Orexins/hypocretins in the ob/ob mouse: hypothalamic gene expression, peptide content and metabolic effects.
Orexins (forms A and B) belong to a new family of peptides that, as neuropeptide Y (NPY), stimulate food intake when centrally injected. The ob/ob mouse is a well-characterized model of hyperphagia and obesity associated with strong metabolic disturbances and a central dysregulation of peptides involved in the control of feeding. In the present report, we investigated the hypocretin (Hcrt)/orexin (OX) peptide pathway in lean and ob/ob mice. Prepro-Hcrt/OX mRNA expression, measured by in situ hybridization was restricted to the lateral hypothalamus area. It was significantly decreased in ob/ob mice (-18%; p<0.01). When estimated by real time RT-PCR in the whole hypothalamus, this decrease amounted to 65% (p<0.001). Hcrt-1/OX-A peptide concentrations, measured by RIA in microdissected hypothalamic nuclei were high in the lateral hypothalamus (LH) and lower in the arcuate (ARC) and paraventricular nuclei (PVN). In ob/ob mice, OX-A levels were significantly lower than in lean mice in the LH (-34%; p<0.02) and in the PVN (-72%; p<0.005). Acute intracerebroventricular injection of Hcrt-1/OX-A (1-10 nmol) stimulated feeding in lean, but not in ob/ob mice, whereas Hcrt-2/OX-B (1-10 nmol) had the opposite effect. Acute third ventricle (i3vt) injections of Hcrt/OX peptides in ob/ob mice transiently increased their metabolic rate and stimulated lipid substrate utilization. These findings provide direct evidence that Hcrt/OX peptides are down-regulated in the hypothalamus of ob/ob mice, contrary to the NPY system. The present data argues that Hcrt/OX peptides are not primarily responsible for the metabolic syndrome of the ob/ob mice. The diminution in the OX tone might participate in a counterregulatory system necessary to limit the adverse effects of NPY on food intake and body weight.


PCR cloning and detection of point mutations in the eburicol 14alpha-demethylase (CYP51) gene from Erysiphe graminis f. sp. hordei, a "recalcitrant" fungus.
Molecular studies of some micro-organisms are hampered by the difficulty of obtaining sufficient amounts of nucleic acids. A cloning strategy based on PCR has therefore been used to clone the eburicol 14alpha-demethylase (CYP51) gene of the obligate fungus Erysiphe graminis f. sp. hordei (Egh) using minute amounts of genomic DNA. The CYP51 gene encodes the enzymatic target of a major group of fungicides. Sequencing CYP51 from different Egh isolates revealed the occurrence of two alleles for this gene. An allele-specific PCR assay was developed to detect each CYP51 allele.


Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma.
Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study, ex vivo metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (1H HR-MAS). Distinct spectral profiles were observed for lesions with IDH-mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for in vivo characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy.


To dialyse or delay: a qualitative study of older New Zealanders' perceptions and experiences of decision-making, with stage 5 chronic kidney disease.
Issues related to renal replacement therapy in elderly people with end stage kidney disease (ESKD) are complex. There is inadequate empirical data related to: decision-making by older populations, treatment experiences, implications of dialysis treatment and treatment modality on quality of life, and how these link to expectations of ageing. Participants for this study were selected from a larger quantitative study of dialysis and predialysis patients aged 65 years or older recruited from three nephrology services across New Zealand. All participants had reached chronic kidney disease (CKD) stage 5 and had undergone dialysis education but had not started dialysis or recently started dialysis within the past 6 months. Serial qualitative interviews were undertaken to explore the decision-making processes and subsequent treatment experiences of patients with ESKD.Analytical approach: A framework method guided the iterative process of analysis. Decision-making codes were generated within NVivo software and then compared with the body of the interviews. Interviews were undertaken with 17 participants. We observed that decision-making was often a fluid process, rather than occurring at a single point in time, and was heavily influenced by perceptions of oneself as becoming old, social circumstances, life events and health status. This study focuses on participants' experiences of decision-making about treatment and does not include perspectives of their nephrologists or other members of the nephrology team. Older patients often delay dialysis as an act of self-efficacy. They often do not commit to a dialysis decision following predialysis education. Delaying decision-making and initiating dialysis were common. This was not seen by participants as a final decision about therapy. Predialysis care and education should be different for older patients, who will delay decision-making until the time of facing obvious uraemic symptoms, threatening blood tests or paternalistic guidance from their nephrologist. Australasian Clinical Trials Registry ACTRN 12611000024943; results.


The fine structure of stratified ependyma in the ventricular wall of N-ethyl-N-nitrosourea-treated rats.
Ependymal stratifications, up to 15 cell layers in thickness at the floor of the lateral ventricle of rats treated transplacentally with N-ethyl-N-nitrosourea (ENU), are described. Ultrastructurally the constituent ependymal cells are well-differentiated and show no morphological signs of neoplasia. The possibility that these findings are due to the toxicity or carcinogenicity of ENU is discussed.


A clinical study of tuberculous colitis.
During the last 8 years, the diagnosis of tuberculous colitis has been made radiologically in 22 cases. Twelve were confirmed by histological or bacteriological evidences. The X-ray findings are classified into three types as follows: Type A, showing an extensive scarred area in the ileocecum and ascending colon. Type B, showing annular stricture in the ascending colon and dilatation of its oral side. Type C, showing pouchformation (pseudo-diverticulum) and deformity in the cecum. We emphasize that histological examination and culture of the biopsy specimens by endoscopy were useful for the diagnosis of tuberculous colitis. Furthermore, radiologic changes of the colon by administration of antituberculous drugs were observed.


Considerations of the chemical complexity of ETS with regard to inhalation studies.
Any inhalation study that investigates environmental tobacco smoke, ETS, is considering a very complex entity. ETS contains numerous chemicals that are continuously changing both in their absolute concentration, in the ratio of concentration between one and another, and even in their particulate to vapour phase distribution. Moreover, when considering ETS in real-life situations, many of the chemical components of ETS will be present as a result of sources other than tobacco smoking. This paper emphasises that the chemical and physical nature of ETS must be considered in the design and interpretation of any inhalation study on ETS, and illustrates the difficulty in defining precisely what constitutes ETS in such studies.


Detection of coronary artery disease with gated cardiac blood-pool scintigraphy: comparison of cold pressor test and dynamic exercise.
Forty-six subjects (11 normals with no cardiac disease, 13 persons with a 'false' positive exercise ECG test, and 22 patients with coronary artery disease) were investigated with ECG-gated cardiac blood-pool imaging at rest, during cold pressor stimulation, and during supine bicycle exercise. Changes in left ventricular ejection fraction and intervention induced regional wall motion abnormalities were measured. Cold pressure stimulation did not induce anginal pain in any person, but were generally found more unpleasant than dynamic exercise. Dynamic exercise detected significantly more coronary artery disease patients (20/22, 91%) than did cold stimulation (13/22, 59%) (P less than 0.02). Specificity of dynamic exercise and cold stimulation was not significantly different. It is concluded that cold stimulation is less sensitive than dynamic exercise in the detection of patients with ischaemic heart disease with gated cardiac blood-pool imaging.


Rankin to focus on advocacy, unity, and diversity as president of AAOS.
In this issue of Orthopedics, Dr E. Anthony Rankin, new president of the American Academy of Orthopaedic Surgeons, discusses his role with the organization, his plans for the year, and his priorities in life.


The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome.
Is the sole measurement of total testosterone sufficient to assess the presence of hyperandrogenism in women with polycystic ovary syndrome (PCOS)? Serum samples from 294 patients with PCOS who met the Rotterdam criteria were used for the analysis of total testosterone by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) and chemiluminescent immunoassay (CLIA). The free androgen index (FAI) was calculated as total testosterone (TT)/sex hormone-binding globulin (SHBG) × 100%, and the presence/degree of hirsutism were assessed using the modified and simplified Ferriman-Gallwey (mFG and sFG, respectively) scoring systems. The hirsute subjects presented higher LC-MS/MS-based total testosterone and FAI values than the non-hirsute subjects (all P < 0.001), including those defined based on mFG ≥5 or sFG ≥3. Total testosterone and FAI were both positively correlated with the mFG (rank correlation coefficient [RCC] 0.598 and 0.443, P < 0.001) or sFG (RCC 0.747 and 0.568, P < 0.001) score, and a receiver operating characteristic curve analysis indicated that both parameters could significantly predict the presence of hirsutism determined by the mFG (area under the curve [AUC] 0.797 and 0.725, P < 0.001) or sFG (AUC 0.894 and 0.817, P < 0.001) score. However, similar results were not obtained with the CLIA platform. In this East Asian population, total testosterone was found to be a strong predictor of the presence and degree of hyperandrogenism (i.e. assessed by the presence and degree of hirsutism), but this finding was obtained only if the total testosterone level was measured by LC-MS/MS and not by CLIA. These findings might have important implications for global epidemiologic, phenotypic and clinical studies of PCOS.


Glucagon-like peptide 1 and appetite.
Glucagon-like peptide 1 (GLP-1) and GLP-1 analogs have received much recent attention due to the success of GLP-1 mimetics in treating type II diabetes mellitus (T2DM), but these compounds may also have the potential to treat obesity. The satiety effect of GLP-1 may involve both within-meal enteroenteric reflexes, and across-meal central signaling mechanisms, that mediate changes in appetite and promote satiety. Here, we review data supporting the role of both peripheral and central GLP-1 signaling in the control of gastrointestinal motility and food intake. Understanding the mechanisms underlying the appetite-suppressive effects of GLP-1 may help in developing targeted treatments for obesity.


Effect of upper thoracic manipulation on mouth opening and electromyographic activity of masticatory muscles in women with temporomandibular disorder: a randomized clinical trial.
The purpose of this study was to assess the effect of upper thoracic manipulation on vertical mouth opening (VMO) and electromyographic activity of the masticatory muscles in women with temporomandibular disorder (TMD). A randomized, controlled, blinded study involving 32 women (mean age of 24.78 ± 5.41 years) diagnosed with TMD was performed. Subjects were randomly allocated to an experimental group (n = 16) or a sham manipulation (placebo) group (n = 16). A single session of manipulation was administered to the T1 vertebral area. Electromyography was used to determine activity of masticatory muscles with the mandible at rest and during isometric contraction. Vertical mouth opening was measured using a ruler. Measurements were made before manipulation, immediately after manipulation, and at the short-term follow-up (2 to 4 days after manipulation). No significant differences were found in any of the comparisons of mandibular VMO or electromyographic activity of the masticatory muscles at rest or during isometric contraction of mandibular elevator muscles (P > .05). Regarding isometric contraction of the mandibular depressors, an immediate increase in muscle activity was found in the suprahyoid (P = .014) and left masseter (P = .005) muscles. In the present study, no significant differences were found regarding VMO between the experimental and placebo groups or among the different evaluations times in each group. Moreover, Cohen d test revealed no clinical effect of the technique. Therefore, based upon the findings of this study, manipulation administered to the T1 vertebral area appears to have no effect on VMO and electromyographic activity of the masticatory muscles in women with TMD.


