Sensorimotor memory of weight asymmetry in object manipulation.
Using a precision grip-lifting task, we examined how sensorimotor memory for weight asymmetry transfers across changes in hand and object configuration. We measured object tilt when participants lifted a visually symmetric box with an offset centre of mass. Transfer was assessed after participants lifted the box 10 times, during which the large tilt observed in the first lift was reduced. Consistent with previous work of Salimi et al. (J Neurophysiol 84:2390-2397, 2000), we found that when the object was rotated 180 degrees , participants failed to update their sensorimotor memory appropriately. Instead, participants acted as if the object did not rotate and negative transfer was observed. However, when the hand was rotated 180 degrees around the object, participants were able to correctly update sensorimotor memory and positive transfer was observed. This finding argues against the hypothesis that sensorimotor memory is digit-specific because the rotation of the hand (like rotation of the object) changes the forces that each digit must generate to prevent tilt. Positive transfer was also observed when both the hand and object were rotated. This suggests that the rotation of the hand may facilitate rotation of an internal representation of the object. Finally, we found positive transfer of weight asymmetry across the two hands but only when the second hand was rotated such that homologous digits of each hand gripped the same contact surfaces. We suggest that good transfer is observed under these conditions because, when we pass objects from hand to hand, we typically place homologous digits of the two hands in similar locations on the object.


Clinical, electrophysiological and immunological remissions after thymectomy in myasthenia gravis.
Approximately 50% of patients treated with thymectomy have a chance for symptom-free life. However, immunological and neurophysiological abnormalities may be detected in patients with clinical remission. Although improvement usually parallels decrease in acetylcholine receptor antibody (AChRAb) levels and jitter values, there is a question what factors influence immunological and electrophysiological remission in a population of myasthenia gravis (MG) patients. We analyzed retrospectively clinical data of 32 MG patients operated for generalized MG, followed-up at our department for 17.2 (4-31) years. They were in clinical remission for 12.8 (2-25) years. All of them had single fiber electromyograhy (SFEMG) of extensor digitorum communis muscle (EDC) muscle and estimation of AChRAb level at the end of follow-up. Their age at onset of MG was 17 years (6-48) and at thymectomy 19 (6.4-58) years. Tensilon test was positive in 30, repetitive nerve stimulation in 29 cases. Clinical remission was reached on average 4.2 years after thymectomy. SFEMG jitter value normalized in 60% of cases. AChRAb were negative only in 34% of patients. Jitter values correlated with AChRAb levels (P=0.006, r=0.5) but were not related to clinical factors. Only time to thymectomy correlated with time from thymectomy to clinical remission (P=0.001, r=0.5). Clinical remission is not always accompanied by normalization of SFEMG and AChRAb. Although normalization of neuromuscular transmission in patients with remission of MG is individual, short duration of MG before thymectomy increases the chance of early remission.


Mucinous tubular and spindle cell renal cell carcinoma: a review of clinicopathologic aspects.
Mucinous tubular and spindle cell renal cell carcinoma is a rare, recently described variant of renal cell carcinoma characterized by an admixture of cuboidal cells in tubules and sheets of spindle cells, and variable amounts of mucinous stroma. It has been recognized as a distinct entity in the 2004 World Health Organization tumor classification. Since then, several dozen of these tumor have been reported with additional complementary morphologic characteristics, immunohistochemical profile, and molecular genetic features that have further clarified its clinicopathologic aspects. Although originally considered as a low grade renal cell carcinoma on the basis of its bland appearing nuclear features and indolent clinical course, mucinous tubular and spindle cell renal cell carcinoma has currently been proven to be a tumor that has a histological spectrum ranging from low to high grade that includes sarcomatoid differentiation. In this review, we present a detailed summary of the current knowledge regarding the clinicopathologic, immunohistochemical, molecular genetic, and prognostic characteristics, as well as differential diagnoses of mucinous tubular and spindle cell renal cell carcinoma.


Adaptive genetic changes related to haemoglobin concentration in native high-altitude Tibetans.
What is the topic of this review? Tibetans have genetic adaptations that are hypothesized to underlie the distinct set of traits they exhibit at altitude. What advances does it highlight? Several adaptive signatures in the same genomic regions have been identified among Tibetan populations resident throughout the Qinghai-Tibetan Plateau. Many highland Tibetans exhibit a haemoglobin concentration within the range expected at sea level, and this trait is associated with putatively adaptive regions harbouring the hypoxia-inducible factor pathway genes EGLN1, EPAS1 and PPARA. Precise functional variants at adaptive loci and relationships to physiological traits, beyond haemoglobin concentration, are currently being examined in this population. Some native Tibetan, Andean and Ethiopian populations have lived at altitudes ranging from 3000 to >4000 m above sea level for hundreds of generations and exhibit distinct combinations of traits at altitude. It was long hypothesized that genetic factors contribute to adaptive differences in these populations, and recent advances in genomics provide evidence that some of the strongest signatures of positive selection in humans are those identified in Tibetans. Many of the top adaptive genomic regions highlighted thus far harbour genes related to hypoxia sensing and response. Putatively adaptive copies of three hypoxia-inducible factor pathway genes, EPAS1, EGLN1 and PPARA, are associated with sea-level range, rather than elevated, haemoglobin concentration observed in many Tibetans at high altitude, and recent studies provide insight into some of the precise adaptive variants, timing of adaptive events and functional roles. While several studies in highland Tibetans have converged on a few hypoxia-inducible factor pathway genes, additional candidates have been reported in independent studies of Tibetans located throughout the Qinghai-Tibetan Plateau. Various aspects of adaptive significance have yet to be identified, integrated, and fully explored. Given the rapid technological advances and interdisciplinary efforts in genomics, physiology and molecular biology, careful examination of Tibetans and comparisons with other distinctively adapted highland populations will provide valuable insight into evolutionary processes and models for both basic and clinical research.


Shape-dependent cellular toxicity on renal epithelial cells and stone risk of calcium oxalate dihydrate crystals.
Renal epithelial cell injury causes crystal retention and leads to renal stone formation. However, the effects of crystal shape on cell injury and stone risk remain unclear. This study compared the cytotoxicity degrees of calcium oxalate dihydrate (COD) crystals having different shapes toward human kidney proximal tubular epithelial (HK-2) cells to reveal the effect of crystal shape on cell injury and to elucidate the pathological mechanism of calcium oxalate kidney stones. The effects of exposure to cross-shaped (COD-CS), flower-like (COD-FL), bipyramid (COD-BD), and elongated-bipyramid (COD-EBD) COD crystals on HK-2 cells were investigated by examining the cell viability, cell membrane integrity, cell morphology change, intracellular reactive oxygen species, mitochondrial membrane potential (Δψm), and apoptotic and/or necrotic rate. Crystals with large (100) faces (COD-EBD) and sharp edges (COD-CS) showed higher toxicity than COD-BD and COD-FL, respectively. COD crystal exposure caused cell membrane rupture, upregulated intracellular reactive oxygen, and decreased Δψm. This series of phenomena ultimately led to a high apoptotic rate and a low necrotic rate. Crystals with large active faces have a large contact area with epithelial cell surface, and crystals with sharp edges can easily scratch epithelial cells; these factors could promote crystal adhesion and aggregation, thus increasing stone risk.


Oogenesis and ovulation in normal conditions or induced by homologous hypophysis in Hoplias m. malabaricus (Pisces, Erythrynidae).
The macroscopical, histological and histochemical study of the ovary of Hoplias m. malabaricus during its annual cycle makes it possible to classify oocytes in nine stages, which characteristics, inherent to each stage, have given evidence of certain aspects still unknown for this species. The hormonal induction by homologous hypophysis makes it possible to obtain the final oocyte maturation and the ovulation.


Improved technique for induction and monitoring of audiogenic seizure in deer mice.
Epilepsy is a debilitating disease characterized by recurring seizures. Epilepsy can be studied using animal models, such as rodents prone to audiogenic seizure (AGS), which experience generalized seizures (loss of consciousness accompanied by rhythmic muscle spasms and rigid muscle stiffness) after intense sound stimulation. In 1933, a spontaneous mutation resulting in sensitivity to AGS was observed among laboratory stocks of deer mice (Peromyscus maniculatus artemisiae) at the University of Michigan. Since then, AGS-sensitive deer mice have been maintained as a separate stock, currently housed at the Peromyscus Genetic Stock Center. To further characterize AGS, the authors designed reliable and consistent equipment for inducing and monitoring AGS in deer mice.


Spatial distribution and source apportionment of PFASs in surface sediments from five lake regions, China.
Perfluoroalkyl substances (PFASs) have been found in environment globally. However, studies on PFAS occurrence in sediments of lakes or reservoirs remain relatively scarce. In this study, two hundred and sixty-two surface sediment samples were collected from forty-eight lakes and two reservoirs all over China. Average PFAS concentrations in surface sediments from each lake or reservoir varied from 0.086 ng/g dw to 5.79 ng/g dw with an average of 1.15 ng/g dw. Among five lake regions, average PFAS concentrations for the lakes from Eastern Plain Region were the highest. Perfluorooctanoic acid, perfluoroundecanoic acid and perfluorooctane sulfonic acid (PFOS) were the predominant PFASs in surface sediments. The significant positive correlations between PFAS concentrations and total organic carbon, total nitrogen and total phosphorus contents in sediments revealed the influences of sedimentary characteristics on PFAS occurrence. A two-dimensional hierarchical cluster analysis heat map was depicted to analyze the possible origins of sediments and individual PFAS. The food-packaging, textile, electroplating, firefighting and semiconductor industry emission sources and the precious metals and coating industry emission sources were identified as the main sources by two receptor models, with contributions of 77.7 and 22.3% to the total concentrations of C4-C14- perfluoroalkyl carboxylic acids and PFOS, respectively.


Research on the establishment of NDVI long-term data set based on a novel method.
This study compares the relationship between different NDVI (Normalized Difference Vegetation Index), the NDVI of AVHRR (Advanced Very High Resolution Radiometer) (NDVIa), the NDVI of MODIS (Moderate Resolution Imaging Spectrometer) (NDVIm), and the NDVI of VIRR (Visible and Infrared Radiometer) (NDVIv), and found that there is a significant correlation between the NDVIa and the NDVIm, and between the NDVIv and the NDVIa, the relationship between the three is NDVIv < NDVIa < NDVIm. Machine learning is an important method in artificial intelligence. It can solve some complex problems through algorithms. This research uses linear regression algorithm in machine learning to construct the Fengyun Satellite NDVI correction method. By constructing a linear regression model, the NDVI value of Fengyun Satellite VIRR is corrected to a level that is basically the same as NDVIm. The corrected correlation coefficients (R2) were significantly improved, and the corrected correlation coefficients were significantly improved, and the confidence levels were all significant correlations less than 0.01. It is proved that the corrected normalized vegetation index of Fengyun Satellite has significantly improved accuracy and product quality compared with the normalized vegetation index of MODIS.


