Contribution of an Asian-prevalent HLA haplotype to the risk of HBV-related hepatocellular carcinoma.
Liver cancer, particularly hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), is more common in Asians than in Caucasians. This is due, at least in part, to regional differences in the prevalence of exogenous factors such as HBV; however, endogenous factors specific to Asia might also play a role. Such endogenous factors include HLA (human leukocyte antigen) genes, which are considered candidates due to their high racial diversity. Here, we performed a pancancer association analysis of 147 alleles of HLA-class I/II genes (HLA-A, B, and C/DRB1, DQA1, DQB1, DPA1, and DPB1) in 31,727 cases of 12 cancer types, including 1684 liver cancer cases and 107,103 controls. HLA alleles comprising a haplotype prevalent in Asia were significantly associated with pancancer risk (e.g., odds ratio [OR] for a DRB1*15:02 allele = 1.12, P = 2.7 × 10-15), and the associations were particularly strong in HBV-related HCC (OR 1.95, P = 2.8 × 10-5). In silico prediction suggested that the DRB1*15:02 molecule encoded by the haplotype does not bind efficiently to HBV-derived peptides. RNA sequencing indicated that HBV-related HCC in carriers of the haplotype shows low infiltration by NK cells. These results indicate that the Asian-prevalent HLA haplotype increases the risk of HBV-related liver cancer risk by attenuating immune activity against HBV infection, and by reducing NK cell infiltration into the tumor.


Magnetic circular dichroism of Pseudomonas putida cytochrome P-450 in near infrared region.
Magnetic circular dichroism spectra of oxidized, reduced and carbonmonoxy reduced forms of cytochrome P-450 from D-camphor grown Pseudomonas putida (P-450cam) were studied in the near infrared region (650 to 1200 nm) at various temperatures in the presence of D-camphor. Oxidized P-450cam with camphor exhibited positive (+) and negative (-) magnetic CD bands at 825 and 970 nm, respectively, and both of them were assigned to Faraday B terms. The magnetic CD spectrum of reduced P-450cam in the presence of D-camphor exhibited at least five components in the region between 650 to 1175 nm and one of them at 760 nm showed considerably smaller magnitude than that of the corresponding band of deoxymyoglobin. These results were interpreted to mean that the heme-iron in both oxidized and reduced P-450cam has a ligand field symmetry lower than C4v, i.e. a strong rhombic character of the heme in cytochrome P-450. Carbonmonoxide complex of reduced P-450cam exhibited no detectable magnitude of magnetic CD in the near infrared region but showed CD bands at 710 (-) and 850 (+) nm. The results were compared and discussed with those of carbonmonoxy hemoglobin and myoglobin. In addition, temperature dependent changes in the spin state of oxidized P-450cam from high to low by decrease of temperature were observed by measuring both magnetic CD and absorption spectra in the near ultraviolet and visible regions (300 to 650 nm), provided that the temperature of the sample was varied slowly (approximately 3 degrees C/min) between room and liquid nitrogen temperature in a 0.03 M phosphate buffer (pH 7.2) containing a saturated amount of D-camphor and 70% (v/v) glycerol. The significance of this phenomenon is also discussed.


Over-adaptation and heart rate variability in Japanese high school girls.
In the field of educational psychology in Japan, a model of "over-adaptation" has been applied to conceptualize the personality of students who are vulnerable to external stressors and prone to developing psychiatric problems. However, the influence of over-adaptation on physiological functions in adolescents is still largely unknown. Therefore, the present study aimed to investigate the association between an over-adapted tendency and autonomic nervous system activities in high school girls. Circadian profiles of cardiac autonomic nervous system activities in 47 normal high school girls were evaluated using time-domain measures of heart rate variability (HRV) taken from 24-h ambulatory electrocardiogram recordings, and their relation to an over-adaptation scale composed of 5 subscales was evaluated. A significant increase in RMSSD (root mean square of successive difference of normal-to-normal beat intervals) during daytime (09:00-14:00) was observed in students who scored high on the sum of the over-adaptation subscales (n=6). Two of the over-adaptation subscales, namely, "self-restraint" and "self-insufficiency", were positively correlated with time-domain measures. Parasympathetic activity in over-adapted students was elevated during school, and this autonomic response was suggested to be linked to over-adaptation subscales related to repressed emotions in over-adapted students. Thus, in over-adapted students, repressing emotions appears to be a style of coping, and may lead to a quiet, emotionally stable life in school, which in turn may result in parasympathetic activation.


Significant association between outdoor NO2 and respiratory symptoms in preschool children.
A study of 1225 preschool children was conducted in four regions of Switzerland with different levels of air pollution to investigate the relationship between air pollution and respiratory symptoms. Daily symptoms were recorded by parents on a diary form and air pollution exposure assessed by personal NO2 samplers. Each family participated for 6 weeks and personal samplers were changed every week. The frequency of respiratory symptoms per child and day was found to increase with increasing levels of NO2 measured outdoors. This relationship remained significant in a multiple regression model in which the factors smoking, origin, indoor air pollution, age and sex, season, and parents appreciation of air pollution at the living site were taken into account.


A case of intramedullary haematoma associated with congenital alpha2-plasmin inhibitor deficiency.
The association of intramedullary haematoma of the left femoral diaphysis and congenital alpha2-plasmin inhibitor deficiency in a 6-year-old boy is reported. Congenital deficiency of this fibrinolytic system component is very rare and can result in severe bleeding. Clinically, an intramedullary haematoma causes pain but no swelling, and there is no history of trauma. X-rays show a hyperlucent lesion without sclerotic edges in the medulla of the diaphysis of a long bone with thinning of the cortex. MRI is diagnostic with the haematoma generating a specific hyperintense signal on T1-weighted and T2-weighted spin-echo images.


Neonatal hyperbilirubinemia and the role of unbound bilirubin.
Neonatal jaundice occurs in more than 80% of newborn infants. Although mild jaundice is physiologic and possibly neuroprotective, severe hyperbilirubinemia can lead to neurologic dysfunction and death. Hyperbilirubinemia is due to an imbalance between bilirubin production and the developing excretory capacity in the first days of life. Management utilizes total serum bilirubin (TSB) levels, although recent advances suggest a role for unbound bilirubin. The goal of this review is to examine bilirubin biology, toxicology, and clinical effects, discuss preventive and therapeutic measures, describe neurodevelopmental consequences, and propose that, with the advent of new technology, unbound bilirubin is the optimal measurement for the management. Comprehensive review on neonatal hyperbilirubinemia. Neonatal hyperbilirubinemia can be prevented by tin mesoporphyrin to limit heme oxygenase activity, a key enzyme in bilirubin production, or restricting bilirubin's absorption from the gastrointestinal tract. Treatment modalities include removing bilirubin from the body by exchange transfusion, binding to immunoglobulin, or converting it to a water-soluble isomer with phototherapy. While these approaches have evolved during the past decades, the diagnosis, intervention indications, and prognosis have consistently relied on TSB concentration despite its poor ability to predict an outcome. Total serum bilirubin is inadequate to optimize care of the term and preterm infant with hyperbilirubinemia. A rapid, accurate, and more effective indicator of bilirubin neurotoxicity is needed to manage jaundiced infants and for the universal screening of newborn infants. Future measurements of free bilirubin unattached to albumin will improve the management of neonatal hyperbilirubinemia.


Brain stem auditory, pattern-reversal visual, and short-latency somatosensory evoked potentials: latencies in relation to age, sex, and brain and body size.
To determine standards of normality for auditory, somatosensory and visual evoked potentials commonly used in the assessment of neurological disease, 8 AEP, 1 VEP and 12 SEP components were recorded to stimulation of left and right ears, eyes, and median nerves in 286 normal subjects ranging in age from 4 to 95 years. Peak and interpeak latencies, and left-right differences in latency, were analyzed as a function of age, sex, and estimates of brain and body size. Major features of the results were: (1) Peak latencies of all components showed statistically significant increases in latency with age except that VEP P100 latency decreased significantly between 4 and 19 years and did not change between 20 and 59 years. (2) In adults the peak latencies of all components were significantly later in males than in females. For AEPs and VEPs these differences were explained by sex differences in brain size, and for adult SEPs were explained by sex differences in arm and shoulder dimensions. No significant sex differences in VEP and SEP latencies were seen in children. (3) Most interpeak latencies showed significant differences in relation to age or sex. (4) Age and sex are useful predictors of latency for nearly all peak and interpeak latencies; in addition, height is a useful predictor of SEP peak latencies. (5) Left-right latency differences showed little age-related, and no sex-related, change. The interlaboratory use of these or other normative data was discussed. It was concluded that these AEP and SEP norms can probably be used in other laboratories if stimulating and recording conditions are similar. However, VEP results are difficult to transfer due to the poorly understood effects of variation in stimulus conditions. Some issues regarding the optimal characterization of norms were also discussed.


Effects of the residue adjacent to the reactive serine on the substrate interactions of Drosophila esterase 6.
Esterase 6 from Drosophila melanogaster is a carboxylesterase that belongs to the serine esterase multigene family. It has a basic histidine (His) at residue 187, adjacent to the reactive serine (Ser) at residue 188, whereas most other characterized members of the family have an acidic glutamate (Glu) in the equivalent position. We have used site-directed in vitro mutagenesis to replace the His codon of the esterase 6 gene with either Gln or Glu codons. The enzymes encoded by these active-site mutants and a wild-type control have been expressed, purified, and characterized. Substitution of Gln for His at position 187 has little effect on the biochemical properties of esterase 6, but the presence of Glu at this position is associated with three major differences. First, the pH optimum is increased from 7 to 9. Second, the mutant enzyme shows decreased activity for beta-naphthyl esters and p-nitrophenyl acetate but has gained the ability to hydrolyze acetylthiocholine. Finally, the Gibb's free energy of activation for the enzyme is increased. These results suggest that residue 187 interacts directly with the substrate alkyl group and that this interaction is fully realized in the transition state. We further propose that the presence of His rather than Glu at position 187 in esterase 6 contributes significantly to its functional divergence from the cholinesterases and that this divergence is due to different interactions between residue 187 and the substrate alkyl group.