Dexmedetomidine at Home for Intractable Dystonia and Insomnia in Children With Special Needs: A Case Series.
We know that syndromic conditions and severe chronic diseases can be associated with symptoms that may interfere with sleep, significantly impacting the life quality of children and caregivers. Drugs commonly used in treating insomnia, such as melatonin, benzodiazepines, niaprazine, and antihistamines, are often either ineffective or associated with adverse effects, requiring new therapeutic perspectives. Dexmedetomidine is a selective alpha-2 agonist with hypnotic and anxiolytic effects, which, by stimulating alpha-2 adrenergic receptors in the locus coeruleus, induces sleep comparable to stages 2-3 of the non-REM phase without substantially affecting the respiratory drive during sedation. Its use has already been extensively described in pediatric intensive care or procedural sedation literature. In 2018, the Italian Medicines Agency (Agenzia Italiana Del Farmaco AIFA) authorized the off-label use of dexmedetomidine outside of intensive care in Children undergoing palliative treatment to control distressing symptoms related to pathology and refractory sleep disorders, and the literature reported cases of children who received dexmedetomidine at home. Our study aims to describe the home use of dexmedetomidine in children with insomnia or intractable dystonic states. We conducted a retrospective analysis through a questionnaire addressed to 12 Italian pediatric palliative care centers regarding the home use of dexmedetomidine in sleep disorders and intractable dystonic states. We collected a case series of 9 children treated with dexmedetomidine at home, 8 via intranasal and 1 via intravenous route. All children received the first drug administration in the hospital or hospice during a dedicated admission, under close monitoring of vital signs parameters for 72 hours (3 days, range 2-7 days). After discharge, the potential side effects of the drug were explained to the patient's families, and, once informed consent was obtained, the home administration of dexmedetomidine continued, with follow-up by the palliative care team. At home, dexmedetomidine was administered for 3000 days (minimum 1 month, maximum 36 months). The first patient was treated for 1095 days, from 2019 to 2021 (discontinued due to underlying condition-related death). All patients observed a persistent benefit from the treatment on symptoms, and none of them discontinued dexmedetomidine administration due to drug-related adverse effects or perceived lack of therapeutic efficacy. Therefore, its use at home may represent a promising therapeutic approach for intractable sleep disorders or dystonic states in pediatric palliative care children. Further studies are needed to confirm our results.


A novel algorithm to determine the scattering coefficient of ambient organic aerosols.
In the present work, we propose a novel algorithm to determine the scattering coefficient of OA by evaluating the relationships of the MSEs for primary organic aerosol (POA) and secondary organic aerosol (SOA) with their mass concentrations at three distinct sites, i.e. an urban site, a rural site, and a background site in China. Our results showed that the MSEs for POA and SOA increased rapidly as a function of mass concentration in low mass loading. While the increasing rate declined after a threshold of mass loading of 50 μg/m3 for POA, and 15 μg/m3 for SOA, respectively. The dry scattering coefficients of submicron particles (PM1) were reconstructed based on the algorithm for POA and SOA scattering coefficient and further verified by using multi-site data. The calculated dry scattering coefficients using our reconstructing algorithm have good consistency with the measured ones, with the high correlation and small deviation in Shanghai (R2 = 0.98; deviations: 2.9%) and Dezhou (R2 = 0.90; deviations: 4.7%), indicating that our algorithms for OA and PM1 are applicable to predict the scattering coefficient of OA and Submicron particle (PM1) in China.


Risk factors for the development of postoperative pneumonia after cardiac surgery.
Identify risk factors that determine pneumonia development in patients who have undergone cardiac surgery. Prospective study of a single cohort in a postoperative intensive care unit at a tertiary care center, encompassing all patients undergoing cardiac surgery from January to July 2014. 31 postoperative pneumonia cases were enrolled out of 211 patients (14.6%). The following independent risk factors were identified: hypertension (OR: 3.94, p=0.01), chronic renal failure (OR: 13.67, p=0.02), reintubation (OR: 22.29, p=0.001) and extubation after 6h (OR: 15.81, p=0.005). Main determinants for pneumonia after surgery were hypertension, chronic renal failure, extubation after 6h and reintubation.


Small mammals (Insectivora, Rodentia, Lagomorpha) from the Early Pleistocene hominin-bearing site of Dmanisi (Georgia).
Small mammals (insectivores, rodents, and lagomorphs) from Dmanisi are here reviewed for the first time and used as a tool for paleoenvironmental proxies. The small mammal faunal list is composed of shrews (Beremendia fissidens, cf. Beremendia minor, Crocidura kornfeldi), hamsters (Cricetulus sp., Allocricetus bursae), gerbils (Parameriones aff. obeidiyensis), murids (Apodemus cf. atavus), arvicolids (Mimomys pliocaenicus, Mimomys aff. pusillus), and pikas (Ochotona sp.). A paleoenvironmental reconstruction based on the habitat weighting method has been applied to the rodent assemblage. According to this method, the most common elements indicate an open-dry habitat (36.5%), followed by water edge (25.7%) and rocky (21.0%) elements. Open-wet (15.5%) and woodland elements (1.3%) are rare. Therefore, the habitat occupied by the hominids of Dmanisi was characterized by the prevalence of arid conditions, from steppe or semi-desert to open Mediterranean forest, with stony or rocky substrate and bushy areas. The presence of permanent aquatic environments is also documented. From a biogeographic point of view, the small mammal community from Dmanisi is composed mainly by Western or Central Asian elements, with a poor representation of European elements (Mimomys, Apodemus). It is concluded that Dmanisi hominins most possibly had ecological requirements which were different from those of the Early Pleistocene hominins from Western Europe, which settled on wetter habitats. It could be also possible that Dmanisi hominins entered Southern Caucasus at an interglacial phase before the deposition of the Dmanisi site.


Environmental influences on immunologically associated spontaneous abortion in CBA/J mice.
CBA/J female mice mated to DBA/2 male mice have a high level of fetal resorption. The rate of resorption can be influenced by the environment in which the animals are maintained.


In vitro allograft irradiation prevents graft-versus-host disease in small-bowel transplantation.
In small-bowel transplantation, the transfer of large numbers of donor lymphocytes with the intestinal allograft may provoke a lethal graft-versus-host reaction. The effectiveness of allograft irradiation in vitro as a method of preventing graft-versus-host disease (GVHD) was studied in a rat model of small-bowel transplantation, with the Lewis----Lewis X Brown Norway F1 hybrid strain combination. Cold harvested small-bowel allografts were irradiated immediately prior to heterotopic or orthotopic transplantation. Animals that had received heterotopic allografts irradiated with 0, 250, or 500 rad all died of GVHD after 14.4 +/- 3.0, 15.0 +/- 1.3, and 14.2 +/- 1.9 days, respectively. None of the animals that had received allografts treated with 1000 rad developed clinical or pathologic evidence of GVHD, however, and all survived for more than 6 months (P less than 0.001). Allograft function was studied in animals that underwent orthotopic transplantation. Recipients of nonirradiated orthotopic allografts all died of GVHD after 14.0 +/- 0.7 days, whereas recipients of allografts irradiated with 1000 rad all survived for more than 5 months (P less than 0.001). After 120 days, weight gain (51.8 +/- 11.7%), serum albumin (3.9 +/- 0.7 g/dl), serum triglycerides (67.0 +/- 24.3 mg/dl), CBC, and differential in these animals were not statistically different from those in either age-matched isograft recipients or normal animals, and when the rats were sacrificed, irradiated allografts showed no changes suggestive of radiation injury. These results indicate that irradiation of small-bowel allografts in vitro prevents development of GVHD, and that this can be achieved at a dose which does not cause injury to or malfunction of the allograft.


Near-infrared fluorescence imaging during ex vivo lung perfusion: Noninvasive real-time evaluation of regional lung perfusion and edema.
Ex vivo lung perfusion (EVLP) is an excellent platform to evaluate donor lung function before transplantation, but novel methods are needed to accurately confirm transplant quality. Near-infrared fluorescence (NIRF) imaging with indocyanine green (ICG) has been used in various clinical perioperative applications to evaluate tissue perfusion. We used NIRF imaging during pig and human EVLP to evaluate donor lung perfusion and edema. Pig lungs with various degrees of lung injury (n = 10) and human lungs rejected from clinical transplantation (n = 3) were imaged during EVLP using intravascular ICG and a SPY Elite (Stryker) NIRF imaging unit. Optimal ICG and imaging conditions, and perfusion and edema quantification methods, were established. Pig lung transplants with extended graft preservation (n = 5) and control native lungs (n = 6) were also imaged. A single ICG dose resulted in sustained donor lung NIRF throughout the EVLP. Even and homogenous ICG signal was demonstrated in areas of normal lung. Low NIRF was present in regions with poor tissue perfusion, and rapid, intense ICG accumulation occurred in damaged and edematous areas. Segmental perfusion defects were common in the peripheral and elevated regions of the lungs, and serial imaging showed gradual perfusion recovery during EVLP. Impaired microvascular reperfusion, indicated by a decreased NIRF ingress rate, was detected in transplanted pig lungs early after reperfusion. NIRF imaging enables noninvasive real-time evaluation of lung perfusion and edema during EVLP. Prospective clinical studies are needed to determine the role of NIRF imaging in donor lung assessment and selection, and prediction of posttransplant outcomes.


Randomized controlled study of a cosmetic treatment for mild acne.
Cosmetic products are not tested with the same rigour as medical treatments, but recent high-quality studies have shown significant reductions in changes of skin ageing with use of cosmetic antiageing products. To test whether a cosmetic 'anti-spot' two-step treatment containing a complex of seaweed-derived oligosaccharide and zinc would produce a significant improvement in mild acne. A double-blind, vehicle-controlled trial of this treatment was performed for 8 weeks on 60 age-matched participants with mild acne. They were divided into two groups: 30 participants were treated with vehicle control and 30 with the active treatment containing a seaweed-derived oligosaccharide complexed with 0.1% zinc pyrrolidone. After 8 weeks, both groups had a reduction in comedones, papules and pustules, and this was significantly greater in the active than control group at 2, 4 and 8 weeks. Cosmetic products may offer some benefit for mild acne and still meet the requirements of the European Cosmetic Directive. In particular, the seaweed-derived oligosaccharide complexed with 0.1% zinc pyrrolidone used in this study produced a significant reduction in acne vs. a control treatment. Cosmetic companies should conduct blinded controlled trials of their product's efficacy and publish the results.


