Cancer incidence in Thailand, 1995-1997.
There are five population-based cancer registries in Thailand in different regions of the country. Four of them (Chiang Mai, Khon Kaen, Bangkok, and Songkhla) have been operating since 1988 and the other (Lampang) since the early 1990s. These registries have published regular 3-year cancer incidence reports since the first in 1993 for the period 1989-1991. The objective of this article is to summarize the figures of cancer incidence in Thailand during 1995-1997. The population of Thailand in 1996, at the middle of the period, was 27 million males and 27.5 million females. Information of cancer cases residing in the five provinces was collected and abstracted from different sources. Age-standardized incidence rate (ASR) of cancer in males and females was calculated for each registry and that for the whole country was estimated using the five registries as representatives for the four geographical regions of Thailand. The estimated number of new cancer cases in 1996 for the whole country was 35,539 men and 38,476 women and the ASRs were 149.2 and 125.0 per 10(5) population in men and women respectively. Cancer incidences greatly differed from region to region. Lung cancer was the commonest in Chiang Mai and Lampang in the Northern region in both sexes. The incidence of liver cancer in Khon Kaen in the Northeastern region outnumbered all the others in both sexes; cholangiocarcinoma was the major type of liver cancer. In Bangkok, lung cancer was the most important cancer in males and breast cancer was in females. Though it was lung and cervix uteri cancer that ranked the first in men and women in Songkhla, the rate of oral and pharyngeal cancer was exceptionally higher than in other registries. The geographical variability in cancer patterns in Thailand reflects exposure of the population to different risk factors unique to the different regions. In the study as a whole, there are some methodological weak points in estimating the ASRs and number of cancer cases for the whole country, but the results are the most reliable cancer statistics from Thailand at the moment. In conclusion, both a country-wide and region-specific cancer control programmes are needed for Thailand. The national one would be for the cancers common to all regions, and the provincial-level emphasis should be on cancers which are the major problems in the area.


A linguistic investigation of mediators between religious commitment and health behaviors in older adolescents.
Social scientists are beginning to take an interest in the role that religiosity plays in the development of health behaviors throughout adolescence. Although there is mounting evidence of a relationship between these constructs, how and why such relationships exist is not well understood. In this exploratory study of 28 racially diverse university students, we examined whether the relationship between religious commitment and health behaviors could be detected through written language. The results indicated that religious commitment and various indices of healthy lifestyle practices were strongly correlated, that healthy lifestyle practices were related to use of causal words (representing cognitive attempts at understanding causes and effects) and first person plural words (representing social connectedness). The results were consistent with a model in which participants' use of causal words partially or fully mediated the relations between religious commitment and healthy lifestyle practices. Implications of findings and directions for future research are discussed.


Duchenne Muscular Dystrophy: Genetic and Clinical Profile in the Population of Rajasthan, India.
Duchenne Muscular Dystrophy (DMD) is an X-linked recessive muscular dystrophy that affects young boys and is caused by mutation of the dystrophin gene located over X chromosome. In this prospective study, 120 clinically diagnosed DMD patients were tested for exon deletions, duplication or point mutation. Of the 120 clinically suspected DMD patients, the diagnosis of DMD was confirmed by the genetic study or muscle biopsy in 116 patients. The mean age of onset was 3.2 years and the mean age at presentation was 7.2 years. 110/120 cases were confirmed by genetic testing and six were by absence of staining for dystrophin on muscle biopsy. DMD gene deletion was present in 78.5%, duplication in 5.3% and point mutation in 11.2% cases. 70.3% of patients had deletion located at a distal hot spot region. Single exon deletion was found in 16.5%. Distal hotspot exons 47, 48 and 50 were the commonly deleted exons. In our study, 94.8% cases showed genetic change in the DMD gene. Muscle biopsy was the choice of investigation in earlier days. Detection of DMD by DNA based method eliminates the need to do an invasive procedure for diagnosis. Hence the genetic testing should be the investigation of choice in suspected cases of DMD. The pattern of deletion, obtained in the population of Rajasthan was similar when compared with other ethnic groups of the Indian population. It would be helpful for researchers to develop drugs specific to exons or for ongoing mutation-specific therapies.


Are macrophages in tumors good targets for novel therapeutic approaches?
The development of cancer has been an extensively researched topic over the past few decades. Although great strides have been made in cancer prevention, diagnosis, and treatment, there is still much to be learned about cancer's micro-environmental mechanisms that contribute to cancer formation and aggressiveness. Macrophages, lymphocytes which originate from monocytes, are involved in the inflammatory response and often dispersed to areas of infection to fight harmful antigens and mutated cells in tissues. Macrophages have a plethora of roles including tissue development and repair, immune system functions, and inflammation. We discuss various pathways by which macrophages get activated, various approaches that can regulate the function of macrophages, and how these approaches can be helpful in developing new cancer therapies.


Electrostatically driven second-sphere ligand switch between high and low reorganization energy forms of native cytochrome c.
We have employed a combination of protein film voltammetry, time-resolved vibrational spectroelectrochemistry and molecular dynamics simulations to evaluate the electron-transfer reorganization free energy (λ) of cytochrome c (Cyt) in electrostatic complexes that mimic some basic features of protein-protein and protein-lipid interactions. The results reveal the existence of two native-like conformations of Cyt that present significantly different λ values. Conversion from the high to the low λ forms is triggered by electrostatic interactions, and involves the rupture of a weak H-bond between first- (M80) and second-sphere (Y67) ligands of the heme iron, as a distinctive feature of the conformational switch. The two flexible Ω loops operate as transducers of the electrostatic signal. This fine-tuning effect is abolished in the Y67F Cyt mutant, which presents a λ value similar to the WT protein in electrostatic complexes. We propose that interactions of Cyt with the natural redox partner proteins activate a similar mechanism to minimize the reorganization energy of interprotein electron transfer.


Autologous stem cell transplantation for patients with active Hodgkin's lymphoma: long-term outcome of 61 patients from a single institution.
Sixty-one patients with refractory or relapsed Hodgkin's lymphoma (HL) underwent high-dose chemotherapy and autologous stem cell transplantation (ASCT). All patients had active HL at the time of ASCT: 13 patients had partial remission, 14 refractory disease, 18 sensitive relapse, 4 resistant relapse, and 12 nontreated relapse. Overall transplant-related mortality (TRM) was 16.4% at 1 year. Twenty-eight patients (46%) achieved complete remission (CR). Actuarial 5-year overall survival (OS) and progression-free survival (PFS) were 51% and 47%, respectively. Patients with positive gallium-67 scintigraphy at 3 - 6 months after transplantation had a worse PFS at 5 years (28%) than those with negative 67Ga scan (80%) (p = 0.016), whereas no statistical differences were observed between patients with residual mass and those in CR according to computed tomography scan. In multivariate analysis, bulky disease at diagnosis, bone marrow stem cells, and stage IV at transplant were the only adverse prognostic factors significantly influencing OS. Bulky disease at diagnosis and stage IV at transplant adversely influenced PFS. Although long-term outcome of patients with active HL at the time of ASCT is poor due to a high TRM and a low CR after transplantation, a subgroup of patients with no adverse prognostic factors at ASCT gain benefit from this treatment.


Radiation-induced impairment in lung lymphatic vasculature.
The lymphatic vasculature has been shown to play important roles in lung injury and repair, particularly in lung fibrosis. The effects of ionizing radiation on lung lymphatic vasculature have not been previously reported. C57Bl/6 mice were immobilized in a lead shield exposing only the thoracic cavity, and were irradiated with a single dose of 14 Gy. Animals were sacrificed and lungs collected at different time points (1, 4, 8, and 16 weeks) following radiation. To identify lymphatic vessels in lung tissue sections, we used antibodies that are specific for lymphatic vessel endothelial receptor 1 (LYVE-1), a marker of lymphatic endothelial cells (LEC). To evaluate LEC cell death and oxidative damage, lung tissue sections were stained for LYVE-1 and with TUNEL staining, or 8-oxo-dG respectively. Images were imported into ImageJ v1.36b and analyzed. Compared to a non-irradiated control group, we observed a durable and progressive decrease in the density, perimeter, and area of lymphatic vessels over the study period. The decline in the density of lymphatic vessels was observed in both subpleural and interstitial lymphatics. Histopathologically discernible pulmonary fibrosis was not apparent until 16 weeks after irradiation. Furthermore, there was significantly increased LEC apoptosis and oxidative damage at one week post-irradiation that persisted at 16 weeks. There is impairment of lymphatic vasculature after a single dose of ionizing radiation that precedes architectural distortion and fibrosis, suggesting important roles for the lymphatic circulation in the pathogenesis of the radiation-induced lung injury.


Pre-morbid body size and the prognosis of women with breast cancer.
Obesity has been associated with poor prognosis of breast cancer, but studies investigating indicators of adiposity, independent of height, such as skinfold thickness and weight/height ratio, have been limited. From a cohort of 89,835 women in the National Breast Screening Study, data on histologically confirmed, incident cases of invasive carcinoma of breast, diagnosed between January 1981 to June 1992, were analyzed. Body measurements were taken at enrollment and other risk-factor information from a self-administered questionnaire completed prior to diagnosis of the breast cancer. Mortality data were obtained by linkage to Statistics Canada, provincial cancer registries, and annual follow-up of cases through physicians. Of the 5 measures of body size studied among cases, poor prognosis was associated with higher triceps skinfold thickness only. With every 5 mm increase in skinfold, the risk of dying increased approximately 12% (relative risk, 1.12; 95% confidence intervals, 1.01 to 1.24) in the 1033 cases examined and adjusted for age at diagnosis, number of positive axillary nodes involved, and body weight. Compared with women in the lowest quartile of skinfold thickness, women in the fourth quartile had a relative risk (RR) of 1.64 (95% CI, 0.99 to 2.73). None of the other measures--weight, height, body mass index or weight/height ratio--reached any statistical significance. Since the reliability and validity of skinfold measures used in our study were never established, and no data were available for changes in body size after diagnosis, the results of this study on skinfold thickness should be used only as indicative of a need for further studies.