Concentration of elements in human brain: glioblastoma multiforme.
In this paper the results of two coordinated biomedical research projects are presented. The first project involves the determination of the average values of elements in normal human brain (20 individuals, age-group 65-75). 21 brain parts were selected from both hemispheres. Determinations were carried out by ICP-AES and INAA methods. The main (Na, K, Mg, Ca, Fe, P, S) and trace elements (Al, B, Ba, Co, Cr, Mn, Ni, Pb, Sr, Zn) were investigated. Quality control was ensured by using NBS Bovine Liver SRMs. On the basis of our investigations the regional distribution of elements can be given. The second goal was to detect the possible trace element changes in histopathologically selected brain regions from patients with glioblastoma multiforme. The majority of elements displayed no statistically significant differences between the studied groups, except the reduced levels of B and Zn and the increased level of Sr compared to the tissue from control individuals.


Aptamers: Functional-Structural Studies and Biomedical Applications.
Aptamers are synthetic molecules of different natures (mostly, DNA or RNA) that recognize a target molecule with high affinity and specificity [...].


Hysterectomy and risk of stress-urinary-incontinence surgery: nationwide cohort study.
Hysterectomy for benign indications has been associated with an increased risk for lower-urinary-tract sequela, but results have been inconclusive. We aimed to establish the risk for stress-urinary-incontinence surgery after hysterectomy for benign indications. We did a nationwide, population-based, cohort study from 1973 to 2003 in Sweden. We identified our population from the Swedish Inpatient Registry. We selected 165 260 women who had undergone hysterectomy (exposed cohort) and a control group of 479 506 individuals who had not had this procedure (unexposed cohort), matched by year of birth and county of residence. In both cohorts, occurrence of stress-urinary-incontinence surgery was established from the Swedish Inpatient Registry. Hazard ratios with 95% CIs were calculated by Cox's proportional-hazards regression. During the 30-year observational period, the rate of stress-urinary-incontinence surgery per 100,000 person-years was 179 (95% CI 173-186) in the exposed cohort versus 76 (73-79) in the unexposed cohort. Correspondingly, individuals in the exposed cohort were at increased risk for stress-urinary-incontinence surgery compared with those in the unexposed cohort (hazard ratio 2.4; 95% CI 2.3-2.5), irrespective of surgical technique. Risk for stress-urinary-incontinence surgery varied slightly with time of follow-up: the highest overall risk was recorded within 5 years of surgery (2.7; 2.5-2.9) and the lowest risk was seen after an observation period of 10 years or more (2.1, 1.9-2.2). Hysterectomy for benign indications, irrespective of surgical technique, increases the risk for subsequent stress-urinary-incontinence surgery. Women should be counselled on associated risks related to hysterectomy, and other treatment options should be considered before surgery.


Angiotensin receptor blockers and risk of myocardial infarction: systematic review.
To evaluate the effect of angiotensin receptor blockers on the risk of myocardial infarction in patients at risk for cardiovascular events. Systematic review of controlled trials of angiotensin receptor blockers. Medline, Embase, Cochrane central register of controlled trials, hand search, and contact with investigators. Predefined criteria were used to select controlled clinical trials comparing use of angiotensin receptor blockers with angiotensin converting enzyme (ACE) inhibitors or placebo in patients at risk for cardiovascular events. Data were extracted for patients' characteristics, interventions, quality of trials, and rates of myocardial infarction. 19 studies with 31,569 patients were included in the analysis. Two studies investigated the use of angiotensin receptor blockers in hypertensive patients, four studies in patients with diabetes and nephropathy, 10 studies in patients with heart failure, and three in patients with recent myocardial infarction or ischaemic syndrome. 11 studies of 21,062 patients allowed for comparison between angiotensin receptor blockers and placebo; nine studies of 10,625 patients allowed for comparison between angiotensin receptor blockers and ACE inhibitors. Use of angiotensin receptor blockers was not associated with increased risk of myocardial infarction compared with placebo (odds ratio 0.94, 95% confidence interval 0.75 to 1.16) nor with increased risk of myocardial infarction compared with ACE inhibitors (1.01, 0.87 to 1.16). Treatment with angiotensin receptor blockers was not associated with a significantly increased risk of myocardial infarction. The 95% confidence intervals do, however, not exclude an increase of up to 16% in the risk of myocardial infarction or a reduction in risk of up to 25%. Until further information specifically dealing with this issue is available from large prospective trials, our findings may alleviate recent concerns over the safety of this class of medications.


Sodium 4-phenylbutyrate protects against spinal cord ischemia by inhibition of endoplasmic reticulum stress.
Delayed paraplegia after operation on the thoracoabdominal aorta is considered to be related to vulnerability of motor neurons to ischemia. Previous studies have demonstrated the relationship between neuronal vulnerability and endoplasmic reticulum (ER) stress after transient ischemia in the spinal cord. The aim of this study was to investigate whether sodium 4-phenylbutyrate (PBA), a chemical chaperone that reduces the load of mutant or unfolded proteins retained in the ER during cellular stress, can protect against ischemic spinal cord damage. Spinal cord ischemia was induced in rabbits by direct aortic cross-clamping (below the renal artery and above the bifurcation) for 15 minutes at normothermia. Group A (n = 6) was a sham operation control group. In group B (n = 6) and group C (n = 6), vehicle or 15 mg/kg/h of sodium 4-PBA was infused intravenously, respectively, from 30 minutes before the induction of ischemia until 30 minutes after reperfusion. Neurologic function was assessed at 8 hours, and 2 and 7 days after reperfusion with a Tarlov score. Histologic changes were studied with hematoxylin-eosin staining. Immunohistochemistry analysis for ER stress-related molecules, including caspase12 and GRP78 were examined. The mean Tarlov scores were 4.0 in every group at 8 hours, but were 4.0, 2.5, and 3.9 at 2 days; and 4.0, 0.7, and 4.0 at 7 days in groups A, B, and C, respectively. The numbers of intact motor neurons at 7 days after reperfusion were 47.4, 21.5, and 44.9 in groups A, B, and C, respectively. There was no significant difference in terms of viable neurons between groups A and C. Caspase12 and GRP78 immunoreactivities were induced in motor neurons in group B, whereas they were not observed in groups A and C. Reduction in ER stress-induced spinal cord injury was achieved by the administration of 4-PBA. 4-PBA may be a strong candidate for use as a therapeutic agent in the treatment of ischemic spinal cord injury.


A nitrate sensitive planar optode; performance and interferences.
We present a newly developed nitrate sensitive planar optode. It exhibits a linear response to nitrate from 1 to 50 mM at pH 8.0, a fast response time below 10 s and a good lifetime, allowing for fast two dimensional nitrate measurements over long periods of time. Interference from nitrite, chloride and thiocyanate, however, limits the optode's application in environments where these are encountered, notably seawater with its high chloride content.


Combination of high-density cholesterol level, elastic score, and severity of exocrine pancreatic dysfunction may be useful for a predictive factor for patients with early chronic pancreatitis.
This study aimed to clarify whether any risk factors including clinical characteristics, endosonographic features, and exocrine pancreatic dysfunction may be useful for a predictive factor for patients with early chronic pancreatitis. A total of 163 consecutive patients that presented with functional dyspepsia with pancreatic enzyme abnormalities (FD-P) (n = 46), early chronic pancreatitis (ECP) (n = 47), and asymptomatic patients with pancreatic enzyme abnormalities (AP-P) (n = 70) based on the Rome III classification and the Japan Pancreatic Association were included in this study. The enrolled patients were evaluated using endosonography (EUS) and EUS elastography. The levels of the five pancreatic enzymes were measured. Pancreatic exocrine function was analyzed using N-benzoyl-l-tyrosyl-p-aminobenzoic acid (BT-PABA). There were no significant differences in clinical characteristics such as age, gender, body mass index, alcohol consumption, and smoking among patients with AP-P, FD-P, and ECP. The ratio of BT-PABA test less than 35% in patients with ECP was significantly (P = 0.043) higher than in AP-P patients. Elastic score was a useful tool to differentiate the FD-P group from the ECP group. The high-density cholesterol levels in patients with ECP were significantly lower than those in AP-P. In addition, the combination of total and high-density cholesterol levels, BT-PABA test, and elastic score has a higher area under the curve value (0.708) of patients with ECP than in the other groups. The combination of high-density cholesterol levels, elastic score, and severity of exocrine pancreatic dysfunction may be useful for a predictive factor for patients with ECP.


Radiology of the lymphomas.
Lymphomas are a group of diseases that provide the radiologist and clinician with unusual challenges. In most cases, an understanding of the histologic classification and staging is essential to design the imaging workup for the patient. Precise staging is critical, particularly for patients with HD and extranodal NHL. The malignant lymphomas share many similar radiographic features, yet have notable differences. An understanding of the pattern of extension of HD is useful in choosing an imaging modality for both staging and follow-up. Contiguous extension of HD follows lymphatic channels and is primarily limited to nodal compartments in the mediastinum and retroperitoneal lymph nodes. On the other hand, NHL may be either widespread or extranodal and localized. In the first instance, the histology will be low grade; in the second, intermediate or high grade. An understanding of these histologic clues is critical to the structuring of an efficient staging workup for the patient with NHL. Posttreatment follow-up imaging strategies should be governed by the fact that in both HD and NHL, recurrences are usually apparent within two years following initial treatment. Treatment complications must be separated from the manifestations of recurrent disease, a particularly important consideration in following up the patient with HD.


Women exposure to household air pollution after an improved cookstove program in rural San Luis Potosi, Mexico.
The state government of San Luis Potosí (SLP), Mexico implemented an improved cookstove (ICS) program in rural areas. As part of the comprehensive program evaluation, we compared fine particulate material (PM2.5) concentrations in kitchens and patios in treated (TH), and non-treated households (NTH), and analyzed pollutant levels according to patterns of fuels and devices use reported by the women. A panel study was conducted in 728 households (357 TH and 371 NTH) in three regions of SLP including two sampling rounds in 2015-16. Data on exposure determinants, ICS conditions and cooking practices were collected. Daily PM2.5 in kitchen and patio was measured in a subsample. The average treatment effect was estimated using the double difference method. We constructed a mixed linear model to estimate PM2.5 levels for the entire study sample and obtained personal exposure according to time-activity logs. NTH had lower socioeconomic status compared to TH. The average daily PM2.5 concentrations in NTH compared to TH were 155.2 and 92.6 μg/m3 for kitchen and 35.4 and 39.8 μg/m3 for patio, respectively. PM2.5 levels showed significant regional differences but no significant treatment effect. In many cases, the ICS was added to previous open fire and LPG use (stacking). The household size, kitchen ventilation, relative humidity, temperature and the ratio of indoor/outdoor PM2.5 concentration were significant predictors of kitchen PM2.5 levels. The daily PM2.5 personal exposure was significantly reduced using ICS in good conditions or LPG (57 μg/m3) compared to the traditional open fire (86 μg/m3). This study strengthens the evidence on the potential daily PM2.5 exposure reduction for women using an ICS in good conditions or LPG, displacing the polluting open fire. Comprehensive strategies tailored to the sociocultural context of the communities are needed to implement clean energy programs that achieve adoption and sustained use of ICS or LPG.