Antinociceptive effectiveness of triterpenes from rosemary in visceral nociception.
Rosemary is a species used worldwide as a common spice, but also in folk medicine for their therapeutic properties against abdominal pain. The rationale of this study was to examine the involvement of triterpenes and to compare their effectiveness in the antinociceptive effect of an ethanol extract of Rosmarinus officinalis L. (Lamiaceae). Fractionation and HPLC analyses allowed the identification of a mixture of micromeric (121 mg/g), oleanolic (64 mg/g) and ursolic (83 mg/g) acids as partial antinociceptive responsible in an ethyl acetate fraction of R. officinalis by using the acetic acid-induced abdominal constrictions model in mice. These triterpenes individually evaluated produced a significant and dose-dependent antinociceptive response with similar potency as follows: ED₅₀=1.1 mg/kg (0.9-1.3 mg/kg), 2.1 mg/kg (1.6-2.6 mg/kg) and 1.6 mg/kg (1.1-2.1 mg/kg), respectively, by using the intraperitoneal (i.p.) route of administration in mice. Their maximal antinociceptive efficacy resembled that produced by ketorolac (10 mg/kg, i.p.), a common clinic analgesic. Our results provide evidence that these triterpenes participate in the antinociceptive activity of R. officinalis. In addition, each individual triterpene showed a similar potency to that observed with ketorolac, a non-steroidal anti-inflammatory drug, in this experimental model.


Mepolizumab: Therapeutic strategy for a pediatric patient with eosinophilic granulomatosis with polyangiitis.
Eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) is classified as an antineutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis. It is a multisystem disorder and can affect every organ system. EGPA is a rare disease, with an estimated prevalence of 1/70,000-100,000 in Europe. As its onset usually occurs in adulthood, data from pediatric patients are limited. We present here a very rare practical EGPA clinical case involving a pediatric patient. Presently, data on mepolizumab usage in pediatric patients are limited, with only a few case reports published.


Association of uric acid with cardiovascular risk in Brazilian children and adolescents.
Hyperuricemia in adults is associated with cardiovascular risk factors. However, there is less data regarding this association in children and adolescents. Our purpose was to determine association between serum uric acid (SUA) and cardiovascular risk. A fasting blood sample was collected from 1750 participants aged 6-17 years enrolled in a social project and public schools in Espírito Santo, Brazil. Internal cut-offs were generated to define high SUA (≥90th percentile of SUA concentration for sex and age group). Body mass index percentile (pBMI), body fat percentage (BFP) and muscle mass were determined by bioimpedance. Data are given as mean ± standard deviation. High SUA was associated with overweight/obesity (OR 3.7 CI 95% 2.7-5.0), high waist circumference (WC) (OR 3.9 CI 95% 2.9-5.4), low HDL (OR 2.0 CI 95% 1.5-2.8), high blood pressure (BP) (OR 1.8 CI 95% 1.1-3.2), high BFP (OR 4.1 CI 95% 2.7-6.4), metabolic syndrome (MetS) (OR 3.6 CI 95% 1.8-7.1) and insulin resistance (OR 1.7 CI 95% 1.1-2.7). Individuals in the fourth quartile of SUA, compared to those in the first quartile, showed higher age, pBMI, WC, BFP and muscle mass. Using a reference value of 5.5 mg/dL, the prevalence of hyperuricemia in the sample was 10.3% (CI 95% 8.9-11.7%). Higher SUA values are associated with higher cardiovascular risk in childhood and adolescence. The main cardiovascular risk factors associated with hyperuricemia were overweight/obesity, high WC, dyslipidemia, high BFP, high BP, insulin resistance and MetS.


Stability of beta-carotene in spray dried preparation of Rhodotorula glutinis mutant 32.
To obtain beta-carotene-rich dry cell preparation from mutant 32 of Rhodotorula glutinis and determination of its pigment stability. The mutant 32 of R. glutinis was grown in a 14 l stirred tank fermenter. Cell mass was concentrated 10-fold by cross-flow microfiltration and then spray dried. Butylated hydroxy toluene (BHT) and d-tocopherol were used as protecting agents. A two-level, three-variable, factorial optimization was performed to achieve moisture-free, non-viable and beta-carotene-rich feed additive. The beta-carotene and cell mass in stirred tank fermenter were found to be 54 +/- 5 mg l-1 and 12.8 +/- 2 g l-1, respectively. In the presence of BHT, 97 +/- 3% (w/w) beta-carotene was recovered for all the inlet temperatures studied. The best beta-carotene and yeast powder recoveries were obtained at 160 degrees C, 11.6% (w/v) cell mass concentration and 1 g l-1 BHT. The pigments inside dried yeast powder were stable in dark and cold condition for at least 10 weeks. The purified beta-carotene got almost totally denatured, under similar conditions of storage, within 76 h. Spray dried and stable preparation of beta-carotene-rich yeast, R. glutinis can provide alternative source of beta-carotene for use in animal nutrition.


Some precautions in using chelators to buffer metals in biological solutions.
Chelators and associated computer programs are commonly used to buffer metal ions in biological experiments. This communication discusses common misunderstandings and pitfalls in use of these buffers and provides information on choosing the best metal buffer for different experimental situations.


Cup-to-disc ratio, intraocular pressure, and primary open-angle glaucoma in retinal venous occlusion.
To investigate the association of cup-to-disc ratio (CDR), intraocular pressure (IOP), and primary open-angle glaucoma (POAG) with the site of retinal venous occlusion (RVO) and optic nerve head swelling (ONHS). Prospective observational case series. Four hundred fifty consecutive cases from a single tertiary referral center. Fundus photography of the retinopathy, 30 degrees stereo photography of the optic disc, and Goldmann applanation tonometry were the main parameters studied. The diagnosis of POAG was obtained from the referring ophthalmologist. The main outcome measures were the CDR, measured vertically through the center of the optic disc, and the site of RVO, identified as an arteriovenous (AV) crossing, optic cup, or optic nerve. Retinal venous occlusions occurring within the optic nerve were subdivided on the basis of the presence or absence of ONHS. There were poor correlations between CDR and IOP (r = 0.18; P = 0.000209) and CDR and age (r = 0.21; P = 0.000012). There were 197 AV crossing-sited RVOs (AV-RVOs) (43.8%) and 46 optic cup (OC)-sited RVOs (10.2%). The remainder occurred within the optic nerve; the ONHS group had 80 cases (17.8%) and the nonoptic nerve head swelling group (NONHS) had 127 cases (28.2%). The OC-RVO group tended to be the oldest of the four groups, whereas the ONHS group was the youngest (P < 0.000001). The mean CDR was significantly higher in the OC-RVO (0.65) compared with the rest of the groups (0.45-0.48). The proportion of cases with CDR > or = 0.7 was significantly higher in the OC-RVO group (39.1%) compared with the rest of the groups (0-6.3%). There was a trend (P = 0.000012) for IOP in the OC-RVO group (19.0 mmHg) and NONHS group (17.6 mmHg); the proportion of cases with IOP more than 21 mmHg was also higher in these cases (P = 0.00033). The prevalence of POAG was highest (P < 0.000001) in the OC-RVO group (39.1%) followed by the NONHS group (18.1%), ONHS group (8.8%), and AV-RVO (4.1%) group, respectively. Optic cup and optic nerve-sited RVO without ONHS are associated with raised IOP and may share a common management strategy aimed at controlling ocular pressure. Glaucomatous optic disc cupping, in contrast, seems to be important in the OC-sited RVO group only. Intraocular pressure, POAG, and glaucomatous optic disc cupping do not significantly seem to contribute to the development of RVO at an AV crossing or when the occlusion occurs within the optic nerve in association with ONHS.


Factors associated with withdrawal symptoms and anger among people resuscitated from an opioid overdose by take-home naloxone: Exploratory mixed methods analysis.
Take-home naloxone (THN) is a clinically effective and cost-effective means of reducing opioid overdose fatality. Nonetheless, naloxone administration that successfully saves a person's life can still produce undesirable and harmful effects. To better understand factors associated with two widely reported adverse outcomes following naloxone administration; namely the person resuscitated displays: i. withdrawal symptoms and ii. anger. A mixed methods study combining a randomized controlled trial of overdose education and naloxone prescribing to people with opioid use disorder and semi-structured qualitative interviews with trial participants who had responded to an overdose whilst in the trial. All data were collected in New York City (2014-2019). A dataset (comprising demographic, pharmacological, situational, interpersonal, and overdose training related variables) was generated by transforming qualitative interview data from 47 overdose events into dichotomous variables and then combining these with quantitative demographic and overdose training related data from the main trial. Associations between variables within the dataset and reports of: i. withdrawal symptoms and ii. anger were explored using chi-squared tests, t-tests, and logistic regressions. A multivariate logistic regression found that people who had overdosed were significantly more likely to display anger if the person resuscitating them criticized, berated or chastised them during resuscitation (adjusted OR = 27 [95% CI = 4.0-295]). In contrast, they were significantly less likely to display anger if the person resuscitating them communicated positively with them (OR = 0.10 [95% CI = 0.01-0.78]). Both positive and negative communication styles were independently associated with anger, and communication was associated with 59% of the variance in anger. There was no evidence that people who displayed withdrawal symptoms were more likely to display anger than those not displaying withdrawal symptoms, and neither displaying withdrawal symptoms nor displaying anger were associated with using more drugs after resuscitation. Contrary to common assumptions, withdrawal symptoms and anger following naloxone administration may be unrelated phenomena. Findings are consistent with previous research that has suggested that a lay responder's positive or reassuring communication style may lessen anger post overdose. Implications for improving THN programmes and naloxone administration are discussed.


Population study of common glucose-6-phosphate dehydrogenase mutations in Kuwait.
DNA samples from 206 unrelated Kuwaitis of both sexes, i.e. 200 randomly selected individuals and 6 glucose-6-phosphate-dehydrogenase (G6PD)-deficient probands, have been analyzed by the PCR/RFLP technique for mutations underlying the most common G6PD-deficient variants (Mediterranean and A-). At the first step all samples were studied for the 563C-->T and 376A-->G mutations, then the samples positive for 376A-->G were further analyzed for 202G-->A, 680G-->T and 968T-->C mutations. Three mutations (563C-->T, 376A-->G and 202G-->A) were found to be present in the Kuwaiti population at polymorphic frequencies (0.0503, 0.0215 and 0.0111, respectively). Nineteen out of 20 unrelated Kuwaiti chromosomes with 563C-->T had Mediterranean haplotype as judged by 1311C-->T polymorphism. The frequency of G6PD-deficient genotypes was 4.5% (5.73% in males and 2.56% in females).


