Effects of zinc supplementation in patients with type 1 diabetes.
The purpose of this study was to identify the effect of oral zinc supplementation in patients with type 1 diabetes (T1DM) on metabolic control and zinc blood concentrations. The sample consisted of 20 patients with T1DM and a control group (n=17). Metabolic control was evaluated by glycemia at fast, 24 h glycosuria, and HbA1c. Zinc concentrations were measured in plasma and erythrocytes. After the first collection of biological material, oral zinc supplementation was initiated and continued for 4 mo in T1MD patients (T1). Daily dosages were established based on Dietary Recommended Intakes (DRIs), considering zinc intake based on data from other studies previously performed with this population. All analyses were repeated after supplementation (T2). Metabolic control was unsatisfactory, with an HbA1c increase at T2. There was no difference in zinc concentrations in plasma and erythrocytes between patients with T1DM and control. Zinc concentrations in plasma were within the normal range in T1MD before and after supplementation and the control. Zinc concentrations in erythrocyte presented lower than normal values for all groups. A zinc increase in erythrocyte after supplementation was observed in T1DM patients, although without statistical significance. More studies are needed to confirm oral zinc supplementation as nutritional management in diabetes.


The use of povidone-iodine and hydrogen peroxide mixture as an adjunct to non-surgical treatment of slight to moderate chronic periodontitis.
The aim of this study was to evaluate the clinical effects of the adjunctive use of povidone-iodine with or without hydrogen peroxide as coolant and disinfectant during ultrasonic scaling and root planing in the treatment of chronic periodontitis. Sixteen patients initially participated in the study. Thirteen patients (8 males and 5 females) completed the 3-month follow-up period. Their mean (±SD) age was 42.92 ± 7.55 years. In each experimental subject, the mouth was split into four quadrants. A randomly selected quadrant was chosen to receive one of the three treatment group modalities which were: Group 1 - ultrasonic scaling and root planing plus irrigation with 1% povidone-iodine and 3.0% hydrogen peroxide mixture; Group 2 - ultrasonic scaling and root planing plus irrigation with 1% povidone-iodine; Group 3 - ultrasonic scaling and root planing plus irrigation with normal saline. The fourth quadrant served as a control group. At the 3-month evaluation, there was no significant difference between the three treatment groups in terms of probing depth reduction, clinical attachment gain, gingival recession increase, reduction in the bleeding upon probing or plaque score reduction (P > 0.05). However, the three treatment groups had statistically significant higher mean reduction in the probing depth, gain in the clinical attachment level and reduction in the bleeding upon probing than the control group (P < 0.05). There were no added benefits of using a mixture of povidone-iodine and hydrogen peroxide or povidone-iodine as disinfectants during ultrasonic scaling and root planing in the treatment of chronic periodontitis.


Single oral acute fluoride exposure causes changes in cardiac expression of oxidant and antioxidant enzymes, apoptotic and necrotic markers in male rats.
Several studies have shown that acute fluoride (F(-)) exposure impairs cardiac function, but the molecular mechanism is not clear. In order to study this, male Wistar rats were treated with single oral doses of 45 and 90 mg/kg F(-) for 24 h. A significant accumulation of F(-) was found in the serum and myocardium of experimental rats. F(-) treatment causes myocardial necrosis as evident from increased levels of myocardial troponin I, creatine kinase, lactate dehydrogenase and aspartate transaminase. In addition, F(-) induces myocardial oxidative stress via increased reactive oxygen species, lipid peroxidation, protein carbonyl content and nitrate levels along with decreased in the levels of enzymatic (superoxide dismutase 2, catalase, glutathione peroxidase and glutathione s transferase pi class) and non-enzymatic (reduced glutathione) antioxidants. Notably, F(-) triggers myocardial apoptosis through altered Bax/Bcl2 ratio and increased cytochrome c, caspase 3p20 and terminal deoxynucleotidyl transferase dUTP nick end labeled positive cells. An increased cardiac expression of Nox4 and p38α MAPK in F(-) treated rats indicates the oxidative and apoptotic damage. Moreover, ultra-structural changes, histopathological and luxol fast blue staining demonstrates the degree of myocardial damage at subcellular level. Taken together, these findings reveal that acute F(-) exposure causes cardiac impairment by altering the expression of oxidative stress, apoptosis and necrotic markers.


Clinical-parasitological response and in-vitro sensitivity of Plasmodium vivax to chloroquine and quinine on the western border of Thailand.
This study was conducted during 2002-2004 at Mae Sot District, on the Thai-Myanmar border, an area of multidrug-resistant Plasmodium falciparum malaria. Sixty-two patients with P. vivax malaria were included in the study. All were randomized into two groups to receive a 3-day regimen of chloroquine or a 3-day regimen of quinine. Primaquine was given to patients in both groups for the elimination of hepatic stages. Results from the present study suggest that the standard regimen of chloroquine and a 3-day course of quinine at the dose regimens under investigation were very effective and well tolerated for the treatment of P. vivax malaria in this area. All patients responded well to both drug regimens; the cure rates with chloroquine or quinine, when given concurrently with the tissue schizontocidal drug primaquine, were virtually 100% within 28 days of follow-up. No significant correlations between parasite clearance time (PCT) or fever clearance time (FCT) and inhibitory concentration 50 (IC50) were found. Patients who had PCT < or = 24 h and those with PCT >24 h had comparable IC50 to chloroquine (alone and plus primaquine) and quinine, as well as similar concentrations of chloroquine/desethylchloroquine (in blood) or quinine (in plasma) at the investigated time points.


Healing characteristics of acellular porcine corneal stroma following therapeutic keratoplasty.
Acellular porcine corneal stroma (APCS) has proven to be a promising alternative to traditional corneal grafts. This prospective case series was conducted to further investigate the healing characteristics of APCS following keratoplasty. Twenty-seven patients undergoing APCS implantation to treat infectious keratitis were included. The patients were followed up for 12 months after surgery. The main outcome measures included visual acuity, corneal transparency, graft thickness, and cellular and nerve regeneration. In the operated eyes, the best-corrected visual acuity (BCVA, in logarithm of the minimal angle of resolution [logMAR] units) increased from 1.23 ± 0.95 logMAR before surgery to 0.23 ± 0.18 logMAR at 12 months after surgery (P < .001). The contrast sensitivity was still evidently reduced, especially at higher spatial frequencies. Gradual transparency improvement was observed in APCS grafts post-operatively. After implantation, the APCS graft thickness initially increased (day 1 = 592.41 ± 52.69 µm) but then continuously decreased until 3 months after surgery (1 month = 449.26 ± 50.38 µm; 3 months = 359.63 ± 34.14 µm, P < .001). Graft reepithelialization was completed within 1 week. In the in vivo confocal microscopy scans, host keratocytes began to repopulate the APCS grafts between 3 and 6 months post-operatively; subbasal nerve regeneration was only noted in 18.52% (5/27) of the eyes by 12 months after surgery. Acellular porcine corneal stroma functions as an effective alternative to human corneal tissue in lamellar keratoplasty. However, APCS is somewhat different from fresh human cornea in term of the post-operative healing process, which warrants the attention of both clinicians and patients.


Testing aspects of Carl Rogers's theory of creative environments: child-rearing antecedents of creative potential in young adolescents.
Longitudinal data involving 106 children and their parents were used to test preschool child-rearing implications of Carl Rogers's theory of creativity-fostering environments (Rogers, 1954). Indices were developed for each parent and for each mother-father combination that reflected the degree to which the parents' child-rearing practices and interactions with their preschool children matched the recommendations implicit in Rogers's description of a creativity-fostering environment. The three indices of Rogers-prescribed child-rearing practices each correlated positively (rs = .38 to .46) and significantly (all ps less than .001) with a composite index of creative potential in early adolescence, 7 to 11 years later. Rogers-prescribed preschool child-rearing practices also emerged as significant antecedents of adolescent creative potential in regression/path analyses that held constant the influence of sex, preschool intelligence, and preschool creative potential. Theoretical and methodological aspects of the study are discussed.