Teacher- and school-level predictors of teacher efficacy and burnout: identifying potential areas for support.
Although several studies relate low teacher efficacy and high burnout to the quality of instruction and students' academic achievement, there has been limited research examining factors that predict teacher efficacy and burnout. The current study employed a longitudinal, multilevel modeling approach to examine the influence of teacher- and school-level factors on the development of both teacher efficacy and burnout. Data were collected 3 times across 2 academic years from 600 teachers at 31 elementary schools. The results indicated that both teacher efficacy and burnout increased over time. Teacher preparedness and perceptions of teacher affiliation and leadership were significantly associated with both the intercept and growth of teacher efficacy and burnout; however, school-level factors were generally unrelated to both outcomes. Implications for screenings and teacher-targeted interventions are discussed.


Bone metabolism and formation of mice bred in a 2 G environment.
The purpose of this study is to reveal the effect of chronic hypergravity exposure on the bone formation and the bone metabolism when mammals produce offspring in a 2 G environment. We measured the length and width of the thighbone, the length of the pelvis, the width of the pelvic cavity and the width of the fourth cervical vertebra on the second (F2) and the third (F3) generation mice bred in a 2 G environment every ten days from 20 days old to 60 days old in an experiment on bone formation. In an experiment on bone metabolism, we measured calcium and phosphorus in the bones of the F3 in the 2 G group. Ratios of the thighbone length, pelvis length, pelvic cavity width, and fourth cervical vertebra width versus the body length were calculated. These ratios were higher in the 2 G group than the control group during all measuring periods. Calcium and phosphorus concentrations in the thighbone and the lumbar vertebra were lower in the 2 G group than in the control group. However, the calcium and phosphorus concentrations in the cervical vertebrae of the 2 G group were higher. These results suggest that the influence of gravity load may vary in the bones.


Urodynamic effects of finasteride in the treatment of bladder outlet obstruction due to benign prostatic hyperplasia.
Urodynamic effects of the 5-alpha-reductase inhibitor, finasteride, were studied in the treatment of patients with bladder outlet obstruction due to benign prostatic hyperplasia (BPH). A total of 36 patients was randomly assigned in a double-bind manner to receive either 5 mg. finasteride daily (19) or placebo (17) for 6 months. The possible relief of bladder outlet obstruction was monitored with uroflowmetry and repeated urodynamics. The mean flow rate, detrusor opening pressure, detrusor pressure at maximum flow and maximum detrusor pressure improved significantly in the patients treated with finasteride. There were no significant differences in the improvement of symptom score or peak flow rate, or in the reduction of residual urine between the finasteride and placebo groups. The treatment resulted in 30% average decrease in prostatic size and 46% decrease in prostate specific antigen concentration. The efficacy of finasteride in relief of bladder outlet obstruction caused by BPH seems to be of the same degree as that achieved by chemical castration therapy but without any significant side effects. There were wide variations among BPH patient response to finasteride treatment. Further studies are needed to define the responders who benefit from this treatment.


Calculations of energy deposition and ionization in the 2019 novel coronavirus by electron beam irradiation.
Using Monte Carlo methods, this study investigates energy deposition of energetic electrons and ionization in the 2019 novel coronavirus by electron irradiation, which are important characteristic quantities related with biological damage formation. The inelastic scattering of low-energy electrons (<10 keV) was calculated by dielectric theory. The optical energy-loss functions of viral proteins and RNA were derived from an empirical method in the energy-loss range <40 eV and the calculation of optical parameters of the biomolecules. The densities and distributions of energy deposition and ionization were calculated from the stopping power and inelastic cross-sections in the electron-cascade simulation. Electrons with primary energies of approximately 1-3 keV produced significant energy deposition and ionization in the target coronavirus. More energetic electrons were less effective due to the larger electron range and fewer scattering events in the coronavirus.


Genetic analysis of an avoidance-avoidance response in Mus domesticus.
Latency to leave a lighted platform and enter a novel chamber in which other mice had received shock was measured in 2592 mice from eight inbred strains and all 56 F1 crosses. An analysis of the diallel matrix indicated a clear genetic architecture, although genetic effects accounted for only 10% of the total phenotypic variance. Dominance favoring a slight delay in chamber entry suggested a selective advantage in spending a longer time on some elements in the behavioral chain involved in avoidance-avoidance responses. Inbred strains showed greater litter variance than F1 hybrids, suggesting greater developmental buffering of heterozygotes. Both the genetic architecture and the strain rankings differ from those typically found in open field and similar tests of locomotor activity. The results illustrate the problem of interpreting behavior genetic results in terms of proportions of total phenotypic variance and difficulties in generalizing to ancestral or other populations in an attempt to interpret genetic results in an evolutionary context when reliability is low.


Inhibition of Akt signaling by SN-38 induces apoptosis in cervical cancer.
Cervical cancer still remains a major health problem in women worldwide. Inhibitors of topoisomerase I have proven to be among the most promising new classes of anti-neoplastic agents introducing into the clinic in recent years. CPT-11 is one of the most widely used Camptothecin analogues and is converted to form the active metabolite SN-38. The study tried to explore the in vitro mechanisms of apoptosis induced by SN-38 in cervical cancer cell lines HeLa and SiHa. The results demonstrated here that SN-38 inhibited cell proliferation in a time- and dose-dependant manner. Western Blot showed that SN-38 down-regulated protein expression of p-Akt and increased protein expression of p53 and p21, but it had no effects on protein expression of Bax, Bcl-2 and Akt. Transfection of the full-length Akt cDNA into HeLa and SiHa cells resulted in the reduction of apoptosis induced by SN-38, and Akt kinase activity regulated the p53 pathway, indicating that inhibition of the Akt pathway played an important role in exhibition of SN-38-mediated cytotoxic effect. Our data suggested that SN-38 could induce apoptosis through a p53 pathway and that activation of p53 in response to S-38 is governed by Akt.


Biphasic developmental changes in Ca2+/calmodulin-dependent proteins in R6/2 Huntington's disease mice.
Widespread disturbances in calcium-dependent proteins are reported both in humans with advanced Huntington's disease (HD) and in symptomatic HD transgenic mice. Using a HD mouse model transgenic for exon 1 of the abnormal gene (e.g. the Bates R6/2 mouse), we found increased expression of calmodulin kinase IV and neuronal nitric oxide synthase (NOS) in 3-week-old presymptomatic HD mice striatum and cortex. Conversely, reduced expression was found at 6 weeks (early symptom onset) and 11 weeks (advanced disease) of age. The changes in protein expression may have a broad impact on the HD striatum. Calmodulin kinase IV directly regulates the activation of the transcription factors CREB (cyclic AMP response element binding protein) and CREM (cyclic AMP response element modulator) and, as well, modulates the activity of neuronal NOS. In homeostasis, nitric oxide is involved in long-term potentiation, neurotransmission, endocrine regulation and cerebral blood flow regulation, among others, while under pathological conditions nitric oxide combines with superoxide to produce the potent neurotoxin peroxynitrite. The current findings suggest that mutant HD protein may alter these processes by disturbing the regulation of calmodulin kinase IV and neuronal NOS expression across the lifespan of the HD mouse.


Fabrication and characterization of microelectromechanical systems-based gas chromatography column with embedded micro-posts for separation of environmental carcinogens.
In this paper, a micro gas chromatography (μGC) column with embedded micro-posts was developed for increasing overall surface area of the columns which is able to support more of the stationary phase and reducing the effective width of the column, leading to higher separation efficiency. The proposed columns have a higher sample capacity as the overall surface area is about 3 times larger than that of open columns with the same dimensions. In order to achieve an even flow velocity in the channels, the location of the micro-posts in the linear channels and the configuration of curved channels were optimized by numerical simulation. The results have indicated that the proposed column separated 5 environmental carcinogens in less than 50s, achieved a separation efficiency of about 9500plates/m and eluted highly symmetrical Gaussian peaks.


Cytomegalovirus peritonitis in a patient with the acquired immunodeficiency syndrome.
Peritonitis has been reported infrequently in patients with the acquired immunodeficiency syndrome (AIDS). Intestinal or colonic perforation resulting from cytomegalovirus (CMV) enteritis is the most common cause of peritonitis in these patients. We report a patient with CMV peritonitis occurring in the absence of perforation (primary peritonitis) to alert physicians to this potentially treatable disorder.


Phospholipid membranes as regulators of localized activity.
In a recent article, Tsuji and Yoshikawa (2010) report that the interaction of long DNA with phospholipids on the surface of aqueous microdroplets can lead to changes of the DNA conformation, and as consequence, to a remarkable alteration of the DNA's transcriptional activity.


ENDOGENOUS ENDOPHTHALMITIS DUE TO STREPTOCOCCUS ANGINOSUS IN A HEALTHY, YOUNG WOMAN.
The purpose of this study was to present a case of indolent endogenous endophthalmitis in a young, seemingly healthy woman. This study is a retrospective case report. A 25-year-old woman with no significant medical history presented with vision loss in the left eye over the course of 1 month. Examination showed vitritis and a white-yellow lesion overlying the macula and optic nerve in the left eye. Initial laboratory testing for infectious and inflammatory causes was unrevealing. A diagnostic vitrectomy was performed, and the patient was found to have presumed endogenous endophthalmitis due to Streptococcus anginosus, an extremely uncommon bacterium. Subsequent workup did not reveal evidence of bacteremia, endocarditis, or orbital infection. This case is unique because, unlike the three previously reported cases of S. anginosus endophthalmitis, this patient was seemingly healthy, never had an elevated white blood cell count, never had documented bacteremia, had a normal echocardiogram, and had normal orbital findings on magnetic resonance imaging and computed tomography scans. Further questioning revealed a remote history of facial cellulitis and possible sinusitis treated with oral antibiotics, which are the presumed etiology. Streptococcus anginosus endophthalmitis can occur in young, seemingly healthy patients. Endogenous endophthalmitis should be considered in the differential diagnosis even without systemic comorbidities or other risk factors. Detailed questioning about medical history and thorough review of systems, including nonocular symptoms, are essential.


The case for an upper dose limit of 1000 mg/kg in rodent carcinogenicity tests.
We examined two rodent carcinogenicity data bases comprising 301 chemicals from the US National Toxicology Program (NTP) and 241 pharmaceuticals from the US Physicians' Desk Reference (PDR) to determine the nature of the tumors produced at dose levels > 1000 mg/kg (or equivalent dietary concentrations). Ten chemicals increased tumors only at dose levels greater than 1000 mg/kg. For six of these, the lowest dose tested was > 1000 mg/kg, so they may be active at dose levels below 1000 mg/kg. One chemical was active in rats and mice, 2 in rats only and 7 in mice only. Four of the chemicals were mutagenic to Salmonella. The tumor types produced by the other six putatively non-genotoxic chemicals suggest that a high dose limit of 1000 mg/kg is appropriate for rodent bioassays. Overtly genotoxic chemicals are no longer routinely subjected to bioassays.