Transport of branched-chain amino acids in Corynebacterium glutamicum.
The transport of branched-chain amino acids was characterized in intact cells of Corynebacterium glutamicum ATCC 13032. Uptake and accumulation of these amino acids occur via a common specific carrier with slightly different affinities for each substrate (Km[Ile] = 5.4 microM, Km[Leu] = 9.0 microM, Km[Val] = 9.5 microM). The maximal uptake rates for all three substrates were very similar (0.94 - 1.30 nmol/mg dw.min). The optimum of amino acid uptake was at pH 8.5 and the activation energy was determined to be 80 kJ/mol. The transport activity showed a marked dependence on the presence of Na+ ions and on the membrane potential, but was independent of an existing proton gradient. It is concluded, that uptake of branched-chain amino acid transport proceeds via a secondary active Na+-coupled symport mechanism.


Protective effect of Bu-7, a flavonoid extracted from Clausena lansium, against rotenone injury in PC12 cells.
To investigate the protective effect and underlying mechanisms of Bu-7, a flavonoid isolated from the leaves of Clausena lansium, against rotenone-induced injury in PC12 cells. The cell viability was evaluated using MTT assay. The cell apoptosis rate was analyzed using flow cytometry. JC-1 staining was used to detect the mitochondrial membrane potential (MMP). Western blotting analysis was used to determine the phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38), tumor protein 53 (p53), Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), and caspase 3. Treatment of PC12 cells with rotenone (1-20 μmol/L) significantly reduced the cell viability in a concentration-dependent manner. Pretreatment with Bu-7 (0.1 and 10 μmol/L) prevented PC12 cells from rotenone injury, whereas Bu-7 (1 μmol/L) had no significant effect. Pretreatment with Bu-7 (0.1 and 10 μmol/L) decreased rotenone-induced apoptosis, attenuated rotenone-induced mitochondrial potential reduction and suppressed rotenone-induced protein phosphorylation and expression, whereas Bu-7 (1 μmol/L) did not cause similar effects. Bu-7 showed inverted bell-shaped dose-response relationship in all the effects. Bu-7 protects PC12 cells against rotenone injury, which may be attributed to MAP kinase cascade (JNK and p38) signaling pathway. Thus, Bu-7 may be a potential bioactive compound for the treatment of Parkinson's disease.


Functional and structural neuroimaging in trigeminal autonomic cephalalgias.
The trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders characterized by unilateral trigeminal distribution pain that occurs in association with ipsilateral cranial autonomic features. They include cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing. Until recently, primary headache disorders, including the TACs, were widely considered to be caused by peripheral mechanisms such as vascular changes or neurogenic inflammation. Developments in neuroimaging are revolutionizing our understanding of the pathophysiology of primary headache syndromes. Functional imaging studies have demonstrated hypothalamic activation in all the TACs. Furthermore, neuroimaging studies using voxel-based morphometry and magnetic resonance spectroscopy techniques have demonstrated structural and biochemical alterations, respectively, in the hypothalamus of patients with cluster headache. These studies suggest that the hypothalamus plays a crucial role in the pathophysiology of TACs, thereby supporting the notion that these disorders are primarily due to central rather than peripheral mechanisms.


The effect of prostaglandin inhibition on the natriuresis of drug-induced renal vasodilatation.
It has been suggested that increased prostaglandin release may mediate the natriuresis seen during the administration of renal vasodilators. To further investigate this possibility, either acetylcholine (40 microgram/min) or bradykinin (5 microgram/min) was infused into the left renal artery of anesthetized dogs previously given an inhibitor of prostaglandin synthesis. During the infusion of either vasodilator drug in the prostaglandin-inhibited dogs, urinary sodium excretion increased to a similar degree as in a group of normal dogs with intact prostaglandin synthesis. These studies therefore do not confirm that prostaglandins play a significant role in the natriuresis of drug-induced vasodilatation.


Clinical efficacy and safety of laparoscopic nerve-sparing radical hysterectomy for locally advanced cervical cancer.
To evaluate the feasibility and safety of laparoscopic nerve-sparing radical hysterectomy (LNRH) for locally advanced cervical cancer (LACC) after neoadjuvant chemotherapy (NACT). 120 patients with stage Ib2 and IIa2 cervical cancer were treated with surgery combined with preoperative NACT in the Department of Obstetrics and Gynecology, PLA General Hospital. Eligible patients were divided into two groups according to surgery type: patients who underwent LNRH were assigned to one group, while the second group included patients who underwent laparoscopic radical hysterectomy (LRH) after administration of NACT. We compared these patients' general clinical information and surgical characteristics, and we assessed their bladder function and intestinal function recovery by questionnaire. No significant differences were found between the groups in patients' age or surgical characteristics. The mean duration of postoperative catheterization in the LNRH group was shorter than in the LRH group (P < 0.001). The intestinal and bladder function of patients in the LNRH group also recovered better than that of patients in the LRH group. LNRH is a feasible and safe procedure for LACC after NACT and reduces surgical complications.


High glucose suppresses embryonic stem cell differentiation into neural lineage cells.
Abnormal neurogenesis occurs during embryonic development in human diabetic pregnancies and in animal models of diabetic embryopathy. Our previous studies in a mouse model of diabetic embryopathy have implicated that high glucose of maternal diabetes delays neurogenesis in the developing neuroepithelium leading to neural tube defects. However, the underlying process in high glucose-impaired neurogenesis is uncharacterized. Neurogenesis from embryonic stem (ES) cells provides a valuable model for understanding the abnormal neural lineage development under high glucose conditions. ES cells are commonly generated and maintained in high glucose (approximately 25 mM glucose). Here, the mouse ES cell line, E14, was gradually adapted to and maintained in low glucose (5 mM), and became a glucose responsive E14 (GR-E14) line. High glucose induced the endoplasmic reticulum stress marker, CHOP, in GR-E14 cells. Under low glucose conditions, the GR-E14 cells retained their pluripotency and capability to differentiate into neural lineage cells. GR-E14 cell differentiation into neural stem cells (Sox1 and nestin positive cells) was inhibited by high glucose. Neuron (Tuj1 positive cells) and glia (GFAP positive cells) differentiation from GR-E14 cells was also suppressed by high glucose. In addition, high glucose delayed GR-E14 differentiation into neural crest cells by decreasing neural crest markers, paired box 3 (Pax3) and paired box 7 (Pax7). Thus, high glucose impairs ES cell differentiation into neural lineage cells. The low glucose adapted and high glucose responsive GR-E14 cell line is a useful in vitro model for assessing the adverse effect of high glucose on the development of the central nervous system.


Dihydroartemisinin inhibits the growth of pancreatic cells by inducing ferroptosis and activating antitumor immunity.
Dihydroartemisinin (DHA) exhibits a direct antitumor effect in various tumor models. However, the mechanism of DHA inducing ferroptosis and activating antitumor immunity remains obscure. Therefore, our study was dedicated to investigate the effect of DHA on ferroptosis and tumor microenvironment and elucidate the underlying molecular mechanism. PDAC orthotopic tumor model was used to investigate tumor proliferation and the population of immune cell in vivo, including M2-type macrophages (M2), myeloid-derived suppressor cells (MDSCs), CD4+T cells, CD8+T cells, NK cells and NKT cells. Levels of GPX4, SLC7A11, P53 and ALOX12 were determined by Real-time PCR and Western blot. CCK8 assay was performed to detect cell viability, and the ferroptosis was distinguished by flow cytometry. Our results showed that DHA inhibited pancreatic cancer cell proliferation. In addition, DHA induced cell ferroptosis by up-regulating the expression of P53 and ALOX12, which was blocked by baicalein (a selective ALOX12 inhibitor). However, DHA also up-regulated the expression of GPX4 and SLC7A11. On the other hand, DHA significantly decreased the suppressive expansion of M2 and MDSCs. Moreover, DHA increased the immune cell population of CD8+T cells, NK cells and NKT cells in the tumor tissues of the tumor-bearing mice. Whereas, the DHA treatment did not affect the frequencies of M2, MDSCs, CD4+T, CD8+T, NK and NKT cells in the spleen. Our research provided experimental evidences on the activity and mechanism of ferroptosis induced by DHA and revealed that DHA regulated tumor local immunosuppressive microenvironment.


E2F1 transcription factor and its impact on growth factor and cytokine signaling.
E2F1 is a transcription factor involved in cell cycle regulation and apoptosis. The transactivation capacity of E2F1 is regulated by pRb. In its hypophosphorylated form, pRb binds and inactivates DNA binding and transactivating functions of E2F1. The growth factor stimulation of cells leads to activation of CDKs (cyclin dependent kinases), which in turn phosphorylate Rb and hyperphosphorylated Rb is released from E2F1 or E2F1/DP complex, and free E2F1 can induce transcription of several genes involved in cell cycle entry, induction or inhibition of apoptosis. Thus, growth factors and cytokines generally utilize E2F1 to direct cells to either fate. Furthermore, E2F1 regulates expressions of various cytokines and growth factor receptors, establishing positive or negative feedback mechanisms. This review focuses on the relationship between E2F1 transcription factor and cytokines (IL-1, IL-2, IL-3, IL-6, TGF-beta, G-CSF, LIF), growth factors (EGF, KGF, VEGF, IGF, FGF, PDGF, HGF, NGF), and interferons (IFN-α, IFN-β and IFN-γ).


Independent and synergistic effects of pain, insomnia, and depression on falls among older adults: a longitudinal study.
Few studies have examined the relationship between falls and pain, insomnia and depressive symptoms which are common and risk factors in older adults. We aimed to examine the independent and synergistic effects of these risk factors on future falls among older adults. We used data of 2558 community-dwelling older adults from 2011 (Y1) to 2015 (Y5) of the National Health and Aging Trends Study (NHATS). Pain was determined by whether participants reported bothersome pain in the last month. Insomnia was assessed by two questions about how often the participants had trouble falling asleep and maintaining sleep. Depressive symptoms were assessed by Patient Health Questionnaire-2. Generalized estimation equation (GEE) models were used to examine the independent effects of pain, insomnia and depressive symptoms at prior-wave (period y-1) on falls at current wave (period y) adjusting for covariates (age, sex, education, race/ethnicity, living arrangement, BMI, smoking, vigorous activities, number of chronic illnesses and hospitalization). The significance of the three-way interaction of these factors (pain*insomnia*depression) was tested using the aforementioned GEE models to determine their synergistic effects on falls. Overall, the participants were mainly 65-79 years old (68%), female (57%) and non-Hispanic White (70%). At Y1, 50.0% of the participants reported pain, 22.6% reported insomnia and 9.9% reported depressive symptoms. The incidence of falls from Y2 to Y5 was 22.4, 26.0, 28.3, and 28.9%, respectively. Participants with pain (Odds ratio [OR], 95% confidence interval [CI] = 1.36, 1.23-1.50) and depressive symptoms (OR, 95% CI = 1.43, 1.23-1.67) had high rates of falling adjusting for covariates. After further adjustment for insomnia and depressive symptoms, pain independently predicted falls (OR, 95% CI = 1.36, 1.22-1.51). Depressive symptoms also independently predicted falls after further adjusting for pain and insomnia (OR, 95% CI = 1.40, 1.20-1.63). After adjusting for pain and depression, the independent effects of insomnia were not significant. None of the interaction terms of the three risk factors were significant, suggesting an absence of their synergistic effects. Pain and depressive symptoms independently predict falls, but synergistic effects seem absent. Further research is needed to develop effective strategies for reducing falls in older adults, particularly with pain and depressive symptoms.