Estimation of fluoride uptake in soil and staple food crops produced in highly fluoridated and non-fluoridated regions of Raichur District, Karnataka.
A staple food crops have varied role in diet of people living in particular regions of world; hence, it is critical to recognize their productivity. Therefore, the purpose of this study was to estimate fluoride concentration in staple food crops grown in highly fluoridated and non-fluoridated regions and its correlation with soil. Total 36 samples were collected of which 18 samples consisting of each three samples of rice, redgram and jowar were selected. Likewise 18 corresponding soil samples from both areas were collected. All samples were ashed for 4-6 hours at 550°C in muffle furnace. The samples were allowed to cool, after which 10 ml distilled water was added to each sample and fluoride concentration was determined using ion selective electrode method, before each sample analysis the instrument was standardized using fluoride containing TISAB (III) buffer solution. The data was tabulated and subjected to cross-sectional observational statistical analysis using SPSS software applying unpaired t-test and Pearson's test. The mean fluoride concentration in crops and soils were rice (0.79 ppm), redgram (4.26 ppm), jowar (8.8 ppm) and in soil of rice (1.23 ppm), redgram (1.23 ppm) and jowar (1.21 ppm) respectively in fluoridated area. Where as in non-fluoridated area rice (0.07 ppm), redgram (0.81 ppm), jowar (0.81 ppm) and in soil of rice (0.61 ppm), redgram (0.07 ppm) and jowar (0.52 ppm) respectively. The resultant correlation between staple food crops with their corresponding soils were found highly significant in both regions with P value <0.005; hence, crops in fluoridated region exhibited increased fluoride retention, whereas crops in non-fluoridated region had optimal fluoride levels. Fluoride concentration in food crops has strong correlation with their respective soils and water irrigation properties.


Eco-friendly and enhanced colorimetric detection of aluminum ions using pectin-rich apple extract-based gold nanoparticles.
Aluminum ions are very toxic to human health, especially in relation to neurodegenerative diseases. However, conventional methods of detecting such toxic ions suffer from the use of poisonous chemical probes and complex processes. Herein, we report an eco-friendly and enhanced colorimetric method of aluminum ion detection using green-synthesized gold nanoparticles (AuNPs) from apple (Malus domestica) extract. The apple extract-based AuNPs (AX-AuNPs) contain abundant pectin different from citrate-based AuNPs. The pectin-rich AX-AuNPs improved the sensitivity of the colorimetric detection of aluminum ions. The detection limit was about 20 μM both in artificial and drinking water-based real samples. Interestingly, it is turned out that the AX-AuNPs were aggregated naturally after the chemical assay because of solution getting decayed. For the environmental perspective, it was great that the lump of AX-AuNP aggregates could easily be removed from the solutions before solution discard. Overall, our results indicate that AX-AuNPs offer a high-selectivity, enhanced colorimetric detection of aluminum ions in a short time (less than 1 min), based on an eco-friend synthesis and disposal manner of AuNPs.


Effect of a conserved mutation in uridine diphosphate glucuronosyltransferase 1A1 and 1A6 on glucuronidation of a metabolite of flutamide.
We investigated how the conserved mutation (Y486D) changed the kinetic parameters of uridine diphosphate glucuronosyltransferase 1A1 and 1A6 (UGT1A1 and 1A6) for 2-amino-5-nitro-4-trifluoromethylphenol, which is a major metabolite of flutamide, a nonsteroidal antiandrogenic agent. The wild-type or mutant cDNA-expressed UGT was co-incubated with 2-amino-5-nitro-4-trifluoromethylphenol (aglycone) and uridine diphosphate-glucuronic acid (UDP-GA, donor substrate). The glucuronidation of the aglycone was determined. The maximum velocities of the mutant UGT1A1 and UGT1A6 were about 12% and less than 1% of the corresponding wild-type, respectively. The Michaelis constant (K(M)) for the aglycone of the wild-type UGT1A1 was double that of the mutant, but the K(M) for UDP-GA of the wild-type UGT1A1 was not significantly different from that of the mutant. Patients with Y486D may accumulate excessive 2-amino-5-nitro-4-trifluoromethylphenol, which might lead to unexpected toxicity.


Human beta-mercaptopyruvate sulfurtransferase: distribution in cellular compartments of blood and activity in erythrocytes from patients with hematological disorders.
The distribution of mercaptopyruvate sulfurtransferase (EC 188.8.131.52) in human blood cell compartments has been studied. Almost all of the enzyme activity in whole blood was confined to erythrocytes, but the activity per litre cell volume was higher in platelets than in erythrocytes. Leukocytes contained very low concentrations of the sulfurtransferase and plasma was devoid of activity. The enzyme activity of blood hemolysates from normal subjects and patients with various erythrocyte disorders was also determined. Significantly higher sulfur transferase activity was found in male subjects in comparison with females. The enzyme activity per litre erythrocytes was increased in blood from patients with iron deficiency anemia, whereas less clear-cut differences with respect to normals were found in other diseases studied.


Facile hydrothermal synthesis and characterization of Co2GeO4/r-GO@C ternary nanocomposite as negative electrode for Li-ion batteries.
Ternary nanocomposite of Co2GeO4/r-GO@C is synthesized by single step hydrothermal method followed by calcination. The XRD analysis reveals the formation of cubic structured Co2GeO4 and their corresponding functional groups identified through Raman analysis. The TEM analysis assures that uniform distribution of Co2GeO4 nanoparticles on the r-GO layers. The Galvanostatic charge-discharge (GCD) curve demonstrates that the initial discharge capacity of pristine Co2GeO4, Co2GeO4/r-GO and Co2GeO4/r-GO@C composite is 1400, 1284 and 1594mAhg-1 at 50mAg-1, respectively. The cycling stability curve shows the specific capacity of 609, 970 and 1180mAhg-1 for pristine, Co2GeO4/r-GO and Co2GeO4/r-GO@C composite, respectively over 15 cycles. The ternary composite of Co2GeO4/r-GO@C delivers the discharge capacity of 323mAhg-1 at high current density of 1Ag-1 over 500 cycles with capacity retention of 71%. The rate capability curve indicates that Co2GeO4/r-GO@C composite shows the better rate capability.


A Retrospective Study from a Single Center of 208 Patients with Unilateral Chronic Subdural Hematoma to Compare Outcomes Following Burr Hole Craniotomy and Hematoma Drainage Within 48 Hours and Between 48 Hours and 5 Days.
BACKGROUND This retrospective study from a single center aimed to compare patient outcomes following burr hole craniotomy (BHC) and hematoma drainage within 48 hours and between 48 hours and 5 days in 208 patients with unilateral chronic subdural hematoma (CSDH). MATERIAL AND METHODS Patients were divided into 2 groups according to the duration of drainage: early (1 or 2 days, n=100) and late (3-5 days, n=108) drain removal. We compared the clinical outcomes, recurrence rate, time to recurrence, and complications between the groups. Quantitative analysis of computed tomography parameters at various time points (postoperative, day of drain removal, and postoperative day 7) was also performed to compare radiologic outcomes. RESULTS Clinical outcomes and recurrence rate were similar in both groups. We found no significant differences in radiologic outcomes of both groups through all chronologies, although the total drainage volume was significantly greater in the late removal group (P.


p53 allele deletion and protein accumulation occurs in the absence of p53 gene mutation in T-prolymphocytic leukaemia and Sezary syndrome.
In a series of 24 patients with chronic T-lymphoid disorders [13 T-prolymphocytic leukaemia (T-PLL) and 11 Sezary syndrome] we have studied (i) chromosome 17p abnormalities and p53 allele deletion by fluorescence in situ hybridization; (ii) mutation in the exons of the p53 gene by direct DNA sequencing; and (iii) p53 protein expression by immunocytochemistry and, in some cases, also by flow cytometry with DO-1, a monoclonal antibody to the p53 protein. The study revealed p53 deletion and accumulation of p53 protein in the absence of mutation in the exons that included the hot-spots and differs from that described in B-prolymphocytic leukaemia. Seven T-PLL and five Sezary syndrome patients had p53 overexpression, and five T-PLL and nine Sezary syndrome patients showed p53 deletion. Although the majority of cases with p53 accumulation had p53 deletion, the proportion of cells with the deletion did not correlate with the proportion of cells positive for p53 expression. Two cases of T-PLL showed strong p53 expression in the absence of p53 deletion, and one case of Sezary syndrome with p53 deletion in 97% of cells did not express p53. These findings suggest that a non-mutational mechanism exists for the accumulation of p53 protein in these T-cell disorders. The oncogenic effect of the accumulating wild-type protein has been reported in other malignancies. Whether haploidy resulting from p53 deletion contributes to this mechanism has yet to be determined. Alternatively, the frequent loss of the p53 gene could be associated with the deletion of an adjacent gene, which could be involved in the pathogenesis of these diseases.


