tryptophan methyl ester. The activities of both supports were decreased by known enzyme inhibitors and the activity of the IAM-ACHT was affected by changes in pH and temperature. When a substrate was chromatographed on an IAM-ACHT HPLC, the hydrolytic activity of the immobilized enzyme could be determined from the resulting substrate/product ratios. These data were obtained either directly from the IAM-ACHT chromatogram or from the chromatogram produced by a coupled column system. The results of this study indicate that IAM-immobilized alpha-chymotrypsin and trypsin can be used as chromatographic probes for the qualitative determination of enzyme/substrate and enzyme/inhibitor interactions.


HLA-E: Presentation of a Broader Peptide Repertoire Impacts the Cellular Immune Response-Implications on HSCT Outcome.
The HLA-E locus encodes a nonclassical class Ib molecule that serves many immune functions from inhibiting NK cells to activating CTLs. Structural analysis of HLA-E/NKG2A complexes visualized fine-tuning of protective immune responses through AA interactions between HLA-E, the bound peptide, and NKG2A/CD94. A loss of cellular protection through abrogation of the HLA-E/NKG2A engagement is dependent on the HLA-E bound peptide. The role of HLA-E in posttransplant outcomes is not well understood but might be attributed to its peptide repertoire. To investigate the self-peptide repertoire of HLA-E (∗) 01:01 in the absence of protective HLA class I signal peptides, we utilized soluble HLA technology in class I negative LCL cells in order to characterize HLA-E (∗) 01:01-bound ligands by mass-spectrometry. To understand the immunological impact of these analyzed ligands on NK cell reactivity, we performed cellular assays. Synthesized peptides were loaded onto recombinant T2 cells expressing HLA-E (∗) 01:01 molecules and applied in cytotoxicity assays using the leukemia derived NK cell line (NKL) as effector. HLA-E in complex with the self-peptides demonstrated a shift towards cytotoxicity and a loss of cell protection. Our data highlights the fact that the HLA-E-peptidome is not as restricted as previously thought and support the suggestion of a posttransplant role for HLA-E.


Dual associations between hand preference and visual asymmetry in perception of faces.
A hand preference questionnaire and a face-matching task were administered to 83 female college students. Although the first and the second factor scores of hand preference correlated with a leftward perceptual bias on the face-matching task, the first factor correlated positively and the second negatively. Consistently, all of hand-preference items loading on the first factor correlated positively, and most items loading on the second factor negatively. Further, the bias for right-hand use of each hand-preference item correlated with the leftward perceptual bias. Hand preference may have independent dual associations with perceptual asymmetries, and factors of hand preference and bias for the right hand use may distinguish between the associations.


TNM classification for lung cancer.
The international tumor-node-metastasis (TNM) staging system is the "international language" in cancer diagnosis and treatment. Six revisions of the TNM staging system for lung cancer have been repeated over the past 35 years after the beginning of UICC-TNM classification in 1968. The 1997 revision for lung cancer has undergone an extensive correction for many deficiencies of the old staging system. As a result, the new staging system appears to be a great improvement over previous editions. There are, however, still some controversies and proposals for revising, even when the new staging system is applied in daily diagnoses and treatment for lung cancer. In the present paper, these problems are presented and discussed. Main subjects for discussions are as follows: (1). Since the 2nd revision, T1 and T2 lesions were divided at the border of a 3 cm tumor size. Is 3 cm diameter an appropriate cut-off point for dividing T1 and T2 lesions? (2). Is it valid to subdivide T1 and T2 lesions into each A and B? (3). Is it appropriate to down-stage all of T3N0M0 to stage IIB, because there exists heterogeneity of T3? (4). Definitions of T4 lesion. (5). Controversies in three kinds of lymph node maps. Especially, where there is a boundary between N1 and N2 station in each map? (6) How to classify separate tumor nodules (STN) in the same lobe, and in the non-primary lobe. (7) Controversy exists concerning the validity of present stage grouping, because there are no significant difference of survivals between IB and IIA, IIA and IIB in most reports and also between T3N0M0 and T3N1M0 in some reports.


Common permutation methods in animal social network analysis do not control for non-independence.
The non-independence of social network data is a cause for concern among behavioural ecologists conducting social network analysis. This has led to the adoption of several permutation-based methods for testing common hypotheses. One of the most common types of analysis is nodal regression, where the relationships between node-level network metrics and nodal covariates are analysed using a permutation technique known as node-label permutations. We show that, contrary to accepted wisdom, node-label permutations do not automatically account for the non-independences assumed to exist in network data, because regression-based permutation tests still assume exchangeability of residuals. The same assumption also applies to the quadratic assignment procedure (QAP), a permutation-based method often used for conducting dyadic regression. We highlight that node-label permutations produce the same p-values as equivalent parametric regression models, but that in the presence of non-independence, parametric regression models can also produce accurate effect size estimates. We also note that QAP only controls for a specific type of non-independence between edges that are connected to the same nodes, and that appropriate parametric regression models are also able to account for this type of non-independence. Based on this, we suggest that standard parametric models could be used in the place of permutation-based methods. Moving away from permutation-based methods could have several benefits, including reducing over-reliance on p-values, generating more reliable effect size estimates, and facilitating the adoption of causal inference methods and alternative types of statistical analysis. The online version contains supplementary material available at 10.1007/s00265-022-03254-x.