A randomized prospective study comparing single-balloon-assisted colonoscopy and cap-assisted colonoscopy in patients with previous incomplete conventional colonoscopy.
Cecal intubation may be unsuccessful by conventional colonoscopy in some patients. Single-balloon-assisted colonoscopy (SBC) and cap-assisted colonoscopy (CAC) were studied to solve this problem. There was no head-to-head comparison between them. We conducted a randomized study from 2018 to 2021 to compare cecal intubation rate of SBC and CAC in patients with previous incomplete conventional colonoscopy. We recruited patients with incomplete conventional colonoscopy in two hospitals in Hong Kong. Patients were randomized into SBC group and CAC group in 1:1 ratio. In the case of failure in cecal intubation by allocated method, alternative modality would be performed as rescue. Forty-four patients were recruited. Cecal intubation rate was superior in SBC group (22/22, 100%) than CAC group (16/22, 72.7%) (P = 0.02). No difference in cecal intubation time, polyp detection rate, and diagnostic gain in area not examined previously. SBC induced less discomfort (modified Gloucester comfort score 2.14 vs 2.63, P = 0.03) with use of comparable amount of midazolam and fentanyl as CAC. For patients failed cecal intubation by CAC, all (n = 6) were rescued successfully by SBC. Body weight, body mass index (BMI), and waist circumference were greater in rescue subgroup. More patients were obese (BMI ≥ 25 kg/m) in rescue subgroup (67% vs 19%). None in rescue subgroup had history of successful cecal intubation by conventional colonoscopy (0% vs 56%, P = 0.046). However, we failed to demonstrate significant association in multivariate analysis owing to small sample size. No adverse event was noted. SBC is superior to CAC in cecal intubation in patients with previous incomplete conventional colonoscopy.


Safety and effectiveness of perampanel monotherapy after adjunctive therapy through retention rate in subjects with focal-onset seizures with or without focal to bilateral tonic-clonic seizures: A multicenter retrospective study in Korea.
To assess the effectiveness and tolerability of perampanel monotherapy following conversion from adjunctive therapy. This was a multicenter, retrospective, non-interventional study of Korean patients aged ≥12 years with focal-onset seizures (FOS) with or without focal to bilateral tonic-clonic seizures. Data were extracted from electronic medical records of perampanel-treated patients from 1 February 2016 to 31 October 2020. Kaplan-Meier estimated retention rates, effectiveness, and safety were recorded. Subjects (n = 66, mean age 46.2 years) were mostly male (68.2%) with focal to bilateral tonic-clonic seizure (71.2%). Mean duration of illness was 86.3 months. Retention rates after conversion to perampanel monotherapy at 3, 6, and 12 months (primary outcome) were 96.0%, 96.0%, and 75.6%, respectively. Overall retention rates in patients receiving perampanel as adjunctive or monotherapy at 3, 6, 12, 18, and 24 months after perampanel add-on were 100%, 98.3%, 95.9%, 92.6%, and 92.6%, respectively. Mean retention duration was 41.2 months (overall perampanel administration) and 21.4 months (monotherapy). Mean seizure frequency/28 days in the Full Analysis Set (n = 61) was comparable for adjunctive and monotherapy (0.2 ± 0.79 vs 0.2 ± 0.64; change between adjunctive and monotherapy periods: 0.0 ± 0.59; p = 0.498). Perampanel was well tolerated and no new safety signals were identified. Dizziness (4.6%), only reported during adjunctive therapy, was the most common treatment-emergent adverse event. Conversion to perampanel monotherapy from adjunctive therapy showed promising results in subjects with FOS with/without focal to bilateral tonic-clonic seizures; further studies in a larger population are needed to confirm these encouraging data.


A review of clinically relevant human anatomy in emergency medicine.
The objectives of this project were to establish a practical model for the review of clinical anatomy relevant to the assessment and care of the ill and injured patient, and to design practice models for invasive procedures using human cadaver, porcine cadaver, and plastic model material. A practical course based on the human gross anatomy of the face, neck, thorax, airway, arm, and leg was designed. Regional anesthesia techniques, arthrocentesis, saphenous vein cutdown, central venous and arterial cannulation, surgical airway, thoracostomy tube placement and thoracotomy were integrated into the appropriate practice stations. A syllabus was developed. A clinically relevant, online anatomy atlas demonstrating all of the above was developed. In conclusion, an anatomy review course combining clinically relevant, human, gross anatomy and procedure practice stations was established.


Breathing patterns. 1. Normal subjects.
Ventilatory monitoring devices that require mouthpiece breathing produce a rise in tidal volume (VT), a fall in frequency (f) and alterations in periodicity and variability of breathing components. Together with the introduction of the respiratory inductive plethysmograph, a reliable noninvasive monitoring device of ventilation, major advances have taken place in understanding the significance of the components of the breathing pattern. We measured the breathing pattern of normal subjects utilizing respiratory inductive plethysmography and continuously processed these data with a microprocessor system. The mean values of the breathing pattern components in normal subjects were not affected by age, but the rhythmicity was more irregular in the elderly. The values of breathing pattern components obtained noninvasively by respiratory inductive plethysmography in normal subjects are fairly predictable in limits similar to other tests of pulmonary function.


Survey data on political attitudes of China׳s urban residents compiled from the Chinese General Social Survey (CGSS).
The data discussed in this article is related to the article entitled "Identity and trust in government: A comparison of locals and migrants in urban China" (Niu and Zhao, 2018) [1], which analyses the political trust among three groups of urban residents in China (rural-urban migrants, urban-urban migrants, and urban locals) based on a sample with 4059 observations extracted from the 2010 Chinese General Social Survey (CGSS). The dataset contains detailed information on respondents' political and social attitudes, demographic characteristics, and socio-economic status.


Activity and topographic changes in the somatosensory system in embouchure dystonia.
Embouchure dystonia is a highly disabling focal task-specific dystonia affecting professional brass players. This study was designed to analyze activity changes along with topographic representations in primary and nonprimary centers for somatosensory processing in patients with embouchure dystonia. We used event-related functional magnetic resonance imaging with automized tactile stimulation of dystonic (upper lip) and nondystonic (forehead and dorsal hand) body regions in 15 professional brass players with and without embouchure dystonia. Statistical analyses included whole-brain between-group comparisons of stimulation-induced activation and region-of-interest-based single patient analyses of topographic activation characteristics. Affected musicians revealed increased stimulation-induced activity in contralateral primary and bilateral secondary somatosensory representations of dystonic and nondystonic body regions as well as in the cerebellum ipsilateral to the left dystonic upper lip. Changes of somatotopic organization with altered intracortical distances and between-group differences of the centers of representations were found in the right primary and the bilateral secondary somatosensory cortex and in the left cerebellum. Positional variability of dystonic and nondystonic body regions was reduced with an emphasis on face representations. The present findings are supportive of the concept of an abnormal processing of somatosensory information in embouchure dystonia affecting multiple domains. The underlying neurophysiological mechanisms (eg, changes in inhibition, maladaptive plasticity, changes in baseline activity) remain unclear. The involvement of nondystonic body areas can be viewed in the context of possible compensation or an endophenotypic predisposition. © 2016 International Parkinson and Movement Disorder Society.


Prevalence, awareness, treatment and control of type 2 diabetes and its determinants among Mongolians in China: a cross-sectional analysis of IMAGINS 2015-2020.
This study aims to estimate the prevalence, awareness, treatment and control rates of type 2 diabetes (T2D) and pre-diabetes as well as to identify its associated factors among Mongolians living in the Inner Mongolia Autonomous Region, China. Cross-sectional study. This sample included 11 361 Mongolian participants from the Inner Mongolian Healthy Aging Intervention Study, a population-based screening project consisting of 141 255 adults aged above 35 years in Inner Mongolia from 2015 to 31 December 2020. The prevalence and 95% CIs of T2D and pre-diabetes were calculated. Factors associated with the prevalence, awareness, treatment and control of T2D were explored by a binomial logistic regression. A total of 17.2% (95% CI 16.5% to 17.9%) of the sample had T2D, of whom 34.0% (95% CI 31.9% to 36.1%) were aware of their diagnosis, 24.7% (95% CI 22.8% to 26.6%) were taking prescribed antidiabetic medications, 6.7% (95% CI 5.6% to 7.8%) had achieved control and 27.5% (95 % CI 26.7% to 28.3%) had pre-diabetes. The prevalence of T2D increased with increasing age, male, lower education level, smoking, obesity and a history of hypertension or dyslipidaemia (all p<0.05). T2D is highly prevalent, with suboptimal awareness, treatment and control rates, and an escalating health challenge among the Mongolian population. Broad-based strategies, including diabetes prevention education, better screening and affordable treatment, should be implemented to raise awareness, treatment and control rates of T2D in Inner Mongolia.


Transmission of SARS-CoV-2 in children aged 0 to 19 years in childcare facilities and schools after their reopening in May 2020, Baden-Württemberg, Germany.
We investigated data from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected 0-19 year olds, who attended schools/childcare facilities, to assess their role in SARS-CoV-2 transmission after these establishments' reopening in May 2020 in Baden-Württemberg, Germany. Child-to-child transmission in schools/childcare facilities appeared very uncommon. We anticipate that, with face mask use and frequent ventilation of rooms, transmission rates in schools/childcare facilities would remain low in the next term, even if classes' group sizes were increased.


Staging procedures fail to benefit women with borderline ovarian tumours who want to preserve fertility: a retrospective analysis of 448 cases.
To evaluate the effect of clinicopathologic factors on the prognosis and fertility outcomes of BOT patients. We performed a retrospective analysis of BOT patients who underwent surgical procedures in West China Second University Hospital from 2008 to 2015. The DFS outcomes, potential prognostic factors and fertility outcomes were evaluated. Four hundred forty-eight patients were included; 52 recurrences were observed. Ninety-two patients undergoing FSS achieved pregnancy. No significant differences in fertility outcomes were found between the staging and unstaged surgery groups. Staging surgery was not an independent prognostic factor for DFS. Laparoscopy resulted in better prognosis than laparotomy in patients with stage I tumours and a desire for fertility preservation. Patients with BOT fail to benefit from surgical staging. Laparoscopy is recommended for patients with stage I disease who desire to preserve fertility. Physicians should pay more attention to risk of recurrence in patients who want to preserve fertility.