Benefits of diffusion-weighted imaging in pediatric acute osteoarticular infections.
Contrast-enhanced magnetic resonance imaging (MRI) is recommended for the diagnosis of acute osteoarticular infections in children. Diffusion-weighted imaging (DWI) may be an alternative to the injection of gadolinium. To evaluate unenhanced MRI with DWI in comparison to contrast-enhanced MRI for the diagnostic work-up of acute osteoarticular infections in children. This retrospective study included 36 children (age range: 7 months-12 years) with extra-spinal osteoarticular infections and MRI performed within 24 h of admission. MRI protocol included short tau inversion recovery (STIR), water-only T2 Dixon, T1, DWI, and gadolinium-enhanced T1 sequences. Two readers reviewed three sets of images: 1) unenhanced sequences, 2) unenhanced sequences with DWI and 3) unenhanced followed by contrast-enhanced sequences (reference standard). Sensitivity and specificity of sets 1 and 2 were compared to set 3 and assessed to identify osteoarticular infections: osteomyelitis (long bones, metaphyseal equivalents), septic arthritis and abscess (soft tissues, bone). All 14 cases of osteomyelitis in the metaphyses and diaphyses of long bones and all 27 cases of septic arthritis were identified by unenhanced sequences, but 4/16 abscesses were missed. For the diagnosis of abscess, DWI increased sensitivity to 100%. Among the 18 osteomyelitis in metaphyseal equivalents, 4 femoral head chondroepiphyses were identified by contrast-enhanced sequences only. MRI for suspected pediatric acute osteoarticular infections is the best diagnostic modality to guide patient management. An unenhanced protocol with DWI may be an alternative to a contrast-based protocol, even in the presence of an abscess. However, gadolinium remains necessary to assess for chondroepiphyseal involvement of the femoral head.


Breast cancer in pregnancy: A brief clinical review.
As global wealth increases and demographic changes similar to Europe and North America start affecting other societies, the global breast cancer epidemic will coincide with a delayed maternal age during first and subsequent pregnancies. Breast cancer in pregnancy will continue to increase, and standardized treatment strategies are required to be developed. This study will review current diagnostic and treatment approaches.


Large-scale production and properties of a solvent-detergent-treated factor IX concentrate from human plasma.
A human solvent-detergent (SD)-treated factor IX concentrate has been produced from cryoprecipitate-poor plasma using DEAE-Sepharose CL-6B and heparin-Sepharose CL-6B chromatography. The DEAE eluate was incubated with an SD mixture [0.3% tri(n-butyl) phosphate-1% Tween 80, 6-h at 24 degrees C] which was found to inactivate, in less than 1 h, more than 3.8 log10 of vesicular stomatitis virus and more than 4.8 log10 of Sindbis virus; the SD was removed by a subsequent heparin adsorption step. The specific activity of the concentrate was 10.9 +/- 1.3 IU factor IX: c/mg protein (n = 15). The factor IX coagulant to antigen ratio was 0.7 +/- 0.1. The concentrate was essentially free of factors II, VII and X, and protein C. The usual major contaminants of prothrombin complex concentrate (PCC) were absent: the concentrate contained about 94% alpha-1 proteins, and only 4 major proteins were resolved by SDS-PAGE (respective apparent molecular weight: 130, 86, 76 and 69 kilodaltons), and by crossed immunoelectrophoresis against an anti-PCC serum. The nonactivated partial thromboplastin time was equivalent to that of PCC; the product was devoid of factor IXa, of other activated procoagulant factors and of coagulant-active phospholipids (removed with SD in the heparin breakthrough fraction). Animal studies using the Wessler test and acute-toxicity test in rabbits revealed no adverse side effects. SD treatment could thus be used to inactivate viruses in factor IX concentrate and improve the safety of replacement therapy in hemophilia B.


Impact of extraction and processing conditions on betalains and comparison of properties with anthocyanins - A current review.
The search for natural pigments has been driven by growing evidence indicating that synthetic colorants can cause deleterious health effects. Betalains, in addition to anthocyanins, have been proposed as an alternative to address this need. However, the incorporation of natural pigments poses some challenges to the food industry, such as reduced stability in comparison to their synthetic counterparts. Moreover, betalains are not well studied in comparison to anthocyanins and information about the effects of processing on their physicochemical properties and stability is scattered. Thus, this review will provide an overview of the recent research on the extraction and processing of betalains from natural sources, and comparison of their colorant and physicochemical properties with anthocyanins.


Exercise increases pressure pain tolerance but not pressure and heat pain thresholds in healthy young men.
Exercise causes an acute decrease in the pain sensitivity known as exercise-induced hypoalgesia (EIH), but the specificity to certain pain modalities remains unknown. This study aimed to compare the effect of isometric exercise on the heat and pressure pain sensitivity. On three different days, 20 healthy young men performed two submaximal isometric knee extensions (30% maximal voluntary contraction in 3 min) and a control condition (quiet rest). Before and immediately after exercise and rest, the sensitivity to heat pain and pressure pain was assessed in randomized and counterbalanced order. Cuff pressure pain threshold (cPPT) and pain tolerance (cPTT) were assessed on the ipsilateral lower leg by computer-controlled cuff algometry. Heat pain threshold (HPT) was recorded on the ipsilateral foot by a computer-controlled thermal stimulator. Cuff pressure pain tolerance was significantly increased after exercise compared with baseline and rest (p < 0.05). Compared with rest, cPPT and HPT were not significantly increased by exercise. No significant correlation between exercise-induced changes in HPT and cPPT was found. Test-retest reliability before and after the rest condition was better for cPPT and CPTT (intraclass correlation > 0.77) compared with HPT (intraclass correlation = 0.54). The results indicate that hypoalgesia after submaximal isometric exercise is primarily affecting tolerance of pressure pain compared with the pain threshold. These data contribute to the understanding of how isometric exercise influences pain perception, which is necessary to optimize the clinical utility of exercise in management of chronic pain. The effect of isometric exercise on pain tolerance may be relevant for patients in chronic musculoskeletal pain as a pain-coping strategy. WHAT DOES THIS STUDY ADD?: The results indicate that hypoalgesia after submaximal isometric exercise is primarily affecting tolerance of pressure pain compared with the heat and pressure pain threshold. These data contribute to the understanding of how isometric exercise influences pain perception, which is necessary to optimize the clinical utility of exercise in management of chronic pain.


Mass spectrometric analysis of products of metabolic glycan engineering with azido-modification of sialic acids.
Metabolic engineering of glycans present on antibodies and other glycoproteins is becoming an interesting research area for improving our understanding of the glycome. With knowledge of the sialic acid biosynthetic pathways, the experiments described in this report are based on a published procedure involving the addition of a synthesized azido-mannosamine sugar into cell culture media and evaluation of downstream expression as azido-sialic acid. This unique bioorthogonal sugar has the potential for a variety of "click chemistry" reactions through the azide linkage, which allow for it to be isolated and quantified given the choice of label. In this report, mass spectrometry was used to investigate and optimize the cellular absorption of peracetylated N-azidoacetylmannosamine (Ac4ManNAz) to form N-azidoacetylneuraminic acid (SiaNAz) in a Chinese hamster ovary (CHO) cell line transiently expressing a double mutant trastuzumab (TZMm2), human galactosyltransferase 1 (GT), and human α-2,6-sialyltransferase (ST6). This in vivo approach is compared to in vitro enzymatic addition SiaNAz onto TZMm2 using soluble β-galactosamide α-2,6-sialyltransferase 1 and CMP-SiaNAz as donor. The in vivo results suggest that for this mAb, concentrations above 100 μM of Ac4ManNAz are necessary to allow for observation of terminal SiaNAz on tryptic peptides of TZMm2 by matrix-assisted laser desorption ionization (MALDI) mass spectrometry. This is further confirmed by a parallel study on the production of EG2-hFc monoclonal antibody (Zhang J et al. Prot Expr Purific 65(1); 77-82, 2009) in the presence of increasing concentrations of Ac4ManNAz.


Recommendations for treatment of brain metastases.
As treatment options for cerebral metastases have increased, so has controversy regarding relative indications for their use. The therapeutic options, criteria for choice, and recommendations for treatment require careful consideration of available data.


In vitro human phase I metabolism of xenobiotics I: pesticides and related compounds used in agriculture and public health, May 2003.
This is the first revision of a database covering human phase I enzymes and their isoforms that metabolize pesticides and related compounds. The original version included enzymes that metabolize chloroacetamide and triazine herbicides, and organophosphorus insecticides. This revision also includes carbamate, nicotinoid, and pyrethroid insecticides and insect repellents.


Identification of nine novel variants across PAX3, SOX10, EDNRB, and MITF genes in Waardenburg syndrome with next-generation sequencing.
Waardenburg syndrome (WS) is a hereditary, genetically heterogeneous disorder characterized by variable presentations of sensorineural hearing impairment and pigmentation anomalies. This study aimed to investigate the clinical features of WS in detail and determine the genetic causes of patients with clinically suspected WS. A total of 24 patients from 21 Han-Taiwanese families were enrolled and underwent comprehensive physical and audiological examinations. We applied targeted next-generation sequencing (NGS) to investigate the potential causative variants in these patients and further validated the candidate variants through Sanger sequencing. We identified 19 causative variants of WS in our cohort. Of these variants, nine were novel and discovered in PAX3, SOX10, EDNRB, and MITF genes, including missense, nonsense, deletion, and splice site variants. Several patients presented with skeletal deformities, hypotonia, megacolon, and neurological disorders that were rarely seen in WS. This study revealed highly phenotypic variability in Taiwanese WS patients and demonstrated that targeted NGS allowed us to clarify the genetic diagnosis and extend the genetic variant spectrum of WS.