Phycocyanin as a nature-inspired antidiabetic agent: A systematic review.
Nutraceuticals have been important for more than two decades for their safety, efficacy, and outstanding effects. Diabetes is a major metabolic syndrome, which may be improved using nutritional pharmaceuticals. Some microalgae species, such as spirulina, stand out by providing biomass with exceptional nutritional properties. Spirulina has a wide range of pharmacological effects, mostly related to phycocyanin. Phycocyanin is a protein compound with antidiabetic properties, known as a nutraceutical. This review delves into phycocyanin applications in diabetes and its complications and ascertains the mechanisms involved. Scopus, PubMed, Cochrane Library, Web of Science, and ProQuest databases were systematically reviewed (up to April 30, 2023), in which only animal and cellular studies were found. According to animal studies, the administration of phycocyanin affected biochemical parameters (primary outcome) related to diabetes. These results showed an increase in fasting insulin serum and a decrease in fasting blood glucose, glycosylated serum protein, and glycosylated hemoglobin. In cellular studies, though, phycocyanin prevented methylglyoxal and human islet amyloid polypeptide-induced dysfunction in β-cells and induced apoptosis through different molecular pathways (secondary outcome), including activation of Nrf2, PI3K/Akt, and suppression of JNK and p38. Also, phycocyanin exerted its antidiabetic effect by affecting the pathways regulating hepatic glucose metabolism. Thus, based on the available information and literature, targeting these pathways by phycocyanin may unleash an array of benefits, including positive outcomes of the antidiabetic effects of phycocyanin as a nutraceutical. This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) at the National Institute of Health. The registration number is CRD42022307522.


Penile necrosis secondary to an indwelling Foley catheter.
Penile necrosis is a rare entity but it may be brought about more readily if certain risk factors are present. Such factors are discussed in this paper and the reader is forewarned about this problem.


Defects in ribosome function delay the initiation of chromosome replication in Escherichia coli.
The Sra protein is a component of the 30S ribosomal subunit while RimJ is a ribosome-associated protein that plays a role in the maturation of the 30S ribosomal subunit. Here we found that Δsra and ΔrimJ cells showed a delayed initiation of DNA replication, prolonged doubling time, decreased cell size, and decreased amounts of total protein and DnaA per cell compared with these observed for wild-type cells. A temperature sensitivity test demonstrated that absence of the Sra or RimJ protein did not change the temperature sensitivity of the dnaA46, dnaB252, or dnaC2 mutants. Moreover, ectopic expression of Sra reversed the mutant phenotype while cells carrying the pACYC177-rimJ plasmid did not reverse the rimJ mutant phenotype. The results indicate that deletion of sra or rimJ cause defects in ribosomal function and affect the translation process, leading to a decrease in synthesis of proteins including DnaA. Therefore, we conclude that Sra- and RimJ-mediated ribosomal function is required for precise timing of initiation of chromosome replication.


Brief report: risk factors for pneumococcal vaccine refusal in adults: a casecontrol study.
Invasive pneumococcal disease is a significant cause of morbidity and mortality in the United States. Despite availability of an effective vaccine, many patients refuse vaccination. To investigate patient characteristics and features of the patient-provider relationship associated with pneumococcal vaccine refusal. Case-control study using chart review. Five hundred adults from the medical clinics of a 1,000-bed inner-city teaching hospital. Independent risk factors for pneumococcal vaccine refusal included patient-provider gender discordance (odds ratio (OR)=2.09, 95% confidence interval (CI) 1.07 to 4.09); a visit to a not-usual provider at the time of vaccine offering (OR=2.26, 95% CI 1.13 to 4.49); never having received influenza vaccination (OR=7.44, 95% CI 3.76 to 14.76); prior pneumococcal vaccine refusals (OR=3.45, 95% CI 1.60 to 7.43); and a history of ever having refused health maintenance tests (OR=2.86, 95% CI 1.40 to 5.84). We have identified both patient factors and factors related to the patient-provider relationship that are risk factors for pneumococcal vaccine refusal. By identifying patients at risk for pneumococcal vaccine refusal, efforts to increase vaccination rates can be better targeted.


Array-based high-throughput DNA markers for crop improvement.
The last two decades have witnessed a remarkable activity in the development and use of molecular markers both in animal and plant systems. This activity started with low-throughput restriction fragment length polymorphisms and culminated in recent years with single nucleotide polymorphisms (SNPs), which are abundant and uniformly distributed. Although the latter became the markers of choice for many, their discovery needed previous sequence information. However, with the availability of microarrays, SNP platforms have been developed, which allow genotyping of thousands of markers in parallel. Besides SNPs, some other novel marker systems, including single feature polymorphisms, diversity array technology and restriction site-associated DNA markers, have also been developed, where array-based assays have been utilized to provide for the desired ultra-high throughput and low cost. These microarray-based markers are the markers of choice for the future and are already being used for construction of high-density maps, quantitative trait loci (QTL) mapping (including expression QTLs) and genetic diversity analysis with a limited expense in terms of time and money. In this study, we briefly describe the characteristics of these array-based marker systems and review the work that has already been done involving development and use of these markers, not only in simple eukaryotes like yeast, but also in a variety of seed plants with simple or complex genomes.


The tendency of lentiviral open reading frames to become A-rich: constraints imposed by viral genome organization and cellular tRNA availability.
Human immunodeficiency virus type 1 (HIV-1) and other lentiviridae demonstrate a strong preference for the A-nucleotide, which can account for up to 40% of the viral RNA genome. The biological mechanism responsible for this nucleotide bias is currently unknown. The increased A-content of these viral genomes corresponds to the typical use of synonymous codons by all members of the lentiviral family (HIV, SIV, BIV, FIV, CAEV, EIAV, visna) and the human spuma retrovirus, but not by other retroviruses like the human T-cell leukemia viruses HTLV-1 and HTLV-II. In this article, we analyzed A-bias for all codon groups in all open reading frames of several lentiviruses. The extent of lentiviral codon bias could be related to host cellular translation. By calculating codon bias indices (CBIs), we were able to demonstrate an inverse correlation between the extent of codon bias and the rate of translation of individual reading frames in these viruses. Specifically, the shift toward A-rich codons is more pronounced in pol than in gag lentiviral genes. Since it is known that Gag synthesis exceeds Pol synthesis by a factor of 20 due to infrequent ribosomal frame-shifting during translation of the gap-pol mRNA molecule, we propose that the aminoacyl-tRNA availability in the host cell restricts the lentiviral preference for A-rich codons. In addition, less A-nucleotides were found in regions of the viral genome encoding multiple functions; e.g., overlapping reading frames (tat-rev-env) or in genes that overlap regulatory sequences (nef-LTR region).(ABSTRACT TRUNCATED AT 250 WORDS)


T2*-weighted imaging and diffusion kurtosis imaging (DKI) of rectal cancer: correlation with clinical histopathologic prognostic factors.
Histopathologic prognostic factors of rectal cancer are closely associated with local recurrence and distant metastasis. We aim to investigate the feasibility of T2*WI in assessment of clinical prognostic factors of rectal cancer, and compare with DKI. This retrospective study enrolled 50 out of 205 patients with rectal cancer according to the inclusion criteria. The following parameters were obtained: R2* from T2*WI, mean diffusivity (MDk), mean kurtosis (MK), and mean diffusivity (MDt) from DKI using tensor method. Above parameters were compared by Mann-Whitney U-test or students' t test. Spearman correlations between different parameters and histopathological prognostic factors were determined. The diagnostic performances of R2* and DKI-derived parameters were analyzed by receiver operating characteristic curves (ROC), separately and jointly. There were positive correlations between R2* and multiple prognostic factors of rectal cancer such as T category, N category, tumor grade, CEA level, and LVI (P < 0.004). MDk and MDt showed negative correlations with almost all the histopathological prognostic factors except CRM and TIL involvement (P < 0.003). MK correlated positively with the prognostic factors except CA19-9 level and CRM involvement (P < 0.006). The AUC ranges were 0.724-0.950 for R2* and 0.755-0.913 for DKI-derived parameters for differentiation of prognostic factors. However, no significant differences of diagnostic performance were found between T2*WI, DKI, or the combined imaging methods in characterizing rectal cancer. R2* and DKI-derived parameters were associated with different histopathological prognostic factors, and might act as noninvasive biomarkers for histopathological characterization of rectal cancer.


A possible increase in the number of metaphase I spermatocytes in testicular biopsy of infertile men with chromosomal aberrations.
During the histological investigation of testicular biopsy of patients with chromosomal aberrations, it was observed that in some of these patients more of the primary spermatocytes were in metaphase I, in comparison with normal testicular biopsy where, according to our investigations, these cells are only seen occasionally. A possible explanation for this phenomenon, which was mainly observed in patients with autosomal chromosome aberrations, is given.