Optimisation of critical medium components and culture conditions for enhanced biomass and lipid production in the oleaginous diatom Navicula phyllepta: a statistical approach.
Diatoms hold great promise as potential sources of biofuel production. In the present study, the biomass and lipid production in the marine diatom Navicula phyllepta, isolated from Cochin estuary, India and identified as a potential biodiesel feedstock, were optimized using Plackett-Burman (PB) statistical experimental design followed by central composite design (CCD) and response surface methodology (RSM). The growth analyses of the isolate in different nitrogen sources, salinities and five different enriched sea water media showed the best growth in the cheapest medium with minimum components using urea as nitrogen source at salinity between 25 and 40 g kg-1. Plackett-Burman experimental analyses for screening urea, sodium metasilicate, sodium dihydrogen phosphate, ferric chloride, salinity, temperature, pH and agitation influencing lipid and biomass production showed that silicate and temperature had a positive coefficient on biomass production, and temperature had a significant positive coefficient, while urea and phosphate showed a negative coefficient on lipid content. A 24 factorial central composite design (FCCD) was used to optimize the concentration of the factors selected. The optimized media resulted in 1.62-fold increase (64%) in biomass (1.2 ± 0.08 g L-1) and 1.2-fold increase (22%) in estimated total lipid production (0.11 ± 0.003 g L-1) compared to original media within 12 days of culturing. A significantly higher biomass and lipid production in the optimized medium demands further development of a two-stage strategy of biomass production followed by induction of high lipid production under nutrient limitation or varying culture conditions for large-scale production of biodiesel from the marine diatom.


A preliminary study of the interactions between microplastics and citrate-coated silver nanoparticles in aquatic environments.
Microplastics and silver nanoparticles (AgNPs) are considered two emerging environmental contaminants that have adverse effects on aquatic environments. Knowledge on the interactions between AgNPs and microplastics may improve our understanding of these pollutants, posing to surrounding environments and public health. However, current knowledge regarding this issue is limited. Here, we investigate, for the first time, the interactions between AgNPs and the microplastics polyethylene (PE), polypropylene (PP), and polystyrene (PS) in aquatic environments. Results showed no significant interactions between AgNPs and PE or PP microplastics. However, AgNPs were efficiently removed by PS microplastics. These differences are mainly attributed to the presence of π-π interactions. Meanwhile, AgNPs aggregations were generated due to higher concentrations of leaching additives derived from PS microplastics. Interestingly, AgNPs are significantly captured on PS microplastic surfaces in the form of Ag0 rather than Ag+. The capture process is a monolayer adsorption and influenced greatly by the mass ratio of AgNPs and PS microplastics. These observations may provide a novel environmental fate of AgNPs, and indicate a new potential method for their removal to some degree. These findings demonstrate the complexities of AgNPs absorption onto microplastics and enhance present understanding of interactions between nanoparticles and microplastics in aquatic environments.


A model of leaf photosynthesis and respiration for predicting carbon dioxide assimilation in different environments.
A model of leaf photosynthesis and repiration was developed which adequately predicted carbon dioxide assimilation responses by a C 3 species, Atriplex patula, to light, [CO2], [O2] and temperature in controlled environments. Methods were developed for estimating input parameters using laboratory, controlled environment and field data.


A fluorescence polarization-based interaction assay for hypoxia-inducible factor prolyl hydroxylases.
Oxygen-dependent ubiquitination and degradation of hypoxia-inducible factor 1alpha (HIF-1alpha) plays a central role in regulating transcriptional responses to hypoxia. This process requires hydroxylation of specific prolines in HIF-1alpha by HIF prolyl hydroxylase domain (PHD)-containing enzymes, leading to its specific interactions with von Hippel-Lindau protein-Elongin B-Elongin C (VBC). Here we describe a straightforward approach to apply these interactions to measure PHD activities. Employing fluorescently labeled HIF-1alpha peptides containing hydroxyproline, we developed a quantitative method based on fluorescence polarization for a systematic evaluation of binding of hydroxylated HIF-1alpha to recombinant VBC. The method was then successfully utilized for measuring the activity of the truncated, purified PHD2. The applicability of the assay was further demonstrated by examining effects of various cofactors and inhibitors for PHD2. The developed homogeneous assay would provide a convenient way of probing the biochemical properties of the HIF-1alpha-VBC interaction and PHDs, and of screening modulators for the interaction as well as the enzyme.


Computational and experimental investigation of particulate matter deposition in cerebral side aneurysms.
Intracranial aneurysms frequently develop blood clots, plaque and inflammations, which are linked to enhanced particulate mass deposition. In this work, we propose a computational model for particulate deposition, that accounts for the influence of field forces, such as gravity and electrostatics, which produce an additional flux of particles perpendicular to the fluid motion and towards the wall. This field-mediated flux can significantly enhance particle deposition in low-shear environments, such as in aneurysm cavities. Experimental investigation of particle deposition patterns in in vitro models of side aneurysms, demonstrated the ability of the model to predict enhanced particle adhesion at these sites. Our results showed a significant influence of gravity and electrostatic forces (greater than 10%), indicating that the additional terms presented in our models may be necessary for modelling a wide range of physiological flow conditions and not only for ultra-low shear regions. Spatial differences between the computational model and the experimental results suggested that additional transport and fluidic mechanisms affect the deposition pattern within aneurysms. Taken together, the presented findings may enhance our understanding of pathological deposition processes at cardiovascular disease sites, and facilitate rational design and optimization of cardiovascular particulate drug carriers.


Standard of Care for Neuropsychological Monitoring in Pediatric Neuro-Oncology: Lessons From the Children's Oncology Group (COG).
As the mortality of pediatric cancers has decreased, focus on neuropsychological morbidities of treatment sequelae have increased. Neuropsychological evaluations are essential diagnostic tools that assess cognitive functioning and neurobiological integrity. These tests provide vital information to support ongoing medical care, documenting cognitive morbidity and response to interventions. We frame standards for neuropsychological monitoring of pediatric patients with CNS malignancy or who received cancer-directed therapies involving the CNS and discuss billing for these services in the United States in the context of clinical research. We describe a cost-effective, efficient model of neuropsychological monitoring that may increases access to neuropsychological care.


Brain cortical assessment by MRI in fetuses with left congenital diaphragmatic hernia.
To evaluate fetal brain development using MRI (magnetic resonance imaging) in CDH (congenital diaphragmatic hernia). 52 isolated left CDH and 104 control fetuses were imaged using MRI. Brain morphometry (Biparietal diameter-BPD, brain fronto-occipital diameter-BFOD, third ventricle, posterior ventricles, transcerebellar diameter-TCD, anteroposterior and craniocaudal cerebellar vermis diameter-AP and CC) and cortical structures (bilateral cingulate fissure-CF, insular fissure-IF, insular depth - ID) were compared with controls using Mann-Whitney test. Median gestational age at MRI (p = 0.95)and the median biparietal diameter (p = 0.737) were comparable. Among morphometric parameters, only the brain fronto-occipital diameter was significantly smaller in CDH (p = 0.001) and the third ventricle was significantly greater in CDH (<0.0001). Among cortical structures, the cingulate and insular fissures were significantly deeper in CDH fetuses (p < 0.0001) as the insular depth ID was smaller in CDH (p < 0.03). CDH fetuses have a smaller fronto-occipital diameter, reduced insular depth, deeper cingulate and insular fissure, and greater third ventricle width as compared to controls. These findings suggest that left CDH may have an impact on fetal brain development with an overall reduction in brain volume.


Postoperative radiation therapy for muscle-invading bladder carcinoma.
From 1974-1980, 15 patients with pT2-4 bladder carcinoma received adjuvant postoperative radiation therapy (XRT). The extent of initial surgery varied (six radical cystectomy, 5 partial cystectomy, four "total" transurethral resection). The planned XRT was 4,000-5,040 rads in 5-6 weeks to the pelvis (achieved in 14/15 patients) followed by a bladder boost in noncystectomized patients (achieved in 8/9). Survival at two years and five years was 54% (7/13 patients) and 27% (3/11 patients), respectively. Local-regional disease control (minimum two-year follow-up) was achieved in 7/11 (63%). Of seven patients alive at least two years later, small bowel complications (chronic diarrhea, obstruction) occurred in two; these latter patients each had had radical cystectomy. Adjuvant postoperative XRT may be useful in the multimodality management of patients with bladder carcinoma, especially those identified as high risk after pathologic staging and initial surgery. The poor regional control rate and relatively high incidence of complications seen in this and previous studies suggest that improved radiation technique is needed, both to ensure adequate coverage of the volume at risk and to minimize complications. Representative portals are shown to illustrate these features.


Thiazide diuretic effect on medullary collecting duct function in the rat.
The distal convoluted tubule is thought to be the principal site of action of thiazide diuretics, but, to our knowledge, there are no studies of their possible effects on collecting duct transport. Microcatheterization of the inner medullary collecting duct (IMCD) was carried out in rats undergoing a modest diuresis, natriuresis, and chloriuresis from hydro-chlorothiazide (2 mg/kg/hr) and in normal controls. Delivery of fluid, sodium, and chloride to the beginning of the IMCD was increased, but not significantly, while the load remaining at the papillary tip (end) of the duct was increased markedly by hydrochlorothiazide. Chloride reabsorption in the IMCD was affected most markedly; the chloride reabsorption between the beginning and end of the duct, as a fraction of the delivered load, was reduced from 70.4 +/- 5.4% in controls to insignificant amounts with hydrochlorothiazide (8.2 +/- 11.5%, P less than 0.001). The fraction of delivered sodium reabsorbed along the collecting duct was decreased from 78.5 +/- 4.9% in controls to 37.2 +/- 12.4% (P less than 0.005) in thiazide-treated rats and fluid reabsorption was decreased from 59.4 +/- 4.0% in controls to 31.9 +/- 5.1% (P less than 0.005). Small but significant potassium secretion into the IMCD occurred with hydrochlorothiazide, probably secondary to the marked increase in potassium delivery to the duct. Increased potassium excretion could account for a maximum of 50% of chloriuresis with hydrochlorothiazide. The observation that thiazide diuretics decrease chloride, sodium, and fluid reabsorption in the medullary collecting duct, like the recently demonstrated inhibitory effect of furosemide on this nephron segment, has significant implications for the rationale for diuretic use.