The dopamine D4/D2 receptor antagonist affinity ratio as a predictor of anti-aggression medication efficacy.
Aggression is a major clinical problem that spans multiple medical and psychiatric diagnoses. The etiology of aggression is complex, comprising social, psychological, and biological factors. Treatment of aggression is equally heterogeneous with structural (environmental), behavioral, and pharmacologic approaches. Among medications, mood stabilizers and antipsychotics are usually considered first line. Antidepressants are frequently recommended but their anti-aggression effect is limited. Within the available limited data, clozapine stands out as more effective than other antipsychotic medications. One of the prominent differences between clozapine and less effective medications is that the affinity of the compound to the dopamine D4 receptor is quite high and significantly greater than to the D2 receptor (defined as a ratio that is >1). Medications that inhibit both receptors equally, e.g., haloperidol, have anti-aggression properties that are less than seen with clozapine. A specific variant of the D4 receptor with an expansion of the third cytoplasmic loop, which interacts with the G protein second messenger system, has been implicated in the etiology of aggression. The proposal is put forward that blockade of the D4 receptor, without concomitant significant blockade of D2, increases the anti-aggression effect of the medication. This hypothesis can be tested using a new antipsychotic, asenapine, which is the only other antipsychotic with antagonistic affinity ratio of D4/D2>1.


Facilitation of voluntary swallowing by chemical stimulation of the posterior tongue and pharyngeal region in humans.
In this study, we investigated the functional difference between chemical stimulations of the posterior tongue (PT) and pharyngeal region (PR) for facilitation of voluntary swallowing in humans. The PT or PR stimulation consisted of infusion of water (distilled water), 0.3 M NaCl solution or olive oil (non-chemical stimulant) into the PT or the PR through a fine tube at a very slow infusion rate (0.2 ml/min). Water was used as a stimulant of water receptors. A solution of 0.3 M NaCl was used as an inhibitor of the response of water receptors and as a stimulant of salt taste receptors. Excitation of the mucosal receptors would facilitate voluntary swallowing and diminution of sensory inputs from the oral mucosa would induce difficulty in swallowing. Swallowing intervals (SIs) during voluntary swallowing were measured by submental electromyographic activity. Infusion of water into the PR shortened SI (facilitation of swallowing) and infusion of 0.3 M NaCl or olive oil into the same region prolonged it (difficulty in swallowing). On the other hand, infusion of water into the PT prolonged SI and infusion of 0.3 M NaCl into the same region shortened it. The results suggest that water receptors are localized in the PR and that salt taste receptors are almost absent in the PR and present in the PT. With diminution of sensory inputs from the oral mucosa, central inputs would play a dominant role in initiating swallowing voluntarily, and SI would be prolonged. With weak stimulation (infusion of 0.3 M NaCl into the PR or infusion of water into the PT), SI was prolonged and inter-individual variation in SI was pronounced, suggesting that the ability of the central regulation of swallowing to perform repetitive voluntary swallowing varies among subjects. With stimulation of water receptors or salt taste receptors, SI was shortened and inter-individual variation in SI was moderate, suggesting that sensory inputs are important for performing voluntary swallowing smoothly and that the sensory inputs compensate for the difficulty in performing swallowing caused by the central mechanism.


The effects of different intravenous feeding regimens on the rates of synthesis of alpha1-antitrypsin after surgery.
The effects of two nutritional regimens on the synthesis of alpha-1 antitrypsin were investigated postoperatively in gynaecological cancer patients. Total parenteral nutrition (TPN) or a hypocaloric amino acid mixture was administered on the day of surgery and continued for 3 days. The rate of synthesis of alpha-1 antitrypsin was estimated by a computer model from serial plasma concentrations of this protein and a reference protein, albumin. The hypocaloric amino acid mixture resulted in a more negative nitrogen balance than that produced during administration of TPN containing the same amount of nitrogen but more non-protein energy. Urinary excretion of 3-methylhistidine was significantly greater (p = 0.017) in the hypocaloric amino acid group (350 +/- 40 mumol/day; mean +/- SE) on the third postoperative day, as compared to the TPN group (240 +/- 20 mumol/day). In spite of this the synthesis of alpha-1 antitrypsin was apparently greater in the hypocaloric amino acid than in the TPN group. The accumulated plasma appearance rate of alpha-1 antitrypsin was significantly higher (p = 0.0465) in HAA group, at 70 h it was 490 +/- 40 compared to 400 +/- 20 times the pre-operative synthesis in the TPN group.


Gastric duplication-colonic fistula with colonic ulceration and bleeding.
An 11-month-old girl had massive rectal bleeding. A midabdominal mass was palpated. Ultrasound scan showed a large cystic mass with diffusely echogenic contents; Tc-99M radionuclide scan confirmed a duplication. Exploratory surgery and pathology examination showed a gastric duplication with formation of a fistula into the transverse colon with a colonic ulcer and hemorrhage. This combination of findings is presented as a rare cause of lower gastrointestinal hemorrhage in infancy.


Bax siRNA promotes survival of cultured and allografted granule cell precursors through blockade of caspase-3 cleavage.
Transplantation of neuronal precursor cells (NPCs) into the central nervous system could represent a powerful therapeutical tool against neurodegenerative diseases. Unfortunately, numerous NPCs die shortly after transplantation, predominantly due to caspase-dependent apoptosis. Using a culture of cerebellar neuronal precursors, we have previously demonstrated protective effect of the neuropeptide PACAP, which suppresses ceramide-induced apoptosis by blockade of the mitochondrial apoptotic pathway. The main objective of this study was to determine whether Bax repression can promote survival of NPCs allotransplanted into a host animal. In vivo and ex vivo experiments revealed that C2-ceramide increases Bax expression, while PACAP reverses this effect. In vitro tests using cerebellar NPCs demonstrated that the Bax-specific small interfering RNA (siRNA) could reduce their death and caspase-3 cleavage within the first 24 h. BrdU-labelled NPCs were subjected to transfection procedure with or without siRNA introduction before using for in vivo transplantation. Twenty-four hours after, the allografted NPCs containing siRNA showed significantly reduced level of caspase-3 cleavage, and the volume of their implants was almost twofold higher than in the case of empty-transfected precursors. These data evidence an important role of Bax in life/death decision of grafted NPCs and suggest that RNA interference strategy may be applicable for maintaining NPCs survival within the critical first hours after their transplantation.


Global and regional CpG methylation in pheochromocytomas and abdominal paragangliomas: association to malignant behavior.
This study aims to quantitatively assess promoter and global methylation changes in pheochromocytomas and abdominal paragangliomas and its relation to tumor phenotypes. A panel of 53 primary tumors (42 benign, 11 malignant) was analyzed by quantitative bisulfite pyrosequencing. Based on methylation levels in the tumor suppressor genes, p16(INK4A), CDH1, DCR2, RARB, RASSF1A, NORE1A, TP73, APC, DAPK1, p14(ARF), and PTEN, a CpG island methylator phenotype (CIMP) was defined as concerted hypermethylation in three or more genes. Mean Z scores for the hypermethylated promoters were calculated to characterize overall promoter methylation. Global DNA methylation was quantified for LINE-1 promoter sequences and by using luminescent methylation analysis. Five primary tumors (9.4%) exhibited a CIMP phenotype, four of which were malignant paragangliomas. CIMP was significantly associated with malignant behavior (P = 0.005) and younger age at presentation (P < 0.007) but did not result from BRAF V600E mutation. Global hypomethylation of LINE-1 elements was observed in tumors compared with normal adrenal samples (P < 0.02). We here describe the identification of CIMP in abdominal paragangliomas and a strong association of this phenotype with malignant behavior, as well as young age at presentation. The findings raise a prospective for potential benefits of epigenetically acting drugs for a subgroup of young abdominal paraganglioma patients with adverse prognosis.


Catalytic production of cyclic carbonates mediated by lanthanide phenolates under mild conditions.
Readily available lanthanide complexes stabilized by a bridged poly(phenolate) ligand have been used for the first time as efficient catalysts for the insertion of CO2 into epoxides to generate cyclic carbonates with high activity, high selectivity, and a wide substrate scope under mild conditions.


A preliminary study on pain perception and tobacco smoking.
Ischaemic pain onset and tolerance in response to a pneumatic blood pressure cuff were compared in 17 non-deprived smokers, 30 deprived smokers, 15 smokers chewing nicotine gum and 16 non-smokers. Following removal of the cuff, all subjects completed the McGill pain questionnaire, rating pain in terms of its sensory, affective, evaluative and miscellaneous qualities. Group differences were found in the time elapsing before reporting the first twinge of pain. Non-deprived smokers had the shortest period to onset of pain. The longer the smokers had been deprived of cigarettes, the longer before the onset of pain. Non-deprived smokers also had a significantly shorter period of pain tolerance compared to deprived smokers. Non-deprived smokers tended to have a faster pain onset and a shorter tolerance period compared to non-smokers. Smokers' indices of pain were significantly higher on the several sub-scales describing the qualitative pain experience compared to non-smokers and to smokers deprived of cigarettes for more than one hour. Deprivation of cigarettes appears to diminish smokers' sensitivity to pain significantly below that of non-smokers and smoking cigarettes tends to heighten sensitivity to, or beyond, the level of non-smokers.


Amyloid beta-protein precursor deposition in rat hippocampus lesioned by ibotenic acid injection.
Ibotenic acid was injected into 3 parts of the lateral rat hippocampus. The animals were sacrificed 100 days after treatment, and studied immunohistochemically. The lesioned side of the hippocampus was highly atrophic with extensive neuronal loss and gliosis. Although silver staining revealed no particular structures such as neurofibrillary tangles or senile plaques, globular and granular depositions of amyloid beta-protein precursor (APP) immunoreactivity was observed by immunostaining in the lesion with the monoclonal antibody (clone 22C11). Increased immunoreactivities of glial fibrillary acidic protein (GFAP) and ubiquitin were found in the lesioned area, while the immunoreactivities of microtubule-associated protein 2 (MAP2) and 200 kDa neurofilament subunit protein (NF-H) were diminished. The results indicate that APP deposition is formed in the lesioned area where neuronal degeneration is produced by ibotenic acid in rat hippocampus.