Correlation between structure of polyoxotungstates and their inhibitory activity on polymerases.
The 21-tungsto-9-antimonate (TA, HPA 23), a polyoxotungstate, has shown a significant antiviral activity in vivo and in vitro. It inhibits viral and bacterial DNA polymerases. In this paper, several compounds of two polyoxotungstic families, tungstoantimonates and tungstoarsenates, have been used to specify the mechanism of polymerase inhibition. It has been demonstrated that the inhibitory activity of polyoxotungstates is not related to the occupation of their coordinates sites by cations, nor to the nature of these bound cations. Kinetic studies and binding assays have shown that polyoxotungstates bind to the polymerases in competition with the nucleic acid template. This result seems to be related to their polyanionic nature. Furthermore, the size and charge of these compounds may play a prominent part in their affinity for the polymerases.


Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer.
The iMATRIX-atezolizumab study was a phase I/II, multicenter, open-label study designed to assess the safety and pharmacokinetics of atezolizumab in pediatric and young adult patients. We describe the pharmacokinetics (PK), exposure-safety, and immunogenicity of atezolizumab in pediatric and young adults with metastatic solid tumors or hematologic malignancies enrolled in this study. Patients aged < 18 years (n = 69) received a weight-adjusted dose of atezolizumab (15 mg/kg every 3 weeks [q3w]; maximum 1200 mg); those aged ≥ 18 years (n = 18) received a flat dose (1200 mg q3w). A prior two-compartment intravenous infusion input adult population-PK (popPK) model of atezolizumab was used as a basis to model pediatric data. A total of 431 atezolizumab serum concentrations from 87 relapse-refractory pediatric and young adult patients enrolled in the iMATRIX-atezolizumab study were used for the popPK analysis. The dataset comprised predominantly patients aged < 18 years, including two infants aged < 2 years, with a wide body weight and age range. The clearance and volume of distribution estimates of atezolizumab were 0.217 L/day and 3.01 L, respectively. Atezolizumab geometric mean trough exposures were ~ 20% lower in pediatric patients versus young adults; this was not clinically meaningful as both groups achieved the target concentration (6 μg/mL). Safety was similar between pediatric and young adult patients with no exposure-safety relationship observed. Limited responses (4/87) precluded an exposure-response assessment on outcomes. A comparable rate (13% vs 11%) of atezolizumab anti-drug antibodies was seen in pediatric and young adult patients. These findings demonstrate a similar exposure-safety profile of atezolizumab in pediatric and young adult patients, supportive of weight-based dosing in pediatric patients. NCT02541604.


In vitro studies on release and human skin permeation of Australian tea tree oil (TTO) from topical formulations.
Essential oils are widely used in pharmaceutical and cosmetic preparations e.g. as fragrance, active ingredient or penetration enhancer. However, reports on skin absorption are rare. Therefore, the aim of our study was to investigate the capability of terpinen-4-ol, the main compound of Australian tea tree oil (TTO), to permeate human skin. In static Franz diffusion cells permeation experiments with heat separated human epidermis were carried out using infinite dosing conditions and compared to liberation experiments. The flux values of three different semisolid preparations with 5% TTO showed the rank order semisolid O/W emulsion (0.067 microl/cm2 h) > white petrolatum (0.051 microl/cm2 h) > ambiphilic cream (0.022 microl/cm2 h). In comparison to the flux value obtained with the native TTO (0.26 microl/cm2 h), the flux values are remarkably reduced due to the lower amount of terpinen-4-ol. P(app) values for cream (2.74+/-0.06 x 10(-7) cm/s) and native TTO (1.62+/-0.12 x 10(-7) cm/s) are comparable whereas white petrolatum (6.36+/-0.21 x 10(-7) cm/s) and semisolid O/W emulsion (8.41+/-0.15 x 10(-7) cm/s) demonstrated higher values indicating a penetration enhancement. No relationship between permeation and liberation was found.


Epidemiological survey of X-linked bulbar and spinal muscular atrophy, or Kennedy disease, in the province of Reggio Emilia, Italy.
Commencing with the work carried out during the epidemiological survey of amyotrophic lateral sclerosis in the period 1980-1992 and the pathology follow-up, we carried out a perspective incidence, prevalence and mortality survey of X-linked bulbar and spinal muscular atrophy (X-BSMA) in the province of Reggio Emilia in Northern Italy. Based on 11 patients (eight familial and three sporadic cases), the mean incidence per year for the period 1980 through 1997, as evaluated at the onset of symptoms, was 0.09 cases/100,000 for the total population and 0.19 cases/100,000 for the male population. On December 31, 1997, the prevalence rate was 1.6/100,000 for the total population and 3.3/100,000 for the male population. In the 18-year period of 1980-1997, the average yearly mortality rate was: 0.03 cases/100,000 per year for the total population and 0.06 cases/ 100,000 for the male population. The average age at onset was 44.8 +/- 10.1, and the average survival period was 27.3 +/- 2.3 years. The average age of the prevalence day was 58.9 +/- 14.9, and the average age at death was 71.3 +/- 4.7 years. Whereas the incidence rate of X-BSMA in the province of Reggio Emilia is 16 times lower that of amyotrophic lateral sclerosis (ALS), the incidence rate of progressive bulbar palsy in the male population is only slightly higher than X-BSMA; and the prevalence rate of ALS for males is two times the prevalence rate for X-BSMA, with overlapping of confidence intervals. X-BSMA is a rare disease, which is probably under-diagnosed, but due to the long survival period of this disease its frequency is not negligible. Because of the presence of sporadic cases or non-evident familial cases, it is appropriate to consider this diagnostic possibility in making a diagnosis of ALS in patients in whom lower motor neuron dysfunction or bulbar onset predominates.


A sequential study of visual evoked potential in patients with vitamin B12 deficiency neurological syndrome.
Visual pathways are vulnerable to vitamin B(12) deficiency but there is paucity of studies evaluating visual evoked potential (VEP) changes following vitamin B(12) supplementation. Our aim was to evaluate the visual evoked potential changes in patients with vitamin B(12) deficiency neurological syndrome and their changes after vitamin B(12) therapy. Seventeen patients with vitamin B(12) deficiency neurological syndromes diagnosed on the basis of megaloblastic bone marrow or low serum vitamin B(12) level or both were subjected to testing of visual acuity, field of vision, colour vision and neurological examination. Cranial magnetic resonance imaging was done in 9 patients and pattern reversal VEP was carried out on admission. P(100) latency and amplitude were measured. Visual function and VEP studies were repeated at 3 and 6 months after vitamin B(12) therapy. The patients' age ranged between 17 and 69 years; 7 were females and 16 were lactovegetarians. The duration of symptoms ranged between 10 days and 10 years. Visual acuity, colour vision, field of vision and fundus oculi were normal. VEP revealed prolongation of P(100) latency in 10 patients (17 eyes) which was mild in 2, moderate in 10 and marked in 5 eyes. Six months after treatment, P(100) latency improved to normal in all except 4 eyes. VEP abnormality was related to duration of illness and antiparietal cell antibodies. VEP is frequently prolonged in patients with vitamin B(12) deficiency neurological syndrome although asymptomatic. It usually returns to normal after treatment.


Barrier and spermicidal contraceptives in adolescence.
This article describes both barrier and spermicide methods of contraception including the male and female condom, diaphragm, contraceptive sponge, Lea Shield, cervical cap and multiple spermicide options. Their efficacy, differences and proper use are discussed with an emphasis on the adolescent user.


Daily oscillation of gene expression in the retina is phase-advanced with respect to the pineal gland.
The photoreceptive retina and the non-photoreceptive pineal gland are components of the circadian and the melatonin forming system in mammals. To contribute to our understanding of the functional integrity of the circadian system and the melatonin forming system we have compared the daily oscillation of the two tissues under various seasonal lighting conditions. For this purpose, the 24-h profiles of the expression of the genes coding for arylalkylamine N-acetyltransferase (AA-NAT), nerve growth factor inducible gene-A (NGFI-A), nerve growth factor inducible gene-B (NGFI-B), retinoic acid related orphan receptor beta (RORbeta), dopamine D4 receptor, and period2 (Per2) have been simultaneously recorded in the retina and the pineal gland of rats under short day (light/dark 8:16) and long day (light/dark 16:8) conditions. We have found that the cyclical patterns of all genes are phase-advanced in the retina, often with a lengthened temporal interval under short day conditions. In both tissues, the AA-NAT gene expression represents an indication of the output of the relevant pacemakers. The temporal phasing in the AA-NAT transcript amount between the retina and the pineal gland is retained under constant darkness suggesting that the intrinsic self-cycling clock of the retina oscillates in a phase-advanced manner with respect to the self-cycling clock in the suprachiasmatic nucleus, which controls the pineal gland. We therefore conclude that daily rhythms in gene expression in the retina are phase-advanced with respect to the pineal gland, and that the same temporal relationship appears to be valid for the self-cycling clocks influencing the tissues.