A review of evidence of health benefit from artificial neural networks in medical intervention.
The purpose of this review is to assess the evidence of healthcare benefits involving the application of artificial neural networks to the clinical functions of diagnosis, prognosis and survival analysis, in the medical domains of oncology, critical care and cardiovascular medicine. The primary source of publications is PUBMED listings under Randomised Controlled Trials and Clinical Trials. The rĵle of neural networks is introduced within the context of advances in medical decision support arising from parallel developments in statistics and artificial intelligence. This is followed by a survey of published Randomised Controlled Trials and Clinical Trials, leading to recommendations for good practice in the design and evaluation of neural networks for use in medical intervention.


Direct detection of circulating free radicals in the rat using electron spin resonance spectrometry.
We developed a new technique for directly observing in vivo free radical formation in the circulating blood of living rats using electron spin resonance (ESR) spectrometry without any labeling or trapping agents. It was found that a doublet peak spectrum was obtained following ferric citrate and ascorbic acid injection. The signals were confirmed in different ways to be due to ascorbic acid radicals. These results provide evidence to support the involvement of free radical intermediates in iron-ascorbic acid reactions, and further confirm the suggested mechanisms of both the adverse and protective effects of ascorbic acid in biological systems. Furthermore, this method of direct observation is a new application of ESR spectrometry to living animals.


Continuous in vivo activation and transient hyporesponsiveness to TcR/CD3 triggering of human gut lamina propria lymphocytes.
Three-color immunofluorescence and flow cytometric analysis showed that the vast majority of normal human T-lamina propria lymphocytes (LPL) expressed high levels of the early activation antigen CD69, together with CD45R0, irrespective of their CD4, CD8 or gamma/delta-TcR phenotype, indicating that they are continuously stimulated in vivo. Importantly, measurement of cytoplasmic [Ca2+]i showed that T-LPL had significantly higher basal [Ca2+]i levels, compared to autologous peripheral blood lymphocytes (PBL). Both cytoplasmic [Ca2+]i elevation and inositol (1,4,5) trisphosphate generation following CD3 cross-linking by monoclonal antibodies in vitro were essentially abolished in T-LPL, as compared to autologous T-PBL. Moreover, freshly isolated LPL could be induced to proliferate by CD2- or CD28-mediated signals, but not by CD3-mediated signals. Surprisingly however, impairment in TcR/CD3-mediated early signaling and proliferation in T-LPL could be completely reversed by 24 h incubation of the cells at 37 degrees C in culture medium, a condition which allowed basal intracellular [Ca2+]i to return to levels comparable to peripheral T cells. Our data suggest that selective hyporesponsiveness to TcR/CD3-mediated signaling may represent a transient event during continuous in vivo activation of mucosal lymphocytes.


A pediatric case of anaplastic astrocytoma with a gliomatosis cerebri; the growth pattern and changes in serum VEGF-121 levels after bevacizumab treatment.
Gliomatosis cerebri (GC) is a rare diffusely infiltrating glial neoplasm that carries a poor prognosis. Because tumors are undetectable in most patients at early-stage of the onset, a useful diagnostic method is expected. We compared serum vascular endothelial growth factor (VEGF)-121 levels in patients with GC or glioblastoma and controls. VEGF-121 levels were significantly higher in one patient with GC and patients with glioblastoma than in controls. VEGF-121 levels decreased in a patient with GC after bevacizumab-based therapy. Thus, VEGF-121 may be useful for diagnosing GC, its disease-monitoring and understanding its etiology.


A new method for simultaneous determination of bile acids in human bile without hydrolysis.
A method for simultaneous determination of major bile acids in human bile without prior hydrolysis is described. The unconjugated, glycine- and taurine-conjugated bile acids are separated into groups by ion-exchange chromatography on a newly developed lipophilic gel, piperidinohydroxypropyl Sephadex LH-20 (PHP-LH-20). Subsequently, resolution of each group into cholate, ursodeoxycholate, chenodeoxycholate, deoxycholate and lithocholate is attained into two stages by high-performance liquid chromatography on a micron-Bondapak C18 column. First, 0.3% ammonium carbonate/acetonitrile (9 : 4, v/v) is used for separation of the latter three as a mobile phase. Cholate and ursodeoxycholate are separated in 0.3% ammonium carbonate/acetonitrile (11 : 4, v/v). The present method is applicable to quantitation of free and conjugated bile acids in human bile with satisfactory accuracy and precision.


Being invigorated in parenthood: parents' experiences of being supported by professionals when having a disabled child.
The purpose of the study was to know the meaning of parents' experiences of being supported by professionals when having a child with disability. Data were obtained through unstructured interviews with 16 parents within 10 families and analyzed by a phenomenological-hermeneutic approach. Parents narrated experiences of being supported and not being supported, and the findings are presented as contrasting meanings. Being supported by professionals means gaining confidence as a parent and having the child seen as valuable. This is interpreted as being invigorated in parenthood, where sharing the mutual task and goal, which is the child's best, with professionals is a crucial aspect. The meaning of experiences of lack of support illuminates the consequences for the entire family's well-being and the struggle parents experience to gain confidence as parents and recognition of the child as valuable.