Changes in sex hormones and their interactions are related to pain perception between different menstrual subphases.
Whether sex hormones are related to pain perception across the menstrual cycle is unclear. We examined changes in experimental pain perception in healthy young females between the early to midfollicular subphase (emF) and the midluteal subphase (mL) and explored the role of sex hormones. Sixty-six participants were involved in the study. We tested pressure pain, cold pain, ischemic pain, and needle pain, while at the same time we measured sex hormones levels in two menstrual subphases. Only the right ulna pressure test showed a significant reduction in pain threshold (PPTh3) during the mL. The absolute change of PPTh3 (PPTh3mL - PPTh3emF) was related to the absolute change of prolactin. The relative change of the range of pain tolerance for pressure pain of the right ulna (RPT3rc) was related to the relative change of progesterone (Prc) and estradiol (E2rc) levels, and the interaction effects showed that at Prc ≤ 30, E2rc was positively correlated with RPT3rc. The same, the relative change of pressure pain tolerance of the pulp of the middle finger on the right hand (PPTo4rc) was related to E2rc and Prc, and the results of the interaction between E2rc and Prc suggest that when E2rc is ≤0.8, Prc is positively correlated with PPTo4rc. Two different formulas were applied in this study and showed inconsistent results. Most pain tests showed no difference between the two subphases of the menstrual cycle. Only the relative changes of the PPTo4 and RPT3 are related to the E2rc and Prc, respectively, between menstrual subphases in an interactive way in healthy young women.


Femoral neuropathy as a complication of aortic surgery.
In a series of 1006 aortic operations for atherosclerotic occlusive or aneurysmal disease a femoral neuropathy with paresis of the quadriceps femoris muscle and sensory disturbances occurred in 34 patients or 3.4%. The femoral nerve palsy was left-sided 23 times, right-sided 9 times and bilateral twice. Twenty-nine patients had a complete recovery after 1/2 to 1 years. It is suggested that the femoral neuropathy is of ischaemic nature and caused by aortic clamping. The scant blood supply of the intrapelvic section of the femoral nerve is derived from the iliolumbar artery, a branch of the internal iliac artery, and from the deep circumflex iliac artery, a branch of the external iliac artery. On the right side the deep circumflex iliac artery gives more branches to the nerve and there are more anastomoses with the fourth and fifth lumbar arteries, than on the left side. This may be the explanation for the preference of the nerve palsy for the left side.


Content of the Saponin Protodioscin in Brachiaria spp. from the Eastern Plains of Colombia.
Protodioscin is used as a marker of saponin content that could cause hepatotoxicity in ruminants. In Brachiaria spp. from two regions of the Colombian Eastern Plains (east mountain range of the Andean-"piedemonte" and Ariari River Valley) were determined this metabolite at 14 and 28 days post-cutting under different climatic conditions. No protodioscin was detected in B. dictyoneura or B. humidicola. In B. brizantha, B. decumbens and B. ruziziensis x B. decumbens x B. brizantha (hybrid), protodioscin content corresponded to an interaction between species, post-cutting time and season. Concentrations ≥1% (minimum toxic level) were recorded in B. decumbens and the hybrid, and to a lesser extent in B. brizantha. The concentration of protodioscin was higher at 28 days, when the pastures are suitable for consumption. B. brizantha accumulated the lowest saponin concentration, whereas the hybrid had the highest levels, particularly in the "piedemonte" and during drought (3.37%). Dry season favored the protodioscin concentration in B. decumbens (in river valley) and in the hybrid (in "piedemonte"). In the latter, there was a positive correlation with temperature and a negative with humidity, which are typical characteristics of dry periods. This is the first report of protodioscin content in the hybrid.


The value of ADC, T2 signal intensity, and a combination of both parameters to assess Gleason score and primary Gleason grades in patients with known prostate cancer.
The ability to non-invasively analyze tumor aggressiveness is an important predictor for individual treatment stratification and patient outcome in prostate cancer (PCA). To evaluate: (i) whether apparent diffusion coefficient (ADC), the T2 signal intensity (SI), and a combination of both parameters allow for an improved discrimination of Gleason Score (GS) ≥7 (intermediate and high risk) and GS <7 (low risk) in PCA; and (ii) whether ADC may distinguish between 3 + 4 and 4 + 3 PCA (primary Gleason grades [pGG]). Prostatectomy specimens of 66 patients (mean age, 63 ± 5.6 years; 104 PCA foci) with a preceding multiparametric 1.5 T endorectal coil magnetic resonance imaging (MRI) were included. ADC (b values = 0, 100, 400, 800 s/mm(2)), standardized T2 (T2s), and the ADC/T2s ratio were tested for correlation with GS applying multivariate analysis. ADC cutoff values were calculated for prediction of GS and pGG, and logarithm of the odds (LOGIT) was used to express the probability for GS and pGG. Diagnostic accuracy was assessed by ROC analysis. We found an almost linear negative relationship of ADC for GS ≥7 (P = 0.002). The effect of ADC for GS ≥7 (adjusted odds ratio = 0.995) was almost identical for peripheral and transition zone PCA (P = 0.013 and P < 0.001, respectively). ADC showed an AUC of 78.9% for discrimination between GS <7 and GS ≥7. An ADC cutoff of <1.005 × 10(-3 )mm(2)/s indicated a GS ≥7 (90.5% sensitivity, 62.5% specificity). Within the group of GS = 7 PCA, an ADC > 0.762 × 10(-3 )mm(2)/s indicated a pGG of 3 (AUC = 69.6%). T2s and the ADC/T2s ratio do not provide additional information regarding prediction of GS. ADC values have a good discriminatory power to distinguish tumors with GS ≥7 from GS <7 and to predict pGG in GS = 7 PCA.


Depression in parents of children with Duchenne muscular dystrophy.
This study examined depression, self-esteem, and mastery in the family caretakers of a group of males with Duchenne muscular dystrophy in comparison to a control group. A questionnaire based on the National Population Health Survey from Statistics Canada, a survey to collect information on the health of the Canadian population and related sociodemographic information, was conducted by telephone with 42 parents. The results were compared with the national data from the National Population Health Survey (1994 and 1999), matched for province of residence, number of children in the household, age, and marital status of the respondents. Parents of children with Duchenne muscular dystrophy had a higher probability of going through a major depressive episode and had significantly lower self-esteem and mastery scores than the national control group. None of the variables investigated (age, intelligence quotient, and ambulatory status of child or sex, age, and marital status of parent) could predict the depressive episode, with two exceptions. Parents without a partner had lower scores on the mastery scale, and parents of males older than 13 years of age were more likely to experience distress that interfered with life. It is incumbent on those caring for patients with Duchenne muscular dystrophy to counsel families regarding their potential to suffer a major depressive episode and to advise on appropriate therapy.


Assessment of microbiological and parasitological quality of composted wastes: health implications and hygienic measures.
Feedstock and compost samples were collected from twenty composting plants and analysed from the microbiological point of view. Faecal indicator organisms were determined in order to evaluate the efficacy of processes for the removal of pathogenic micro-organisms with similar survival characteristics and to verify their suitability as appropriate markers of microbial quality of composted products. In addition to the classical bacterial indicators, selected organisms, such as Salmonella, Giardia, Cryptosporidium, Clostridium spores and helminth ova, were investigated. Statistically significant differences in the removal of the different micro-organisms were observed with regard to both the different composting plants (P < 0.05) and feedstock composition (P < 0.05). In fact, compost obtained by feedstock containing sewage sludge was shown to have a better hygienic quality in comparison with compost containing green discards and municipal solid waste as raw matter. Giardia cysts, Cryptosporidium oocysts and helminth ova were not effective indicators of hygienic quality of compost, whereas Clostridium perfringens spores, because of their high resistance to treatments, could be considered as an additional model for assessing the composting process, especially with regard to more resistant pathogen reduction.


Treatment adherence in patients with type 2 diabetes mellitus correlates with different coping styles, low perception of self-influence on disease, and depressive symptoms.
Insulin analogs are regarded as more convenient to use than human insulin; however, they require a different administration scheme due to their unique pharmacokinetic and pharmacodynamic properties. This study aimed to assess difficulties with adherence to treatment with insulin analogs in patients with type 2 diabetes mellitus (T2DM), who had previously been treated with human insulin. The associations between difficulties with adherence and clinical, demographic, and psychological characteristics were also evaluated. The study was conducted on 3,467 consecutively enrolled patients with T2DM (54.4% women), mean age 63.9 years (SD =9.57), who had recently undergone a physician-directed change in treatment from human insulin to insulin analogs. The questionnaires addressed difficulties with switching the therapy, coping styles, well-being, and perception of self-influence on the disease. No adherence problems in switching therapy were reported in 56.6% of patients. Specific moderate difficulties were reported in 10.4%-22.1% of patients, major difficulties in 0.7%-6.9% of patients, and very significant difficulties in 0.03%-1.3% of patients. Overall, remembering to modify the insulin dose in the case of additional meals was the most frequently reported difficulty, and problems with identifying hypoglycemic symptoms were the least frequently reported. The increased risk of difficulties was moderately related to low perception of self-influence on diabetes and poor well-being. The intensity of problems was higher among those who were less-educated, lived in rural areas, had complications, and/or reported maladaptive coping styles. Switching from human insulin to an insulin analog did not cause adherence problems in more than half of the patients. In the remaining patients, difficulties in adherence correlated with maladaptive coping styles, low perception of self-influence on disease course, and depressive symptoms.


The human first hypothesis: identification of conspecifics and individuation of objects in the young infant.
How do infants individuate and track objects, and among them objects belonging to their species, when they can only rely on information about the properties of those objects? We propose the Human First Hypothesis (HFH), which posits that infants possess information about their conspecifics and use it to identify and count objects. F. Xu and S. Carey [Cognitive Psychology, 30(2), 111-153, 1996] argued that before the age of 1 year, infants fail to use property information. To explain their results, Xu and Carey proposed the Object First Hypothesis (OFH), according to which infants under 1 year of age have only the general concept of physical object to identify and count objects. We show that infants have a more extensive knowledge of sortals than that claimed by the OFH. When 10-month-olds see one humanlike and one non-humanlike object, they successfully identify and count them by using the contrast in their properties, as predicted by the HFH. We also show that infants succeed even when they make a decision based on differences between two close basic-level categories such as humanlike objects and doglike objects, but fail when they have to use differences within the human category. Thus, infants treat "human" as a basic sortal, as predicted by the HFH. We argue that our results cannot be accounted for by general purpose mechanisms. Neither the strong version of the OFH and its explanation in terms of object indexing mechanisms [A. M. Leslie, F. Xu, P. Tremoulet, & B. J. Scholl, Trends in Cognitive Sciences, 2(1), 10-18, 1998] nor explanations in terms of task demands [T. Wilcox & R. Baillargeon, Cognitive Psychology, 37(2), 97-155, 1998] are sufficient to explain our results.