Risk of birth defects by parental occupational exposure to 50 Hz electromagnetic fields: a population based study.
To study the risk of birth defects by parental occupational exposure to 50 Hz electromagnetic fields. The Medical Birth Registry of Norway was linked with census data on parental occupation. An expert panel constructed a job exposure matrix of parental occupational exposure to 50 Hz magnetic fields. Exposure to magnetic fields was estimated by combining branch and occupation into one of three exposure levels: <4 hours, 4-24 hours, and >24 hours/week above approximately 0.1 mu T. Risks of 24 categories of birth defects were compared across exposure levels. Out of all 1.6 million births in Norway in the period 1967-95, 836,475 and 1,290,298 births had information on maternal and paternal exposure, respectively. Analyses were based on tests for trend and were adjusted for parents' educational level, place of birth, maternal age, and year of birth. The total risk of birth defects was not associated with parental exposure. Maternal exposure was associated with increased risks of spina bifida (p=0.04) and clubfoot (p=0.04). A negative association was found for isolated cleft palate (p=0.01). Paternal exposure was associated with increased risks of anencephaly (p=0.01) and a category of "other defects" (p=0.02). The present study gives an indication of an association between selected disorders of the central nervous system and parental exposure to 50 Hz magnetic fields. Given the crude exposure assessment, lack of comparable studies, and the high number of outcomes considered, the results should be interpreted with caution.


Clinical characteristics of patients with confirmed and suspected COVID-19.
To compare the differences between two groups of patients with confirmed and suspected COVID-19. We retrospectively collected and analyzed the data of confirmed and suspected patients, including demographic, epidemic, laboratory, clinical, radiologic, and treatment data, at the fever clinic and isolation ward of our hospital from December 1, 2019 to December 30, 2019. The study included 73 patients with confirmed or suspected COVID-19. The median age was 43.6 years old, and 41 patients (56.2%) were male. Patients in the suspected group (SG) (n=47) were significantly older than those in the confirmed group (CG) (n=26). Among 73 patients, 18 (24.6%) had comorbidities. Most laboratory test results in this study were normal, except for total lymphocyte counts and C-reactive protein levels. Patients in the CG had fewer lymphocyte count abnormalities than those of the SG. More patients in the CG (13 cases, 50%) displayed involvement of three or more lobes than those in the SG (8 cases, 17%). More patients in the SG (36 cases, 76.6%) displayed involvement of 1-2 lobes than those in the CG (12 cases, 46.2%). In the CG, computed tomography (CT) lung lesions were mainly distributed in the left lower lung lobe (65.4%) and left upper lung lobe (80.8%). The reference standard for detecting COVID-19 is still RT-PCR. However, characteristic chest CT results and a history of close contact strongly suggest COVID-19 infection.


Changing the rules of the game.
Genomics researchers have built a Facebook game that allows members of the public to join the effort to understand a disease that has killed millions of ash trees across Europe.


Characteristics of 40 primary extranodal non-Hodgkin lymphomas of the oral cavity in perspective of the new WHO classification and the International Prognostic Index.
Non-Hodgkin lymphomas (NHLs) are often present outside the lymph nodes. Although primary extranodal NHLs (PE-NHL) form a substantial part of all NHLs, reports on oral PE-NHLs are rare. Forty patients with PE-NHL of the oral cavity have been studied for the distribution of gender, age, oral subsite and presenting complaint, histological subtype according to the WHO classification, clinical stage, treatment, and follow-up. The data are reviewed against the background of the literature. Furthermore, the International Prognostic Index has been taken into consideration. All patients had a lymphoma of B-cell lineage. Two-thirds of patients presented with locoregional disease. Mean survival time was 38 months, with a mean recurrence-free survival time of 31 months. There was no statistically significant difference in survival time between patients with bone versus soft tissue localisation of the PE-NHL. In view of the rarity of PE-NHL involving the oral region multicenter studies are needed for evaluation of the usefulness of the International Prognostic Index for non-Hodgkin lymphoma in this particular part of the body.


Inter-alpha-trypsin-inhibitor (ITI): two distinct mRNAs in baboon liver argue for a discrete synthesis of ITI and ITI derivatives.
Human serum inter-alpha-trypsin-inhibitor (ITI) has so far been assumed to be comprised of a single polypeptide chain which can undergo fragmentation, whereby inhibitory ITI derivatives are released into the blood stream. In contrast, the analysis of the baboon liver mRNA translation products showed that ITI is made up of heavy and light chain(s). The latter may be excreted independently and very likely corresponds to the so-called ITI derivatives.


[Twenty-four hour blood pressure rhythm in patients with hypertension and ischemic heart disease].
To elucidate relationship between presence of ischemic heart disease and 24-hour blood pressure (BP) profile. Twenty four hour BP index characterizing degree of nocturnal blood pressure fall was measured in patients with hypertension without coronary heart disease (n=65, group 1), with hypertension and effort angina (n=35, group 2), with effort angina and normal BP (n=25, group 3). Values of 24-hour BP systolic and diastolic index were in group 1 12.7+/-1.3 and 16.0+/-1.1%, respectively, in group 2 5.8+/-2.4 and 7.4+/-3.6%, respectively, in group 3, 6.0+/-2.2 and 6.0+/-3.0%, respectively (p<0.05, groups 2 and 3 vs group 1). Decreased nocturnal BP lowering could be a compensatory reaction aimed at maintenance of adequate blood flow through stenosed coronary vessels.


Diagnostic Role of Extracellular Vesicles in Cancer: A Comprehensive Systematic Review and Meta-Analysis.
Background: Cancer-derived extracellular vesicles (EVs) are regarded to have significant function in most steps during cancer progression. This meta-analysis aims to investigate the accuracy of EVs as a biomarker in cancer diagnosis. Methods: The diagnostic efficacy of EVs for different cancers was assessed using pooled sensitivity and specificity, diagnostic odds ratio (DOR), and overall area under the curve (AUC) of the summary receiver operating characteristic (SROC). The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were verified to estimate the diagnostic efficacy of EV at a clinical level. Results: In all, 6,183 cancer patients and 2,437 healthy controls from 75 eligible studies reported in 42 publications were included in the study. The overall pooled sensitivity, specificity, PLR, NLR, and DOR were 0.62 (95% CI: 0.60-0.63), 0.76 (95% CI: 0.75-0.78), 3.07 (95% CI: 2.52-3.75), 0.34 (95% CI: 0.28-0.41), and 10.98 (95% CI: 7.53-16.00), respectively. Similarly, the AUC of the SROC was 0.88, indicating a high conservation of EVs as an early diagnostic marker. Furthermore, subgroup analysis suggested that the use of small EVs as a biomarker was more accurate in serum-based samples of nervous system cancer (p < 0.001). As a result, ultracentrifugation and quantification and size determination methods, such as Western blotting and ELISA were the most reliable identification methods for EV detection. We also indicated that increased secretion of EVs made them a capable biomarker for diagnosing cancer in elderly European individuals. Conclusions: Our study provides evidence that EVs are a promising non-invasive biomarker for cancer diagnosis. Well-designed cohort studies should be conducted to warrant the clinical diagnostic value of EVs.