Evaluation of ActiTrac (ambulatory activity monitor) in Parkinson's Disease.
At present, the evaluation of Parkinson's Disease (PD) relies mainly on Unified Parkinson's Disease Rating Scale (UPDRS). Other objective measures have been proposed, including functional studies, timed tests and ambulatory activity monitors (AAM). We carried out a prospective study to analyze the utility and correlation of the AAM: ActiTrac with UPDRS scores and timed tests in patients with PD. We studied 28 patients with idiopathic PD (age: 62 +/- 11 years; duration of illness: 7.7 +/- 4.4 years; clinical stage 2.3 +/- 0.39). Motor evaluation included UPDRS and five timed tests: Purdue Pegboard test and those proposed in CAPIT protocol, pronation-supination (PS), finger dexterity (FD), movement between two points (MTP) and walking test (WT). Clinical evaluation was performed in off condition, at 9 a.m., (12h off their medication). Finally, ActiTrac was placed on the wrist (more affected side) continuously for at least 72h. ActiTrac activity was correlated (Spearman) with total UPDRS (r: - 0.53, p < 0.005) and motor UPDRS (r:- 0.46, p: 0.01); UPDRS rigidity subscore (r:- 0.52, p < 0.01); UPDRS bradykinesia subscore (r:- 0.48; p:0.01); FD (r: - 0.47 p: 0.01), WT (r: - 0.49, p < 0.01) and Purdue test (r:0.54; p < 0.01). ActiTrac seems to be a reasonably accurate method to evaluate motor activity in PD.


A collaborative study of the progesterone intrauterine device (Progestasert). The World Health Organization Task Force on Methods for the Regulation of Implantation.
A randomised double blind study of a plain T-shaped IUD and an active T-shaped IUD releasing 65 micrograms/day of progesterone, has been completed in four centres. A study of 1320 progesterone-releasing IUD's in parous women for 9660 women months of use significant to 18 months, gave a pregnancy rate of 1.0 +/- 0.4, expulsion of 4.7 +/- 0.6 and removals for pain and bleeding of 6.0 +/- 0.7. A detailed analysis of the menstrual bleeding patterns in these patients gave details of the number and length of bleeding and spotting episodes, count of bleeding days, and count of spotting episodes and days for four one-hundred-day reference periods. While the plain IUD contributed a significant number of intermenstrual spotting and bleeding days, the progesterone-releasing IUD contributed more spotting days.


Nitric oxide mediates the insulin sensitizing effects of β-sitosterol in high fat diet-fed rats.
β-Sitosterol has been shown to have antidiabetic and antioxidant effects in animal models. The objective of the study is to investigate the effects of β-sitosterol on insulin sensitivity, oxidative and nitrosative stress and lipid abnormalities in liver of high fat-fed rat model of insulin resistance (IR) and to assess whether nitric oxide (NO) is involved in its action. Adult male albino Wistar rats of body weight 150-180g were fed either control diet (CON) or high fat diet (HFD). Each dietary group was divided into two and treated or untreated with β-sitosterol (10mg/kgb.w.(-1)day(-1)) for 4weeks. Inhibition of total nitric oxide synthase (NOS) by administration of nitro-l-arginine methyl ester (L-NAME) and inducible NOS (iNOS) by aminoguanidine (AG) in HFD and HFD+ β-sitosterol groups were accomplished to identify the role of NO. After 28days, assays were performed in plasma and liver. HFD-fed rats showed hyperglycemia, hyperinsulinemia, IR, oxidative damage, nitrosative stress, lipid accumulation and elevated serum aminotransferases. Increased expression of iNOS and decreased expression of endothelial NOS (eNOS) were observed in them. Hepatic fat accumulation was further confirmed by histology. The biochemical and histological abnormalities associated with HFD feeding were significantly reduced by β-sitosterol administration. Administration of L-NAME to HFD-fed rats caused decrease in insulin sensitivity and increase in oxidative stress. Co-administration of L-NAME for the last seven days to β-sitosterol-treated HFD rats abolished the glucose lowering effect of β-sitosterol, but the ability to decrease oxidative stress remained unaltered. On the other hand, administration of AG resulted in improved glucose homeostasis and antioxidant levels but decreased oxidative stress and enhanced antioxidant potential in both HFD and HFD+ β-sitosterol treated groups. Thus, β-sitosterol promotes insulin sensitivity in rats fed HFD possibly by improving NO levels. With additional studies, β-sitosterol might be used as a functional drug or as an adjuvant in the management of IR and associated fatty liver disease.


Redox Dynamics of Active VO x Sites Promoted by TiO x during Oxidative Dehydrogenation of Ethanol Detected by Operando Quick XAS.
Titania-supported vanadia (VO x /TiO2) catalysts exhibit outstanding catalytic in a number of selective oxidation and reduction processes. In spite of numerous investigations, the nature of redox transformations of vanadium and titanium involved in various catalytic processes remains difficult to detect and correlate to the rate of products formation. In this work, we studied the redox dynamics of active sites in a bilayered 5% V2O5/15% TiO2/SiO2 catalyst (consisting of submonolayer VO x species anchored onto a TiO x monolayer, which in turn is supported on SiO2) during the oxidative dehydrogenation of ethanol. The VO x species in 5% V2O5/15% TiO2/SiO2 show high selectivity to acetaldehyde and an ca. 40 times higher acetaldehyde formation rate in comparison to VO x species supported on SiO2 with a similar density. Operando time-resolved V and Ti K-edge X-ray absorption near-edge spectroscopy, coupled with a transient experimental strategy, quantitatively showed that the formation of acetaldehyde over 5% V2O5/15% TiO2/SiO2 is kinetically coupled to the formation of a V4+ intermediate, while the formation of V3+ is delayed and 10-70 times slower. The low-coordinated nature of various redox states of VO x species (V5+, V4+, and V3+) in the 5% V2O5/15% TiO2/SiO2 catalyst is confirmed using the extensive database of V K-edge XANES spectra of standards and specially synthesized molecular crystals. Much weaker redox activity of the Ti4+/Ti3+ couple was also detected; however, it was found to not be kinetically coupled to the rate-determining step of ethanol oxidation. Thus, the promoter effect of TiO x is rather complex. TiO x species might be involved in a fast electron transport between VO x species and might affect the electronic structure of VO x , thereby promoting their reducibility. This study demonstrates the high potential of element-specific operando X-ray absorption spectroscopy for uncovering complex catalytic mechanisms involving the redox kinetics of various metal oxides.


Protective Effect of Curcumin, Chrysin and Thymoquinone Injection on Trastuzumab-Induced Cardiotoxicity via Mitochondrial Protection.
Mitochondrial dysfunction may lead to cardiomyocyte death in trastuzumab (TZM)-induced cardiotoxicity. Accordingly, this study was designed to evaluate the mitochondrial protective effects of curcumin, chrysin and thymoquinone alone in TZM-induced cardiotoxicity in the rats. Forty-eight male adult Wistar rats were divided into eight groups: control group (normal saline), TZM group (2.5 mg/kg I.P. injection, daily), TZM + curcumin group (10 mg/kg, I.P. injection, daily), TZM + chrysin (10 mg/kg, I.P. injection, daily), TZM + thymoquinone (0.5 mg/kg, I.P. injection, daily), curcumin group (10 mg/kg, I.P. injection, daily), chrysin group (10 mg/kg, I.P. injection, daily) and thymoquinone group (10 mg/kg, I.P. injection, daily). Blood and tissue were collected on day 11 and used for assessment of creatine phosphokinase, lactate dehydrogenase (LDH), troponin, malondialdehyde (MDA) amount, glutathione levels and mitochondrial toxicity parameters. TZM increased mitochondrial impairments (reactive oxygen species formation, mitochondrial swelling, mitochondrial membrane potential collapse and decline in succinate dehydrogenase activity) and histopathological alterations (hypertrophy, enlarged cell, disarrangement, myocytes degeneration, infiltration of fat in some areas, hemorrhage and focal vascular thrombosis) in rat heart. As well as TZM produced a significant increase in the level of CK, LDH, troponin, MDA, glutathione disulfide. In most experiments, the co-injection of curcumin, chrysin and thymoquinone with TZM restored the level of CK, LDH, troponin, MDA, GSH, mitochondrial impairments and histopathological alterations. The study revealed the cardioprotective effects of curcumin, chrysin and thymoquinone against TZM-induced cardiotoxicity which could be attributed to their antioxidant and mitochondrial protection activities.


Maintenance of Human Embryonic Stem Cells by Sphingosine-1-Phosphate and Platelet-Derived Growth Factor.
Human embryonic stem cells (hESCs) have historically been cultivated on feeder layers of primary mouse embryonic fibroblasts (MEF) in a medium supplemented with fetal calf serum (FCS). However, serum contains a wide variety of biologically active compounds that might adversely affect hESC growth and differentiation. Thus, cultivation of stem cells in FCS complicates experimental approaches to define the intracellular mechanisms required for hESC maintenance. This chapter describes the serum-free maintenance of hESCs in culture by addition of sphingosine-1-phosphate (S1P) and platelet-derived growth factor (PDGF). This complete protocol provides a simple alternative chemically defined serum-free system that is relatively inexpensive and advantageous for studying signaling pathways involved in hESC pluripotency.


A positive feedback pathway of estrogen biosynthesis in breast cancer cells is contained by resveratrol.
Cytochrome P450 (CYP) 19 enzyme or aromatase catalyses the rate-determining step of estrogen synthesis. The transcriptional control of CYP19 gene is highly specific in different cell types, for instance, Promoter I.3/II is commonly used for regulation in breast cancer cells. Recently, a positive feedback pathway for estrogen synthesis has been identified in ER alpha expressing SK-BR-3 cells. CYP19 mRNA abundance and activity are increased in this pathway and the promoter usage is switched from Promoter I.3/II to I.1 through a non-genomic process. In the present study, effect of the phytocompound resveratrol on this Promoter I.1-controlled expression of aromatase was investigated. Results indicated that resveratrol reduced the estradiol-induced mRNA abundance in SK-BR-3 cells expressing ER alpha. Luciferase reporter gene assays revealed that resveratrol could also repress the transcriptional control dictated by Promoter I.1. Since the ERE-driven luciferase activity was not repressed by resveratrol, the nuclear events of estrogen were unlikely to be suppressed by resveratrol. Instead the phytochemical reduced the amount of ERK activated by estradiol, which could be the pathway responsible for Promoter I.1 transactivation and the induced CYP19 expression. The present study illustrated that resveratrol impeded the non-genomic induction of estrogen on CYP19.