Serum Levels of 1,5-Anhydroglucitol and Risk of Incident End-Stage Renal Disease.
Glycemic excursions, independent of average glucose, have been implicated in the development of diabetic complications. It is unknown whether low levels of 1,5-anhydroglucitol (1,5-AG) are associated with advanced stages of kidney disease independent of kidney function and glycemia. In the Atherosclerosis Risk in Communities Study (n = 13,277 from 4 US communities), we used structural equation modeling to estimate the association between serum 1,5-AG levels and end-stage renal disease (ESRD) from baseline (1990-1992) through 2013 with adjustment for demographics, risk factors, a latent variable for glycemia (diabetes status, fasting glucose, glycated hemoglobin (HbA1c), fructosamine, glycated albumin), and a latent variable for kidney function (creatinine, cystatin C, β2-microglobulin). After adjusting for demographics, risk factors, and the latent variable for kidney function, the linear spline terms representing 1,5-AG levels <6.0 μg/mL (incidence rate ratio (IRR) = 0.79, 95% confidence interval (CI): 0.70, 0.88) and 6.0-9.9 μg/mL (IRR = 0.80, 95% CI: 0.70, 0.92) were significantly associated with ESRD. After additionally adjusting for the latent variable for glycemia, low 1,5-AG levels (<6.0 μg/mL) were no longer significantly associated with ESRD (IRR = 0.92, 95% CI: 0.81, 1.05). In conclusion, low 1,5-AG levels are associated with higher risk of incident ESRD independent of baseline kidney function but not independent of glycemia.


Group-Based Active Learning of Classification Models.
Learning of classification models from real-world data often requires additional human expert effort to annotate the data. However, this process can be rather costly and finding ways of reducing the human annotation effort is critical for this task. The objective of this paper is to develop and study new ways of providing human feedback for efficient learning of classification models by labeling groups of examples. Briefly, unlike traditional active learning methods that seek feedback on individual examples, we develop a new group-based active learning framework that solicits label information on groups of multiple examples. In order to describe groups in a user-friendly way, conjunctive patterns are used to compactly represent groups. Our empirical study on 12 UCI data sets demonstrates the advantages and superiority of our approach over both classic instance-based active learning work, as well as existing group-based active-learning methods.


The INTEGRITY Trial: Preservation of Uterine-Wall Integrity 12 Months After Transcervical Fibroid Ablation with the Sonata System.
Objective: The aim of this research was to evaluate uterine-wall integrity 12 months after transcervical fibroid ablation (TFA) of uterine fibroids with the Sonata® system (Gynesonics Inc., Redwood City, CA). Materials and Methods: INTEGRITY is a secondary analysis of the FAST-EU clinical trial, a prospective, longitudinal, multicenter single-armed trial involving women with heavy menstrual bleeding secondary to fibroids who were treated at 7 academic and community hospitals in the United Kingdom, the Netherlands, and Mexico with transcervical, intrauterine, ultrasound-guided radiofrequency ablation (the Sonata system). TFA was performed on up to 5 fibroids per subject ranging from 1-5 cm in diameter as determined by magnetic resonance imaging (MRI). All measurements and comparisons, including uterine-wall thicknesses were derived from baseline and 12-month MRI scans by an independent core MRI center. Scans were analyzed to assess preservation of uterine-wall integrity and reviewed for uterine-wall anomalies after TFA with the Sonata system. Results: Twenty-nine patients had baseline and 12-month MRI with contrast enhancement. Minimum uterine-wall thicknesses in all visible slices were >2.5 mm in diameter. No areas on MRI indicated any loss of uterine-wall integrity, compared with baseline imaging; comparison of baseline and postablation uterine-wall thicknesses revealed no significant changes. Conclusion: Transcervical fibroid ablation with the Sonata system was associated with preservation of uterine-wall integrity in this patient cohort.


Copy number variation of ubiquitin- specific proteases genes in blood leukocytes and colorectal cancer.
Ubiquitin-specific proteases (USPs) play important roles in the regulation of many cancer-related biological processes. USPs copy number variation (CNVs) may affect the risk and prognosis of colorectal cancer (CRC). We detected CNVs of USPs genes in 468 matched CRC patients and controls, estimated the associations between the USPs genes CNVs and CRC risk and prognosis and their interactions with environmental factors on CRC risk. Finally, we generated five CRC risk predictive models with different CNVs patterns combining with environmental factors (EF). We identified significant association between CYLD deletion and CRC risk (ORadj = 4.18, 95% CI: 2.03-8.62), significant association between USP9X amplification and CRC risk (ORadj = 2.30, 95% CI: 1.48-3.57), and significant association between USP11 deletion and CRC risk (ORadj = 3.49, 95% CI: 1.49-8.64). There were significant gene-environment and gene-gene interactions on CRC risk. The area under the receiver operating characteristic curve (AUC) of EF + SIG (deletion of CYLD and USP11, amplification of USP9X) model was significantly larger than any other models (AUC = 0.75, 95% CI: 0.74-0.77). We did not identify significant associations between CNVs of the three genes and CRC prognosis. CNVs of CYLD, USP9X, and USP11 are significantly associated with the risk of CRC. Gene-gene and gene-environment interactions might also play an important role in the development of CRC.


Stereoselective Construction of Orthogonally Protected, N-O Interlinked Disaccharide Mimetics Using N-Substituted β-Aminooxy Donors.
Orthogonally protected N-substituted β-aminooxy sugars can be stereoselectively synthesized from sugar epoxides and nitrones derived from aromatic aldehydes. Both the ether- and ester-protected sugar epoxides can be employed. The synthesized aminooxy sugars could be reacted with aldehyde bearing/free reducing sugars under the heating condition to afford N-O-linked 1,1-/1,5/1,6-disaccharide mimetics in a good yield.


Ethics in psychiatry and psychoanalysis.
Ethics plays a dual role in psychiatry. The extrinsic role is in defining the rules of ethical conduct for the psychiatrist as a professional dealing with patients, peers and society at large. The intrinsic role is in defining ethical or moral conflict as a determining component in the construction of symptoms of mental disorder. Ethical considerations play a role in the truthful description of the disorder, diagnosis, dynamic formulation and the doctor-patient relationship in treatment. In treatment, there is a need to acknowledge 2 dimensions of psychological conflict: (1) an appraisal of the actual realistic moral conflicts due to symptomatic unethical conduct that goes against one's normative conscience, and (2) resolution of past conflicts arising from unconscious or repressed aspects of the neurotic conscience or superego, i.e. a holdover of unreflected obedience to parental authority. The resolution of past and ongoing conflicts promotes growth toward autonomy of moral judgment, free choice and moral responsibility.


Decoding the Structural Basis For Carbapenem Hydrolysis By Class A β-lactamases: Fishing For A Pharmacophore.
Nowadays clinical therapy witnesses a challenging bacterial resistance limiting the available armament of antibiotics. Over the decades strains resistant to all antibiotics have been selected while medicinal chemists were not able to develop agents capable of destroying them or to prevent their extension. In particular, carbapenem-resistant Enterobacteriaceae (CRE), representing one of the most common human pathogens, have been reported with increased frequency since their first identification twenty years ago. The enterobacterial carbapenemases differ from the extended spectrum β-lactamases (ESBL) in their ability to hydrolyze β-lactams, cephalosporins and most importantly monobactams and carbapenems. They are progressively spreading throughout the world, therefore leaving no effective β-lactam to cure bacterial infections. Several BLs-carbapenemase Xray structures have been determined making these enzymes attractive targets for structure-based drug design studies. However, very little has been done so far to powerfully address the inhibitor design issues for this emerging type of BLs. Here, we focus on the structural basis for molecular recognition and for broad spectrum activity of class A carbapenemases: based on available 3-dimensional structural information we identify a theoretical pharmacophoric model as a starting point for the development of needed carbapenemases inhibitors.


In-vitro and in-vivo activity of roxithromycin against Chlamydia trachomatis.
The object of study was the evaluation of both the in-vitro and in-vivo activity of roxithromycin against Chlamydia trachomatis. In-vitro activity against C. trachomatis was achieved by means of minimum inhibitory concentration (MIC) determinations and was recorded as 0.05 mg/l. In vivo activity was tested in 15 of 60 women, attending the Planning Clinic, who were positive for C. trachomatis. Microbiological diagnosis of chlamydial infection was achieved by using a monoclonal direct smear test (Biomerieux-C trachomatis direct IF). All the patients and their partners were treated with 150 mg of roxithromycin twice a day for 15 days. All the patients were requested to avoid unprotected sexual intercourse up to the end of the therapy. The criterion for clinical efficacy was defined as disappearance of clinical signs and the criterion for microbiological efficacy was evidence of eradication of C. trachomatis at the follow-up (mean time: 30 days). A clinical cure and chlamydial eradication was recorded for all the patients at the end of the treatment and at follow-up. Clinical safety was also satisfactory.


Pathology of the insular cortex in Alzheimer disease depends on cortical architecture.
The insular cortex plays important roles in a variety of regulatory mechanisms ranging from visceral control and sensation to covert judgments regarding inner well-being. The dementia of Alzheimer disease (AD) often includes behavioral dyscontrol and visceral dysfunction not observed in other diseases affecting cognition. This could be related to autonomic instability and to loss of the sense of self, and pathologic changes within the insula may play essential roles. The pattern of insular pathology of 17 patients with AD was examined and the severity of pathology was compared with that of the entorhinal cortex (EC), a region involved early in AD with reciprocal connections to the insula. Thioflavin S staining and Alz-50 immunostaining revealed that the insula carries a heavy burden of pathology in AD. Neurofibrillary tangles (NFTs) were largely confined to the deep layers of the cortex, whereas neuritic plaques (NPs) were distributed throughout the cellular layers and subcortical white matter. The density of NFTs, but not NPs, was highly correlated with the degree of EC pathology. However, NFTs were not seen in the insula until EC pathology reached a relatively advanced level. The density of insular NFTs varied according to architectonic type, with agranular cortex most affected, dysgranular cortex less affected, and granular cortex least affected. Thus, the insula is often involved in AD, and some of the behavioral abnormalities in AD may reflect insular pathology.


Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer.
Thyroid cancer is the most common cancer in Korea. Several susceptibility loci of differentiated thyroid cancer (DTC) were identified by previous genome-wide association studies (GWASs) in Europeans only. Here we conducted a GWAS and a replication study in Koreans using a total of 1,085 DTC cases and 8,884 controls, and validated these results using expression quantitative trait loci (eQTL) analysis and clinical phenotypes. The most robust associations were observed in the NRG1 gene (rs6996585, P=1.08 × 10-10) and this SNP was also associated with NRG1 expression in thyroid tissues. In addition, we confirmed three previously reported loci (FOXE1, NKX2-1 and DIRC3) and identified seven novel susceptibility loci (VAV3, PCNXL2, INSR, MRSB3, FHIT, SEPT11 and SLC24A6) associated with DTC. Furthermore, we identified specific variants of DTC that have different effects according to cancer type or ethnicity. Our findings provide deeper insight into the genetic contribution to thyroid cancer in different populations.