Abundance, composition and sources of beach litter on the Cape Verdean island São Vicente.
This study represents the first assessment of beach litter on an island of the west African archipelagic state of Cape Verde. On five beaches of São Vicente, litter was collected along transects and classified according to the OSPAR protocol, with the Matrix Scoring Technique used to allocate it to four sources. Beach litter on São Vicente is highly variable in both amount and composition, while land- and sea-based sources contribute to litter loads to different extents depending on the use and geographic orientation of the beach. Four of the five surveyed beaches exhibited litter loads that were similar to pollution levels previously described for other oceanic islands, while a north-eastern-facing beach featured exceptionally high loads. This was presumably because it receives litter from distant sources due to its exposure to a major ocean surface current.


Liensinine, a alkaloid from lotus plumule, mitigates lipopolysaccharide-induced sepsis-associated encephalopathy through modulation of nuclear factor erythroid 2-related factor-mediated inflammatory biomarkers and mitochondria apoptosis.
The present study aims to investigate the role of liensinine in life-threatened sepsis-associated encephalopathy (SAE) mice and the underlying mechanism. Here, seventy-two mice were divided into six groups, including the control group, SAE group, liensinine-treated group, and three doses of liensinine-treated SAE groups. Lipopolysaccharide triggered cerebrum necrosis and disrupted the integrity and permeability of blood-brain barrier (BBB). While liensinine restored cerebrum structure and improved BBB integrity with upregulated tight junction proteins, decreased evans blue leakage and fibrinogen expression with decreased matrix metalloproteinases 2/9 in serum, thereby reducing BBB permeability. Moreover, lipopolysaccharide triggered cerebrum oxidative stress and inflammation, whereas liensinine enhanced antioxidant enzymes activities and weakened malondialdehyde through nuclear factor erythroid 2-related factor. Meanwhile, liensinine inhibited inflammation by activating inducible nitric oxide synthase. Tunel staining combined with transmission electron microscope indicated that lipopolysaccharide induced cerebrum apoptosis, whereas liensinine blocked apoptosis through decreasing B-cell lymphoma-2 associated X (Bax) expression and cytochrome C (Cyto-c) release, increasing B-cell lymphoma-2 (Bcl-2) expression, blocking apoptosome assembly, inhibiting caspase-3 activation, thereby suppressing intrinsic mitochondria apoptosis. Recovering of inflammatory homeostasis and inhibition of mitochondria apoptosis by liensinine ultimately restored cognitive function in SAE mice. Altogether, liensinine attenuated lipopolysaccharide-induced SAE via modulation of Nrf2-mediated inflammatory biomarkers and mitochondria apoptosis.


Construct validation of the Greek SF-36 Health Survey.
To test the construct validity of the Short-Form 36 (SF-36) Health Survey, using structural equation modeling (SEM). Cross-sectional survey was conducted. Data were collected from 1007 participants in a stratified sample of adult general population, interviewed face-to-face by trained interviewers. SEM analyses supported the superiority of the eight first-order factor model of health. Higher-order analyses suggested that a model with three correlated second-order factors (physical health, general well-being, general mental health) and one third-order factor (health) provided a satisfactory fit to the data. These results confirm the multidimensional structure of the SF-36 and underscore the feasibility of multinational comparisons of health status using this instrument. They also support the use of eight subscale scores in parallel with three second-order summary scores rather than one overall score.


Structural insights into genetic variants of Na(+)/glucose cotransporter SGLT1 causing glucose-galactose malabsorption: vSGLT as a model structure.
Current advances in structural biology provide valuable insights into structure-function relationship of membrane transporters by solving crystal structures of bacterial homologs of human transporters. Therefore, scientists consider bacterial transporters as useful structural models for designing of drugs targeted in human diseases. The functional homology between Vibrio parahaemolyticus Na(+)/galactose transporter (vSGLT) and Na(+)/glucose cotransporter SGLT1 has been well established a decade ago. Now the crystal structure of vSGLT is considered quite valuable in explaining not only the cotransport mechanisms, but it also acts as a representative protein in understanding the protein stability and amino acid interactions within the core structure. We investigated the molecular mechanisms of genetic variations in SGLT1 that cause glucose-galactose malabsorption (GGM) defects using the crystal structure of vSGLT as a model sugar transporter. Our in silico mutagenesis and modeling analysis suggest that the GGM genetic variations lead to conformational changes either by structure destabilization or by formation of unnecessary interaction within the core structure of SGLT1 thereby explaining the genetic defects in Na(+) dependent sugar translocation across the cell membrane.