Topical tacrolimus 0.1% ointment (protopic) reverses nickel contact dermatitis elicited by allergen challenge to a similar degree to mometasone furoate 0.1% with greater suppression of late erythema.
The aim of this study was to evaluate the ability of topical tacrolimus 0.1% under occlusion for 48 h to suppress nickel-elicited allergic contact dermatitis in a randomized, petrolatum- and mometasone furoate 0.1% ointment-controlled double-blind, intra-individual study which included 28 women volunteers. 3 closed patch tests (Finn Chambers on Scanpor, Epitest Ltd Oy, Tuusula, Finland) containing 0.1 ml of 5% nickel sulfate in petrolatum were applied on day 0. After removal on day 2, the study compounds were applied under occlusion for 48 h. The eczema reaction and the degree of erythema were evaluated clinically and by reflectance spectrophotometry at days 4 and 7, respectively. Mean visual scores corresponding to petrolatum-treated sites were significantly higher than those corresponding to both mometasone furoate and tacrolimus at days 4 (P < 0.001) and 7 (P < 0.001). In both tacrolimus- and mometasone furoate-treated sites, there was a significant decrease in visual scores with time (P < 0.001) from day 2 to day 7, and the corresponding mean decreases in scores were 0.73 and 1.04, respectively. The difference between both was 0.30 in favour of tacrolimus (95% confidence intervals, -0.04 and 0.65), although this did not reach statistical significance (P = 0.084). Mean erythema index values were similar at day 2. Significant differences among treatment sites were seen at days 4 (P < 0.001) and 7 (P < 0.001). The decrease was significantly more pronounced on day 7 in patches where tacrolimus had been supplied (P < 0.5). This method might provide useful means to compare different concentrations and/or presentations of tacrolimus or other calcineurin inhibitors and topical anti-inflammatory agents.


Chitosan grafted-poly(ethylene glycol) methacrylate nanoparticles as carrier for controlled release of bevacizumab.
The aim of the present study is to obtain, for the first time, polymeric nanocarriers based on the chitosan grafted-poly(ethylene glycol) methacrylate derivative. The strategy involves the use of chitosan grafted-poly(ethylene glycol) methacrylate with high solubility in water, obtained via Michael addition, in order to prepare potentially non-toxic micro/nanoparticles (MNPs). By modifying chitosan, its solubility in aqueous media was improved. Micro/nanoparticles-based chitosan grafted-poly(ethylene glycol) methacrylate were obtained under mild condition, with good and controlled swelling properties in acetate buffer solution (ABS) and phosphate buffer solution (PBS). The technique selected for the preparation of the MNPs was a double crosslinking (ionic and covalent) process in reverse emulsion which provide the mechanical stability of the polymeric nanocarrier. The chitosan derivative and MNPs were thoroughly characterized by Fourier Transform Infrared Spectroscopy (FT-IR), Thermogravimetric Analysis (TGA), Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM). The Scanning Electron Microscopy photographs revealed that prepared MNPs have different diameters depending on the used stirring rate and polymer concentration. Nanoparticles potential as drug delivery system was analyzed by loading bevacizumab (BEV) a full-length monoclonal antibody. Also, the prepared particles were found suitable from the cytotoxicity and hemocompatibility point of view enabling their potential use as delivery system for the treatment of posterior segment of the eye conditions.


Correction to: Genetic variation of Mycoplasma hyopneumoniae from Brazilian field samples.
Following publication of the original article [1], we have been notified that two of the author names were incomplete or incorrect.


Overlapping transcripts, double-stranded RNA and antisense regulation: a genomic perspective.
Bioinformatic analysis of the transcriptomes of diverse eukaryotes has demonstrated the ubiquity and structural diversity of complementary antisense RNAs. These include both trans-encoded microRNAs and a large population of cis-encoded antisense RNAs that encompasses both coding and non-coding RNAs. Antisense regulation has previously been characterized primarily as a post-transcriptional response affecting RNA stability, nuclear processing, export, or translation. However, the formation of double-stranded (ds) RNAs by base-pairing between complementary RNAs may elicit regulatory responses at the transcriptional level as well. Analysis of antisense transcription at several imprinted loci has suggested a number of other mechanisms that may not require formation of dsRNA. Understanding the integration of transcriptional and post-transcriptional regulatory mechanisms represents a major challenge for understanding antisense regulation in eukaryotes. Such insight is also essential for understanding general principles of genetic regulation within the complex genomes characteristic of mouse and man as well as those of other eukaryotes.


Bone marrow transplantation for adults with acute leukaemia and 11q23 chromosomal abnormalities.
Adults with acute leukaemia and abnormalities of chromosome 11q23 have a poor prognosis when treated with conventional chemotherapy. To determine whether more intensive therapy can improve outcome for patients with this karyotypic finding, a retrospective analysis of all patients with acute leukaemia and 11q23 abnormalities treated at our centre was performed. 12 patients were treated with conventional chemotherapy alone (CC); 20 patients received high-dose chemo/radiotherapy (HDCT) with autologous (seven patients) or allogeneic (13 patients) bone marrow transplantation (BMT). The treatment-related mortality was 25% [95% Confidence Interval (CI) 7-69%] for the CC group and 46% (CI 25-73%) for the BMT group (P = 0.69). Cumulative risk of leukaemia progression was 89% (CI 61-100%) in the CC patients and 38% (CI 12-69%) in the BMT patients (P = 0.001). The 2-year event-free survival for patients treated with CC was 8% (CI 0-31%) and for patients receiving HDCT and BMT was 34% (CI 14-54%) (P = 0.03). These results confirm that conventional chemotherapy is rarely curative for adults with acute leukaemia and 11q23 abnormalities but that HDCT with BMT can result in long-term survival in a significant proportion of patients.


Modulation of in vivo cardiac hypertrophy with insulin-like growth factor-1 and angiotensin-converting enzyme inhibitor: relationship between change in myosin isoform and progression of left ventricular dysfunction.
Supplemental myocardial hypertrophy induced by insulin-like growth factor (IGF)-1 may prevent transition from hypertrophy to heart failure under chronic mechanical overload. Several studies have suggested that IGF-1 treatment may be beneficial in chronic heart failure. In addition, recent studies indicated that the amount of alpha-myosin heavy chain (MHC) plays a significant hemodynamic role in large animals including humans. We treated Dahl salt-sensitive hypertensive rats on a long-term basis with IGF-1. The effects were compared with those produced by treatment using a sub-antihypertensive dose of temocapril, an angiotensin-converting enzyme (ACE) inhibitor. At 11 weeks, when these rats displayed compensated left ventricular hypertrophy (LVH), they were randomized to three groups: 1) IGF group (3 mg/kg/day); 2) temocapril group (1 mg/kg/day); and 3) vehicle (control) group. After 15 weeks, the control rats showed left ventricular (LV) enlargement and severe LV dysfunction and rapidly died of pulmonary congestion (mean survival time: 16.8+/-0.5 weeks). The survival time was significantly shortened (15.6+/-0.3 weeks) in the IGF-1 group but significantly prolonged (19.5+/-0.6 weeks) in the temocapril group. The rats in the IGF-1 group showed accelerated LV dilation and dysfunction. Of the several parameters investigated, it was found that the relative amounts of MHC isoforms differed among the three groups. The alpha-MHC mRNA level was decreased by 52% (p<0.01) in the IGF group, while it increased by 58% (p<0.01) in the temocapril group compared with the control group. These changes were related to the progression of LV dysfunction. Supplemental myocardial hypertrophy with long-term IGF-1 treatment may not be beneficial if concentric LVH already exists. Our data suggest that IGF-1 may not protect myocardial performance when its hypertrophic effect aggravates the reduction of alpha-MHC. By contrast, the ACE inhibitor may improve myocardial function and prognosis by preventing the down-regulation of this isoform.


Formation and properties of a stable 'high-potential' copper-iron-sulphur cluster in a ferredoxin.
A ferredoxin isolated from Desulfovibrio africanus contains a [3Fe-4S] cluster that reversibly binds a copper atom, yielding a stable product with a greatly increased reduction potential. The reaction is readily detected in protein molecules adsorbed as a film on an electrode surface. Electron paramagnetic resonance (EPR) and magnetic circular dichroism (MCD) spectra of oxidized and reduced bulk solution products support their assignment as [Cu3Fe-4S]2+ (S = 1/2) and [Cu3Fe-4S]1+ (S = 2) respectively, with copper bound formally as Cu(I). Cyanide causes selective loss of copper and regeneration of the [3Fe-4S] reactant. The results demonstrate the chemical feasibility of CuFeS clusters and suggest that they could exist naturally in biological systems.