Toward a better understanding of preeclampsia: Comparative proteomic analysis of preeclamptic placentas.
Preeclampsia (PE), a pregnancy-specific syndrome of hypertension, proteinuria, and other systemic disturbances, is a state of widespread endothelial dysfunction secondary to defective placentation. Morphologically, the current data displayed degenerative and apoptotic changes in the mitochondria and villous trophoblasts of preeclamptic placenta. To reveal the superimposing alterations in placental proteins that might explain the pathophysiology of PE, we performed 2-DE MALDI-TOF MS/MS proteomics analysis of differentially expressed placental proteins with placenta from eight normal and eight preeclamptic pregnancies. The identified proteins were confirmed by Western blot analysis. We also performed morphologic evaluation of preeclamptic placentas under both electron and light microscopy. The results disclosed the marked overexpression of chaperonin 60, GST, VDAC, ERp29, and cathepsin D in PE. These proteomics findings clearly suggest the possible cellular battle against mitochondria-originated oxidative stress during PE that either end up with recovery or apoptosis. These results provide a better understanding of proteomic alterations and may help in clarification of stress-related changes in preeclamptic placentas.


[Histological study on occlusal bearing capability of apatite implant in maxilla].
The focus of this study is aimed on the degree of occlusal bearing capability of the dense apatite implant in the maxilla and its histological alteration. The implants were placed in the [symbol: see text] areas of the adult monkeys. The vertical dimension was raised by the implants, the opposite [symbol: see text] were splinted together with the connected crowns. At 1, 3 and 7 months after loading, the tissue surrounding the implants and opposing [symbol: see text] was examined histologically with the following results: 1. The formed and newly compacted lamellae and woven bone were seen along the implant supporting the trabeculae and the compact bone that supports the implant and gradually getting thicker until the third month. 2. Realignment and remodelling of the trabeculae and compact bone continuously progressed from 3 months onward. 3. Bone formation and bone remodelling were also observed to have progressed widely towards the neighboring teeth, and bone remodelling in the maxillary sutures similarly occurred. 4. The splinted opposite teeth intruded gradually during the experiment. 5. In some implants, few fracture areas close to the surface were observed in the bone that was in contact with the implant.


Inflammatory factors are crucial for the pathogenesis of post-traumatic osteoarthritis confirmed by a novel porcine model: "Idealized" anterior cruciate ligament reconstruction" and gait analysis.
To determine whether idealized anterior cruciate ligament reconstruction (IACL-R) restores normal gait features, and whether inflammatory factors are involved in the pathogenesisof post-traumatic osteoarthritis (PTOA). Fourteen mature female minipigs were allocated to a sham group (n = 7) or an IACL-R group (n = 7). Load asymmetry during gait was recorded using a pressure-sensing walkway measurement system to evaluate the gait features of the right knee joint before and after surgery. Inflammatory factors (including interleukin [IL]-1α, IL-1β, IL-2, IL-6, IL-8, IL-18, tumor necrosis factor-α, and granulocyte-macrophage colony-stimulating factor) in synovial fluid were measured using Luminex assays before and after surgery. Cartilage integrity and the subchondral bone plate of the right knee were evaluated using histology and imaging at 3 months postoperatively. Swing time and stance time returned to their preoperative values on day 31, while maximum force, contact area, peak force ,and impulse returned to their preoperative values on day 45 after the surgery in the IACL-R group (P = 0.073, 0.053, 0.107, 0.052, 0.152, and 0.059, respectively).Thus, IACL-R restored normal gait. Compared with their preoperative concentrations, all tested inflammatory factors showed significantly increased concentrations in the synovial fluid in the IACL-R group, especially at 3, 7, and 15 days postoperatively. X-ray, computed tomography, magnetic resonance imaging, and histological data showed severe cartilage damage in the IACL-R model. IACL-R restored normal gait features but caused significant cartilage damage, indicating that significantly elevated inflammatory factors maybe crucial for the pathogenesis of PTOA.


Fluctuation-dissipation relations and field-free algorithms for the computation of response functions.
We discuss the relation between the fluctuation-dissipation relation derived by Chatelain and Ricci-Tersenghi [C. Chatelain, J. Phys. A 36, 10739 (2003); F. Ricci-Tersenghi, Phys. Rev. E 68, 065104(R) (2003)] and that by Lippiello-Corberi-Zannetti [E. Lippiello, F. Corberi, and M. Zannetti, Phys. Rev. E 71, 036104 (2005)]. In order to do that, we rederive the fluctuation-dissipation relation for systems of discrete variables evolving in discrete time via a stochastic nonequilibrium Markov process. The calculation is carried out in a general formalism comprising the Chatelain, Ricci-Tersenghi, result and that by Lippiello-Corberi-Zannetti as special cases. The applicability, generality, and experimental feasibility of the two approaches are thoroughly discussed. Extending the analytical calculation to the variance of the response function, we show the advantage of field-free numerical methods with respect to the standard method, where the perturbation is applied. We also show that the signal-to-noise ratio is better (by a factor square root of 2) in the algorithm of Lippiello-Corberi-Zannetti with respect to that of Chatelain-Ricci Tersenghi.


Structure-activity relationships among dithiocarbamate antidotes for acute cadmium chloride intoxication.
Eight sodium dithiocarbamates (NaS2CNR1R2) have been examined as antidotes for acute cadmium intoxication. While all of them possess an ability to increase survival when given to mice 2 hr after a lethal (greater than 99%) intraperitoneal injection of 10 mg/kg of CdCl2 X 2.5H2O, their effects on the organ distribution of cadmium vary considerably. It has been possible to show that the accumulation of cadmium in the brain and kidney as well as the survival rates can be correlated with a numerical measure of the polarity of the groups R1 and R2. Each factor has a different dependence on the polarity, but it is possible to construct a composite factor for antidotal efficacy which incorporates survival rate, brain cadmium levels and kidney cadmium levels. The factor constructed here exhibits an optimal value approximately in the middle of the polarity range studied. Compounds which have R1 = -CH2CH1OH and R2 = -CH2CH2OH, or -CH3 or -C2H5 appear to be the most effective antidotes of the compounds examined.


Prospective randomized comparison of coronary bypass grafting with minimal extracorporeal circulation system (MECC) versus off-pump coronary surgery.
We aimed to evaluate the clinical results and biocompatibility of the minimal extracorporeal circulation system (MECC) compared with off-pump coronary revascularization (OPCABG). In a prospective randomized study, 150 patients underwent coronary surgery with the use of MECC and 150 underwent OPCABG. End points were (1) circulating markers of inflammation and organ injury, (2) operative results, and (3) outcome at 1-year follow-up. Operative mortality and morbidity were comparable between the groups. Release of inflammatory markers was similar between groups at all time points (peak interleukin-6 167.2+/-13.5 versus 181+/-6.5 pg/mL, P=0.14, OPCABG versus MECC group, respectively). Peak creatine kinase was 419.3+/-103.5 versus 326+/-84.2 mg/dL (P=0.28), and peak S-100 protein was 0.13+/-0.08 versus 0.29+/-0.1 pg/mL (P=0.058, OPCABG versus MECC group, respectively). Length of hospital stay and use of blood products were similar between groups. Two cases of angina recurrence at 1 year in the MECC group were observed versus 5 cases observed in the OPCABG group (P=0.44). A residual perfusion defect at myocardial nuclear scan was less frequent among patients in the MECC group (3 versus 9 cases, P=0.14; odds ratio 0.32, 95% confidence interval 0.07 to 1.32). Six (OPCABG group) versus 3 (MECC group) coronary grafts were occluded or severely stenotic at 1 year (P=0.33, odds ratio 0.47, 95% confidence interval 0.09 to 2.14). Clinical results of coronary revascularization with MECC are optimal when this procedure is performed by experienced teams. Postoperative morbidity is comparable to that with OPCABG. MECC is associated with little pump-related systemic and organ injury. It may achieve the benefits of OPCABG (less morbidity in high-risk patients) while facilitating complete revascularization in the case of complex lesions unsuitable for OPCABG.


[Using vein grafts in living donor liver transplantation].
To study the use of vein grafts in adult-to-adult (AA) living donor liver transplantation (LDLT), we transplanted recipient vena saphena magna grafts for drainage of the paramedian portion of the right lobe liver grafts without a middle hepatic vein in LDLT. From January 2002 to March 2006, 26 patients underwent A-A LDLT, and recipient saphenous vein grafts were used for revascularization of veins and arteries such as: tributaries of the middle hepatic vein from V5, V8; right inferior hepatic vein; injured portal vein; and hepatic artery. Total outflow reconstruction ratio of V5, V8 and right inferior hepatic vein was 76.9% (20/26), the ratio of one-vein reconstruction was 57.7%, and the ratio of two-vein reconstruction was 19.2%. Reconstruction patterns and cases were demonstrated as follows: V5 (n=3), V8 (n=2), V5 and V8 (n=3), V5 and right inferior hepatic vein (n=1), V8 and right inferior hepatic vein (n=1), right inferior hepatic vein (n=10), injured portal vein of the donor (n=1). Total ratio of hepatic artery bypass grafting was 11.5% (3/26), anastomosis between hepatic artery and abdominal aorta (n=2), and anastomosis between hepatic artery and hepatic artery (n=1). Doppler ultrasound showed no thrombosis and the blood flowed smoothly and without venous outflow obstruction during the 2 to 48 months follow-up period. Reconstruction of V5 or V8 outflow and hepatic artery bypass grafting using vena saphena magna of the recipients can provide sufficient venous outflow and prevent the small-for-size syndrome and solve hepatic artery complications. This approach can be recommended.