Lymphadenectomy During Pulmonary Metastasectomy.
Pulmonary metastasectomy continues to be an effective approach to prolong survival in appropriately selected patients. The incidence of lymphatic spread is more common than previously recognized, with an estimate of 20% to 25% across multiple tumor types. The presence of metastatically involved lymph nodes adversely affects survival. What remains unclear is whether N1 vs N2, or the number of stations involved affects survival differently. The role of surgery for pulmonary metastasectomy in the patient with nodal metastases will likely expand with ongoing improvements in targeted and immunotherapies.


Production of Phenolic Compounds by Aspergillus S-4 in Sake Cake Medium and Identification of Terrein.
High performance liquid chromatography (HPLC) analysis of the culture filtrate of an isolated mold, Aspergillus terreus S-4, showed a larger peak of a terrein-like substance than those of gallic acid and protocatechuic acid. The chemical structure of this substance was investigated and identified as terrein, 4,5-dihydroxy-3-propenyl- 2-cyclopenten-1-one. We also examined some culture conditions for the production of terrein using a sake cake medium for strain S-4.


Posttraumatic Stress Disorder, Depression, Anxiety, and Persistence of Methotrexate and TNF Inhibitors in Patients with Rheumatoid Arthritis.
To examine the relationship of posttraumatic stress disorder (PTSD) with earlier treatment discontinuation and medication adherence in US veterans with rheumatoid arthritis (RA). Veterans Affairs (VA) administrative data (2005-2014) were used to define unique dispensing episodes of methotrexate (MTX) and tumor necrosis factor inhibitors (TNFi) for veterans with RA. Diagnosis codes were used to categorize patients into mutually exclusive groups: PTSD (with/without depression/anxiety), depression/anxiety without PTSD, and neither psychiatric diagnosis. Multivariable Cox proportional hazards models were used to evaluate associations between psychiatric diagnoses and time to disease-modifying antirheumatic drug discontinuation (lapse in refill >90 days). Multivariable logistic regression was used to examine associations of diagnoses with medication nonadherence (proportion of days covered <0.8). There were 15 081 dispensing episodes of MTX and 8412 dispensing episodes of TNFi. PTSD was independently associated with a greater likelihood of earlier discontinuation of both MTX (hazard ratio [HR] 1.15 [1.10-1.21]) and TNFi (HR 1.20 [1.13-1.28]). Depression/anxiety had a comparable risk of discontinuation for both MTX (HR 1.14 [1.10-1.19]) and TNFi (HR 1.16 [1.10-1.22]). Depression/anxiety, but not PTSD, was associated with higher odds of MTX (odds ratio [OR] 1.12 [1.03-1.22]) and TNFi (OR 1.14 [1.02-1.27]) nonadherence. Veterans with RA and comorbid PTSD, depression, or anxiety had poor persistence of MTX and TNFi therapies. These results suggest that earlier discontinuation and low adherence to therapy among patients with RA with these psychiatric comorbidities may contribute to worse disease outcomes. Mechanisms by which these comorbidities contribute to lower adherence deserve further investigation and may lead to targeted interventions to improve disease outcomes.


A Technical Note of Improvement of the Elnady Technique for Tissue Preservation in Veterinary Anatomy.
Teaching veterinary anatomy has been subjected to changes and restrictions that have promoted the development of new techniques for preserving organs and cadavers. The Elnady technique is a recent method for the conservation of tissues. Specimens produced with this technique are realistic, durable, soft, and flexible, but an undesirable feature is the discoloration of tissues. In the present study, we describe modifications of the Elnady technique for organ and tissue preservation. Specimens were prepared on the theoretical basis of the Elnady technique, but at low temperatures and with longer durations for the fixation, dehydration, glycerin impregnation and curing processes. Furthermore, the tissues were pigmented with a red vegetable pigment before dehydration or in the glycerin impregnation process. The results show high-quality specimens with minimal shrinkage and natural color aspects. The modified Elnady technique is adequate for producing specimens of better contrast for education purposes.


Leu-enkephalin induced alteration of enzymes and sialic acid levels in vivo.
The influence in mice of 10 mg/kg Leu-enkephalin (LENK) on the activity of hepatic enzymes in serum and liver and sialic acid concentration in serum and spleen is described. The activity of acid and alkaline phosphatase and lactate dehydrogenase in serum was significantly enhanced 6 h after a single (10 mg/kg) LENK injection. This effect was not dose-dependent. The increase of acid phosphatase in serum was accompanied by a simultaneous decrease in the liver. While the level of serum sialic acid remained unchanged, it decreased in the spleen 6 h after a single LENK injection. The effect of LENK in the spleen and liver was dose-dependent; ie, the higher the dose the greater the effect. Multiple injections of Leu-enkephalin (6 x 10 mg/kg) induced the same degree of increase but an earlier rise in serum alkaline, acid phosphatase and lactate dehydrogenase levels than with a single injection. This was not accompanied by a change of activity in liver and spleen. These data may be relevant for use of LENK in combined chemo-immunotherapy, since liver enzyme changes may alter drug metabolism, and since sialic acid plays a regulatory role in immune processes.