[Cerebral sinovenous thrombosis in a girl with acute lymphoblastic leukaemia carrying the prothrombin G20210A variant].
Although cerebral venous thrombosis is rare, it is more commonly associated with children suffering from acute lymphoblastic leukaemia. We report the case of a 7-year-old girl who developed massive cerebral sinovenous thrombosis on day 22 of induction therapy for high-risk acute lymphoblastic leukaemia. Clinical symptoms were gradual onset of headache, decreasing consciousness, and ensuing left hemiplegia. A subsequent prothrombotic study revealed a heterozygous prothrombin G20210A variant in the child and mother. We analysed the prothrombotic factors found in the case before and after thrombosis. We confirm the importance of early exploration of patients for clinical predisposing risk factors of thrombosis and primary prothrombotic states in children with acute lymphoblastic leukaemia. This might help identify patients at particular risk from thrombosis and so administer thromboprophylaxis.


Arthroscopic Antegrade Cancellous Bone Autotransplantation for Osteochondral Lesions of the Tibial Plafond.
Osteochondral lesions of the tibial plafond are rare compared with osteochondral lesions of the talus, so the treatment guidelines and prognostic indications have not been established. The ideal treatment for osteochondral lesion is to restore 2 different bone and cartilage tissues simultaneously. We introduce a technique of arthroscopic antegrade cancellous bone autotransplantation; fibrocartilage regeneration can be expected for the cartilaginous lesion while bony lesion is replaced with the normal bone using this technique.


Streptococcus pneumoniae as a Cause of Salpingitis.
A case of pneumococcal septicemia associated with laparoscopically documented acute salpingitis is reported. Gram-stained cul-de-sac pus revealed gram-positive encapsulated diplococci. This case coupled with reanalysis of prior genital tract involvement in nonpregnant individuals argues that Streptococcus pneumoniae can mimic gonococcal diseases.


Simulations of peritoneal solute transport during CAPD. Application of two-pore formalism.
Blood peritoneal clearances of various endogenous solutes in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) were evaluated according to recent developments of the two-pore theory of membrane permeability, using a non-linear transport formalism for the analysis. Based on results obtained from these calculations and taking lymphatic drainage into account, transport from peritoneal cavity to the blood was also simulated. With respect to solute transport the data were compatible with a functional blood-peritoneal barrier consisting of a two-pore membrane containing a large number of paracellular "small pores" of radius 40 to 55 A and a small number of "large pores" of radius 200 to 300 A. Solutes smaller than 25 A in radius were found to be permeating across the peritoneal membrane mainly by means of diffusion across the small pores, whereas solutes larger than 40 A were calculated to reach the peritoneal cavity exclusively by unidirectional convection across the large pores. In addition, water was simulated to be transported through transcellular "ultrapores" (radius less than 8 A) not accessible to hydrophilic solute permeation. Small solute absorption from the peritoneal cavity was found to occur by diffusion across small pores. Molecules larger than 25 to 30 A in radius (molecular weight above 25,000) were simulated to be absorbed from the peritoneal cavity exclusively via non-size-selective lymphatic drainage.


Protocol to Study West Nile Virus Infection in Brain Slices In Vitro.
Ex vivo slice cultures of the brain tissue can maintain the cytoarchitecture of the central nervous system (CNS), which allows a thorough understanding of the functions of multiple interconnected cells in a culture system that closely resembles the in vivo environment. Additionally, slice cultures of the brain tissue are advantageous in tracking complex connectivity between neurons and glia both under normal and pathologic conditions, which is not possible in in vitro cell lines. Here, we describe the method of preparing ex vivo slice culture from the mouse cerebellum and the protocol of studying the effects of West Nile virus infection on cerebellar cells.


Cardiac syndrome X in Ireland: incidence and phenotype.
Cardiac syndrome X (CSX) is typical angina pectoris with objective signs of myocardial ischaemia despite a normal coronary angiogram and may be due to microvascular dysfunction. The incidence of CSX has not been greatly investigated worldwide and its incidence in Ireland is unknown. We aimed to determine the incidence of CSX in Cork University Hospital (CUH) and to establish the phenotype of the typical Irish CSX patient. All patients undergoing coronary angiography in CUH during regular working hours over a 3-month period were investigated. CSX was diagnosed using standard criteria. An extended recruitment period of 14 months allowed enrolment of a sufficient number of CSX patients to enable phenotyping. Only 5 of 372 (1.3 %) patients undergoing angiography to investigate chest pain met the diagnostic criteria for CSX. None were given a discharge diagnosis of CSX or received cardiology follow-up. Irish CSX patients were predominantly female (88 %) with a mean age of 59.2 ± 6.6 years. Although they were significantly less functionally limited than patients with obstructive CAD, they had an equally substantial impairment in quality of life. CSX is relatively uncommon in Ireland and is most frequently seen in middle-aged women with hyperlipidaemia. It has significant impacts on patients' quality of life. None of the CSX patients were diagnosed as such, highlighting the lack of awareness or acceptance of this condition in Ireland. These patients require diagnosis and active cardiology follow-up to effectively manage their symptoms.


Interactions between brain and spinal cord mediate value effects in nocebo hyperalgesia.
Value information about a drug, such as the price tag, can strongly affect its therapeutic effect. We discovered that value information influences adverse treatment outcomes in humans even in the absence of an active substance. Labeling an inert treatment as expensive medication led to stronger nocebo hyperalgesia than labeling it as cheap medication. This effect was mediated by neural interactions between cortex, brainstem, and spinal cord. In particular, activity in the prefrontal cortex mediated the effect of value on nocebo hyperalgesia. Value furthermore modulated coupling between prefrontal areas, brainstem, and spinal cord, which might represent a flexible mechanism through which higher-cognitive representations, such as value, can modulate early pain processing.


Mechanisms of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity to striatal dopamine neurons in mice.
MPTP given to mice in 4 daily doses (20 mg/kg s.c.) resulted in 56-70% depletion of striatal dopamine 1 week after the last dose. Pretreatment with deprenyl or MD 240928, selective inhibitors of monoamine oxidase type B, or with amfonelic acid or nomifensine, selective inhibitors of dopamine uptake, prevented the depletion of striatal dopamine. In contrast, pretreatment with alpha-methyl-tyrosine, Ro 4-1284 or haloperidol did not prevent the depletion of striatal dopamine by MPTP. The results are compatible with the view that dopamine itself is not involved in the neurotoxic effect of MPTP but that MPP+, a metabolite of MPTP formed by MAO-B and accumulated by the dopamine uptake carrier, is responsible for the neurotoxicity.


Combined use of rapamycin and leflunomide in prevention of acute cardiac allografts rejection in rats.
This study aimed to evaluate the role of combined use of rapamycin and leflunomide(Lef) on the prevention of acute allograft rejection in rats. After cardiac transplantations, rats were randomly divided into untreated group, rapamycin group, Lef group and rapamycin+Lef group. The drugs were given by gavage from day 0 to day 9 after transplantations. Graft survival time was observed. Some grafts were harvested for histopathological investigation on day 10 after transplantations. The levels of CD(4)(+) and CD(8)(+) T lymphocytes and the concentrations of interleukin 2(IL-2) and interferon (IFN)γ in peripheral blood were examined on day 10 after transplantations. At the same time, the body weight, the hepatic function, renal function and the haemoglobin of the recipients were also examined. The graft survival time of untreated group was 7.14 ± 1.07 days. Rapamycin group was 11.14 ± 1.35 days. Lef group was 11.29 ± 1.80 days. While in rapamycin+Lef group, the graft survival time was prolonged to 13.86 ± 1.57 days(P<0.05). Histological changes of the allografts in rapamycin+Lef group were much milder than either of the two single drug groups. The absolute number and the percentage of CD(4)(+) T lymphocytes in peripheral blood in rapamycin+Lef group were lower than those of rapamycin or Lef group on day 10 after transplantations(P<0.05), while the percentage of CD(8)(+) T lymphocytes in rapamycin+Lef group was higher than that of rapamycin or Lef group(P<0.05). The absolute number of CD(8)(+) T lymphocytes was not significantly different among rapamycin group, Lef group and rapamycin+Lef group. The levels of IL-2 and IFN-γ in rapamycin+Lef group were significantly lower than that of rapamycin group or Lef group(P<0.05). The body weight, the hepatic function, renal function and the haemoglobin were not significantly different among rapamycin group, Lef group and rapamycin+Lef group (P>0.05). Combined use of rapamycin and Lef had better effect on the prevention of acute cardiac allografts rejection in rats than monotherapy.


Combinational effects of hexane insoluble fraction of Ficus septica Burm. F. and doxorubicin chemotherapy on T47D breast cancer cells.
To evaluate the effects of n-hexane insoluble fraction (HIF) of Ficus septica leaves in combination with doxorubicin on cytotoxicity, cell cycle and apoptosis induction of breast cancer T47D cell lines. The in vitro drugs-stimulated cytotoxic effects were determined using MTT assay. Analysis of cell cycle distribution was performed using flowcytometer and the data was analyzed using ModFit LT 3.0 program. Apoptosis assay was carried out by double staining method using ethydium bromide-acridin orange. The expression of cleaved-poly (ADP-ribose) polymerase (PARP) on T47D cell lines was identified using immunocytochemistry. The combination exhibited higher inhibitory effect on cell growth than the single treatment of doxorubicin in T47D cells. In addition, combination of doxorubicin and HIF increased the incidence of cells undergoing apoptosis. HIF could improve doxorubicin cytotoxic effect by changing the accumulation of cell cycle phase from G2/M to G1 phase. The combination also exhibited upregulation of cleaved-PARP in T47D cells. Based on this results, HIF is potential to be developed as co-chemotherapeutic agent for breast cancer by inducing apoptosis and cell cycle arrest. However, the molecular mechanism need to be explored further.


Reduction of Blood Loss by Means of the Cavitron Ultrasonic Surgical Aspirator for Thoracoscopic Salvage Anatomic Lung Resections.
In centrally located lung tumors, salvage pulmonary resections pose challenges due to adhesions between the pulmonary parenchyma, chest wall, and hilum. This study aimed to investigate the surgical outcomes associated with Cavitron Ultrasonic Surgical Aspirator (CUSA) usage in thoracoscopic salvage pulmonary resections. Patients with centrally located advanced-stage lung tumors who underwent salvage anatomic resections following systemic or radiotherapy were included. They were categorized into CUSA and non-CUSA groups, and perioperative parameters and surgical outcomes were analyzed. Results: The study included 7 patients in the CUSA group and 15 in the non-CUSA group. Despite a longer median surgical time in the CUSA group (3.8 h vs. 6.0 h, p = 0.021), there was a significant reduction in blood loss (100 mL vs. 250 mL, p = 0.014). Multivariate analyses revealed that the use of CUSA and radiotherapy had opposing effects on blood loss (β: -296.7, 95% CI: -24.8 to -568.6, p = 0.034 and β: 282.9, 95% CI: 19.7 to 546.3, p = 0.037, respectively). In conclusion, while using CUSA in the salvage anatomic resection of centrally located lung cancer may result in a longer surgical time, it is crucial in minimizing blood loss during the procedure.