Drosophila DJ-1 mutants show oxidative stress-sensitive locomotive dysfunction.
DJ-1 is linked to an early-onset autosomal recessive Parkinson's disease (PD) characterized primarily by selective loss of dopaminergic (DA) neurons, which results in motor disturbances. However, our understanding on how mutations in DJ-1 are related to PD is unclear. Here, we isolated the DJ-1 orthologue, DJ-1beta, in Drosophila and characterized its expression and loss-of-function mutants. We observed its strongest expression in the adult stage of development and ubiquitous expression in the larval brain. Our homozygous mutants showed severe defects in locomotor ability without loss of DA neurons, consistent with the previous mice DJ-1 mutant studies ([Goldberg, M.S., Pisani, A., Haburcak, M., Vortherms, T.A., Kitada, T., Costa, C., Tong, Y., Martella, G., Tscherter, A., Martins, A., et al., 2005. Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron 45, 489-496.]; [Kim, R.H., Smith, P.D., Aleyasin, H., Hayley, S., Mount, M.P., Pownall, S., Wakeham, A., You-Ten, A.J., Kalia, S.K., Horne, P., Westaway, D., Lozano, A.M., Anisman, H., Park, D.S., Mak, T.W., 2005. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and oxidative stress. Proc. Natl. Acad. Sci. USA 102, 5215-5220.]; [Chen, L., Cagniard, B., Mathews, T., Jones, S., Koh, H.C., Ding, Y., Carvey, P.M., Ling, Z., Kang, U.J., Zhuang, X., 2005. Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. J. Biol. Chem. 280, 21418-21426.]). The locomotor activity of DJ-1beta mutants was further decreased by paraquat-induced oxidative stress. Moreover, we found that Drosophila DJ-1 is prominently localized in mitochondria, suggesting that DJ-1 functions as a protector against oxidative stress in mitochondria.


Accessibility of nucleosomal DNA to V(D)J cleavage is modulated by RSS positioning and HMG1.
B and T cell receptor gene assembly by V(D)J recombination is tightly regulated during lymphoid development. The mechanisms involved in this regulation are poorly understood. Here we show that nucleosomal DNA is refractory to V(D)J cleavage. However, the presence of HMG1, a chromatin-associated nonhistone DNA-binding protein, stimulates V(D)J cleavage of nucleosomal templates. This HMG1 stimulation is differentially affected by the rotational or translational positioning of the recombination signal sequence on the histone octamer, with cleavage of the 12 bp spacer RSS showing sensitivity to rotational position and the 23 bp spacer RSS affected by its displacement from the dyad. These results suggest that V(D)J recombination can be modulated by controlling substrate accessibility and cleavage at the level of an individual nucleosome.


Epigenetic reprogramming of cell cycle genes by ACK1 promotes breast cancer resistance to CDK4/6 inhibitor.
Hormone receptor-positive, HER2-negative advanced breast cancers exhibit high sensitivity to CDK4/6 inhibitors such as palbociclib. However, most patients inevitably develop resistance, thus identification of new actionable therapeutic targets to overcome the recurrent disease is an urgent need. Immunohistochemical studies of tissue microarray revealed increased activation of non-receptor tyrosine kinase, ACK1 (also known as TNK2) in most of the breast cancer subtypes, independent of their hormone receptor status. Chromatin immunoprecipitation studies demonstrated that the nuclear target of activated ACK1, pY88-H4 epigenetic marks, were deposited at cell cycle genes, CCNB1, CCNB2 and CDC20, which in turn initiated their efficient transcription. Pharmacological inhibition of ACK1 using its inhibitor, (R)-9b dampened CCNB1, CCNB2 and CDC20 expression, caused G2/M arrest, culminating in regression of palbociclib-resistant breast tumor growth. Further, (R)-9b suppressed expression of CXCR4 receptor, which resulted in significant impairment of metastasis of breast cancer cells to lung. Overall, our pre-clinical data identifies activated ACK1 as an oncogene that epigenetically controls the cell cycle genes governing the G2/M transition in breast cancer cells. ACK1 inhibitor, (R)-9b could be a novel therapeutic option for the breast cancer patients that have developed resistance to CDK4/6 inhibitors.


Realising the full potential of MR-PHeWAS in cancer.
MR-PHeWAS is a powerful new design for discovering causal mechanisms between a disease and its many candidate risk factors in a hypothesis-free manner. This technique has great potential in the field of cancer research, provided that both powerful and principled statistical approaches are used.


Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation.
Gli family members mediate constitutive Hedgehog signaling in the common skin cancer, basal cell carcinoma (BCC). Snail/Snai1 is rapidly induced by Gli1 in vitro, and is coexpressed with Gli1 in human hair follicles and skin tumors. In the current study, we generated a dominant-negative allele of Snail, SnaZFD, composed of the zinc-finger domain and flanking sequence. In promoter-reporter assays, SnaZFD blocked the activity of wild-type Snail on the E-cadherin promoter. Snail loss-of-function mediated by SnaZFD or by one of several short hairpin RNAs inhibited transformation of RK3E epithelial cells by Gli1. Conversely, enforced expression of Snail promoted transformation in vitro by Gli1, but not by other genes that were tested, including Notch1, ErbB2, and N-Ras. As observed for Gli1, wild-type Snail repressed E-cadherin in RK3E cells and induced blebbing of the cytoplasmic membrane. Induction of a conditional Gli1 transgene in the basal keratinocytes of mouse skin led to rapid upregulation of Snail transcripts and to cell proliferation in the interfollicular epidermis. Established Gli1-induced skin lesions exhibited molecular similarities to BCC, including loss of E-cadherin. The results identify Snail as a Gli1-inducible effector of transformation in vitro, and an early Gli1-responsive gene in the skin.


Qualitative evaluation of the general practitioner chronic non-communicable diseases training programme.
In China, general practitioners have limited ability to provide care for common chronic non-communicable diseases because they lack postgraduate training. In an attempt to improve general practitioners' skills in this regard, the present authors previously launched the Chronic Non-Communicable Diseases Training Programme. The present study aims to evaluate the effectiveness of this programme. Thirty-nine trainee general practitioners who participated in the programme underwent semi-structured interviews, which explored how they performed the training, what they achieved from the programme, and their suggestions for future programmes. The interview data were analysed using a thematic analysis approach. Under the guidance of supervisors, the thirty-nine trainee general practitioners completed the structured but individualised training plan, which comprised a four-day basic theory class, 3 months practising in a ward, and 6 months assisting in an outpatient clinic. They reported an improvement in their ability to provide care for chronic non-communicable diseases and perform two-way referral, as well as their communication with patients. They also reported that, since returning to their communities, they had become more confident, were building better relationships with their patients, and had changed their clinic behaviours from copying prescriptions to making medical decisions independently. Their principal suggestion for the training programme was to alter the order of the training, as they preferred to practice in the ward before assisting in the outpatient clinic. The course comprised a learner-centred, practice- and apprenticeship-based, general-practitioner training programme. Given the participants' progress and the beneficial effects of the programme reported in the interview data, it appears to be worthwhile to extend the General Practitioner Chronic Non-Communicable Diseases Training Programme.


Critical discussion in epidemiology: problems with the Popperian approach.
There has been a renewed interest in the philosophical and scientific basis of epidemiology in recent years. In particular, it has been argued that Popper's philosophy should be adopted by epidemiologists, an assertion that has met with some scepticism. However, most criticisms of Popper's approach have been from an inductivist viewpoint, concerned with the generation of theories, whereas Popper's concern is with the testing of theories, and the two schools have been largely "talking past each other". We present a critique of Popper from within his own domain of interest. Examples are presented to show that Popper's philosophy is incomplete even for the physical sciences on which it is based, and that it is particularly inappropriate for epidemiology. Popper's approach makes sense only under the narrow way he has chosen to define science, and thus provides only a possible answer to a small set of fundamental problems of science and its use in society. The recent Popperian "trend" has a positive aspect in that it has fostered deductive thinking, and exposed the shortcomings of induction. However, the restrictive Popperian framework actually inhibits discussion despite its veneer of "critical discussion". A more pluralistic approach is needed at this stage of the development of epidemiology.


BAR the door: cancer suppression by amphiphysin-like genes.
The evolutionarily conserved amphiphysin-like genes Bin1 and Bin3 function in membrane and actin dynamics, cell polarity, and stress signaling. Recent genetic studies in mice discriminate non-essential roles in endocytic processes commonly ascribed to amphiphysins from essential roles in cancer suppression. Bin1 acts in default pathways of apoptosis and senescence that are triggered by the Myc and Raf oncogenes in primary cells, and Bin1 gene products display a 'moonlighting function' in the nucleus where a variety of other 'endocytic' proteins are also found. Together, genetic investigations in yeast, flies, and mice suggest that amphiphysin-like adapter proteins may suppress cancer by helping integrate cell polarity signals generated by actin and vesicle dynamics with central regulators of cell cycle arrest, apoptosis, and immune surveillance.


Three-dimensional networks based on trinuclear motifs with tricomponent azide-carboxylate-tetrazolate cobridges: synthesis, structure and magnetic properties.
Two 3D coordination polymers of Mn(II) with azide and bifunctional zwitterionic ligands bearing both carboxylate and tetrazolate groups, 1-(carboxylatomethyl)-3-(5-tetrazolato)pyridinium (L(1)) and 1-(carboxylatoethyl)-4-(5-tetrazolato)pyridinium (L(2)), were synthesized, and structurally and magnetically characterized. They are formulated as [Mn(3)(L(1))(2)(N(3))(4)(H(2)O)(2)](n)·4nH(2)O (1) and [Mn(3)(L(2))(2)(N(3))(4)(H(2)O)(3)](n)·3.5nH(2)O (2). In both compounds, octahedral Mn(II) ions are linked by the mixed (μ(2)-EO-N(3))(μ(2)-syn,syn-COO)(μ(2)-N(2),N(3)-CN(4)) (CN(4) = tetrazolate and EO = end-on) triple bridges to give anionic linear trinuclear motifs. The motifs are connected through EE-N(3) (EE = end-to-end) bridges to give layers and chains in 1 and 2, respectively, and the cationic pyridinium spacers serve to interlink the layers or chains into three-dimensional frameworks with the α-Po and CdSO(4)-type topology, respectively. Magnetic studies demonstrated that the magnetic interactions within and between the trinuclear motifs, through the tricomponent and EE-N(3) bridges, respectively, are both antiferromagnetic in both compounds.