University professors' mental and physical well-being during the COVID-19 pandemic and distance teaching.
Strict strategies including lockdowns and working from home were adopted worldwide during the coronavirus (COVID-19) pandemic. University professors suddenly shifted to work from home adopting distance teaching. This study aimed to investigate Health-Related Quality of Life (HRQoL) and its associated occupational and health factors during COVID-19 among university professors. A cross-sectional design targeted university professors of all majors in Jordan. The study self-administered survey included demographics and lifestyle data, 12-item Short Form health survey (SF-12), Depression Anxiety Stress Scale (DASS 21), professor' evaluation of distance teaching, Neck Disability Index (NDI), and International Physical Activity Questionnaire (IPAQ). Descriptive analyses were conducted to demonstrate primary outcome measures data. Factors associated with HRQoL were determined using a multiple variable linear regression analysis. A total of 299 university professors successfully completed the study. Participants' SF-12 physical health component score was 74.08 (±18.5) and 65.74 (±21.4) for mental health component. Higher depression, stress, neck disability, and weight change were significantly associated with lower HRQoL level. While higher satisfaction with distance teaching, health self-evaluation, and work load change were significantly associated with higher HRQoL level. The regression model explained 66.7%of the variance in professors' HRQoL (r2 = 0.667, F = 82.83, P < 0.001). Jordanian university professors demonstrated good HRQoL and mental health levels during COVID-19 lockdown. Factors associated with professors' HRQoL should be considered by academic institutions in determining the best occupational setup of teaching activities in future pandemics.


Mitochondrial dynamics in peripheral neuropathies.
Mitochondrial dynamics describes the continuous change in the position, size, and shape of mitochondria within cells. The morphological and functional complexity of neurons, the remarkable length of their processes, and the rapid changes in metabolic requirements arising from their intrinsic excitability render these cells particularly dependent on effective mitochondrial function and positioning. The rules that govern these changes and their functional significance are not fully understood, yet the dysfunction of mitochondrial dynamics has been implicated as a pathogenetic factor in a number of diseases, including disorders of the central and peripheral nervous systems. In recent years, a number of mutations of genes encoding proteins that play important roles in mitochondrial dynamics and function have been discovered in patients with Charcot-Marie-Tooth (CMT) disease, a hereditary peripheral neuropathy. These findings have directly linked mitochondrial pathology to the pathology of peripheral nerve and have identified certain aspects of mitochondrial dynamics as potential early events in the pathogenesis of CMT. In addition, mitochondrial dysfunction has now been implicated in the pathogenesis of noninherited neuropathies, including diabetic and inflammatory neuropathies. The role of mitochondria in peripheral nerve diseases has been mostly examined in vitro, and less so in animal models. This review examines available evidence for the role of mitochondrial dynamics in the pathogenesis of peripheral neuropathies, their relevance in human diseases, and future challenges for research in this field.


[Diabetes mellitus as a rare complication of hemolytic uremic syndrome--case report].
A 4-year-old girl was hospitalized in a local hospital with bloody diarrhoea, vomitus and abdominal pain. Because of acute abdominal symptoms she underwent appendectomy after which convulsions and acute respiratory distress were noticed. The child was transferred to the intensive care unit. During the examination she was unconscious, pale, oedematous with scattered ecchymoses, severe hypertension and urine output diminished to several ml per day. Routine blood tests showed microangiopathic anaemia, thrombocytopenia (52000/ul.) and uremia. Proteinuria and hematuria were revealed on urine examination. Among coagulation parameters kaolin-kefalin time (69 s) and D-dimers (2000-4000/ul.) were abnormal. On the strength of history, clinical and laboratory investigation the diagnosis of D-positive hemolytic uremic syndrome was established. Controlled artificial respiration (for 10 weeks), total parenteral alimentation (TPN), antihypertensive treatment and diuretics (furosemide, dopamine) were introduced. Daily temporary access hemodialyses were performed for 4 weeks. Subsequently peritoneal dialysis was started for 2 weeks. Despite the appropriate TPN glucose blood levels were unexpectedly high from first days from admission (200-330 mg%). Intensive intravenous insulin therapy was performed for 50 days. The child was discharged after 72 days with moderate renal function impairment (blood urea-53 mg%, creatinine-1,2 mg%), mild hypertension and proteinuria. Additional factor prone to thrombotic events was the 4G/4G genotype responsible for increased PAI-1 blood concentration, which may result in intensified fibrinolysis inhibition. Diabetes mellitus as a rare immunological complication of haemolytic uremic syndrome was suspected on the following evidence: positive anti-GAD antibodies (ELISA), elevated levels of glycosylated haemoglobin A1c, three-fold reduction of blood C-peptide concentration, negative family history for diabetes. After 12 y of follow up glucose and C-peptide concentrations were normal. Glucose loading test gave adequate response. Kidney function was decreased with serum creatinine 1.7-1.9 mg/dl and urea 60-75 mg/dl.


Clinician-friendly lower extremity physical performance measures in athletes: a systematic review of measurement properties and correlation with injury, part 1. The tests for knee function including the hop tests.
To review the measurement properties of physical performance tests (PPTs) of the knee as each pertain to athletes, and to determine the relationship between PPTs and injury in athletes age 12 years to adult. A search strategy was constructed by combining the terms 'lower extremity' and synonyms for 'performance test', and names of performance tests with variants of the term 'athlete'. In this, part 1, we report on findings in the knee. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were followed and the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist was used to critique the methodological quality of each paper. A second measure was used to analyse the quality of the measurement properties of each test. In the final analysis, we found 29 articles pertinent to the knee detailing 19 PPTs, of which six were compiled in a best evidence synthesis. The six tests were: one leg hop for distance (single and triple hop), 6 m timed hop, crossover hop for distance, triple jump and single leg vertical jump. The one leg hop for distance is the most often studied PPT. There is conflicting evidence regarding the validity of the hop and moderate evidence that the hop test is responsive to changes during rehabilitation. No test has established reliability or measurement error as assessed by the minimal important change or smallest detectable change. No test predicts knee injury in athletes. Despite numerous published articles addressing PPTs at the knee, there is predominantly limited and conflicting evidence regarding the reliability, agreement, construct validity, criterion validity and responsiveness of commonly used PPTs. There is a great opportunity for further study of these tests and the measurement properties of each in athletes.


Molecular-recognition-assisted pKa shifts and metal-ion-induced fluorescence regeneration in p-sulfonatocalix[6]arene-encapsulated acridine.
The host-guest interactions of cationic (AcH(+) ) and neutral (Ac) forms of the dye acridine with the macrocyclic host p-sulfonatocalix[6]arene (SCX6) were investigated by using ground-state absorption, steady-state and time-resolved fluorescence, and NMR measurements. The cationic form undergoes significant complexation with SCX6 (Keq =2.5×10(4) M(-1) ), causing a sharp decrease in the fluorescence intensity and severe quenching in the excited-state lifetime of the dye. The strong binding of the AcH(+) form of the dye with SCX6 is attributed to ion-ion interactions involving the sulfonato groups (SO3 (-) ) of SCX6 and the positively charged AcH(+) at pH of approximately 4.3. Whereas, the neutral Ac form of the dye undergoes weak complexation with SCX6 (Keq =0.9×10(3) M(-1) ) and the binding constant is lowered by one order of magnitude compared with that of the SCX6-AcH(+) system. The strong affinity of SCX6 to the protonated form leads to a large upward pKa shift (≈2 units) in the dye. In contrast, strong emission quenching upon SCX6 interaction and the regeneration of fluorescence intensity of the dye in the presence of Gd(3+) through competitive binding have also been demonstrated.


Tuftsin stimulates IL-1 production by human mononuclear cells, human spleen cells and mouse spleen cells in vitro.
Human peripheral adherent cells from splenectomized subjects, human spleen cells and mouse spleen cells were tested for IL-1 production in vitro in presence or absence of synthetic tuftsin (Thr-Lys-Pro-Arg). Application of synthetic tuftsin to peripheral blood adherent cells from normal donors as well as from splenectomized subjects induces IL-1 production. In splenectomized subjects the extent of induction was more evident than in controls. In human splenic cells tuftsin stimulates IL-1 production without KLH or LPS. In mouse spleen cells tuftsin alone did not stimulate the IL-1 secretion. However, addition of tuftsin to mouse spleen cells incubated with KLH augmented significantly the IL-1 secretion. As removal of the spleen leads to tuftsin deficiency, our present findings may perhaps explain the fulminant nature of the postplenectomy sepsis and some immune disturbances described in the postplenectomy state.


aPKCλ/ι and aPKCζ contribute to podocyte differentiation and glomerular maturation.
Precise positioning of the highly complex interdigitating podocyte foot processes is critical to form the normal glomerular filtration barrier, but the molecular programs driving this process are unknown. The protein atypical protein kinase C (aPKC)--a component of the Par complex, which localizes to tight junctions and interacts with slit diaphragm proteins--may play a role. Here, we found that the combined deletion of the aPKCλ/ι and aPKCζ isoforms in podocytes associated with incorrectly positioned centrosomes and Golgi apparatus and mislocalized molecules of the slit diaphragm. Furthermore, aPKC-deficient podocytes failed to form the normal network of foot processes, leading to defective glomerular maturation with incomplete capillary formation and mesangiolysis. Our results suggest that aPKC isoforms orchestrate the formation of the podocyte processes essential for normal glomerular development and kidney function. Defective aPKC signaling results in a dramatically simplified glomerular architecture, causing severe proteinuria and perinatal death.


Social Determinants of Disparities in Mortality Outcomes in Congenital Heart Disease: A Systematic Review and Meta-Analysis.
Social determinants of health (SDoH) affect congenital heart disease (CHD) mortality across all forms and age groups. We sought to evaluate risk of mortality from specific SDoH stratified across CHD to guide interventions to alleviate this risk. We searched electronic databases between January 1980 and June 2019 and included studies that evaluated occurrence of CHD deaths and SDoH in English articles. Meta-analysis was performed if SDoH data were available in >3 studies. We included race/ethnicity, deprivation, insurance status, maternal age, maternal education, single/multiple pregnancy, hospital volume, and geographic location of patients as SDoH. Data were pooled using random-effects model and outcome was reported as odds ratio (OR) with 95% confidence interval (CI). Of 17,716 citations reviewed, 65 met inclusion criteria. Sixty-three were observational retrospective studies and two prospective. Of 546,981 patients, 34,080 died. Black patients with non-critical CHD in the first year of life (Odds Ratio 1.62 [95% confidence interval 1.47-1.79], I2 = 7.1%), with critical CHD as neonates (OR 1.27 [CI 1.05-1.55], I2 = 0%) and in the first year (OR 1.68, [1.45-1.95], I2 = 0.3%) had increased mortality. Deprived patients, multiple pregnancies, patients born to mothers <18 years and with education <12 years, and patients on public insurance with critical CHD have greater likelihood of death after the neonatal period. This systematic review and meta-analysis found that Black patients with CHD are particularly vulnerable for mortality. Numerous SDoH that affect mortality were identified for specific time points in CHD course that may guide interventions, future research and policy. [https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42019139466&ID=CRD42019139466], identifier [CRD42019139466].