Predictive value of umbilical cord blood bilirubin for postnatal hyperbilirubinaemia.
The study investigated the predictive value of umbilical cord serum (UCS) bilirubin for the postnatal course of bilirubinaemia in healthy term and near-term newborns. Term appropriate-for-gestational-age (AGA; n=1100), small-for-gestational-age (SGA; n=163) and near-term infants (GA 34-36 wk; n=78) were included and separated according to their UCS bilirubin levels, starting from <20 (group 1), 20-<30 (2), 30-40 (3) and >40 (4) micromol/l. The newborns were followed for at least 5 postnatal days, and UCS bilirubin values were correlated with the development of hyperbilirubinaemia and phototherapy (PT) treatment. A clear relation between UCS bilirubin and the development of hyperbilirubinaemia was found in all three patient populations. None of the 75 AGA patients of group 1 developed postnatal bilirubin values above 300 micromol/l, whereas 0.3, 3.4 and 8.6% of the patients in groups 2-4, respectively, did so. The frequency of PT increased from 0% in group 1 up to 9.6% in group 4. For the prediction of further need of PT using a UCS bilirubin cut-off level of 30 micromol/l, we found a sensitivity of 90% and a negative predictive value of 99.1%, indicating that all patients with UCS bilirubin values below 30 micromol/l (443/1100 or 40.2%) were at a very low risk of developing dangerous hyperbilirubinaemia. Similar results were obtained in SGA children with a sensitivity of 94.1% and a negative predictive value of 98.6%. In comparison to term newborns, we generally found higher bilirubin values in preterms. A total of 6.4% of preterm children developed bilirubin values over 300 micromol/l, compared with 3% of term children, and 47.4% of preterms had to be treated with PT. Predicting the need of PT by using a UCS bilirubin cut-off level of 30 micromol/l revealed a sensitivity of 70.3% and a negative predictive value of 65.6%. These data suggest that UCS bilirubin is useful in predicting the postnatal bilirubin values in term and near-term newborns. We presume that the use of UCS bilirubin values may help detect infants at low risk for postnatal hyperbilirubinaemia and minimize an unnecessary prolongation of hospitalization.


Migration of encephalitogenic CD8 T cells into the central nervous system is dependent on the α4β1-integrin.
Although CD8 T cells are key players in neuroinflammation, little is known about their trafficking cues into the central nervous system (CNS). We used a murine model of CNS autoimmunity to define the molecules involved in cytotoxic CD8 T-cell migration into the CNS. Using a panel of mAbs, we here show that the α4β1-integrin is essential for CD8 T-cell interaction with CNS endothelium. We also investigated which α4β1-integrin ligands expressed by endothelial cells are implicated. The blockade of VCAM-1 did not protect against autoimmune encephalomyelitis, and only partly decreased the CD8(+) T-cell infiltration into the CNS. In addition, inhibition of junctional adhesion molecule-B expressed by CNS endothelial cells also decreases CD8 T-cell infiltration. CD8 T cells may use additional and possibly unidentified adhesion molecules to gain access to the CNS.


Automated, accurate, and three-dimensional method for calculating sagittal slope of the tibial plateau.
Increased posterior-inferior directed slope of the subchondral bone of the lateral tibial plateau is a risk factor for noncontact rupture of the anterior cruciate ligament (ACL). Previous measures of lateral tibial slope, however, vary from study to study and often lack documentation of their accuracy. These factors impede identifying the magnitude of lateral tibial slope that increases risk of noncontact ACL rupture. Therefore, we developed and evaluated a new method that (1) requires minimal user input; (2) employs 3D renderings of the tibia that are referenced to a 3D anatomic coordinate system; and (3) is precise, reliable, and accurate. The user first isolated the proximal tibia from computed tomography (CT) scans. Then, the algorithm placed the proximal tibia in an automatically generated tibial coordinate system. Next, it identified points along the rim of subchondral bone around the lateral tibial plateau, iteratively fit a plane to this rim of points, and, finally, referenced the plane to the tibial coordinate system. Precision and reliability of the lateral slope measurements were respectively assessed via standard deviation and intra- and inter-class correlation coefficients using CT scans of three cadaveric tibia. Accuracy was quantified by comparing changes in lateral tibial slope calculated by our algorithm to predefined in silico changes in slope. Precision, reliability, and accuracy were ≤0.18°, ≥0.998, and ≤0.13°, respectively. We will use our novel method to better understand the relationship between lateral tibial slope and knee biomechanics towards preventing ACL rupture and improving its treatment.


Predictors of mental complaints among Norwegian male farmers.
In the Job Demand-Control (JDC) model and the Job Demand-Resource (JDR) model, the individual worker's potential to influence their work, through job control, is associated with better health. Among self-employed farmers, this job control dimension could be analogous to a sense of independence as this occupational group often highlights this as the best thing about the profession. To analyse how work demands, sense of independence and number of close friends, and the interaction between independence and work demands predicted mental health among male farmers in Norway. The sample consisted of male farmers working 1700h or more on the farm annually in 2012. We used the Lisrel structural equation modelling to estimate the direct effects and the interactive effect of independence and work demands. There were 926 participants. Decrease in work demands, a strong sense of independence and a high number of close friends predicted lower levels of mental complaints. A strong sense of independence buffered the adverse consequences of work demands on mental health. In this sample of self-employed full-time male farmers in Norway, we found that sense of independence was important for their mental health; farmers with a high sense of independence seemed to be able to manage high work demands more effectively, thus reducing the level of mental health problems. In addition, we also found that work demands and social relationships were associated with mental health outcomes.


Efficacy of S-2441, a synthetic oligopeptide, in a rat model for gram-negative bacteremia.
In vitro effects of S-2441, H-D-Pro-Phe-Arg-NH-Heptyl, include potent anti-bradykinin activity and broad-spectrum inhibition of serine proteases involved in the coagulation cascade. In this study, rats infused with 7.8 X 10(8) viable Escherichia coli were treated either with saline (group A) or with intravenous (0.1 mg) and intraperitoneal (0.4 mg) doses of S-2441 (group B). Survival rates for groups A and B were 68% and 98%, at 12 hours (P less than 0.001), and 37% and 73% at 24 hours (P less than 0.001), respectively. Hematologic studies revealed that S-2441 significantly inhibited E. coli-induced prolongation of prothrombin time and partial thromboplastin time as well as a rapid decrease in the values of factor X, anti-thrombin III, and fibrinogen. In addition, S-2441 attenuated E. coli-induced hypoglycemia and a marked reduction of serum complement level. Ultrastructural evaluation of the liver demonstrated that S-2441 prevented the development of extensive sinusosoidal microthrombosis and hepatocellular necrosis. The results indicate that S-2441 affords protection in lethal gram-negative bacteremia owing in part to attenuation of disseminated intravascular coagulation and complement-mediated reactions. The findings are consistent with the concept that S-2441 and related oligopeptides modulate serine protease-mediated responses involving inhibition of active enzymes with competitive antagonism of pharmcologically active products formed during the activation of coagulation, fibrinolytic, kallikrein, and complement systems.


Lack of correlation between two methods for the assessment of salt sensitivity in essential hypertension.
The existence of a heterogeneous blood pressure (BP) response to salt intake, a phenomenon known as salt sensitivity, has increasingly become a subject of clinical hypertension research, and has important clinical and prognostic implications. However, two different methodologies are currently used to diagnose salt sensitivity. The aim of the present study was to compare the BP response to intravenous sodium load and depletion on the one hand, and to changes in dietary salt intake on the other, in order to assess salt sensitivity in a group of essential hypertensive patients. Twenty-nine essential hypertensives underwent two different procedures separated by 1 month: a dietary test consisting of a 2-week period of low (20 mmol/day) and high (260 mmol/day) salt intakes, and an intravenous test consisting of a 2 litre saline load over a 4-h period, followed by 1 day of low (20 mmol) salt intake and furosemide (40 mg/8 h orally) administration. BP was registered at the end of every period using 24-h ambulatory BP monitoring. In the whole group of hypertensive patients studied, both low salt intake and furosemide administration significantly (P < 0.01) decreased mean BP. Correlation coefficients of BP changes obtained using the two methodologies were between 0.3 and 0.4. Moreover, coefficients of agreement between the oral and the intravenous tests, using several cut points for BP changes, were systematically below 0.5, thus indicating a misclassification of salt sensitivity greater than 50%, depending on the method used. None of the cut points for BP changes during furosemide administration showed a good combination of sensitivity and specificity compared with changes in response to low dietary salt. The present results indicate that the diagnosis of salt-sensitive hypertension should be based on the BP response to changes in dietary salt intake, while BP response to saline and furosemide administration leads to a systematic misclassification of more than 50% of patients, even using different cutpoints for changes in BP.