Ultrasonographic Assessment of Diaphragmatic Inspiratory Amplitude and Its Association with Postoperative Pulmonary Complications in Upper Abdominal Surgery: A Prospective, Longitudinal, Observational Study.
Diaphragmatic dysfunction following upper abdominal surgery is less recognized due to a lack of diagnostic modality for bedside evaluation. We used point-of-care ultrasound to evaluate the diaphragmatic inspiratory amplitude (DIA) in upper abdominal surgery for cancer. Our primary hypothesis was DIA would be reduced in the immediate postoperative period in patients with postoperative pulmonary complications (PPCs). Our aim was to identify an optimal cutoff of DIA for the diagnosis of PPCs. We conducted a prospective, observational study in patients aged 18-75 years undergoing elective, upper abdominal oncological surgeries under combined general and epidural anesthesia. Ultrasound evaluation of the diaphragm was done by measuring the DIA in the right and left hemidiaphragms during quiet and deep breathing on the day before surgery and postoperative days (PODs) 1, 2, and 3. Patients were followed up for PPCs until POD 7. The linear mixed-effects model examined the association between DIA and PPCs and other perioperative factors. Receiver-operating characteristics analysis was done to determine the optimal cutoff of DIA in diagnosing PPCs. DIA measured in the 162 patients showed a significant decrease in their absolute values postoperatively from its preoperative baseline measurement. This decrease in DIA was significantly associated with PPC [right hemidiaphragm, β = -0.17, 95% confidence interval (CI) -0.31 to -0.02, p = 0.001 during quiet breathing; left hemidiaphragm, β = -0.24, 95% CI = -0.44 to -0.04, p = 0.018 and β = -0.40, 95% CI = -0.71 to -0.09, p = 0.012 during quiet and deep breathing, respectively]. A cutoff value of DIA of left hemidiaphragm at 1.3 cm during quiet breathing and 1.6 cm during deep breathing had a sensitivity of 77 and 75%, respectively, in their ability to diagnose PPCs [left hemidiaphragm quiet breathing, area under the curve (AUC): 0.653, 95% CI 0.539-0.768, p = 0.015; left hemidiaphragm deep breathing, AUC: 0.675, 95% CI 0.577-0.773, p = 0.007]. Following upper abdominal surgery, the DIA is decreased and associated with PPCs. DIA of left hemidiaphragm less than 1.3 cm during quiet breathing and 1.6 cm during deep breathing has a sensitivity of 77 and 75%, respectively, in diagnosing PPCs following upper abdominal surgery. Vanamail PV, Balakrishnan K, Prahlad S, Chockalingam P, Dash R, Soundararajan DK. Ultrasonographic Assessment of Diaphragmatic Inspiratory Amplitude and Its Association with Postoperative Pulmonary Complications in Upper Abdominal Surgery: A Prospective, Longitudinal, Observational Study. Indian J Crit Care Med 2021;25(9):1031-1039.


The use of vascular closure devices outside the catheterization laboratory after neurointerventional procedures is safe and effective: evidence from a retrospective study.
To investigate the feasibility and safety of vascular closure device (VCD) deployment outside the catheterization laboratory. Medical records were reviewed of all 799 patients (396 men; mean age 56 ± 16 years) who underwent deployment of 918 VCDs following diagnostic or therapeutic neurointerventional procedures over a 2-year period at 2 comprehensive stroke centers. The rates of major vascular complications in patients undergoing VCD deployment in and outside the catheterization laboratory were compared. Major vascular complications were adjudicated using definitions by the Society of Interventional Radiology; comparisons were made between different procedure types and closure devices. During the observation period, 103 (11.2%) of 918 VCD deployments were performed outside the catheterization laboratory. Age, gender, procedure type, and device types were not different between the groups. A total of 10 (1.1%) major vascular complications occurred, including dissection requiring angioplasty (n = 1), hematoma requiring blood transfusion (n = 4), pseudoaneurysm requiring thrombin injection (n = 2), and lower limb ischemia necessitating surgical removal of the VCD (n = 3). Rates of major vascular complications were not significantly different between VCDs deployed inside the catheterization laboratory [1.0% (8/815)] compared to outside [1.9% (2/103), p = 0.3]. VCD deployment outside the catheterization laboratory does not increase the rate of major vascular complications and may be an alternative approach for femoral artery hemostasis when VCD deployment needs to be deferred.


β-catenin-driven binary cell fate decisions in animal development.
The Wnt/β-catenin pathway plays key roles during animal development. In several species, β-catenin is used in a reiterative manner to regulate cell fate diversification between daughter cells following division. This binary cell fate specification mechanism has been observed in animals that belong to very diverse phyla: the nematode Caenorhabditis elegans, the annelid Platynereis, and the ascidian Ciona. It may also play a role in the regulation of several stem cell lineages in vertebrates. While the molecular mechanism behind this binary cell fate switch is not fully understood, it appears that both secreted Wnt ligands and asymmetric cortical factors contribute to the generation of the difference in nuclear β-catenin levels between daughter cells. β-Catenin then cooperates with lineage specific transcription factors to induce the expression of novel sets of transcription factors at each round of divisions, thereby diversifying cell fate. For further resources related to this article, please visit the WIREs website.


Genetic and environmental determinants of serum lipids and lipoproteins in French Canadian families.
The contribution of genetic and environmental factors in serum triglycerides (TG), total cholesterol (CHOL), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and HDL-C/CHOL ratio were studied in 1630 subjects from 375 families of French descent by using a path analysis procedure. Familial correlations were computed in several pairs of biological relatives and relatives by adoption after adjustment for age and gender effects and after further adjustment for physical fitness, level of habitual physical activity, total body fat and fat distribution, diet, smoking, and alcohol consumption. The model of path analysis allowed the separation of transmissible variance (t2) into genetic (h2) and cultural (b2) components of inheritance. Under the most parsimonious solution and after adjustment for age, gender, and concomitants, the transmissible variance was entirely accounted for by genetic factors (t2 = h2), with h2 estimates of 0.52, 0.55, 0.60, and 0.63 for TG, CHOL, LDL-C, HDL-C, and HDL-C/CHOL, respectively. These estimates were similar to those obtained after adjustment for age and gender effects only. The contribution of nontransmissible environmental factors ranged from 0.48 for TG to 0.37 for HDL-C/CHOL ratio. These results suggest that both genetic and environmental factors contribute to the variation in blood lipids and lipoproteins in this population and that nongenetic influences are not associated with cultural factors transmitted across generations.


The operon that encodes the sigma subunit of RNA polymerase also encodes ribosomal protein S21 and DNA primase in E. coli K12.
The sigma subunit of E. coli RNA polymerase is encoded by the rpoD gene. Within the sequence upstream from rpoD, we have identified the structural genes rpsU and dnaG, which encode the 30S ribosomal protein S21 and DNA primase, respectively. The three genes are in the order rpsU, dnaG rpoD, and are all encoded by the same DNA strand. Analysis of in vivo transcripts from this region shows that these genes are all within the same operon. By correlating the 5' and 3' ends of in vivo transcripts with our DNA sequence, we have identified several regulatory features of the operon. These features include tandem promoters upstream from rpsU, a terminator between rpsU and dnaG, an RNA processing site separating dnaG and rpoD, and the operon terminator just downstream from rpoD. Immediately upstream of the operon promoters is an active promoter for an unidentified gene. We discuss the regulatory significance of the operon features and the biological significance of an operon encoding proteins essential for translation, replication and transcription.


Exploring how ecological and epidemiological processes shape multi-host disease dynamics using global sensitivity analysis.
We use global sensitivity analysis (specifically, Partial Rank Correlation Coefficients) to explore the roles of ecological and epidemiological processes in shaping the temporal dynamics of a parameterized SIR-type model of two host species and an environmentally transmitted pathogen. We compute the sensitivities of disease prevalence in each host species to model parameters. Sensitivity rankings are calculated, interpreted biologically, and contrasted for cases where the pathogen is introduced into a disease-free community and cases where a second host species is introduced into an endemic single-host community. In some cases the magnitudes and dynamics of the sensitivities can be predicted only by knowing the host species' characteristics (i.e., their competitive abilities and disease competence) whereas in other cases they can be predicted by factors independent of the species' characteristics (specifically, intraspecific versus interspecific processes or a species' roles of invader versus resident). For example, when a pathogen is initially introduced into a disease-free community, disease prevalence in both hosts is more sensitive to the burst size of the first host than the second host. In comparison, disease prevalence in each host is more sensitive to its own infection rate than the infection rate of the other host species. In total, this study illustrates that global sensitivity analysis can provide useful insight into how ecological and epidemiological processes shape disease dynamics and how those effects vary across time and system conditions. Our results show that sensitivity analysis can provide quantification and direction when exploring biological hypotheses.


Refractory Hyperlactatemia and Hypoglycemia in an Adult with Non-Hodgkin's Lymphoma: A Case Report and Review of the Warburg Effect.
Lactate is a byproduct of anaerobic glycolysis, and hyperlactatemia is commonly seen in critically ill patients. We report a case of an elderly male presenting with undifferentiated constitutional symptoms, anemia, thrombocytopenia, severe lactic acidosis, refractory hypoglycemia, and a newly detected abdominal mass. A dedicated workup ruled out infectious etiologies and revealed metastatic non-Hodgkin's lymphoma. This study explores etiologies of type B lactic acidosis in oncology patients, with a focus on Warburg's effect, and its potential for prognostication.


Fear-avoidance, pain acceptance and adjustment to chronic pain: a cross-sectional study on a sample of 686 patients with chronic spinal pain.
Prior studies found a range of psychological factors related to the perception of pain, maintenance of pain and disability. The aim of this study was to investigate the role of pain fear-avoidance and pain acceptance in chronic pain adjustment. The influence of two diathesis variables (resilience and experiential avoidance) was also analyzed. The sample was composed of 686 patients with chronic spinal pain. Structural equation modelling analyses were used to test the hypothetical model. Experiential avoidance was associated with pain fear-avoidance, and resilience was strongly associated with pain acceptance. Pain acceptance was negatively associated with negative mood, functional impairment and pain intensity. However, pain fear-avoidance was positively and significantly associated with negative mood but had no association with pain intensity. There was a path from functional impairment to pain fear-avoidance. Resilience and experiential avoidance appear as variables which could explain individual differences in pain experience.


Hedgehog pathway activation in human transitional cell carcinoma of the bladder.
The Hedgehog (Hh) signalling pathway functions as an organiser in embryonic development. Recent studies have shown constitutive activation of this pathway in various malignancies, but its role in bladder cancer remains poorly studied. Expression levels of 31 genes and 9 microRNAs (miRNAs) involved in the Hh pathway were determined by quantitative real-time RT-PCR in 71 bladder tumour samples (21 muscle-invasive (MIBC) and 50 non-muscle-invasive (NMIBC) bladder cancers), as well as in 6 bladder cancer cell lines. The SHH ligand gene and Gli-inducible target genes (FOXM1, IGF2, OSF2, H19, and SPP1) were overexpressed in tumour samples as compared with normal bladder tissue. SHH overexpression was found in 96% of NMIBC and 52% of MIBC samples, as well as in two bladder cancer cell lines. Altered expression of miRNAs supported their oncogene or tumour-suppressor gene status. In univariate analysis, high expression levels of PTCH2, miRNA-92A, miRNA-19A, and miRNA-20A were associated with poorer overall survival in MIBC (P=0.02, P=0.012, P=0.047, and P=0.036, respectively). We observed constitutive activation of the Hh pathway in most NMIBC and about 50% of MIBC. We also found that some protein-coding genes and miRNAs involved in the Hh pathway may have prognostic value at the individual level.