Transbronchial needle injection: a systematic review of a new diagnostic and therapeutic paradigm.
Transbronchial needle catheters are commonly used during flexible and rigid bronchoscopy for needle aspiration. The use of these catheters can be expanded by employing the technique of transbronchial needle injection. By injecting lesions in the airways, peribronchial structures, mediastinum, or lung parenchyma, transbronchial needle injection has been applied to the treatment of lung cancer, inflammatory disorders of the airways, recurrent respiratory papillomatosis, as well as bronchopleural fistulas. Diagnostic applications have included the localization of peripheral lung nodules as well as sentinel lymph nodes. Our review defines this bronchoscopic technique and summarizes its various reported applications.


Relation of serum total cholesterol and high-density lipoprotein cholesterol percentage to the incidence of definite coronary events: twenty-year follow-up of the Donolo-Tel Aviv Prospective Coronary Artery Disease Study.
This 20-year follow-up report presents the incidence of definite coronary events and its relation to serum total cholesterol (TC) and alpha-lipoprotein cholesterol percentage (percentage of serum TC bound with alpha-lipoprotein), now usually called high-density lipoprotein cholesterol percentage (HDL-C%). The cohort consists of 1,454 men and 1,481 women, presumably healthy, aged 35 to 64 years at the time of entrance examination in 1964. During the follow-up period 123 men and 44 women died from coronary disease. Ninety-six men and 42 women had nonfatal myocardial infarctions. The incidence of definite coronary events increased from 6% in men with TC levels of less than 200 mg/dl to 25% in men with levels of more than 264 mg/dl. The corresponding figures in women were 3% and 10%. The incidence of definite coronary events was inversely correlated to HDL-C%. The incidence of definite coronary events in 225 men with HDL-C% of less than 14% was 28%, and in 669 men with HDL-C% of 21% or more, 7%. The corresponding figures in 234 women with HDL-C% of less than 17% was 14%, and in 853 women with HDL-C% of 23% or more, 2%. Two HDL-C% subsets were assessed: "low" and "high" subsets refer to HDL-C% of less than 21% and 21% or more, respectively, in men and less than 23% and 23% or more in women.(ABSTRACT TRUNCATED AT 250 WORDS)


Ascorbic and dehydroascorbic acids simultaneously quantified in biological fluids by liquid chromatography with fluorescence detection, and comparison with a colorimetric assay.
We describe a "high-performance" liquid-chromatographic method for separating and quantifying ascorbic acid (AA) and dehydroascorbic acid (DHA) in plasma and urine. We used a reversed-phase C18 column with an ion-pair reagent and detected the analytes by post-column reaction with 4,5-dimethyl-o-phenylenediamine to form a fluorescent derivative (measured at excitation and emission wavelengths of 365 and 440 nm, respectively). Isoascorbic acid (IA) is the internal standard. Retention times for DHA, AA, and IA are 5.6, 15.5, and 19.9 min, respectively. Between-day CVs for AA in plasma in concentrations of 8 and 20 mg/L were 9% and 7%, respectively. The limit of detection is 10 and 4 ng for AA and DHA, respectively. Results by the present method and the methoxyaniline colorimetric method for AA are comparably accurate.


Lipoprotein abnormalities in cholestasis. II. Isolation, characterization and clinical evaluation of an additional cholestatic lipoprotein (slow-migrating HDL).
An additional cholestatic lipoprotein with a slower mobility than the usual alpha-lipoprotein on polyacrylamide-gel disc-electrophoresis was found in the serum of patients with cholestasis. This abnormal lipoprotein was referred to as Slwo-migrating HDL (HDL-S), because it was mostly recovered in the high density lipoprotein (HDL) fraction after preparative ultracentrifugation. HDL-S was precipitated by dextran sulfate and Mg++ but did not react with either concanavalin A or anti-beta-lipoprotein serum. The main apoprotein of HDL-S was Apo A-I, and a trace of Apo E was also present. HDL-S was relatively enriched in free cholesterol and triglycerides and had a density in the range of 1.063 to 1.083. The appearance of HDL-S in serum or plasma was closely associated with chronic mild intrahepatic cholestasis, particularly as in primary biliary cirrhosis and related conditions.


In Vitro 3D Spheroid Model Preserves Tumor Microenvironment of Hot and Cold Breast Cancer Subtypes.
Dynamic interaction of cancer, immune, and stromal cells with extracellular matrix components modulates and resists the response of standard care therapies. To mimic this, an in vitro 3D spheroid model is designed using liquid overlay method to simulate hot (MDA-MB-231) and cold (MCF-7) breast tumor microenvironment (TME). This study shows increased mesenchymal phenotype, stemness, and suppressive microenvironment in MDA-MB-231-spheroids upon exposure to doxorubicin. Intriguingly, the presence of human dermal fibroblasts enhances cancer-associated fibroblast phenotype in MDA-MB-231-spheroids through increased expression of CXCL12 and FSP-1, leading to higher infiltration of immune cells (THP-1 monocytes). However, a suppressive TME is observed in both subtypes, as seen by upregulation of M2-macrophage-specific CD68 and CD206 markers. Specifically, increased PDL-1 expressing tumor-associated macrophages along with FoxP3 expressing T regulatory cells are found in MDA-MB-231-spheroids when cultured with peripheral blood mononuclear cells. Further, it is found that the addition of 1-methyl-tryptophan, a potent indoleamine-2,3-dioxygenase-1 inhibitor, subsides the suppressive phenotype by decreasing the M2 polarization via downregulation of tryptophan metabolism and IL10 expression, particularly in MCF-7 triculture spheroids. Thus, the in vitro 3D spheroid model of TME can be utilized in therapeutics to validate immunomodulatory drugs for various breast cancer subtypes.


Demonstration of the adhesive properties of the medium-chain-length polyhydroxyalkanoate produced by Pseudomonas chlororaphis subsp. aurantiaca from glycerol.
Pseudomonas chlororaphis subsp. aurantiaca (DSM 19603) was grown on crude glycerol from biodiesel production to produce a medium-chain-length polyhydroxyalkanoate (mcl-PHA), composed of 3-hydroxydodecanoate (43 ± 1.8 mol%), 3-hydroxydecanoate (29 ± 3.1 mol%), 3-hydroxytetradecanoate (12 ± 0.4 mol%), 3-hydroxyoctanoate (10 ± 1.5 mol%) and 3-hydroxyhexanoate (6 ± 0.3 mol%). The biopolymer had an average molecular weight of 1.1 × 105 Da, with a polydispersity index of 1.5, and was semi-crystalline, as shown by its crystallinity index of 37 ± 0.2%. It had low melting (44 °C) and glass transition (-48 °C) temperatures, and was thermally stable up to 285 °C. The biopolymer films were elastic and translucid, were hydrophobic and presented relatively high permeability to oxygen and carbon dioxide. The films demonstrated to have good adhesion properties towards porcine skin and human skin. The tension (61.1 ± 20.6 kPa) and shear (12.7 ± 2.14 kPa) bond strength of the mcl-PHA for porcine skin suggest its potential as a biomaterial for the development of novel natural adhesives for wound closure or wound dressings.


Palladium-catalyzed multi-component synthesis of steroidal A- and D-ring fused 5,6-disubstituted pyridines under microwave irradiation.
The preparation of steroidal A-, D-ring fused 5,6-disubstituted pyridines and nonsteroidal substituted pyridines is described form Pd(OAc)2 catalyzed multi-component reaction of steroidal/nonsteroidal β-halovinyl aldehyde, alkyne and benzylamine in solvent-free condition under microwave irradiation.


Abnormal biomechanics: a precursor or result of knee osteoarthritis?
Biomedical studies are required to differentiate between the causes and results of knee osteoarthritis.


Brachytherapy and bivalirudin evaluation study.
Bivalirudin is shown to be a competent substitute for heparin in percutaneous coronary intervention (PCI). The safety and efficacy of bivalirudin in patients undergoing PCI and vascular brachytherapy (VBT) are not known. This study aimed to assess the safety and efficacy of bivalirudin as a single antithrombotic agent in patients undergoing PCI and VBT. A total of 152 patients enrolled in the Brachytherapy and Bivalirudin Evaluation Study underwent PCI and VBT with either gamma (n = 8) or beta radiation (n = 144). The main outcome measures were in-hospital events and 30-day clinical outcomes. All patients were treated with bivalirudin (0.75 mg/kg bolus and 1.75 mg/kg per hour infusion for beta radiation, 1 mg/kg bolus and 2.5 mg/kg per hour infusion for gamma radiation) as a single antithrombotic agent during the entire procedure. Baseline clinical and angiographic characteristics were similar between the 2 groups. More than 90% of the patients received beta radiation. In-hospital events showed a higher prevalence of acute procedural intracoronary thrombosis in patients treated with gamma- vs beta radiation (25% vs. 0.7%, P < .001). Thirty-day outcomes including death, Q-wave, and non-Q-wave myocardial infarctions, subacute stent thromboses, and repeat revascularizations were similar in both groups. Bivalirudin, as a single antithrombotic agent during PCI and VBT with beta emitters, may be used safely, but its use in the setting of PCI and gamma radiation may not be acceptable due to an increased incidence of acute procedural intracoronary thrombosis.


Applications of derivative UV spectrophotometry for the determinations of fenbufen and ketoprofen in pharmaceutical preparations.
A methods for the determination of fenbufen and ketoprofen in pharmaceuticals by classical spectrophotometry--zero order derivative, first and second order derivatives spectrophotometry is described. using "peak-peak" (P-P) and, "peak-zero" (P-O) measurements. The calibration curves are linear within the concentration range of 2.0 - 12.0 microg x mL(-1) for fenbufen and ketoprofen. The procedure is simple, rapid and the results are reliable.


Human tibia bone marrow blood perfusion by non-invasive near infrared spectroscopy: a new tool for studies on microgravity.
Human tibia bone marrow (BM) and tibialis anterior muscle (TA) perfusion index (PI) was assessed non-invasively by near infrared spectroscopy. A decrease in the postis-chaemic reperfusion capability of the human tibia BM and TA muscle was observed for increasing age i.e., PI increases linearly as a function of age, starting from 30 years, both for BM (0.062 %/year, from -4.185 to -0.967 %/s) and TA muscle (0.046 %/year, from -5.760 to -3.883 %/s). The results define a "normal" baseline and demonstrate the sensitivity of the method to PI changes. The present technique should allow one to investigate physio-pathological effects induced by microgravity on tibia BM blood perfusion.