The mesencephalic centre controlling locomotion in the rat.
A mesencephalic locomotor region has been located in the rat brain. Electrical stimulation of the mid-brain in decerebrate animals was used to elicit locomotion on a freely mobile treadwheel. The lowest threshold stimulation sites were reconstructed from histology and accumulated from different experiments. An averaging procedure, taking into account the threshold stimulus current used in each experiment, was used to identify the brain region in which neurons would have been activated in most experiments. The mesencephalic locomotor region so defined corresponds closely to nucleus cuneiformis and the immediately surrounding pedunculopontine region.


Severe penile curvature after implantation of an inflatable penile prosthesis.
We describe 6 cases of penile curvature following implantation of inflatable penile prostheses. Exploration revealed severe scarring of the corpora cavernosa, which produced the curvature in 4 patients. In all 4 cases this area was incised and the defect was filled with a polytetrafluoroethylene vascular graft. The penis was straightened and the prosthesis functioned normally. The remaining 2 patients were treated with inflation for 8 weeks with resolution of the curvature. To our knowledge, these cases represent the first reported complications produced by abnormal scar tissue outside of the inflammatory pseudocapsule after implantation of an inflatable penile prosthesis.


Neurological complications of Schoenlein-Henoch syndrome: contribution of MR to the diagnosis. Case report.
In the protean clinical pattern of the Schoenlein-Henoch syndrome the central and peripheral nervous system signs and symptoms are of most uncertain epidemiological importance and of most debatable physiopathological status. In the case reported the contribution of nuclear magnetic resonance to the diagnosis proved to be greater than that of computed tomography because it imaged the CNS lesions.


Midwifery care of non-vaccinating families - Insights from the Byron Shire.
Midwives may feel ill-equipped to manage clinical encounters with non-vaccinating parents. Pregnancy is a peak time in the formation of parents' vaccination views and intention. Midwives are central to maternity care in Australia. While most midwives will have infrequent contact with families who intend not to vaccinate, when they do, they must feel equipped to communicate with them in a manner which fulfils their professional responsibilities, acknowledges parental autonomy and facilitates continued engagement. To understand how midwives can most effectively communicate with non-vaccinating parents. We conducted in-depth interviews with 32 non-vaccinating parents and six key informant health professionals, and a focus group of six midwives. Data collection occurred in the Byron Shire of New South Wales, where childhood vaccination rates are persistently lower than national averages. This study explores four central codes. The first, 'hold on…I'm not sure about this' providing insights into moments of doubt preceding parents' decisions not to vaccinate. The second 'Pregnancy: a decision-making focal point' reinforces the importance of effective vaccination recommendations in the antenatal period. 'Manipulation and ambivalence' examines why overzealous or unclear recommendations about vaccination are unhelpful, and the fourth central code 'engage, inform and encourage' summarise recommendations from health professionals who are experienced in communicating, apparently effectively, with non-vaccinating families. Insights from this study are used to recommend practical strategies which may be employed by midwives and maternity units to successfully and professionally manage clinical encounters with non-vaccinating parents. Midwives are well positioned to provide clear recommendations to parents regarding childhood vaccination whilst maintaining engagement and meeting the goals of woman-centred care.


Associations of ambient temperature with mortality for ischemic and hemorrhagic stroke and the modification effects of greenness in Shandong Province, China.
Evidence is scant on the relative and attributable contributions of ambient temperature on stroke subtypes mortality. Few studies have examined modification effects of multiple greenness indicators on such contributions, especially in China. We quantified the associations between ambient temperature and overall, ischemic, and hemorrhagic stroke mortality; further examined whether the associations were modified by greenness. We conducted a multicenter time-series analysis from January 1, 2013 to December 31, 2019. we adopted a distributed lag non-linear model to evaluate county-specific temperature-stroke mortality associations. We then applied a random-effects meta-analysis to pool county-specific effects. Attributable mortality was calculated for cold and heat, defined as temperatures below and above the minimum mortality temperature (MMT). Finally, We conducted a multivariate meta-regression to determine associations between greenness and stroke mortality risks for cold and heat, using normalized difference vegetation index (NDVI), soil adjusted vegetation index (SAVI), and enhanced vegetation index (EVI) as quantitative indicators of greenness exposure. In the study period, 138,749 deaths from total stroke were reported: 86,873 ischemic and 51,876 hemorrhagic stroke. We observed significant W-shaped relationships between temperature and stroke mortality, with substantial differences among counties and regions. With MMT as the temperature threshold, 17.16 % (95 % empirical CI, 13.38 %-19.75 %) of overall, 20.05 % (95 % eCI, 16.46 %-22.70 %) of ischemic, and 12.55 % (95 % eCI, 5.59 %-16.24 %) of hemorrhagic stroke mortality were attributable to non-optimum temperature (combining cold and heat), more mortality was caused by cold (14.94 %; 95 % eCI, 11.57 %-17.34 %) than by heat (2.22 %; 95 % eCI, 1.54 %-2.72 %). Higher levels of NDVI, SAVI and EVI were related to mitigated effects of non-optimum temperatures-especially heat. Exposure to non-optimum temperatures aggravated stroke mortality risks; increasing greenness could alleviate that risks. This evidence has important implications for local communities in developing adaptive strategies to minimize the health consequences of adverse temperatures.