SGK1 is necessary to FoxO3a negative regulation, oxidative stress and cardiac fibroblast activation induced by TGF-β1.
Cardiac fibroblasts (CFs) activation is a common response to most pathological conditions affecting the heart, characterized by increased cellular secretory capacity and increased expression of fibrotic markers, such as collagen I and smooth muscle actin type alpha (α-SMA). Fibrotic activation of CFs induces the increase in tissue protein content, with the consequent tissue stiffness, diastolic dysfunction, and heart failure. Therefore, the search for new mechanisms of CFs activation is important to find novel treatments for cardiac diseases characterized by fibrosis. In this regard, TGF-β1, a cytokine with proinflammatory and fibrotic properties, is crucial in the CFs activation and the development of fibrotic diseases, whereas its molecular targets are not completely known. Serum and glucocorticoid-regulated kinase (SGK1) is a protein involved in various pathophysiological phenomena, especially cardiac and renal diseases that curse with fibrosis. Additionally, SGK1 phosphorylates and regulates the activity and expression of several targets, highlighting FoxO3a for its role in the regulation of oxidative stress and CFs activation induced by TGF-β1. However, the regulation of SGK1 by TGF-β1 and its role in CFs activation have not been studied. In this work, we evaluate the role of SGK1 in CFs isolated from neonatal Sprague-Dawley rats. The participation of SGK1 in the fibrotic activation of CFs induced by TGF-β1 was analyzed, using an inhibitor or siRNA of SGK1. In addition, the role of SGK1 on the regulation of FoxO3a and oxidative stress induced by TGF-β1 was analyzed. Our results indicate that TGF-β1 increased both the activity and expression of SGK1 in CFs, requiring the activation of MAPKs, ERK1/2, p38 and JNK, while inhibition and silencing of SGK1 prevented TGF-β1-induced fibrotic activation of CFs. In addition, SGK1 inhibition prevented FoxO3a inactivation and expression reduction, catalase and SOD2 expression decrease, and the increase of oxidative stress induced by TGF-β1. Taken together, our results position SGK1 as an important regulator of CFs activation driven by TGF-β1, at least in part, through the regulation of FoxO3a and oxidative stress.


Production of in-situ macropores in an injectable calcium phosphate cement by introduction of cetyltrimethyl ammonium bromide.
In the present study, cetyltrimethyl ammonium bromide (CTAB) was introduced to an injectable calcium phosphate cement (CPC) to produce macropores during the setting process to accelerate the absorbing ability in vivo. The effects of CTAB on the rheological properties, injectability, setting time, compressive strength, phase evolution, microstructure and degradation rate of CPC were studied. The results showed that the addition of CTAB increased the viscosity and yield stress, and decreased the injectability of the cement pastes. The macroporosity and total porosity increased and the compressive strength of the cement obviously decreased with the increase of CTAB. The macroporosity of the CPC prepared at 5 mM CTAB solution reached 44.2+/-2.5% and the mass loss of the cement increased almost 50% as compared with the cement without CTAB. Considering the injectability, compressive strength and degradation rate of CPC, the preferred CTAB concentration was 5 mM. The injectable CPC with macropores is promising to be used in minimally invasive approach.


Investigation of polycapillary half lenses for quantitative confocal micro-X-ray fluorescence analysis.
The use of polycapillary optics in confocal micro-X-ray fluorescence analysis (CMXRF) enables the destruction-free 3D investigation of the elemental composition of samples. The energy-dependent transmission properties, concerning intensity and spatial beam propagation of three polycapillary half lenses, which are vital for the quantitative interpretation of such CMXRF measurements, are investigated in a monochromatic confocal laboratory setup at the Atominstitut of TU Wien, and a synchrotron setup on the BAMline beamline at the BESSY II Synchrotron, Helmholtz-Zentrum-Berlin. The empirically established results, concerning the intensity of the transmitted beam, are compared with theoretical values calculated with the polycap software package and a newly presented analytical model for the transmission function. The resulting form of the newly modelled energy-dependent transmission function is shown to be in good agreement with Monte Carlo simulated results for the complete energy regime, as well as the empirically established results for the energy regime between 6 keV and 20 keV. An analysis of possible fabrication errors was conducted via pinhole scans showing only minor fabrication errors in two of the investigated polycapillary optics. The energy-dependent focal spot size of the primary polycapillary was investigated in the laboratory via the channel-wise evaluation of knife-edge scans. Experimental results are compared with data given by the manufacturer as well as geometric estimations for the minimal focal spot size. Again, the resulting measurement points show a trend in agreement with geometrically estimated results and manufacturer data.


Brachytherapy for Organ and Function Preservation in Soft-Tissue Sarcomas in Adult and Paediatric Patients.
Adjuvant radiotherapy is an integral component in the management of soft-tissue sarcomas. Brachytherapy is a very convenient and conformal way of delivering adjuvant radiotherapy in such tumours, which spares the surrounding normal tissue. Randomised studies have established the efficacy of brachytherapy in the adjuvant setting, with a 5-year local control of 80-85%. High dose rate, low dose rate and pulsed dose rate have shown equivalent local control, but high dose rate has gained popularity owing to patient convenience, radiation safety and flexibility in dose optimisation. Freehand insertion perioperative brachytherapy (intraoperative placement and postoperative treatment) is the most commonly used technique in soft-tissue sarcomas, with intraoperative radiotherapy and radioactive seed placement being the less commonly used techniques. Brachytherapy can be used as monotherapy or in combination with external beam radiotherapy, such as in cases of close/positive margins for safe dose escalation. Although the quantum of side-effects with external beam radiotherapy has considerably reduced with the evolution of technology and the introduction of intensity modulation (intensity-modulated radiotherapy), brachytherapy still scores better in terms of dose conformality, especially in recurrent tumours (previously irradiated) and when used to treat paediatric and geriatric patients.


Beta-amyloid deposition in the brains of rats chronically infused with thiorphan or lipopolysaccharide: the role of ascorbic acid in the vehicle.
Beta-amyloid deposition and neuroinflammation are two important features of Alzheimer's disease (AD) that may influence its progression. Chronic infusion of lipopolysaccharide (LPS) into the rodent 4th ventricle reproduces many of the neurobiological changes seen in AD. Chronic infusion of ascorbic acid containing thiorphan, an inhibitor of the enzyme neprilysin that catabolizes beta-amyloid, into the hippocampus induces extracellular deposition of beta-amyloid fibrils. We investigated whether the combined presence of chronic neuroinflammation could exacerbate the deposition of beta-amyloid induced by thiorphan. The infusion of any solution containing ascorbic acid alone or with thiorphan or LPS increased the level of intraneuronal beta-amyloid immunoreactivity. Solutions that did not contain ascorbic acid were not associated with increased intraneuronal beta-amyloid immunoreactivity. The role of neprilysin in the deposition of beta-amyloid in AD brains remains undetermined.


OSNA: A Fast Molecular Test Based on CK19 mRNA Concentration for Assessment of EBUS-TBNA Samples in Lung Cancer Patients.
Lung cancer is the major cause of cancer death worldwide. Mediastinal lymph node staging is important for pretreatment lung cancer management. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a well established method for mediastinal lymph node staging. Although EBUS-TBNA samples are much smaller than surgical lymph node biopsies, histopathological evaluation and molecular testing can successfully be performed. One step nucleic acid amplification (OSNA), which measures cytokeratin 19 (CK19) mRNA concentration, is a target marker that is gaining importance in quick detection of lymph node metastases in breast cancer and other cancers. Recent publications suggest accurate and rapid detection of lung cancer metastases in surgically removed lymph nodes. In this study we aimed to investigate if CK19 mRNA detection via OSNA is feasible to accurately detect lymph node metastases in lung cancer patients using EBUS-TBNA samples. A total of 102 EBUS-TBNA samples of 55 patients were collected. EBUS-TBNA was performed in lymph nodes exceeding 5 mm. OSNA was performed using a ready to use amplification kit (Lynoamp; Sysmex, Kobe, Japan) in the RD-100 I, an automated real-time detection system (Sysmex). Histopathological analysis confirmed malignancy in 90 cases and excluded malignancy in 12 cases. Overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 78.9%, 58.3%, 93.4%, 26.9%, and 76.5%, respectively. One step nucleic acid amplification is feasible for EBUS-TBNA lymph node samples of lung cancer patients, but CK19 mRNA is an inaccurate marker, which is unlikely to be useful as an adjuvant test for EBUS-TBNA. Further studies are required to define the optimal sample size and sampling method.


Benzodiazepines are synergic with gamma-aminobutyric acid. Microiontophoretic evidence.
By means of microiontophoresis chlordiazepoxide (CDP) was applied to the neurons of rabbit sensorimotor cortex. CDP decreased the frequency of spontaneous electrical activity of all the neurons studied in a dose-dependent manner. During simultaneous CDP and gamma-aminobutyric acid (GABA) application an additive effect of the agents was observed. No antagonism between CDP and GABA was found. Probable reasons for contradictory data obtained by different AA. dealing with benzodiazepine effect on GABA-ergic inhibitory processes are discussed.


C3'-cis-Substituted carboxycyclopropyl glycines as metabotropic glutamate 2/3 receptor agonists: synthesis and SAR studies.
The synthesis of a series of C3'-cis-substituted carboxycyclopropyl glycines bearing a wide variety of functional groups is described, and the structure-activity relationship for this series as agonists of group II metabotropic glutamate receptors is reported.


Clonal growth of human tumor xenografts. First experiences in drug testing.
Human tumors growing as nude mice xenografts were investigated for growth in a clonogenic assay. Colony formation of more than 30 colonies per plate was obtained in 47 of 63 tumors examined (74.6%). The growth rate was enhanced by raising the concentration of fetal calf serum in the culture medium. Plating efficiency ranged from 0.0003% to 5.5%. To study the applicability of this model for screening new anticancer drugs, preliminary studies in drug sensitivity were conducted with continuous incubation of different anticancer drugs in a dose range of 1/10 to 10 times the maximum achievable plasma level. The highest concentration almost always led to a complete suppression of colony growth. In our opinion the procedure described may be a useful combination of two methods in predictive drug testing, provided drug concentration and mode of drug incubation are adequately considered.


Possible alternative carcinogenesis pathway featuring microsatellite instability in colorectal cancer stroma.
Differential microsatellite instability (MSI) in tumour epithelial and stromal compartments has not been well examined for colorectal cancers. Using laser-captured microdissection, separate specimens of these compartments of 40 sporadic colorectal cancers were sampled and MSI was tested with four markers. To examine the relation between the MSI phenotype in the stroma and other genetic events and histopathological features, p53 and K-ras gene mutations were analysed, and the expression of p53, hMLH1, and hMSH2 protein was determined by immunohistochemistry. Microsatellite instability positive results were obtained for both epithelium (34%) and stromal tissue (41%). While MSI in epithelium correlated with differentiation and Dukes' stage, that in stroma demonstrated an inverse relation, being particularly frequent in well-differentiated adenocarcinomas (54%) and Dukes' A lesions (55%). Further, a significant inverse correlation between p53 protein overexpression in the epithelium and MSI in the stroma was found (P=0.02475). The results suggest an alternative pathway of carcinogenesis involving stromal genetic instability in the development of colorectal cancers.