Complete mitogenome of Kashmir musk deer (Moschus cupreus) and its comparative phylogenetic relationships.
Kashmir musk deer, Moschus cupreus (KMD) is one the most threatened species endemic to the Himalayan region of Kashmir, Pakistan and Afghanistan. Herein, we have sequenced, annotated and characterized the complete mitogenome of M. cupreus. The investigation and comparison of the mitogenome provide crucial information for phylogenetic analysis to understand the evolutionary relationships. The mitogenome of KMD was 16,354 bp long, comprising 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), two ribosomal RNA genes (rRNAs) and non-coding control region. Its composition was highly A+T biased 68.42%, and exhibited a positive AT-skew (0.082) and negative GC-skew (- 0.307). The phylogenetic analysis suggested that KMD was a primitive and extant species in the genus Moschus, whereas Alpine musk deer (M. chrysogaster) and Himalayan musk deer (M. leucogaster) were the closest relatives. It indicated the placement of M. cupreus within the monotypic family Moschidae of musk deer. Hence, it provides a better understanding of lineage identification and musk deer evolution for further research.


The gene for the serpin thrombin inhibitor (PI7), protease nexin I, is located on human chromosome 2q33-q35 and on syntenic regions in the mouse and sheep genomes.
Protease nexin I (PNI) is the most important physiologic regulator of alpha-thrombin in tissues. PNI is highly expressed and developmentally regulated in the nervous system where it is concentrated at neuromuscular junctions and also central synapses in the hippocampus and striatum. Approximately 10% of identified proteins at mammalian neuromuscular junctions are serine protease inhibitors, consistent with their central role in balancing serine protease activity to develop, maintain, and remodel synapses. Southern blot hybridization of PNI cDNA to somatic cell hybrids placed the structural gene for PNI (locus PI7) on human chromosome 2q33-q35 and to syntenic chromosomes in the mouse (chromosome 1) and sheep (chromosome 2).


Diffusion-weighted MR imaging in normal human brains in various age groups.
Few studies have concerned the absolute apparent diffusion coefficient (ADC) values in the normal human brain and the effect of aging on diffusion. Therefore, our purpose was to determine whether the average ADC (ADC(av)) values in the various regions of the brain differ with age, sex, or hemisphere and to establish reference values of the absolute ADC(av) for further studies. Subjects (40 men and 40 women) were chosen from a healthy population; age groups were 20-34, 35-49, and 50-64 years and 65 years or older (n = 20 each). All subjects were examined with MR imaging, including conventional and diffusion-weighted imaging in three orthogonal directions with two b values (0 and 1000 s/mm(2)) at 1.5 T. Bilateral ADC(av) values were determined in 36 regions of interest encompassing the entire brain. ADC(av) values were highest in the cortical gray matter ([0.89 +/- 0.04] x 10(-3) mm(2)/s; range, 0.78-1.09 x 10(-3)), lower in the deep gray matter ([0.75 +/- 0.03] x 10(-3) mm(2)/s; range, 0.64-0.83 x 10(-3)), and lowest in the white matter ([0.70 +/- 0.03] x 10(-3) mm(2)/s; range, 0.62-0.79 x 10(-3)). The ADC(av) values did not significantly change with aging, except for an increase in the lateral ventricles. No difference was observed between women and men or between the hemispheres. The data reported herein are representative, and the ADC(av) values can be used for reference in future studies and in clinical settings.


[Endothyroid (non-chromaffin) branchiomeric paraganglioma. Description of a clinical case].
A case of endothyroid paraganglioma in a 9-yr-old girl is described. Subtotal lobectomy was performed and the tumour was not recognised until a histological examination has been carried out on a section embedded in paraffin. Only two other cases could be found in the literature. An account is given of the diagnosis of this form, and reference is made to its prognostic aspects since there is a remote possibility that metastasis may occur many years after surgery.


Sagittal alignment of spine and pelvis regulated by pelvic incidence: standard values and prediction of lordosis.
Pelvis and spinal curves were studied with an angular parameter typical of pelvis morphology: pelvic incidence. A significant chain of correlations between positional pelvic and spinal parameters and incidence is known. This study investigated standards of incidence and a predictive equation of lordosis from selective pelvic and spinal individual parameters. One hundred and forty nine (78 men and 71 women) healthy adults, aged 19-50 years, with no spinal disorders, were included and had a full-spine lateral X-ray in a standardised upright position. Computerised technology was used for the measurement of angular parameters. Mean-deviation section of each parameter and Pearson correlation test were calculated. A multivariate selection algorithm was running with the lordosis (predicted variable) and the other spinal and pelvic parameters (predictor variables), to determine the best sets of predictors to include in the model. A low incidence (<44 degrees ) decreased sacral-slope and the lordosis is flattened. A high incidence (>62 degrees ) increased sacral-slope and the lordosis is more pronounced. Lordosis predictive equation is based on incidence, kyphosis, sacral-slope and +/-T9 tilt. The confidence limits and the residuals (the difference between measured and predicted lordosis) assessed the predicted lordosis accuracy of the model: respectively, +/-1.65 and 2.41 degrees with the 4-item model; +/-1.73 and 3.62 degrees with the 3-item model. The ability of the functional spine-pelvis unit to search for a sagittal balance depended both on the incidence and on the variation section of the other positional parameters. Incidence gave an adaptation potential at two levels of positional compensation: overlying state (kyphosis, T9 tilt), underlying state (sacral slope, pelvic tilt). The biomechanical and clinical conditions of the standing posture (as in scoliosis, low back pain, spondylisthesis, spine surgery, obesity and postural impairments) can be studied by comparing the measured lordosis with the predicted lordosis.


Metagenomic Next-Generation Sequencing (mNGS): SARS-CoV-2 as an Example of the Technology's Potential Pediatric Infectious Disease Applications.
Metagenomic next-generation sequencing (mNGS) has emerged as a potentially powerful tool in clinical diagnosis, hospital epidemiology, microbial evolutionary biology, and studies of host-pathogen interaction. The SARS-CoV-2 pandemic provides a framework for demonstrating the applications of this technology in each of these areas. In this Supplement, we review applications of mNGS within the discipline of pediatric infectious diseases.


Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period.
A retrospective study covering a 14-year period was carried out to estimate the incidence and assess the clinical features of benzodiazepine (BZD) poisoning. The annual contribution of BZDs to the total number of drug overdose cases admitted to an intensive care unit displayed an increasing trend over the period, and during the last years BZDs were involved in nearly one-third of all cases. Among the 702 cases of BZD overdosage, 144 had ingested BZD alone, 200 had poisoned themselves with BZD combined with alcohol and 358 had taken BZD with other miscellaneous drugs. In 56% of all the cases the patients had severe central nervous system depression on admission. In 47% orotracheal intubation was performed and in 18% artificial ventilation was administered. Complications were recorded in 69 of the 702 cases (9.8%) and five cases were fatal. These clinical features were essentially the same in the group that had overdosed with just BZD. In conclusion, patients with drug overdosage involving BZD have a low hospital mortality, but the acute somatic risk is not negligible. Moreover, they consume a substantial proportion of the resources in the emergency room and the intensive care unit.


Microarray Genotyping Identifies New Loci Associated with Dementia in Parkinson's Disease.
Dementia is one of the most disabling nonmotor symptoms of Parkinson's disease (PD). However, the risk factors contributing to its development remain unclear. To investigate genetic variants associated with dementia in PD, we performed microarray genotyping based on a customized platform utilizing variants identified in previous genetic studies. Microarray genotyping was performed in 313 PD patients with dementia, 321 PD patients without dementia, and 635 healthy controls. The primary analysis was performed using a multiple logistic regression model adjusted for age and sex. SNCA single nucleotide polymorphism (SNP) rs11931074 was determined to be most significantly associated with PD (odds ratio = 0.66, 95% confidence interval = 0.56-0.78, p = 7.75 × 10-7). In the analysis performed for patients with PD only, MUL1 SNP rs3738128 (odds ratio = 2.52, 95% confidence interval = 1.68-3.79, p = 8.75 × 10-6) was found to be most significantly associated with dementia in PD. SNPs in ZHX2 and ERP29 were also associated with dementia in PD. This microarray genomic study identified new loci of MUL1 associated with dementia in PD, suggesting an essential role of mitochondrial dysfunction in the development of dementia in patients with PD.


Effect of dextran-coated charcoal on radioimmunoassays of unconjugated estriol in serum.
Lipid interference in the radioimmunoassay of steroids can cause an apparent variation in post-prandial serum concentrations of unconjugated estriol. The effects of increased concentrations of dextran-coated charcoal (15--60 g/l) in the radioimmunoassay of estriol standards with and without triglycerides were studied. All concentrations of dextran-coated charcoal used in this study eliminated the previously observed effects of estriol-lipid partitioning. When we used similar concentrations of dextran-coated charcoal, we found that serum cortisol levels in pregnant women declined significantly during the day (P less than 0.001), but no significant variation in estriol concentrations was observed. These results indicate that the previously reported diurnal variation in serum unconjugated estriol concentrations attributed to steroid-lipid partitioning can be eliminated by increasing the concentration of dextran-coated charcoal in assays using this method of separation.


Disjunctive inference in preverbal infants.
Can preverbal infants utilize logical reasoning such as disjunctive inference? This logical operation requires keeping two alternatives open (A or B), until one of them is eliminated (if not A), allowing the inference: B is true. We presented to 10-month-old infants an ambiguous situation in which a female voice was paired with two faces. Subsequently, one of the two faces was presented with the voice of a male. We measured infants' preference for the correct face when both faces and the initial voice were presented again. Infant pupillary response was measured and utilized as an indicator of cognitive load at the critical moment of disjunctive inference. We controlled for other possible explanations in three additional experiments. Our results show that 10-month-olds can correctly deploy disjunction and negation to disambiguate scenes, suggesting that disjunctive inference does not rely on linguistic constructs.


Active hospital-based surveillance of invasive pneumococcal disease and clinical pneumonia in infants and young children in two Polish counties.
Invasive pneumococcal disease (IPD) incidence, serotype distribution, and antibiotic susceptibility of Streptococcus pneumoniae were estimated in children aged 28 days to < 60 months. One-year prospective, hospital-based surveillance was conducted starting on February 15, 2008, at two children's hospitals serving the city and surrounding county of Poznań and Poznański, Poland. Eligible children had fever ≥ 39.0°C or physician-suspected IPD. Blood cultures were obtained from all children, cerebrospinal fluid in suspected meningitis cases, and chest radiographs (CXRs) in suspected pneumonia cases. Seven of 1,581 eligible children had confirmed IPD. Estimated IPD incidence per 100,000 children was 11.89 (95% CI: 4.78-24.50) overall and 20.1 (95% CI: 6.52-46.84) in subjects aged 28 days to < 24 months. One S. pneumoniae isolate of each of the following serotypes was obtained: 6B, 14, 23A, 23F, and 33F. Two isolates were resistant to both trimethoprim-sulfamethoxazole and erythromycin. Clinical pneumonia incidence among children aged 28 days to < 24 months and 24 months to < 60 months was 3,151.3 (95% CI: 2934.7-3379.7) and 962.7 (95% CI: 861.2-10,072.9) per 100,000 children, respectively. CXR-confirmed pneumonia rates in the same groups were 1,035.7 (95% CI: 913.2-1,170.1) and 379.8 (95% CI: 317.1-451.3) per 100,000 children, respectively. IPD is an important cause of morbidity in Poznań and Poznański county, Poland. Among participants aged < 5 years with fever or suspected IPD, pneumonia was the most common diagnosis and was highest in children aged < 24 months.