Cemented vs. uncemented glenoid fixation in total shoulder arthroplasty for osteoarthritis: a New Zealand Joint Registry study.
Total shoulder arthroplasty (TSA) is commonly performed for shoulder osteoarthritis (OA). Uncemented metal-backed (MB) glenoid components were introduced in an attempt to avoid glenoid loosening. New Zealand and Australian Joint Registry studies have shown significantly higher revision rates when uncemented MB glenoids are used. We used the New Zealand Joint Registry (NZJR) to compare all-cause revision rates and functional scores for TSA and investigated the trends of glenoid fixation used in New Zealand. The NZJR was accessed for all primary TSA undertaken for OA from January 2000 to December 2017. Patient demographics were collated. All-cause revision rates were reported as rate per 100 component-years. Analysis was repeated excluding the uncemented SMR L2 glenoid (LimaCorporate), as it was a potential confounder. Kaplan-Meier survival analysis was performed. Oxford Shoulder Scores at both 6 months and 5 years were analyzed. A total of 2613 TSAs were performed for OA during the study period, representing 85.0% of all TSAs in New Zealand. Overall, 62.1% of the patients were female. In addition, 69.6% of glenoids were cemented and 30.4% uncemented. The most common uncemented MB glenoid was SMR 86.6% (LimaCorporate), and cemented was Global (DePuy) 49.8%. The revision rate for TSA with uncemented glenoids was significantly higher at 2.03 compared with cemented at 0.41 per 100 component-years (P < .001). Hazard ratio 5.0 for revision of uncemented glenoids. No significant difference was found in Oxford Scores at 6 months (39.7 vs. 40.3, P = .13) or 5 years (42.1 vs. 42.8, P = .22). The most common mode of failure was glenoid loosening in cemented glenoids (44.4%), and component failure in uncemented (34.8%). Revision for rotator cuff, deep infection, and instability were comparable between groups. When excluding SMR L2, uncemented MB glenoid all-cause revision rates remained significantly higher than cemented (1.42 vs. 0.41 per 100 component-years, P < .001). SMR L1 uncemented MB glenoids had a higher revision rate than the non-SMR uncemented glenoids (1.61 vs. 0.18 per 100 component-years, P = .009). Uncemented glenoid use peaked in New Zealand in 2011 at 46.7% of TSAs but declined to 20.1% in 2017. In the NZJR, primary TSAs undertaken for OA have a significantly higher all-cause revision rate when the glenoid component is uncemented. Uncemented glenoids have a 5.0 times higher revision rate. Excluding SMR L2 glenoids from the analysis, the significantly higher revision rate remained for uncemented glenoids. These data reaffirm that uncemented MB glenoids are associated with higher revision rates.


Assessment of patient flow and optimized use of lean thinking transformation from the perspective of graph theory and spectral graph theory: A case study.
Hospital re-engineering initiatives aiming to meet the requirement for patient-centered care often face significant barriers. Opportunities from the optimization of patient flow logistics are often overlooked due to the perception that patient transport related services are ancillary. To reorganize patient pathways by optimizing inpatient assignment and outpatient unit relocation. Our analysis was conducted in a campus-based hospital hosting 1694 inpatient beds. Patient flow data was used for algorithm-based optimization to minimize the sum of the distances due to visits to outpatient units and visits by consulting physicians. Inpatients were reordered and outpatient units were relocated to minimize transport need. Optimized schemes were analyzed using graph- and spectral graph theory. Both optimizations yielded an altered hospital layout in which the need for patient transfers decreased (over 30% and 23% in terms of total distance and transfer episodes, respectively). The optimized systems gave rise to buildings with greater specialization, higher importance in terms of contributing to the network architecture, greater synchronization and robustness. The top-down algorithm-based optimization scheme yielded a system in which the need for cross-building patient transfer decreased. We suggest that network analysis may be a useful tool for capacity planning.


Rat liver cysteine sulfinate decarboxylase: purification, new appraisal of the molecular weight and determination of catalytic properties.
Rat liver cystein sulfinate decarboxylase (L-cystein sulfinate carboxylase) was purified approximately 500-fold. By cellulose acetate and polyacrylamide gel electrophoresis or by analytical ultracentrifugation, the purified enzyme appears to be nearly homogeneous. The Stokes radius (3.4 nm) and sedimentation coefficient (6.5 S) were determined. The molecular weight, calculated and experimentally estimated is around 100 000 and the enzyme is constituted of two identical subunits whose molecular weights are 55 000. The role of pyridoxal phosphate as coenzyme was demonstrated and the requirement for free sulhydryl groups for activity was studied. The ability of native pure cysteine sulfinate decarboxylase to also decarboxylate cysteate was stressed: therefore, we concluded that in rat liver a single protein catalyzed both reactions, although only the decarboxylation of cysteine sulfinate is of physiological interest.