Receptor-mediated gene transfer vectors: progress towards genetic pharmaceuticals.
Although specific delivery to tissues and unique cell types in vivo has been demonstrated for many non-viral vectors, current methods are still inadequate for human applications, mainly because of limitations on their efficiencies. All the steps required for an efficient receptor-mediated gene transfer process may in principle be exploited to enhance targeted gene delivery. These steps are: DNA/vector binding, internalization, subcellular trafficking, vesicular escape, nuclear import, and unpacking either for transcription or other functions (i.e., antisense, RNA interference, etc.). The large variety of vector designs that are currently available, usually aimed at improving the efficiency of these steps, has complicated the evaluation of data obtained from specific derivatives of such vectors. The importance of the structure of the final vector and the consequences of design decisions at specific steps on the overall efficiency of the vector will be discussed in detail. We emphasize in this review that stability in serum and thus, proper bioavailability of vectors to their specific receptors may be the single greatest limiting factor on the overall gene transfer efficiency in vivo. We discuss current approaches to overcome the intrinsic instability of synthetic vectors in the blood. In this regard, a summary of the structural features of the vectors obtained from current protocols will be presented and their functional characteristics evaluated. Dissecting information on molecular conjugates obtained by such methodologies, when carefully evaluated, should provide important guidelines for the creation of effective, targeted and safe DNA therapeutics.


An unusual case of intestinal obstruction due to Meckel's diverticulum with vitelline cyst: Case report.
Meckel's diverticulum (MD)1, the most common congenital anomaly of the gastrointestinal tract, occurs in 2% of the population with males being more symptomatic than females. In this case, a 32-year-old male presented with sudden onset colicky abdominal pain, bilious vomiting, and absolute constipation. Emergency laparotomy was done on his virgin abdomen, as a result MD and vitelline cyst along with a fibrous cord connecting the two were identified. Knotting of an ileal loop around this cord had resulted in intestinal obstruction. Meckel's diverticulectomy, along with cord resection, was carried out. The patient made smooth recovery and was discharged on the fifth postoperative day with no complications. The importance of this study is to highlight the case of symptomatic MD in an adult male as it can be a cause of intestinal obstruction and should always be considered in a patient presenting with symptoms of intestinal obstruction.


Quality of life in advanced non-small cell lung cancer receiving chemotherapy of platinum combination in old versus new standard chemotherapy regimen.
Non-small cell lung cancers (NSCLC) mostly are adenocarcinoma but minor squamous cell carcinoma is related to smoking. Surgery has a major role in early stage with chemotherapy or radiation in advanced stage. Platinum combination chemotherapy could increase the progression free survival which may be combined with etoposide as the old standard regimen or paclitaxel/gemcitabine as the new standard regimen with slightly more benefit. This study was conducted to evaluate quality of life (QoL) and response of chemotherapy. The prospective study in advanced NSCLC enrolled 88 patients receiving chemotherapy with old or new standard regimen in the Oncology Unit, Medicine Department of Rajavithi Hospital from January 2004 to December 2009. The assessments were composed of the result of treatment and QoL evaluated by Functional Assessment of Cancer Therapy-Lung Cancer (FACT-L) in both groups. The 88 advanced NSCLC patients received old standard chemotherapy 49 cases and new standard chemotherapy 39 cases. No statistically significant difference was found in baseline characteristics and most had adenocarcinoma subtype. The overall QoL scores before and after treatment were similar except a slight decrease in social/family well-being. The overall response rate was increased in the new standard regimen group compared with the old regimen group (61.5% versus 24.5%) but without statistical difference in median progression free survival (23 and 20 weeks, respectively). New standard chemotherapy regimen demonstrated increased overall response rate and without decreased QoL.


Misidentification of unusual Aeromonas species as members of the genus Vibrio: a continuing problem.
Two unusual cases of Aeromonas infection are described, one associated with bacteremia (Aeromonas schubertii) and another in which the organism was recovered from an infected gall bladder (Aeromonas veronii biotype veronii). These strains were initially identified as Vibrio damsela and Vibrio cholerae by the Vitek and API 20E systems, respectively. Use of appropriate screening tests and familiarity with the newer Aeromonas species could prevent initial misidentifications and potential public health consequences.


A novel plasmid curing method using incompatibility of plant pathogenic Ti plasmids in Agrobacterium tumefaciens.
Ti (Tumor inducing) plasmids in Agrobacterium tumefaciens can transfer their T-DNA region into dicotyledonous plants, in which the expression of T-DNA genes causes plant tumors and the production of bacterial nutrients, e.g., opines such as nopaline. Naturally occurring Ti plasmids (pTi) are difficult to cure by conventional curing methods because of their high stability. Here, we developed a novel curing method based on plasmid incompatibility. For this, a curing plasmid, pMGTrep1, was newly constructed and subsequently introduced into A. tumefaciens strains harboring pTi by conjugation with Escherichia coli harboring pMGTrep1. The conjugation yielded 32-99% nopaline non-utilizing agrobacterial transconjugants in which pMGTrep1 replaced pTi due to incompatibility. Then, pMGTrep1-less derivatives of the transconjugants are easily selected in the presence of sucrose because pMGTrep1 contains a sucrose-sensitive sacB gene. This efficient method is directly applicable for curing plasmids with the same incompatibility group and shoud also applicable to other types of plasmids in Agrobacterium groups, including A. rhizogenes, by replacing the rep gene region of the curing plasmid with that of the corresponding incompatibility.


miR-204 suppresses porcine reproductive and respiratory syndrome virus (PRRSV) replication via inhibiting LC3B-mediated autophagy.
Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) has been regarded as a persistent challenge for the swine farms worldwide. microRNAs (miRNAs) play key roles in regulating almost every important biological process, including virus-host interaction. In this study, we found that miR-204 was highly expressed in cells that were not permissive to PRRSV infection compared with cells susceptible to PRRSV infection. Subsequently, we demonstrated that overexpression of miR-204 significantly inhibited PRRSV replication in porcine alveolar macrophages (PAMs). Through bioinformatic analysis, we found that there existed a potential binding site of miR-204 on the 3'UTR of microtubule associated protein 1 light chain 3B (MAP1LC3B, LC3B), a hallmark of autophagy. Applying experiments including luciferase reporter assay and UV cross-linking and immunoprecipitation (CLIP) assay, we demonstrated that miR-204 directly targeted LC3B, thereby downregulating autophagy. Meanwhile, we investigated the interplay between autophagy and PRRSV replication in PAMs, confirming that PRRSV infection induces autophagy, which in turn facilitates viral replication. Overall, we verify that miR-204 suppresses PRRSV replication via inhibiting LC3B-mediated autophagy in PAMs. These findings will provide a novel potential approach for us to develop antiviral therapeutic agents and controlling measures for future PRRSV outbreaks.


Screening of human corneas for herpes simplex virus by tissue culture and polymerase chain reaction.
Superficial eye infections by herpes simplex virus (HSV) constitute a major cause of corneal disease, necessitating the need for corneal transplantation in many patients. Eighty-three corneas from 46 post-mortem donors received from the David Lucas Eye Bank in Manchester were analyzed by Vero cell culture and the polymerase chain reaction (PCR) technique to detect HSV. There was no evidence of a characteristic cytopathic effect in any of the cultures. A 350-bp PCR product corresponding to the HSV thymidine kinase (TK) was detected by southern blotting in only 2.4% (2/83) of samples. In contrast, approximately 70% of samples yielded a 758-bp PCR product. Although this low prevalence of HSV in corneas may be encouraging, it is high for the actual transplantation program if the viral DNAs maintain their abilities to replicate.


Novel approaches for assessing acclimatization in birds reveal seasonal changes in peripheral heat exchange and thermoregulatory behaviors.
Using thermography and behavioral analyses, we found that heat exchange and thermoregulatory behaviors changed seasonally in chipping sparrows (Spizella passerina). Studies on seasonal acclimatization in birds have primarily involved metabolic measurements, few of which have investigated behaviors, and none have investigated changes in peripheral heat exchange. We captured chipping sparrows in the winter and summer of 2022 in Wilmington, North Carolina, USA, and we collected thermal images of these birds at 15.0, 27.5 and 40.0°C. We found that heat dissipation through the bill and legs changed seasonally, but surprisingly both were higher in winter than in summer. We found that heat dissipating behaviors were more common in winter, whereas heat conserving behaviors were more common in summer, and that behaviors associated with resource costs (e.g. panting) or predation risk (e.g. bill tucking) showed the most distinct differences between seasons. Meanwhile, low-cost and low-risk postural adjustments (e.g. feather adjustments and tarsus exposure) did not vary as strongly between seasons but followed similar trends. The seasonal adjustments to behaviors suggest that non-acclimatized birds must use costly thermoregulatory behaviors more frequently than acclimatized birds. The use of thermography resulted in the discovery of one completely novel behavior, and the first detection of a known behavior in a new species. Both novel behaviors aided in evaporative heat loss and occurred more commonly in winter, supporting the presence of seasonal acclimatization as evidenced by behavioral adjustments. These results provide novel insights into the process of acclimatization and suggest a role for behavioral adjustments in seasonal acclimatization.


miRNA/siRNA-directed pathway to produce noncoding piRNAs from endogenous protein-coding regions ensures Drosophila spermatogenesis.
PIWI-interacting RNA (piRNA) pathways control transposable elements (TEs) and endogenous genes, playing important roles in animal gamete formation. However, the underlying piRNA biogenesis mechanisms remain elusive. Here, we show that endogenous protein coding sequences (CDSs), which are normally used for translation, serve as origins of noncoding piRNA biogenesis in Drosophila melanogaster testes. The product, namely, CDS-piRNAs, formed silencing complexes with Aubergine (Aub) in germ cells. Proximity proteome and functional analyses show that CDS-piRNAs and cluster/TE-piRNAs are distinct species occupying Aub, the former loading selectively relies on chaperone Cyclophilin 40. Moreover, Argonaute 2 (Ago2) and Dicer-2 activities were found critical for CDS-piRNA production. We provide evidence that Ago2-bound short interfering RNAs (siRNAs) and microRNAs (miRNAs) specify precursors to be processed into piRNAs. We further demonstrate that Aub is crucial in spermatid differentiation, regulating chromatins through mRNA cleavage. Collectively, our data illustrate a unique strategy used by male germ line, expanding piRNA repertoire for silencing of endogenous genes during spermatogenesis.