Influence of Intron II microsatellite polymorphism in human toll-like receptor 2 gene in leprosy.
Leprosy is a chronic granulomatous infection caused by the obligate intracellular organism Mycobacterium leprae. TLR2 plays a key role when activated by M. leprae lipoproteins initiating protective responses which induce bacterial killing and therefore control of disease spread. Microsatellite polymorphisms in intron2 of TLR2 gene have been reported to be associated with development of clinical features of several infectious diseases. The study aims to evaluate the influence of GT microsatellite on the expression of TLR2 which could make humans prone to M. leprae infections. A total of 279 individuals were enrolled in the study, 88 were leprosy patients, 95 were house hold contacts (HHC) and 96 were healthy controls (HC). Genotyping was done using PCR-Sequencing method. TLR2 mRNA expression was analyzed by RT-PCR. IL-10 and IFN-γ levels were measured using ELISA in MLSA stimulated cell culture supernatants. Statistical analysis was performed using Chi-Square (χ(2)) test and t-tests. Allele/genotype of TLR2 microsatellite which includes longer GT repeats was associated with low TLR2 mRNA expression and high IL-10 production while that including shorter GT repeats was associated with high TLR2 mRNA expression and low IL-10 production. High IL10 producing allele of TLR2 microsatellite might predispose house hold contacts to leprosy.


[The role of major histocompatibility complex genes in the reaction of macrophages and thymocytes during induction of T-effectors of the graft vs host reaction. III. Effect of antisera against H-2 complex antigens on the realization of the process].
The data are presented on the influence of antisera to different products of the histocompatibility gene complex on the interaction between macrophages and thymocytes during the formation of T-cell GVH effectors. The intensity of the local GVH reaction was evaluated by the index of the lymph nodes enlargement. The close physical contact between cells was necessary for the induction of T-effectors GVH. Treatment of macrophages or thymocytes with anti-H-2 and anti-H-2K antibodies, prior to the beginning of combined incubation, or addition of these antisera to the cultural media suppressed the formation of T-cell inducing GVH. Anti-H-2 I and anti-H-2 D sera did not affect the formation of GVH T-effectors.


Genetic variation of GPLD1 associates with serum GPI-PLD levels: a preliminary study.
HDL is a heterogeneous mixture of lipoprotein particles varying in composition, size, and function. We and others have described a small (7.0nm), minor (0.1% of total apolipoprotein AI) particle containing apolipoprotein AI, AIV and glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) in humans the function of which is not entirely known. Circulating GPI-PLD levels are regulated by multiple factors including genetics. To determine if genetic variation in GPLD1 affects circulating GPI-PLD levels, we examined the relationship between 32 SNPS upstream, within, and downstream of GPLD1 and circulating GPI-PLD levels in Caucasians (n=77) and African-Americans (n=99). The genotype distribution among races differed at 13 SNPs. Nine SNPS were associated with circulating GPI-PLD levels in Caucasians but not African-Americans. These results suggest that genetic variation of GPLD1 appears to associate with circulating GPI-PLD levels. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).


Immobilization stress induces cell death through production of reactive oxygen species in the mouse cerebral cortex.
Prolonged stress has been shown to impair brain function and increase vulnerability to neuronal injury. To elucidate the in vivo response of neuronal cells to induced stress, we immobilized mice by binding their legs. Levels of reactive oxygen species (ROS) in the cerebral cortex were increased after stress induction. NADPH oxidase, interleukin-1beta (IL-1beta) and cyclooxygenase 2 mRNA (COX-2) expression levels were upregulated, and Fas levels were also increased. The increased expression of these factors was associated with neuronal death, which was confirmed by TUNEL and NeuN staining. OX42 staining was also evident around the TUNEL-stained lesions. From these findings, it appears that immobilization stress induces neuronal death in the mouse cerebral cortex, a process mediated by NADPH oxidase, IL-1beta, COX-2, ROS and Fas. However, this could be inhibited by pretreating the animals with antioxidants such as ebselen or pyrrolidine dithiocarbamate.


Validation of the Idylla GeneFusion assay to detect fusions and MET exon-skipping in non-small cell lung cancers.
Gene fusions and MET exon skipping drive oncogenesis in 8-9% and 3% of non-small cell lung cancers (NSCLC) respectively. Their detection are essential for the management of patients since they confer sensitivity to specific targeted therapies with significant clinical benefit over conventional chemotherapy. Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) account for historical reference techniques however molecular-based technologies (RNA-based sequencing and RT-PCR) are emerging as alternative or complementary methods. Here, we evaluated the analytical performance of the fully-automated RT-PCR Idylla GeneFusion assay compared to reference methods using 35 fixed NSCLC samples. Idylla demonstrated overall agreement, sensitivity and specificity of 100% compared to RNASeq. Interestingly, it succeeded in retrieving 10 out of 11 samples with inconclusive results due to insufficient RNA quality for sequencing. Idylla showed an overall agreement, sensitivity and specificity of 90.32%, 91.67% and 89.47% compared to IHC/FISH respectively. Using commercial standards, the limit of detection of the Idylla system for the most frequent fusions and exon skipping ranges between 5 and 10 ng RNA input. These results support that the Idylla assay is a reliable and rapid option for the detection of these alterations, however a particular attention is needed for the interpretation of the expression imbalance.


Activation of the zinc finger encoding gene krox-20 in adult rat brain: comparison with zif268.
Zif268 and krox-20 are transcription regulatory factors that contain highly homologous zinc finger DNA-binding domains. Recent studies have demonstrated that zif268 expression is rapidly regulated in brain by neuronal stimulation. We now report that, like zif268, krox-20 is rapidly and transiently activated by electroconvulsive shock treatment (ECT), D1 dopamine receptor activation, and opiate withdrawal. These studies indicate that, as found for the leucine zipper family of transcription factors, multiple members of the zinc finger family of transcription factors are induced by neuronal stimulation.


Dimethyl itaconate inhibits LPS-induced inflammatory release and apoptosis in alveolar type II epithelial and bronchial epithelial cells by activating pulmonary surfactant proteins A and D.
Injury to the lung is a common, clinically serious inflammatory disease. However, its pathogenesis remains unclear, and the existing treatments, including cytokine therapy, stem cell therapy, and hormone therapy, are not completely effective in treating this disease. Dimethyl itaconate (DMI) is a surfactant with important anti-inflammatory effects. The present study used alveolar type II (AT II) and bronchial epithelial cells as models to determine the role of DMI in lung injury. First, the effects of DMI were established on the survival, inflammatory release, and apoptosis in lipopolysaccharide (LPS)-induced AT II and bronchial epithelial cells. The association between DMI and Sirtuin1 (SIRT1) was assessed using molecular docking. Next, by constructing interference plasmids to inhibit surfactant protein (SP)-A and SP-D expressions, the effect of DMI was observed on inflammatory release and apoptosis. The results revealed that DMI increased the survival rate and expression levels of SP-A, SP-D, and SIRT1, and inhibited inflammatory factors as well as apoptosis in LPS-induced cells. Furthermore, DMI could bind to SIRT1 to regulate SP-A and SP-D expressions. After SP-A and SP-D expressions were inhibited, the inhibitory effect of DMI was reversed on inflammatory release and apoptosis. The findings of the present study revealed that DMI inhibited LPS-induced inflammatory release and apoptosis in cells by targeting SIRT1 and then activating SP-A and SP-D. This novel insight into the pharmacological mechanism of DMI lays the foundation for its later use for alleviating lung injury.


Clinical characteristics, prognostic factors, and outcomes of patients with essential thrombocythemia in Japan: the JSH-MPN-R18 study.
We conducted a large-scale, nationwide retrospective study of Japanese patients who were diagnosed with essential thrombocythemia based on the diagnostic criteria in the World Health Organization classification. We investigated clinical characteristics, survival rates, and the incidence of thrombohemorrhagic events as well as risk factors for these events. A total of 1152 patients were analyzed in the present study. Median age at diagnosis was 65 years, the median platelet count was 832 × 109/L, and the positive mutation rates of JAK2V617F, CALR, and MPL were 62.8, 25.1, and 4.1%, respectively. Compared with European and American patients, Japanese patients were more likely to have cardiovascular risk factors and less likely to have systemic symptoms including palpable splenomegaly. Thrombocytosis was identified as a risk factor for hemorrhagic events and prognosis, but not for thrombotic events. The prognostic factors and risk classifications reported in Europe and the United States were generally applicable to Japanese patients. Regarding transformations, secondary myelofibrosis progressed in a time-dependent manner, but progression to acute leukemia was low in "true" ET patients. Skin cancers were less common and gastrointestinal cancers more common as secondary malignancies in Japanese patients, suggesting ethnic differences.


[Ultrastructure of the sympathetic paravertebral ganglia in rat embryogenesis. II. The development of the neuropil and the interneuronal connections].
Electron microscopy was used to study the process of ingrowth of nerve terminals in the primordia of sympathetic ganglia and the formation of specialized contacts. Nerve terminals appeared first in 12 day old embryos. In the forming ganglia of 13 day old embryos there are many preganglionic nerve terminals and processes of principal neuroblasts. The growth cones of nerve endings are usually distended and with transparent cytoplasm. The plasmalemmas of growth cones are lacking often the trilaminar structure. Synapses were observed first in 16 day old fetuses. They are axo-dendritic and axo-somatic ones. The number of synaptic contacts does not increase much during prenatal period. Presumptive afferent nerve terminals were found in the late fetuses.


Correlation Between Apparent Diffusion Coefficients and Standardized Uptake Values in Hybrid (18)F-FDG PET/MR: Preliminary Results in Rectal Cancer.
Fluorine-18-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DWI) share the same role in clinical oncology and it is feasible to obtain the standardized uptake value (SUV) and apparent diffusion coefficient (ADC) simultaneously by emerging the hybrid positron emission tomography/magnetic resonance (PET/MR). This study investigated the correlation between the ADCs of rectal cancer lesions and their SUVs derived from hybrid PET/MR. Nine patients with histologically proven rectal adenocarcinoma (5 men, 4 women; mean age, 70 ± 15.91 years) underwent torso (18)F-FDG PET/CT and regional hybrid (18)F-FDG PET/MR sequentially. A fixed threshold value of 40 % of maximum uptake was used to determine tumor volume of interest (VOI) on PET image; SUVmax, SUVpeak, and SUVmean were calculated automatically. A single freehand region of interest (ROI) was drawn on high b-value (b1000) DWI image and copied to corresponding ADC map to determine the ADCmean of rectal cancer lesion. Spearman's rank correlation coefficient (ρ) was calculated to determine the correlation between SUVs and ADC values. SUVmax, SUVpeak, and SUVmean derived by hybrid PET/MR were 12.35 ± 4.66 (mean ± standard deviation), 9.66 ± 3.15 and 7.41 ± 2.54, respectively. The ADCmean value of rectal cancer lesions was 1.02 ± 0.08 × 10(-3)mm(2)/s. ADCmean was significantly and inversely correlated with SUV values (SUVmax, ρ = -0.95, p < 0.001; SUVpeak, ρ = -0.93, p < 0.001; SUVmean, ρ = -0.91, p = 0.001). This preliminary hybrid PET/MR study demonstrates a significant inverse correlation exists between metabolic activity on (18)F-FDG PET and water diffusion on DWI in rectal cancer.