X-ray diffraction studies of lipid phase transitions in cholesterol-rich membranes at sub-zero temperatures.
In X-ray diffraction studies of hydrated (greater than 60%) cholesterol/dioleoylphosphatidylcholine mixtures the lipid packing band showed an abrupt transition from liquid crystal-type to gel-type position and definition at a temperature which decreased progressively to almost -50 degrees C as the proportion of cholesterol was increased to a saturation level of about 50 mol%. Plots of transition temperature against composition (mol% cholesterol) and of peak position against composition provided evidence of a significant change in phospholipid configuration at about 20 mol% cholesterol. However, the data overall suggested a uniform dispersion of the cholesterol molecules in the phospholipid bilayer at all concentrations up to the saturation point. Parallel studies of hydrated lipid extract of erythrocyte membranes and of several cholesterol-rich membrane preparations showed a similar overall change from liquid crystal-type packing at +20 degrees C to a gel-type packing at -30 degrees C to -40 degrees C but without displaying a defined transition temperature.


Structural analysis of CPF_2247, a novel α-amylase from Clostridium perfringens.
CPF_2247 from Clostridium perfringens ATCC 13124 was identified as a putative carbohydrate-active enzyme by its low sequence identity to endo-β-1,4-glucanases belonging to family 8 of the glycoside hydrolase classification. The X-ray crystal structure of CPF_2247 determined to 2.0 Å resolution by single-wavelength anomalous dispersion using seleno-methionine-substituted protein revealed an (α/α)(6) barrel fold. A large cleft on the surface of the protein contains residues that are structurally conserved with key elements of the catalytic machinery in clan GH-M glycoside hydrolases. Assessment of CPF_2247 as a carbohydrate-active enzyme disclosed α-glucanase activity on amylose, glycogen, and malto-oligosaccharides.


Regulation of MSR-1 and CD36 in macrophages by LOX-1 mediated through PPAR-γ.
We observed uniform sustained Dil-ox-LDL uptake in macrophages in the presence or absence of ox-LDL receptor-1 (LOX-1). We wondered if the deficiency of LOX-1 modulates the expression of two other scavenger receptors, macrophage scavenger receptor-1 (MSR1) and CD36, on macrophages to account for the unaltered ox-LDL uptake. Macrophages were isolated from wild-type (WT) and LOX-1 knockout (KO) mice and stimulated with ox-LDL. Dil-ox-LDL uptake and expression of MSR1 and CD36 examined. Abrogation of LOX-1 did not significantly change Dil-ox-LDL uptake by macrophages. LOX-1 KO macrophages showed a significant decrease in CD36 at baseline as well as after ox-LDL stimulation and a marked almost 100% increase in the expression of MSR1, both at mRNA and protein levels (all p<0.05 vs. WT macrophages). Further, we observed a reduction in the expression of PPAR-γ in LOX-1 KO macrophages. To ascertain the role of PPAR-γ in the altered expression of MSR1 and CD36, LOX-1 KO macrophages were treated with troglitazone, a PPAR-γ agonist. Activation of PPAR-γ by troglitazone reversed the increased expression of MSR1 as well as the decreased expression of CD36 in LOX-1 KO macrophages. LOX-1 abrogation induces MSR1 and inhibits CD36 expression. The increase in MSR1 most likely accounts for sustained Dil-ox-LDL uptake despite LOX-1 abrogation. The alterations in CD36 and MSR1 occur through a decrease in PPAR-γ.


Mutations in the von Hippel-Lindau (VHL) gene refine differential diagnostic criteria in renal cell carcinoma.
Renal cell carcinomas (RCC) with abundant granular cytoplasm include oncocytomas, eosinophilic variants of chromophobe RCC, papillary RCC, collecting duct carcinoma, and some conventional (clear cell) RCC. Tumors with predominantly clear cell cytoplasm include typical chromophobe RCC and conventional (clear cell) RCC. The objective of this study was to determine if mutations in the VHL gene can serve as auxiliary diagnostic criteria in refining histology based subtyping of renal epithelial neoplasia. The study cohort of 67 cases included 24 conventional RCC, 14 chromophobe RCC, 14 papillary RCC, and 15 oncocytomas. Single strand conformational polymorphism (SSCP) was used as a screening procedure for mutations followed by automated sequencing to identify mutations. Thirteen of the 14 mutations identified were novel, seven of which were in the coding region. In chromophobe RCC, mutations clustered in the 5'UTR/promoter region and have not been previously reported. Exon 3 appeared to favor conventional (clear cell) RCC and correlated with a more aggressive phenotype. Mutations were absent in the papillary and oncocytoma RCC subtypes. Exon 3 mutations permitted a morphological distinction between conventional (clear cell) RCC and chromophobe RCC with clear cells. Mutations in the VHL gene refine histologic diagnostic criteria in RCC serving as adjuncts to the present morphology based diagnosis of RCC.