Obstetric deaths in Menoufia Governorate, Egypt.
A survey of all registered deaths which occurred during 1981-1983 in women of reproductive age was carried out in Menoufia Governorate, Egypt. Surviving family members were interviewed by trained social workers, and information was collected on symptoms of the disease that led to death. The completed questionnaires were reviewed by a panel of local physicians and a cause of death was assigned by the panel. Maternal mortality was a leading cause of death, second only to heart disease. There were 190 maternal deaths per 100,000 livebirths and 45 maternal deaths per 100,000 married women aged between 15 and 49 years. Most of the maternal deaths (63%) were due to direct obstetric causes of which haemorrhage was the main cause. Another 27% of the maternal deaths were due to indirect obstetric causes of which rheumatic heart disease was the main cause.


Reliability of the Ego-Grasping Scale.
Research using Knoblauch and Falconer's Ego-Grasping Scale is reviewed. Using a sample of 695 undergraduate students, the scale had moderate reliability (Cronbach alpha, odd-even numbered items, and test-retest), but a principal-components analysis with a varimax rotation identified five components, indicating heterogeneity in the content of the items. Lower Ego-Grasping scores appear to be associated with better psychological health. The scale has been translated and used with Korean, Kuwaiti, and Turkish students, indicating that the scale can be useful in cross-cultural studies.


Particle interaction measurements in a Coulomb crystal using caged-particle motion.
A technique for characterizing the particle interaction potential of a Coulomb crystal is developed. The mean-square displacement (MSD) is measured, showing both caged- and superdiffusive-particle motions. By subtracting the center of mass of neighboring particles in computing MSD, only short-wavelength particle motions are retained. This yields the lattice Einstein frequency, which contains information about the interparticle forces and potentials. Video measurements of particle motions in a complex (dusty) plasma are used to demonstrate the technique.


Comparing Prednisone and Methotrexate to Off-label Biologic Infliximab for Management of Ocular Uveitis: A Cost-minimization Analysis.
Background: Approximately 3.75% of cases of blindness in the United States are caused by uveitis. Incurred clinical costs and lost productivity related to vision loss in these cases totals $3.58 billion annually. Objective: To evaluate whether infliximab, a modern off-label biologic, is cost-effective for treating posterior uveitis and panuveitis compared to current standards of care, methotrexate and prednisone. Methods: A cost-effectiveness analysis using a Markov model to simulate a patient cohort with posterior uveitis or panuveitis. The model followed patients' therapy from the onset of posterior uveitis or panuveitis using the U.S. societal perspective. The lifetime model simulated health states that could lead to successful reversal of uveitis with standard or intensified treatment with prednisone, methotrexate, or infliximab. Probabilities, health utilities, and costs were included in the model based on findings from the literature. We conducted univariate sensitivity analyses and a Bayesian multivariate probablistic sensitivity analysis to estimate uncertainty in results. Outcomes were measured in terms of costs ($US, 2010) and effects (qualityadjusted life years; QALYs) discounted at 3% per year were estimated for each simulated treatment. An incremental cost-effectiveness ratio (ICER) for pairwise results was interpretted assuming a predetermined willingness-to-pay threshold of $100,000/QALY. Results: Average lifetime costs and QALYs for each drug were ($306.95; 15.80 QALYs) for prednisone, methotrexate ($36,232.24; 16.21 QALYs), and inflixmab ($74,762.63; 15.04 QALYs). Methotrexate was on average compared to prednisone, with an ICER of $86,901.16/QALY. Prednisone and methotrexate dominated infliximab. Sensitivity analyses suggested that the model was most sensitive to the utility for successful recovery from uveitis. The probabilistic sensitivity analysis returned results similar to the base case. Conclusion: This cost-effectiveness analysis suggests that despite advances in the use of biologics for treating sight-threatening posterior uveitis and panuveitis, infliximab had lower effectiveness and higher costs compared to both prednisone and methotrexate. As compared to prednisone, methotrexate was associated with increased costs and QALYs and was found to be a good value. Clinical trials of infliximab in the uveitis population are needed to reduce the uncertain estimates of inflixmab treatment success and the drug's cost-effectiveness.


Molecular analysis of the KIT gene in gastrointestinal stromal tumors with novel mutations.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT gene mutations have great importance for GISTs. This study evaluated the relationship between KIT mutations and GIST clinicopathologic features to define region-specific and population-specific differences. Genomic DNA was extracted from 60 GISTs, and polymerase chain reaction was performed for KIT gene exons 9, 11, 13, and 17. Polymerase chain reaction amplicons were sequenced in both directions. This study represents the first mutation data of the KIT gene in GISTs from a Turkish population and reports novel mutations. The mutation rate in exon 11 (46.7%) was remarkably higher than those of the other exons (8.3% for exon 9; 11.7% for exon 13; 1.7% for exon 17). There was an association between malignancy potential and the presence of KIT mutations (odds ratio=3.18). Cases with mutations in codons W557-K558 in exon 11 had 11-fold greater risk of malignancy when compared with those without a mutation in this exon (odds ratio=11). We report different mutations than those previously reported, which emphasizes the importance of personalized medicine that could be empowered by the use of bioinformatics tools in the diagnostic process and therapeutic approaches.


UV-Crosslinked Electrospun Zein/PEO Fibroporous Membranes for Wound Dressing.
Electrospun zein membranes are suitable for various biomedical applications. A UV-crosslinked electrospun membrane of a zein/PEO blend for wound healing application was explored in this work. The improvement in mechanical properties of the membrane after UV crosslinking was attributed to the change in protein conformation from an α-helix to a β-sheet. The circular dichroism (CD) spectra and FTIR spectra confirmed this conformational change. XRD analysis was shown to prove the amorphous nature of polymer blends with specific broad peaks at 2θ = 9° and 20°. The water vapor transmission rate (WVTR) of the membrane was found to be in the range of 1500-2000 g m-2 day-1, which was well suited with that of commercially available wound dressing material. Enough number of available functional groups like thiol, amino, and hydroxyl groups supplement a blood clotting index (BCI) to the matrix, causing 99% BCI within 4 min. A 91% cell viability result in the MTT assay with human dermal fibroblast cells confirmed the noncytotoxicity of the membrane. Tripeptides produced after the thermolysin-based hydrolysis of zein caused inhibition of TGF β1 expression and thus increased fibroblast and collagen production. The membrane stimulated 54% more collagen production compared to control cells at day 2 and caused 84% wound closure in human dermal fibroblast cells, which were desirable index markers of a potential wound care material.


The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis.
Liver fibrosis and its end-stage disease cirrhosis are major world health problems arising from chronic injury of the liver by a variety of etiological factors including viruses, alcohol and drug abuse, the metabolic syndrome, autoimmune disease and hereditary disorders of metabolism. Fibrosis is a progressive pathological process in which wound-healing myofibroblasts of the liver respond to injury by promoting replacement of the normal hepatic tissue with a scar-like matrix composed of cross-linked collagen. Until recently it was believed that this process was irreversible. However emerging experimental and clinical evidence is starting to show that even cirrhosis is potentially reversible. Key to this is the discovery that reversion of fibrosis is accompanied by clearance of hepatic stellate cells (HSC) by apoptosis. Furthermore, proof-of-concept studies in rodents have demonstrated that experimental augmentation of HSC apoptosis will promote the resolution of fibrosis. Consequently there is now considerable interest in determining the molecular events that regulate HSC apoptosis and the discovery of drugs that will stimulate HSC apoptosis in a selective manner. This review will consider the regulatory role played by growth factors (e.g. NGF, IGF-1, TGFbeta), death receptor ligands (TRAIL, FAS), components and regulators of extracellular matrix (integrins, collagen, matrix metalloproteinases and their tissue inhibitors) and signal transduction proteins and transcription factors (Rho/Rho kinase, Jun N-terminal Kinase (JNK), IkappaKinase (IKK), NF-kappa B). The potential for known pharmacological agents such as gliotoxin, sulfasalazine, benzodiazepine ligands, curcumin and tanshinone I to induce HSC apoptosis and therefore to be used therapeutically will be explored.


Rimantadine and oseltamivir demonstrate synergistic combination effect in an experimental infection with type A (H3N2) influenza virus in mice.
We studied the combination effect of rimantadine hydrochloride and oseltamivir phosphate on mice infected with influenza A/Aichi/2/68 (H3N2) virus. Compounds were simultaneously administered in a 5-day-treatment course, starting 4 h before intranasal infection with 10 or 20 viral 50% mouse lethal doses. Initially, we tested combinations of oseltamivir (0.05, 0.1 and 0.2 mg/kg/day) and rimantadine (2.5, 5.0 and 7.5 mg/kg/day). Significant differences were recorded between combination-treated groups, and groups with separately applied compounds and the placebo group, such as: protection index of oseltamivir with 5.0 or 7.5 mg/kg rimantadine varied between 34-41% and 43-87%, respectively, whereas the individual effects of oseltamivir, 5 mg/kg of rimantadine and 7.5 mg/kg of rimantadine were 0-10%, 0% and 18.7-29.6%, respectively; mean survival time in combination-treated groups was lengthened by 3.1-6.9 days, in oseltamivir groups by 0-1.9 days, and in rimantadine groups by 0.8-1.3 days at 5 mg/kg and 2.6-3.2 days at 7.5 mg/kg. The three-dimensional method of Prichard and Shipman characterized the combination effect as synergistic. Further, we studied the activity of 0.05 mg/kg/day of oseltamivir combined with 5 mg/kg of rimantadine. Lung virus titre in Madin Darby canine kidney cells, lung index and consolidation score proved the high effectiveness of the combination. When compared with the placebo group, a 2.8 log10 lower titre of 50% cell culture infectious dose (CCID50) was recorded in the combination-treated group at 48-60 h post-infection (the peak of lung virus growth). This is in contrast to the 0.1-1.0 log10 and 1.1-1.4 log10 reduction in CCID50 titre observed in the oseltamivir and rimantadine groups, respectively. These data emphasize the high anti-influenza A potential of the combination.


Cytokines in Endocrine Dysfunction of Plasma Cell Disorders.
Monoclonal gammopathies (MG) are classically associated with lytic bone lesions, hypercalcemia, anemia, and renal insufficiency. However, in some cases, symptoms of endocrine dysfunction are more prominent than these classical signs and misdiagnosis can thus be possible. This concerns especially the situation where the presence of M-protein is limited and the serum protein electrophoresis (sPEP) appears normal. To understand the origin of the endocrine symptoms associated with MG, we overview here the current knowledge on the complexity of interactions between cytokines and the endocrine system in MG and discuss the perspectives for both the diagnosis and treatments for this class of diseases. We also illustrate the role of major cytokines and growth factors such as IL-6, IL-1β, TNF-α, and VEGF in the endocrine system, as these tumor-relevant signaling molecules not only help the clonal expansion and invasion of the tumor cells but also influence cellular metabolism through autocrine, paracrine, and endocrine mechanisms. We further discuss the broader impact of these tumor environment-derived molecules and proinflammatory state on systemic hormone signaling. The diagnostic challenges and clinical work-up are illustrated from the point of view of an endocrinologist.