The effect of progesterone on spontaneous and agonist-evoked contractions of the rat aorta and portal vein.
The mechanisms underlying the suppression of vasocontractility caused by progesterone were investigated by studying changes in the contractile force of rat isolated aorta and portal vein, induced by altering extracellular concentrations of noradrenaline (NA) potassium ions (K+) and calcium ions (Ca2+). In the aorta, progesterone (10 microM) had a general suppressive effect on NA-, Ca2+- and K+-induced contractions. In contrast, in the portal vein a more selective suppression of contractions was observed. Both tonic and phasic components of contractions induced by cumulative addition of Ca2+ to tissues equilibrated in Ca2+-free saline were suppressed. The phasic but not tonic components of contractions induced by NA addition were suppressed. There was no significant effect on tonic contractions induced by elevated (40-120 mM) K+, but a concentration-dependent suppression of the phasic component of contractions was observed during depolarisation with smaller elevations of K+ concentrations (5-20 mM). These results suggest that on the portal vein the suppressive effect of progesterone is due to a potassium channel opening action, whilst on the aorta a different or additional mechanism of suppression exists.


Human thyroid peroxidase: autoantibody recognition depends on the natural conformation.
Thyroid peroxidase (TPO) purified from human thyroid glands was used to study the correlation relation between natural conformation and its ability for binding of autoantibodies in sera from patients with autoimmune lymphocytic thyroiditis (Hashimoto's thyroiditis). Treatment with heat (60 degrees C), urea, sodium dodecylsulfate (SDS), and dithiothreitol (DTT) decreased the autoantigenicity of TPO on average by 73.3%, 74.1%, 86.3%, and 91.8% measured by enzyme-linked immunosorbent assay (ELISA), respectively. These data demonstrate, that the binding of the majority of autoantibodies to human TPO depends on its natural conformation and modification.


gammaH2AX signalling during sperm chromatin remodelling in the mouse zygote.
In the mouse, the paternal post-meiotic chromatin is assumed to be devoid of DNA repair after nuclear elongation and protamine-induced compaction. Hence, DNA lesions induced thereafter will have to be restored upon gamete fusion in the zygote. Misrepair of such lesions often results in chromosome type aberrations at the first cleavage division, suggesting that the repair event takes place prior to S-phase. During this stage of the zygotic cell cycle, the paternal chromatin transits from a protamine- to a nucleosome-based state. We addressed the question whether the canonical signalling pathway to DNA double strand breaks (DSBs), the phosphorylated form of histone H2AX (gammaH2AX) is active during chromatin restructuring of the male genetic complement in the zygote. Here, we describe the detailed characterization of gammaH2AX signalling in the early stages of zygotic development up to the appearance of the pronuclei. We have found the gammaH2AX signalling pathway to be already active during sperm chromatin remodelling after gamete fusion in a dose dependent manner, reflecting the amount of DSBs present in the sperm nucleus after in vivo male irradiation. Using DNA damaging compounds to induce lesions in the early zygote, differences in DSB sensitivity and gammaH2AX processing between paternal and maternal chromatin were found, suggesting differences in DNA repair capacity between the parental chromatin sets.


Serum uric acid change in relation to antihypertensive therapy with the dihydropyridine calcium channel blockers.
We investigated serum uric acid changes in relation to the achieved clinic and ambulatory blood pressure after 8 weeks of antihypertensive therapy with two dihydropyridine calcium channel blockers. The study participants were patients with clinic and ambulatory hypertension, enrolled in a randomised controlled trial that compared amlodipine (5-10 mg, n = 215) and nifedipine gastrointestinal therapeutic system (GITS, 30-60 mg, n = 203). Hyperuricaemia was defined as a serum uric acid concentration of ≥420 µmol/L in men and ≥360 µmol/L in women. Analysis of covariance and multiple regression analyses were performed to study the associations between serum uric acid changes and the achieved clinic and ambulatory blood pressure during follow-up. At baseline, 67 (16.0%) of the 418 patients had hyperuricaemia. Antihypertensive treatment reduced clinic and 24-h daytime and night-time systolic/diastolic blood pressure by a mean (±standard error [SE]) change of -17.4 ± 0.6/-8.6 ± 0.4 mm Hg and -13.7 ± 0.5/-8.3 ± 0.3 mm Hg, -13.8 ± 0.6/-8.4 ± 0.4 mm Hg, and -12.7 ± 0.7/-8.0 ± 0.4 mm Hg, respectively. Antihypertensive treatment reduced serum uric acid by a mean (±SE) change of -9.3 ± 2.8 μmol/L. The serum uric acid changes differed according to the achieved clinic and ambulatory blood pressure, and were statistically significant (mean ± SE -20.6 ± 6.6 to -10.7 ± 2.9 μmol/L, p ≤ 0.04) at the systolic/diastolic ranges of 130-139/≥90 mm Hg in clinic pressure, and <130/75-84 mm Hg, <145/80-84 mm Hg and <120/65-69 mm Hg in 24-h, daytime and night-time ambulatory pressure. Our study showed that antihypertensive therapy with a dihydropyridine calcium channel blocker was associated with reduced serum uric acid, especially when 24-h ambulatory systolic blood pressure was controlled.


Nuclear factor kappaB is downregulated and correlates with p53 in the Min mouse mucosa during an accelerated tumor growth.
The nuclear factor kappaB signaling pathway has gained attention for its role in the carcinogenic process. We have measured the protein levels of the p65 subunit during a growth of adenomas in the Min mouse model for colon cancer. To study how an accelerated growth of adenomas affect cell signalling, adenoma growth was increased by an inulin diet (10%) that we have shown previously to be a promotor of adenoma formation. In our study, the association between NF-kappaB, p53, beta-catenin, Fas and COX-2 were evaluated by measuring their protein levels in 9- and 15-week old Min mouse adenomas and surrounding mucosa. The amount of p65 rouse between 9- and 15-weeks in the mucosa of the control-fed mice (p = 0.032). The inulin-fed mice had less p65 in the nucleus of the mucosa at 15 weeks of age compared to the control (p = 0.064), although the adenomas were significantly larger (1.46 mm +/- 0.12 for inulin, 0.97 mm +/- 0.12 for control, p < 0.001). Nuclear p65 correlated positively with nuclear p53 in the mucosa (p < 0.001) and adenoma (p < 0.001) tissues. Also, p65 correlated positively with nuclear beta-catenin in the mucosa (p = 0.012) and the adenoma (p = 0.001). Fas expression increased in the inulin group between 9-15 weeks (p = 0.034) and correlated negatively with p65 (p = 0.03). The amount of COX-2 in the adenoma tissue increased between 9-15 weeks and did not correlate with p65. The results suggest that p65 is involved in a p53-dependent apoptotic response in the Min mouse.


Synthesis, in vitro cytotoxic activity and molecular docking study of androstene and estrone derivatives.
The development and discovery of steroidal drugs to cure cervical cancer is of the most important. The Claisen condensation of androstene and estrone with aromatic aldehydes was catalyzed by potassium tert. butoxide in tert. butanol to give the corresponding 2-arylidene and 16-arylidene estrone. Subsequently, the 16-arylidene estrone reacted with acid chloride in presence of quaternary amine in halogenated solvent resulting in the steroidal arylidene derivatives. Synthesis, Characterization and in vitro cytotoxic activity of arylidenes are rationalized. Fifteen compounds are synthesized and six of them were evaluated for cytotoxic activity against cervical cancer cell line. HT-3 cell line examination revealed a considerable growth inhibition. Compounds 4a, 4b, 6b, 8c, and 8d, which are estrone-based arylidenes, are the most potent of the series, with IC50 value of 7.15, 10.76, 6.37, 3.56, and 1.55 µM/ml against HT-3 cell line. In addition, molecular docking studies were performed for the steroidal arylidenes to elucidate the binding interactions. Compound 4a, 4b, 6b, 8c and 8d showed excellent binding energy. Docking studies agreed well with in vitro studies. The end result offers an alternative approach to develop steroidal arylidenes that are more effective and are based on estrone, leading to the development of novel anticancer agents.


Super-tough polylactic acid (PLA)/poly(butylene succinate) (PBS) materials prepared through reactive blending with epoxy-functionalized PMMA-GMA copolymer.
High-performance biosourced polylactic acid (PLA)/poly(butylene succinate) (PBS) blends with small amounts of compatibilizer, epoxy-functionalized methyl methacrylate-co-glycidyl methacrylate copolymer (PMMA-GMA), were fabricated by melt compounding. The properties of the modified PLA/PMMA-GMA, PBS/PMMA-GMA, and PLS(PLA/PBS)/PMMA-GMA blends were investigated systematically. DSC combined with X-ray diffraction revealed a low-order semi-crystalline structure for all samples. SEM and DMA showed that the compatibility between PLA and PBS was improved after addition of PMMA-GMA. Rheological behavior of blends showed that the addition of PMMA-GMA resulted in a significant improvement in the viscoelasticity. FT-IR spectra confirmed that the interfacial compatibilization between PLA and PBS phases was improved due to the reaction of epoxy groups with terminal groups of PLA and PBS. Finally, the toughness and notched impact strength of the PLA materials were increased significantly. The elongation at break and notched impact strength of PLS/PMMA-GMA was about 55.7 and 6.2 times than neat PLA after incorporation of 7 wt% PMMA-GMA, respectively.


Specific immunoassay for protein dimers, trimers, and higher oligomers.
An immunoassay is described that discriminates between monomers and oligomers of human leukocyte interferon. The assay in principle can be used to distinguish between monomers and oligomers of any substance.