Association between depression, parameters of adiposity and genetic polymorphisms of pro-inflammatory cytokines: IL-1α, IL-1β, IL-2 and IL-6 in subjects over 55 years old.
During the last few decades, adiposity has become a relatively common phenomenon worldwide. The available data on the effects of pro-inflammatory factors in both depression and adiposity has been attracting great attention. We sought to assess the prevalence of -889C>T IL-1α, -31T>C and -511C>T IL-1β, -330T>G IL-2 and -174G>C IL-6 genes and their association with adiposity and depression in Polish subjects. A cohort study was conducted in 2013/2014, covering a sample of 297 individuals (217 female and 80 male). Anthropometric data was handled using the BIA analysis method, while for genotyping PCR-RFLP techniques were used. A positive correlation between depression and anthropometric parameters: adipose tissue (in kg) and adipose tissue (in %) (R=0.135 and p=0.02, R=0.114 and p<0.05, respectively) was found. No association between studied polymorphisms and depression was observed. Although it was not possible to demonstrate any influence of the studied polymorphisms as the genetic modulator of depression, authors believe that the presented data are noticeable and may provide the basis for future studies on larger groups.


Comparison of platelet count and platelet protein methods for determination of platelet MAO activity.
Platelet monoamine oxidase (MAO) activity in 10 normal volunteers was studied as a function of platelet protein or electronically-determined platelet counts. Comparisons of the two methods were made for samples assayed on the same day as well as one week later. The MAO activities resulting from both methods were significantly correlated and reproducible but the results of the platelet count method were, in most instances, slightly but significantly more reliable than the platelet protein method. The relevance of these results to the controversy concerning platelet MAO activity in schizophrenia is discussed.


Elements of a successful quality improvement and patient safety program in obstetrics and gynecology.
In this article we present the elements of one approach to quality improvement and patient safety that we believe can be successful and sustainable in the field of obstetrics and gynecology, along with several strategies (and caveats) that have worked and are working in academic and nonacademic institutions in the United States. Also included are several noteworthy definitions of quality to provide some additional perspectives on what is meant by quality in health care.


Dry matter production and photosynthetic capacity in Gossypium hirsutum L. under conditions of slightly suboptimum leaf temperatures and high levels of irradiance.
Gossypium hirsutum L. var. Delta Pine 61 was cultivated in controlled-environment chambers at 1000-1100 μmol photosynthetically active photons m-2 s-1 (medium photon flux density) and at 1800-2000 μmol photons m-2 s-1 (high photon flux density), respectively. Air temperatures ranged from 20° to 34°C during 12-h light periods, whereas during dark periods temperature was 25° C in all experiments. As the leaf temperature decreased from about 33° to 27° C, marked reductions in dry matter production, leaf chlorophyll content and photosynthetic capacity occurred in plants growing under high light conditions, to values far below those in plants growing at 27° C and medium photon flux densities. The results show that slightly suboptimum temperatures, well above the so-called chilling range (0-12° C), greatly reduce dry matter production in cotton when combined with high photon flux densities equivalent to full sunlight.


Quantitative evaluation of carotid plaque echogenicity by integrated backscatter analysis: correlation with symptomatic history and histologic findings.
Echogenicity of carotid plaque well reflects the risk of ischemic stroke and may be predictive of the histologic content of the plaque. However, objective evaluation of plaque echogenicity has been hampered by a lack of established quantitative measures. This study examined the relation between echogenicity assessed by integrated backscatter (IBS) analysis and (1) symptomatic history and (2) histologic features of carotid plaques. We used acoustic densitometry to quantify by IBS analysis the echogenicity of 31 carotid plaques of 26 patients undergoing carotid endarterectomy or stenting. IBS was subsequently compared with histologic findings of the respective tissue in 10 patients who underwent endarterectomy. The IBS value was calibrated with 2 reference structures (vessel lumen and adventitia) as the IBS index. The IBS index of symptomatic plaques was lower than that of asymptomatic plaques (23.1 +/- 12.5 vs. 36.5 +/- 18.2, p < 0.05). The IBS index in fatty/necrotic atheromatous sites (n = 20, 16.6 +/- 10.7) was lower than that in fibrous (n = 26, 42.4 +/- 13.6, p < 0.01) or calcified (n = 11, 87.7 +/- 17.4, p < 0.01) sites and the same as that in intraplaque hemorrhagic sites (n = 50, 23.6 +/- 16.9). Carotid plaque echogenicity, as quantitatively assessed by IBS analysis, correlates well with the presence or absence of prior symptoms and histologic contents of the plaques. IBS analysis may aid in the assessment of carotid plaque-related risk of stroke.


Taxonomic significance of trichomes micromorphology in cucurbits.
Studies on trichomes micromorphology using Scanning Electron Microscope (SEM) were undertaken in 23 species with one variety under 13 genera of the family Cucurbitaceae (viz., Benincasa hispida (Thunb.) Cogn., Citrullus lanatus (Thunb.) Matsum. & Nakai, Cucumis melo var. agrestis Naudin, Cucumis sativus L., Diplocyclos palmatus (L.) C. Jeffrey, Edgaria dargeelingensis C.B. Clarke, Gynostemma burmanicum King ex Chakr., Gynostemma pentaphyllum (Thunb.) Makino, Gynostemma pubescens (Gagnep.) C.Y. Wu, Hemsleya dipterygia Kuang & A.M. Lu, Lagenaria siceraria (Molina) Standl., Luffa acutangula (L.) Roxb., Luffa cylindrica M. Roem., Luffa echinata Roxb., Melothria heterophylla (Lour.) Cogn., Melothria leucocarpa (Blume) Cogn., Melothria maderspatana (L.) Cogn., Sechium edule (Jacq.) Sw., Thladiantha cordifolia (Blume) Cogn., Trichosanthes cucumerina L., T. cucumerina var. anguina (L.) Haines, Trichosanthes dioica Roxb., Trichosanthes lepiniana (Naudin) Cogn. and T. tricuspidata Lour.). The trichomes in the family Cucurbitaceae vary from unicellular to multicellular, conical to elongated, smooth to ridges, with or without flattened disk at base and cyctolithic appendages, thin to thick walled, curved at apices to blunt. Trichomes micromorphology in the family Cucurbitaceae was found significant taxonomically.


Organically Modified Bentonite as an Efficient and Reusable Adsorbent for Triclosan Removal from Water.
Triclosan, an antibacterial agent, in the environment is of great concern; thus, an efficient method for its removal from an aqueous system is required. Removal of triclosan from water was achieved by an organically modified bentonite, dioctadecyldimethylammonium bentonite. The highest adsorbed amount achieved under the optimized conditions was 1750 mg·g-1, which is higher than that reported using such adsorbents as activated carbons, carbon nanotubes, zeolites, and other nanoporous materials. Complete removal of triclosan was achieved from the aqueous triclosan solution at a concentration 10 mg·L-1 using 3 mg/60 mL of 2C18-BT. The adsorbent was reusable, as examined by washing and reuse of the adsorbent for 5 cycles.


Evaluating aggregate effects of rare and common variants in the 1000 Genomes Project exon sequencing data using latent variable structural equation modeling.
Methods that can evaluate aggregate effects of rare and common variants are limited. Therefore, we applied a two-stage approach to evaluate aggregate gene effects in the 1000 Genomes Project data, which contain 24,487 single-nucleotide polymorphisms (SNPs) in 697 unrelated individuals from 7 populations. In stage 1, we identified potentially interesting genes (PIGs) as those having at least one SNP meeting Bonferroni correction using univariate, multiple regression models. In stage 2, we evaluate aggregate PIG effects on trait, Q1, by modeling each gene as a latent construct, which is defined by multiple common and rare variants, using the multivariate statistical framework of structural equation modeling (SEM). In stage 1, we found that PIGs varied markedly between a randomly selected replicate (replicate 137) and 100 other replicates, with the exception of FLT1. In stage 1, collapsing rare variants decreased false positives but increased false negatives. In stage 2, we developed a good-fitting SEM model that included all nine genes simulated to affect Q1 (FLT1, KDR, ARNT, ELAV4, FLT4, HIF1A, HIF3A, VEGFA, VEGFC) and found that FLT1 had the largest effect on Q1 (βstd = 0.33 ± 0.05). Using replicate 137 estimates as population values, we found that the mean relative bias in the parameters (loadings, paths, residuals) and their standard errors across 100 replicates was on average, less than 5%. Our latent variable SEM approach provides a viable framework for modeling aggregate effects of rare and common variants in multiple genes, but more elegant methods are needed in stage 1 to minimize type I and type II error.


Association of exercise with smoking-related symptomatology, smoking behavior and impulsivity in men and women.
Despite extensive efforts to develop effective smoking cessation interventions, 70-85% of American cigarette smokers who quit relapse within one year. Exercise has shown promise as an intervention; however, many results have been equivocal. This study explored how exercise is associated with smoking-related symptomatology, smoking behavior and impulsivity in male and female smokers. Participants were recruited throughout the United States using the on-line crowdsourcing platform, Amazon's Mechanical Turk. They completed a survey with self-report measures assessing exercise, smoking-related symptomatology, smoking behavior and impulsivity. Differences between men and women were tested using t- and chi-square tests. Regression analyses tested for associations between exercise and smoking-related symptomatology, smoking behavior and impulsivity. Participants (N = 604) were, on average, 32 (SD = 6.2) years old, mostly Caucasian, with at least some college education and approximately half were women. Women exercised slightly less than men and had more negative affect, craving, physical symptoms and withdrawal. Women smoked more cigarettes per day, had greater nicotine dependency and more years of smoking. Positive affect was positively associated with exercise for both men and women; however, this association was significantly stronger in women. Negative affect and withdrawal were inversely associated with exercise for women only. Impulsivity was inversely associated with exercise for both men and women. Exercise was significantly associated with several smoking-related symptomatology, smoking behavior and impulsivity variables for both men and women, suggesting that exercise may be a useful intervention for smoking cessation. Future prospective research should determine how exercise directly impacts smoking cessation.


[Application of mini-invasive technologies in the treatment of gastrointestinal bezoars].
The data on etiology, clinical signs, diagnosis and variety of approaches to the treatment of gastrointestinal bezoars were presented, basing on the worldwide literature analysis. The results of surgical treatment of patients for bezoars, using miniinvasive methods, are presented.