Osteoporosis due to glucocorticoid use in children with chronic illness.
Osteoporosis is increasingly recognized as a complication of chronic childhood illnesses, particularly when glucocorticoids (GCs) are necessary for treatment. Elucidation of the mechanisms leading to bone fragility in these settings requires disentanglement of the relative contributions of myriad risk factors, including disease activity, muscle weakness, immobilization, delayed growth and puberty, compromised nutrition, and osteotoxic medications. Over the years, bone mass and density evaluations by dual energy X-ray absorptiometry (DXA) have become popular for assessing bone health in children; however, such measurements are difficult to interpret because of the confounding effect of bone size and the lack of DXA-based densitometric criteria for defining osteoporosis in childhood. Recently, a new diagnostic approach for evaluation of densitometric data in children has been suggested, driven by Frost's mechanostat theory. A diagnostic algorithm based on the mechanostat theory of bone-muscle development is proposed for the characterization of bone disease in children with chronic illness. In addition to DXA-based assessments, techniques such as peripheral quantitative computerized tomography and ilial histomorphometry, for which there are pediatric reference data, are gaining ground in the characterization of skeletal changes due to chronic illness. Although these diagnostic techniques expand our understanding of osteoporosis in children, they do not replace clinical assessment. Concrete clinical evidence for GC-induced bone fragility can be seen in spinal changes due to vertebral compression, with spinal morphometry emerging as an essential, but frequently overlooked, tool in the evaluation of children's bone health. Presently, osteoporosis treatment in the chronic illness setting remains experimental and should be restricted to clinical studies. Following an understanding of the natural history of GC-induced osteoporosis in children, randomized, placebo-controlled prevention and intervention trials will be the next step toward the development of clinical practice guidelines.


Ultrastructural changes in the gut autonomic nervous system following laxative abuse and in other conditions.
Electronmicroscopical studies have been carried out on colonic biopsies from patients with long-term laxative abuse, amyloidosis, diabetic autonomic neuropathy or chronic inflammatory bowel disease. The results of these investigations indicate that submucosal nerve fibres are damaged to an extent dependent upon the intensity of the toxic agent. The main pathological features range from distension or ballooning of axons, reduction of nerve-specific cell structures and increase in lysosomes to a total degeneration of whole nerve fibres. While the degenerative process is uniform, differentiation between disease states can be made on the basis of specific additional lesions such as the presence of typical amyloid fibrils, diabetic microangiopathy or the inflammatory process in inflammatory bowel disease. No changes were found in Whipple's disease or gluten-sensitive enteropathy. It is concluded that the structural alterations may provide a morphological explanation for the disturbances in gut motility, as an intact intramural nervous system is a necessary prerequisite for the regular coordination of normal peristalsis.


Enantioselective Total Synthesis of (+)-Penostatins A and C.
A stereoselective and column-economic approach to (+)-penostatins A and C has been developed. The multisubstituted A ring and B/C rings in their unique tricyclic framework are constructed through a Diels-Alder reaction/ozonolysis sequence and an exo intramolecular hetero-Diels-Alder reaction with high chemo-, regio-, and stereoselectivity. Using this route, (+)-penostatins A and C can be synthesized in 19 and 20 steps, respectively, with a good overall yield involving only five or six column chromatographic purifications.


Early arterial stiffness and inflammatory bio-markers in normotensive polycystic kidney disease patients.
Cardiovascular disease is the main cause of morbidity and mortality in autosomal-dominant polycystic kidney disease (ADPKD) patients. To clarify temporal relationship between ADPKD, hypertension and the loss of renal function, we examined these factors in patients with early-stage ADPKD who did not yet have hypertension. Fifty patients with ADPKD (42% males, 36.6 ± 9.9 years, no blood pressure medication) and 50 healthy controls (44% males, 35.4 ± 6.4 years) were studied cross-sectionally. Pulse wave velocity (PWV), cardiac morphology and function, aortic elastic indexes, estimated glomerular filtration rate (eGFR), 24-hour ambulatory blood pressure, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and highly sensitive C-reactive protein (hs-CRP) were measured in all participants, using conventional methods. Despite a normal blood pressure, aortic stiffness index and pulse wave velocity values were increased in patients compared to controls (6.8 ± 4.7 vs. 5.1 ± 3.3, p = 0.043 and 9.6 ± 1.3 vs. 5.8 ± 1.1 m/s, p < 0.001). In univariate analysis, IL-6, TNF-α, hs-CRP and eGFR were all significantly correlated with PWV. The independence of these correlations were analyzed in a regression model, and showed PWV to be significantly predicted by IL-6, TNF-α and hs-CRP. Increased arterial stiffness and pulse wave velocity are early manifestations of ADPKD appearing before hypertension or reduced eGFR. However, these vascular abnormalities are related to signs of systemic low grade inflammation, suggesting a common pathophysiological mechanism apparently present also in other vascular diseases but yet to be elucidated.


CRISPR/Cas9 mediated genetic resource for unknown kinase and phosphatase genes in Drosophila.
Kinases and phosphatases are crucial for cellular processes and animal development. Various sets of resources in Drosophila have contributed significantly to the identification of kinases, phosphatases and their regulators. However, there are still many kinases, phosphatases and associate genes with unknown functions in the Drosophila genome. In this study, we utilized a CRISPR/Cas9 strategy to generate stable mutants for these unknown kinases, phosphatases and associate factors in Drosophila. For all the 156 unknown gene loci, we totally obtained 385 mutant alleles of 105 candidates, with 18 failure due to low efficiency of selected gRNAs and other 33 failure due to few recovered F0, which indicated high probability of lethal genes. From all the 105 mutated genes, we observed 9 whose mutants were lethal and another 4 sterile, most of which with human orthologs referred in OMIM, representing their huge value for human disease research. Here, we deliver these mutants as an open resource for more interesting studies.


Current management of adolescent varicocele.
The finding of varicocele in an adolescent male is common. Varicocele rarely causes symptoms and is often diagnosed on the routine physical examination. There is clear association between varicocele and male factor infertility; however, there is debate about whether, when, and whom to treat when present in adult or adolescent males. This review of the epidemiology, etiology, pathophysiology, and treatment of the adolescent with varicocele will provide the reader with tools to make appropriate decisions in dealing with this condition.


Mucosal immunology--with special reference to specific immune defence of the upper respiratory tract.
The mucosa of the upper respiratory tract is protected by a secretory immune system which is under complex immunoregulatory control. B cells with a potential for J-chain expression are initially stimulated in mucosa-associated lymphoid tissue (probably including the tonsils) and thereafter migrate through lymph and blood to glandular sites where they differentiate to immunoglobulin-producing immunocytes. Most locally produced immunoglobulin normally consists of dimeric IgA which is selectively transported through serous glandular cells by means of an epithelial receptor protein called the secretory component (SC). IgM is also subjected to SC-mediated transport. In patients with selective IgA deficiency, secretory IgA is lacking, but it may be satisfactorily replaced by protective secretory IgM. In other IgA-deficient patients, however, immunoregulatory compensation gives rise to a large number of IgD-producing cells in respiratory mucosae. IgD cannot act as a secretory antibody and these patients are prone to have recurrent infections. There are thus large individual variations in the secretory immune system, which in the future hopefully may be subjected to regulatory manipulation.


Oncogenic dependency on β-catenin in liver cancer cell lines correlates with pathway activation.
Hepatocellular carcinoma (HCC) represents a serious public health challenge with few therapeutic options available to cancer patients.Wnt/β-catenin pathway is thought to play a significant role in HCC pathogenesis. In this study, we confirmed high frequency of CTNNB1 (β-catenin) mutations in two independent cohorts of HCC patients and demonstrated significant upregulation of β-catenin protein in the overwhelming majority of HCC patient samples, patient-derived xenografts (PDX) and established cell lines. Using genetic tools validated for target specificity through phenotypic rescue experiments, we went on to investigate oncogenic dependency on β-catenin in an extensive collection of human HCC cells lines. Our results demonstrate that dependency on β-catenin generally tracks with its activation status. HCC cell lines that harbored activating mutations in CTNNB1 or displayed elevated levels of non-phosphorylated (active) β-catenin were significantly more sensitive to β-catenin siRNA treatment than cell lines with wild-type CTNNB1 and lower active β-catenin. Finally, significant therapeutic benefit of β-catenin knock-down was demonstrated in established HCC tumor xenografts using doxycycline-inducible shRNA system. β-catenin downregulation and tumor growth inhibition was associated with reduction in AXIN2, direct transcriptional target of β-catenin, and decreased cancer cell proliferation as measured by Ki67 staining. Taken together, our data highlight fundamental importance of aberrant β-catenin signaling in the maintenance of oncogenic phenotype in HCC.


[Distractios osteogenesis in maxillofacial surgery].
For more than one decade the extremity surgery already used distraction osteogenesis. This new therapy in the region of the maxillofacial surgery (in the case of malformation of the maxilla and mandible) was adapted from the extremity surgeons. The authors summarized and classified the methods and history of the osteodistraction surgery based on literature. The indication fields, the used protocols and the most common distractor types are listed. The authors emphasized the multidisciplinary feature of the therapies, underlined the leading role of the orthodontist. With presenting their own two mandible distraction case reports they introduced the practical use of the distractors while using intra- and extraoral devices. They also emphasized the difficulties and failure opportunities. Their aim was to make suggestions for the further development of this method in our country.


Digital Dermoscopy Photographs Outperform Handheld Dermoscopy in Melanoma Diagnosis.
Pigmented lesion clinics (PLCs) that use technology such as digital dermoscopy and total-body photography are thought to confer a clinical advantage for patients at high risk of developing melanoma over general dermatology clinics (GDCs) with regular dermoscopy. To examine the difference between depths of melanomas diagnosed in a PLC and a GDC. Medical records from 257 patients at the PLC at The Ottawa Hospital and 441 patients from a GDC were reviewed. Invasive melanoma was less frequent than in situ melanoma at the PLC (7.14% vs 38.27%; P = .02). The average Breslow depth for melanomas at the PLC was also smaller compared with the GDC (0.0371 vs 0.3450 mm; P = .02). The use of digital dermoscopy and total-body photography together in a PLC appears to be an effective way to monitor patients at high risk of melanoma.