Biomechanical differences of the proximal interphalangeal joint volar plate during active and passive motion: a dynamic ultrasonographic study.
To define the biomechanical differences of the volar plate (VP) of the proximal interphalangeal joint during active and passive motion, which may provide clues to understanding the functional importance of the volar elevation of the VP. We imaged the volar aspect of the proximal interphalangeal joint in 10 healthy middle fingers using ultrasonography. Cine videos recorded the movements of the VP during joint motion from full extension to more than 60° of flexion both actively and passively. We plotted 5 points on the volar surface of the VP and traced them for motion analysis. We statistically analyzed the volar distances and volar angulation of the VP in full extension, 30°, 45°, and 60° of flexion to determine the differences between active and passive flexion. In active flexion, the VP showed significantly higher volar distances in 45° and 60° and changed its configuration from the original flattened figure to an inverted U shape, with a significant higher angulation at 45° compared with passive flexion. Conversely, in passive flexion, we did not observe the volar elevation of the VP and the flattened configuration was maintained throughout the motion arc. From an anatomical viewpoint, volar elevation of the VP seen in active flexion could provide dynamic stresses on the adjacent ligaments and contribute to the stability and smooth gliding of the joint.


The Role of Long Noncoding RNAs in the Biology of Pituitary Adenomas.
Long noncoding RNAs (lncRNAs) are a large group of noncoding RNAs 200 nucleotides long. lncRNAs that function as regulatory factors have been identified for several complex cellular processes, such as cell death, growth, differentiation, apoptosis, epigenetic regulation, and so on. Many lncRNAs have altered expression and are likely to play a functional role in oncogenesis. The pituitary adenoma is the second most common intracranial tumor. Despite this situation, the molecular mechanism of pituitary adenoma formation has not yet been fully identified. This review summarizes recent progress in the study of lncRNAs on the pathogenesis of pituitary tumors. We cover the latest results associated with this role and highlight the therapeutic possibilities for pituitary adenomas.


Reviving up dendritic cells can run cancer immune wheel in non-small cell lung cancer: a prospective two-arm study.
Lung cancer is the number one cause of cancer-related deaths. Dendritic cells (DCs) are heterogeneous components of innate immunity that play a crucial role in the anti-tumor T cell immunity and may represent a promising approach for tumor immunotherapy. In this study, we aimed to evaluate the frequency of the two major subsets of DCs; plasmacytoid dendritic cells (pDCs) and monocytic dendritic cells (mDCs) in non-small cell lung cancer (NCSLC) and correlating them with different clinicopathologic features and survival outcomes. This study was a case-controlled one, included 50 patients with denovo pathologically confirmed NSCLC and 20 healthy controls of comparable age and gender. After diagnosis and staging of patients, the frequency of DCs was evaluated using flow cytometry. We unveiled significantly reduced levels of pDCs (P = 0.024), and mDCs (P = 0.013) in NSCLC patients compared to controls. Furthermore, there was a significant accumulation of pDCs in non-metastatic patients compared to metastatic ones (P < 0.0001), while there was no significant (P = 0.6) differences in mDCs, and mDCs/pDCs ratio (P = 0.9). There was a Significant negative correlation (r = - 0.3, P = 0.04) between OS and mDCs. On the other hand, there was a significantly higher OS with pDCs ≥ 0.82 compared to patients with pDCs < 0.82, log rank Ch2 = 12.128, P < 0.0001. Despite the controversy about the prognostic role of pDCs not only in NSCLC but also in other solid tumors, our study sheds light on the possible prognostic impact of pDCs and mDCs on treatment outcomes of NSCLC patients.


Low-energy X-ray irradiation: A novel non-thermal microbial inactivation technology.
Over the last several decades, food irradiation technology has been proven neither to reduce the nutritional value of foods more than other preservation technologies, nor to make foods radioactive or dangerous to eat. Furthermore, food irradiation is a non-thermal food processing technology that helps preserve more heat sensitive nutrients than those found in thermally processed foods. Conventional food irradiation technologies, including γ-ray, electron beam and high energy X-ray, have certain limitations and drawbacks, such as involving radioactive isotopes, low penetration ability, and economical unfeasibility, respectively. Owing to the recent developments in instrumentation technology, more compact and cheaper tabletop low-energy X-ray sources have become available. The generation of low-energy X-ray, unlike γ-ray, does not involve radioactive isotopes and the cost is lower than high energy X-ray. Furthermore, low-energy X-ray possesses unique advantages, i.e., high linear energy transfer (LET) value and high relative biological effect (RBE) value. The advantages allow low-energy X-ray irradiation to provide a higher microbial inactivation efficacy than γ-ray and high energy X-ray irradiation. In the last few years, various applications reported in the literature indicate that low-energy X-ray irradiation has a great potential to become an alternative food preservation technique. This chapter discusses the technical advances of low-energy X-ray irradiation, microbial inactivation mechanism, factors influencing its efficiency, current applications, consumer acceptance, and limitations.


Time-resolved studies of metalloproteins using X-ray free electron laser radiation at SACLA.
The invention of the X-ray free-electron laser (XFEL) has provided unprecedented new opportunities for structural biology. The advantage of XFEL is an intense pulse of X-rays and a very short pulse duration (<10 fs) promising a damage-free and time-resolved crystallography approach. Recent time-resolved crystallographic analyses in XFEL facility SACLA are reviewed. Specifically, metalloproteins involved in the essential reactions of bioenergy conversion including photosystem II, cytochrome c oxidase and nitric oxide reductase are described. XFEL with pump-probe techniques successfully visualized the process of the reaction and the dynamics of a protein. Since the active center of metalloproteins is very sensitive to the X-ray radiation, damage-free structures obtained by XFEL are essential to draw mechanistic conclusions. Methods and tools for sample delivery and reaction initiation are key for successful measurement of the time-resolved data. XFEL is at the center of approaches to gain insight into complex mechanism of structural dynamics and the reactions catalyzed by biological macromolecules. Further development has been carried out to expand the application of time-resolved X-ray crystallography. This article is part of a Special Issue entitled Novel measurement techniques for visualizing 'live' protein molecules.


Right Condylar Jugular Diverticulum: Contrast-enhanced Computed Tomography Findings of a Rare Anatomical Variant of Jugular Bulb.
This is the first description of condylar jugular diverticulum (CJD) by means of contrast-enhanced computed tomography scan in the medical literature. CJD is a rare anatomical variant of jugular bulb that should be known to avoid radiological and surgical errors and achieve an appropriate pre-surgical planning of skull base pathologies.


Selective regulation of beta 2-adrenergic receptor gene expression by interleukin-1 in cultured human lung tumor cells.
The regulation of beta 1- and beta 2-adrenergic receptors (beta 1AR and beta 2AR) and receptor gene expression by interleukin-1 alpha (IL-1 alpha) was studied in cultured A549 human lung adenocarcinoma cells. The density and affinity of beta 1 AR and beta 2 AR were analyzed by computerized curve fitting of 125I-pindolol binding and its displacement by subtype selective antagonists. Steady state levels of receptor mRNAs were quantified by DNA excess solution hybridization assays. A549 cells in preconfluent cultures had fewer beta 1AR than beta 2AR (beta 1: 1.9 +/- 0.3 vs beta 2: 4.0 +/- 0.5 fmol/mg protein, means +/- SE), but lost most of their beta 2 AR upon reaching confluency (beta 1: 2.7 +/- 0.4, beta 2: 0.8 +/- 0.3 fmol/mg). Incubation of preconfluent cells for 24 hr with 20 pM of human recombinant IL-1 alpha did not modify the density of either of the beta AR subtypes. Similar incubations of confluent cells increased the density of beta 2 AR from 0.8 +/- 0.3 to 4.2 +/- 0.9 fmol/mg, while the density of beta 1 AR and the antagonist affinities of both receptors remained unaltered. The IL-1 alpha-induced increase in beta 2 AR density in confluent cells was antagonized in a concentration-dependent manner by a recombinant protein antagonist of type I IL-1 receptors (IC50: 0.2 nM). The IL-1 alpha-induced increase in beta 2AR density was preceded by an increase in the steady state level of beta 2AR mRNA, while levels of beta 1AR mRNA remained unchanged. IL-1 alpha increased the stability as well as the rate of transcription of beta 2AR mRNA. These findings demonstrate for the first time that activation of type I IL-1 receptors in A549 cells leads to a cell density-dependent, selective upregulation of beta 2AR, and that the mechanism of this effect involves increased formation and stability of the beta 2AR message.


[Transcription factor AP-1 components as a psoriasis candidate genes].
Psoriasis is an autoimmune multifactorial dermatological disease frequently occured in European population. As for other multifactorial genetic diseases success in psoriasis treatment may be achieved due to determination of molecular genetic mechanisms of pathogenesis triggering and psoriasis candidate genes and proteins searching as targets for drugs. Using bioinformatic analysis of transcriptome data AP-1 transcriptional factor components were revealed as psoriasis candidate genes.


Hereditary and acquired diseases of acyl-coenzyme A metabolism.
Coenzyme A (CoA) sequestration, toxicity or redistribution (CASTOR) is predicted to occur in many hereditary and acquired conditions in which the degradation of organic acyl esters of CoA is impaired. The resulting accumulation of CoA esters and reduction of acetyl-CoA and free CoA (CoASH) will then trigger a cascade of reactions leading to clinical disease. Most conditions detected by expanded neonatal screening are CASTOR diseases. We review acyl-CoA metabolism, including CoASH synthesis, transesterification of acyl-CoAs to glycine, glutamate or l-carnitine and hydrolysis of CoA esters. Because acyl-CoAs do not cross biological membranes, their main toxicity is intracellular, primarily within mitochondria. Treatment measures directed towards removal of circulating metabolites do not address this central problem of intracellular acyl-CoA accumulation. Treatments usually involve the restriction of dietary precursors and administration of agents like l-carnitine and glycine, which can accept the transfer of acyl groups from acyl-CoA, liberating CoASH. Many hereditary CASTOR patients are chronically ill, with persistent symptoms and continuously abnormal metabolites in blood and urine despite good compliance with treatment. Conversely, asymptomatic patients are also common in hereditary CASTOR conditions. Future challenges include the understanding of pathophysiologic mechanisms in CASTOR diseases, the discovery of reliable predictors of outcome in individual patients and the establishment of therapeutic trials with sufficient numbers of patients to permit solid therapeutic conclusions.


GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates.
Platinum-based cancer therapy is restricted by dose-limiting side effects and is associated with elevation of growth differentiation factor 15 (GDF-15). But whether this elevation contributes to such side effects has been unclear. Here, we explored the effects of GDF-15 blockade on platinum-based chemotherapy-induced emesis, anorexia, and weight loss in mice and/or nonhuman primate models. We found that circulating GDF-15 is higher in subjects with cancer receiving platinum-based chemotherapy and is positively associated with weight loss in colorectal cancer (NCT00609622). Further, chemotherapy agents associated with high clinical emetic score induce circulating GDF-15 and weight loss in mice. Platinum-based treatment-induced anorexia and weight loss are attenuated in GDF-15 knockout mice, while GDF-15 neutralization with the monoclonal antibody mAB1 improves survival. In nonhuman primates, mAB1 treatment attenuates anorexia and emesis. These results suggest that GDF-15 neutralization is a potential therapeutic approach to alleviate chemotherapy-induced side effects and improve the quality of life.