Prevalence of cerebral edema among diabetic ketoacidosis patients.
Cerebral edema (CE) is the most severe complication of diabetic ketoacidosis (DKA) in children. There is no accurate knowledge of CE pathogenesis and its onset has been related to intravenous rehydration therapy during the initial treatment. To estimate the prevalence of CE among DKA patients treated at Hospital General de Niños Pedro de Elizalde with intravenous rehydration and analyze potential risk factors for the development of CE. Cross-sectional prevalence study and exploratory analysis to compare clinical and laboratory characteristics between patients with and without CE. Patients aged 1-18 years hospitalized with the diagnosis of DKA between January 1st, 2005 and December 31st, 2014 were included. A total of 693 DKA events from 561 medical records were analyzed. Ten patients had evidence of CE (1.44 %; 95 % confidence interval: 0.8-2.6). Patients with CE had higher serum urea levels (p < 0.001), lower carbon dioxide pressure (p < 0.001), and lower serum sodium levels (p < 0.001) than those without CE. The prevalence of CE among DKA patients was 1.44 %, smaller than that reported in our country (1.8 %). The risk factors at admission associated with CE development were high serum urea levels, hyponatremia, and hypocapnia.


DNA profiles and numeric histogram classifiers in nephrogenic adenoma.
The malignant potential of nephrogenic adenoma is still a matter of controversy and therapeutic regimens of this morphologic entity range from partial, even total cystectomy to watchful waiting. The objective of the current study was to evaluate several robust image cytometry-DNA histogram classifiers and to search among those for factors that separate a biologically nonaggressive metaplastic lesion from lesions with increased malignant potential. The study included bladder irrigation specimens, 23 preceding transurethral resection of nephrogenic adenoma and 24 preceding resection of papillary bladder carcinoma. Feulgen-stained nuclei were imported to a static image analysis system, and densitometric data were interpreted by two different software programs. Histograms were described numerically by DNA index, 2c deviation index, and by 5c/9c-exceeding and euploid polyploidy rates. In addition, an interpretation algorithm based on a dual parameter analysis with an integrated automatic threshold was used. The numeric classification of DNA histograms of patients suffering from nephrogenic adenoma resulted in DNA indices between 0.91 and 1.15. The 2c deviation indices ranged from 0.03 to 0.43, and the 5c exceeding rates ranged from 0.0 to 1.58. None of the measurements showed nuclei exceeding 9c. The p25-75 ranges of 2c deviation indices in nephrogenic adenoma and papillary urothelial carcinoma did not overlap. These findings might be explained by minor proliferative activity in nephrogenic adenoma. Euploid polyploidy rates less than 5% confirm this explanation. Risk analysis documented high risk only for those patients with nephrogenic adenomas who had proven transitional cell carcinoma in their history. DNA estimation by image cytometry of urinary bladder irrigation specimens appears able to separate papillary bladder lesions. The method detects those lesions with higher malignant potential but is limited in separating entities with low malignant potential. Comparison of the discriminative power of robust numeric DNA classifiers reveals the 2c deviation index superior to the widely used DNA index and the 5c exceeding rate in this material.


Efficacy and safety of nonbiologic immunosuppressants in the treatment of nonrenal systemic lupus erythematosus: a systematic review.
To analyze the efficacy and safety of nonbiologic immunosuppressants in the treatment of nonrenal systemic lupus erythematosus (SLE). We conducted a sensitive literature search in Medline, Embase, and the Cochrane Central Register of Controlled Trials up to October 2011. The selection criteria were studies including adult patients with SLE, a treatment intervention with nonbiologic immunosuppressants, a placebo or active comparator group, and outcome measures assessing efficacy and/or safety. Meta-analyses, systematic reviews, clinical trials, and cohort studies were included. The quality of each study was evaluated using Jadad's scale and the Oxford Levels of Evidence. In total, 158 of the 2,827 initially found articles were selected for detailed review; 65 studies fulfilled the predetermined criteria. Overall, the studies were low quality, with only 11 randomized controlled trials (RCTs). Cyclophosphamide demonstrated efficacy for neuropsychiatric SLE, preventing relapses with an additional steroid sparing effect, although its use was associated with cumulative damage, development of cervical intraepithelial neoplasia,and ovarian failure. Other immunosuppressants (azathioprine, methotrexate, leflunomide, mycophenolate mofetil,and cyclosporin A) demonstrated efficacy in reducing nonrenal activity and flares with a steroid-sparing effect, although only on occasion in non–placebo-controlled RCTs of small numbers of patients. Several immunosuppressants demonstrated their safety and efficacy in nonrenal SLE. A specific drug for each particular manifestation cannot be recommended, although cyclophosphamide may be used in more severe cases, and methotrexate may be the first option in most cases of moderately active SLE. High-quality RCTs of larger numbers of patients are needed.


A unique multiattribute method to predict success of emerging drug targets.
A crucial driver for increased productivity is the identification of potential drug failures at the earliest stages of development, thereby reducing costly, large-scale clinical trials. Here, we present a multiattribute method that utilizes six key aspects of development: (i) target validation and proof-of-mechanism; (ii) target engagement and proof-of-principle; (iii) proof-of-concept; (iv) therapy characteristics such as degree of disruption; (v) stakeholder opinions; and (vi) benchmarking metrics. Through this method, attributes are weighted according to validated characteristics to predict the success of drug targets across all stages of development. Furthermore, using clinical targets for hepatitis B, we demonstrate that our methodology can be validated retrospectively.