Raman spectroscopy combined with comprehensive gas chromatography for label-free characterization of plasma-derived extracellular vesicle subpopulations.
Raman spectroscopy together with comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GCxGC-TOFMS) was employed to characterize exomere- (<50 nm) and exosome-sized (50-80 nm) EVs isolated from human plasma by the novel on-line immunoaffinity chromatography - asymmetric flow field-flow fractionation method. CD9+, CD63+, and CD81+ EVs were selected to represent general EV subpopulations secreted into plasma, while CD61+ EVs represented the specific EV subset derived from platelets. Raman spectroscopy could distinguish EVs from non-EV particles, including apolipoprotein B-100-containing lipoproteins, signifying its potential in EV purity assessment. Moreover, platelet-derived (CD61+) EVs of both exomere and exosome sizes were discriminated from other EV subpopulations due to different biochemical compositions. Further investigations demonstrated composition differences between exomere- and exosome-sized EVs, confirming the applicability of Raman spectroscopy in distinguishing EVs, not only from different origins but also sizes. In addition, fatty acids that act as building blocks for lipids and membranes in EVs were studied by GCxGC-TOF-MS. The results achieved highlighted differences in EV fatty acid compositions in both esterified (membrane lipids) and non-esterified (free fatty acids) fractions, indicating possible differences in membrane structures, biological functions, and roles in cell-to-cell communications of EV subpopulations.


Mild primary hyperparathyroidism as defined in the Italian Society of Endocrinology's Consensus Statement: prevalence and clinical features.
Mild primary hyperparathyroidism (PHPT) was recently clearly defined for the first time. Our study was thus aimed to pinpoint proportion and clinical characteristics of this kind of patients. We retrospectively evaluated our series of 360 consecutive patients with PHPT, selecting those with all features allowing a correct classification (serum total and ionized calcium, phosphate, creatinine, PTH, 25OHD, urinary calcium, renal and neck ultrasound, MIBI scintiscan, and DEXA at lumbar spine, femoral neck, and distal third of radius). Patients were defined asymptomatic (aPHPT) when bone or kidney was not involved and no hypercalcemic symptom occurred; mild PHPT was defined as aPHPT not meeting updated surgical criteria. Seventy-five patients among 172 classified as aPHPT had all available data required for surgical evaluation and could be evaluated. Sixty/75 met surgical criteria and the remaining 15 were classified as mild. Mild PHPT patients had lower total and ionized calcium, urinary calcium, and PTH levels than aPHPT meeting surgical criteria, while vitamin D levels and BMD were similar. Mild PHPT strictly defined according to the last consensus represents a small subgroup with a less active form of the disease.


Institutional review board guidance on pediatric research: missed opportunities.
To examine whether and how institutional review boards (IRBs) are using their web-sites to provide guidance to investigators conducting pediatric research. We studied guidance on pediatric research from IRB web-sites at the 25 US medical schools, plus affiliated hospitals, research centers, and public health schools, and the top National Institutes of Health-funded (>5 million dollars) children's hospitals with separate IRBs. We also included 1 IRB that was not otherwise eligible because other IRBs use its web-based research ethics training program. Our final study population was 39 IRB web-sites. IRB web-sites generally provide basic information about pediatric research. However, few IRBs discuss important ethical issues on which the regulations are silent. Moreover, some IRBs provide incorrect advice about the regulations. More detailed IRB guidance may help pediatric investigators think through ethical issues and protect children in clinical research. Helpful approaches we identified include checklists and "points to consider," concrete examples to illustrate regulatory requirements, and discussion of areas of controversy. Few IRBs present the kind of detailed guidance that investigators might need to ensure ethically designed protocols. IRBs should revise their web-sites to ensure that they provide accurate, comprehensive, and sufficiently detailed guidance.


Risk factors for short- and long-term complications after groin surgery in vulvar cancer.
The cornerstone of treatment in early-stage squamous cell carcinoma (SCC) of the vulva is surgery, predominantly consisting of wide local excision with elective uni- or bi-lateral inguinofemoral lymphadenectomy. This strategy is associated with a good prognosis, but also with impressive treatment-related morbidity. The aim of this study was to determine risk factors for the short-term (wound breakdown, infection and lymphocele) and long-term (lymphoedema and cellulitis/erysipelas) complications after groin surgery as part of the treatment of vulvar SCC. Between January 1988 and June 2009, 164 consecutive patients underwent an inguinofemoral lymphadenectomy as part of their surgical treatment for vulvar SCC at the Department of Gynaecologic Oncology at the Radboud University Nijmegen Medical Centre. The clinical and histopathological data were retrospectively analysed. Multivariate analysis showed that older age, diabetes, 'en bloc' surgery and higher drain production on the last day of drain in situ gave a higher risk of developing short-term complications. Younger age and lymphocele gave higher risk of developing long-term complications. Higher number of lymph nodes dissected seems to protect against developing any long-term complications. Our analysis shows that patient characteristics, extension of surgery and postoperative management influence short- and/or long-term complications after inguinofemoral lymphadenectomy in vulvar SCC patients. Further research of postoperative management is necessary to analyse possibilities to decrease the complication rate of inguinofemoral lymphadenectomy; although the sentinel lymph node procedure appears to be a promising technique, in 50% of the patients an inguinofemoral lymphadenectomy is still indicated.


Sclerotherapy of Venous Malformations Using Polidocanol: Effectiveness, Safety, and Predictors of Outcomes and Adverse Events.
To assess the effectiveness, safety, and predictors of outcomes and adverse events for percutaneous sclerotherapy using polidocanol for the treatment of venous malformations (VMs). A retrospective single-center analysis was performed, including patients with VMs who were treated with sclerotherapy using polidocanol between January 2011 and November 2021 at a tertiary center. Demographic characteristics, clinical data, and radiologic features were analyzed, and the influence of patient- and VM-related factors on the subjective clinical outcome and adverse events were investigated using a multivariate logistic regression analysis. In total, 167 patients who received 325 treatment sessions were included in this study. Overall symptom improvement was observed in 67.5%, stable symptoms were observed in 25.0%, and worsening was reported in 7.5% (clinical follow-up, 1.04 ± 1.67 years). The total adverse event rate was 10.2%, with an overall rate of 4.2% for permanent adverse events within the cohort. In multivariate analysis, the clinical outcome was worse in children (P = .01; 57.1% symptom improvement in children [age, <18 years] and 79.7% in adults), and adverse events were more frequently observed after the treatment of VMs located at the extremities (P < .01; 8.4% for VMs of the extremities and 1.2% for VMs in other locations). Sclerotherapy using polidocanol can be an effective treatment option for VMs with an acceptable safety profile. However, it can be less effective in children, and adverse events can be more frequently expected for VMs of the extremities.


Mentorship in Urology Residency Programs in the United States.
To characterize the status of mentorship programs for Urology residencies in the United States, highlight the importance of mentorship in the career of a urology resident, and identify the obstacles of implementing a mentorship program. With Internal Review Board exemption and approval from the Society of Academic Urologists, a survey was sent to the Program Directors of the Urology Residency programs in the United States containing questions about the presence and structure of a mentorship program in their department. Response rate was 54%. Seventy-five percent of respondents approved of formal mentorship programs. Fifty-eight percent of respondents had 1 established. Five percent of programs had an official training course for faculty mentors. Thirty-eight percent of programs had no requirement on mentor and/or mentee meeting frequency. The most common reason for not having a formal mentorship program was because the program felt that informal mentorship sufficed. While the vast majority of Program Directors for Urology Residency programs in the United States approve of formal mentorship programs, only a little over half have 1 established. Programs should strive to create a formal mentorship program in their residency programs due to their recognized importance.


Isolation, culture and characterization of a primary fibroblast cell line from channel catfish.
A primary cell line (designated as CCf) derived from caudal fin tissue of channel catfish, Ictalurus punctatus, was developed using explant techniques. The cell line grew fastest in media supplied with FBS and channel catfish serum. The duplication time of the cell line under optimal conditions was ∼56 h at a plating density of 1.1 × 10(5) cells/ml. The cell line has been propagated continuously for 25 passages (1:4 dilution per passage), cryopreserved, and recovered successfully at different passages. The cultured cells had fibroblastic morphology, and synthesized fibronectin and Type I and III collagens in the cytoplasm. The cell line maintained the normal diploid chromosome number (58) of channel catfish throughout the experiment. Nucleolus organizer regions were located on the short arms of a pair of medium-sized submetacentrics, which is typical for channel catfish. This study provides a method for acquiring a cell line from juvenile catfish without sacrifice, and is especially useful for early screening of valuable fishes.


Cytotoxic activity of guaiazulene on gingival fibroblasts and the influence of light exposure on guaiazulene-induced cell death.
Guaiazulene (GA) is widely used as a natural ingredient in many health care products and solutions. Although it has been reported to have interesting biological effects, GA and azulene derivatives have been proven to be cytotoxic against normal human cells and human tumor cells; moreover, guaiazulene has shown photomutagenic properties on bacterial strains. Therefore, we evaluated and compared the cytotoxicity of GA at different concentrations on human gingival fibroblast (HGF) cell cultures under normal conditions and under UV irradiation (UV-A dose: 6.4 J/cm(2)). The compound tested was found to significantly reduce cell viability (dose-dependent trend, IC(50) 72.1 μM), decrease protein procollagen α1 type I synthesis, a marker for HGF protein, and COL1A1 mRNA expression. The cytotoxic effects were accompanied by activation of an intrinsic apoptotic pathway, studied using transmission electron microscopy (TEM) and caspase-3 activation. The light exposure of the cell culture treated decreased GA-induced cell death (IC(50) 128.9 μM), suggesting a photoprotective effect due to the photodegradation of the toxic agent, guaiazulene. Furthermore, the products of the photodegradation reaction of GA proved not to be toxic against HGFs.


Changes in the sialic acid content of chick thymus and bursa of Fabricius during age-involution.
The sialic acid content of both thymus and bursa of Fabricius during their growth and involution phases in chick has been reported in this study. It is observed that the sialic acid concentration is very high in 1-week-old chickens. The concentration subsequently decreases to a significant level and rises again prior to the onset of involution. In the post-involution period, a more or less minimal and constant level is maintained. The role of sialic acid in cellular activities of thymo-bursal system has been discussed.


Effect of an electric field on the growth of aluminum film.
An electric field is applied to the substrate during the growth of aluminum films, with the results that the reflectance is increased, scattering is reduced, and the surface is smoothed.