Assessing Multiple-Mini Interview Performance Across Pharmacy Admissions Pathways.
To assess whether students who are admitted to a Doctor of Pharmacy program through different admissions pathways (early assurance vs other pathways) have significantly different affective domain competencies, as measured by multiple-mini interview (MMI) evaluations. A secondary analysis of existing data was conducted at a single pharmacy school in the upper Midwestern U.S. over 3 admissions cycles. The program offers a 6-year, early assurance admission pathway as well as more traditional admissions pathways which can be completed in 7-8 years. Differences in MMI scores, overall and by individual question, were assessed using the Kruskal-Wallis test. No differences in total MMI scores exist between individuals applying through the program's early assurance pathway and those applying through other pathways. In the first admissions cycle, early assurance applicants performed significantly lower on the responsibility MMI item (mean = 7.01 vs 8.50) and significantly higher on the cross-cutting MMI item (mean = 6.95 vs 5.45). In the second admissions cycle, early assurance applicants scored significantly higher on the self-awareness MMI item than other applicants (mean = 8.22 vs 7.14). No statistically significant differences were found between early assurance and non-early assurance applicants during the final admissions cycle. Individuals applying through an early assurance pathway produce MMI scores that are similar to individuals applying through other admissions pathways.


FlyGEM, a full transcriptome array platform for the Drosophila community.
We have constructed a DNA microarray to monitor expression of predicted genes in Drosophila. By using homotypic hybridizations, we show that the array performs reproducibly, that dye effects are minimal, and that array results agree with systematic northern blotting. The array gene list has been extensively annotated and linked-out to other databases. Incyte and the NIH have made the platform available to the community via academic microarray facilities selected by an NIH committee.


Changes in size and shape of liposomes undergoing chain melting transitions as studied by optical microscopy.
Changes in the shape and size of dipalmitoylphosphatidylcholine liposomes at the phase transition at 41.5 degrees C have been monitored by light microscopy. All liposomes change size or shape at the transition and those with simple topologies such as spheres and cylinders can be readily measured. The surface area of these is some 24% greater above the transition than below. This surface area change is virtually identical to that predicted by crystallographic measurements on this system. Also, the rate of transition from one state to another is seen to proceed more rapidly in the smaller liposomes. Optical microscopic observation provides a rapid simple method for monitoring the dependence of the lipid bilayer area on temperature.


Septicemia and lung injury.
The results of investigations undertaken by the authors which deal with the functional and structural changes in the lungs resulting from gram-negative bacterial endotoxemia and the mechanisms of these changes are analyzed. The authors emphasize the major roles played by granulocytes and metabolites of arachidonic acid in mediating endotoxin-induced lung injury.


Merosin (laminin-2/4)-driven survival signaling: complex modulations of Bcl-2 homologs.
We have shown previously that the promotion of myofiber survival by the basement membrane component merosin (laminin-2 [alpha2beta1gamma1]/laminin-4 [alpha2beta2gamma1]) is dependent on the activity of the tyrosine kinase Fyn, whereas myofiber anoikis induced by merosin deficiency is dependent on the stress-activated protein kinase p38alpha. To further understand such merosin-driven survival signaling, we analyzed the expression of five Bcl-2 homologs (Bcl-2, Bcl-X(L), Bax, Bak, Bad) and one non-homologous associated molecule (Bag-1) in normal and merosin-deficient myotubes, with or without pharmacological inhibitors for Fyn and p38. Herein, we report that (1) merosin deficiency induces anoikis and causes decreased Bcl-2, Bcl-X(L), and Bag-1 levels, increased Bax and Bak levels, and decreased Bad phosphorylation; (2) Bcl-2, Bcl-X(L), Bag-1, and Bad phosphorylation are also decreased in anoikis-dying, Fyn-inhibited myotubes; (3) the inhibition of p38alpha in Fyn-inhibited and/or merosin-deficient myotubes protects against anoikis and increases Bcl-2 levels above normal, in addition to restoring Bad phosphorylation and Bag-1 levels to normal; (4) the overexpression of merosin in deficient myotubes also rescues from anoikis and increases Bcl-2 levels and Bad phosphorylation above normal, in addition to restoring Bcl-X(L), Bag-1, Bax, and Bak levels to normal; and (5) Bcl-2 overexpression is sufficient to rescue merosin-deficient myotubes from anoikis, even though the expression/phosphorylation levels of the other homologs analyzed are not restored to normal. These results indicate that merosin-driven myofiber survival signaling affects complex, differential modulations of individual Bcl-2 homologs. These further suggest that Bcl-2 can play a major role in suppressing myofiber anoikis.


Functional architectures based on self-assembly of bio-inspired dipeptides: Structure modulation and its photoelectronic applications.
Getting inspiration from nature and further developing functional architectures provides an effective way to design innovative materials and systems. Among bio-inspired materials, dipeptides and its self-assembled architectures with functionalities have recently been the subject of intensive studies. However, there is still a great challenge to explore its applications likely due to the lack of effective adaptation of their self-assembled structures as well as a lack of understanding of the self-assembly mechanisms. In this context, taking diphenylalanine (FF, a core recognition motif for molecular self-assembly of the Alzheimer's β-amyloid polypeptides) as a model of bio-inspired dipeptides, recent strategies on modulation of dipeptide-based architectures were introduced with regard to both covalent (architectures modulation by coupling functional groups) and non-covalent ways (controlled architectures by different assembly pathways). Then, applications are highlighted in some newly emerging fields of innovative photoelectronic devices and materials, such as artificial photosynthetic systems for renewable solar energy storage and renewable optical waveguiding materials for optoelectronic devices. At last, the challenges and future perspectives of these bio-inspired dipeptides are also addressed.


Arrhythmia after modified total cavopulmonary connection without use of prosthetic material.
Although total cavopulmonary connection without use of prosthetic material appeared to be a promising surgical procedure that would retain potential growth of the intraatrial tunnel, midterm incidence of arrhythmia remains unknown. Twelve patients underwent modified total cavopulmonary connection. A prosthetic material was not used in 5 patients (group F) and was used in 7 patients (group P). A retrospective review of the perioperative electrocardiogram and ambulatory monitoring were performed. All patients revealed regular sinus rhythm before the operation. In the early postoperative period, the incidence of sinus node dysfunction was higher in group F than in group P (80% versus 28.6%). This difference no longer existed by hospital discharge (group F, 20%; group P, 14.3%). In the midterm follow-up period, sinus node dysfunction was detected in 4 patients of group F (80%) and 1 patient of group P (14.3%). Transient tachyarrhythmia was detected in 1 patient of group F and 3 patients of group P. Modified total cavopulmonary connection without use of prosthetic material affected unfavorably the sinus node in the early and midterm postoperative period.


Cell membrane and transepithelial voltages and resistances in isolated rat hepatocyte couplets.
The basic electrical properties of an isolated rat hepatocyte couplet (IRHC) system have been analyzed using classical techniques of epithelial electrophysiology, including measurement of electric potentials, resistances and intracellular ion activities. Applications of these techniques are discussed with respect to their limitations in small isolated cells. Mean intracellular and intracanalicular membrane potentials ranged from -23.7 to -46.7 and -4.3 to -5.9 mV, respectively. Membrane resistances were determined using an equivalent circuit analysis modified according to the geometry of the IRHC system. Resistances of the sinusoidal (basolateral) and canalicular (luminal) cell membranes and tight junctions averaged 0.15 and 0.78 G omega and 25 m omega, respectively. The cells are electrically coupled via low resistance intercellular communications (approximately 58 M omega). Intracellular ion activities for Na+, K+ and Cl- averaged 12.2, 88.1 and 17.7 mmol/liter, respectively. The basolateral membrane potential reveals a permeability sequence of PK greater than PCl greater than PNa. The luminal potential showed minimal dependence on changes in transjunctional ion gradients, indicating a poor ion selectivity of the paracellular pathway. The electrogenic (Na+-K+)-ATPase contributes little to the luminal and cellular negative electric potential. Therefore, the luminal potential probably results from the secretion of impermeant ions and a Donnan distribution of permeant ions, a mechanism which provides the osmotic driving force for bile formation. By providing the unique opportunity to measure luminal potentials, this isolated hepatocyte system permits study of secretory mechanisms for the first time in a mammalian gland using electrophysiologic techniques.


[Morphological characteristics of hippocampal neurons developing in cell cultures].
Using observation of living cells and neurohistological methods, we have investigated growth dynamics, fasciculation of fibers and morphogenesis of neurons in hippocampal cell cultures of 18-19-day-old mouse embryos. The development of the system of neuronal outgrowths with predominant growth of apical dendrite started on the 4th-6th day of cultivation and resulted in the formation of pyramidal neurons possessing the main morphological signs of pyramidal hippocampal neurons developing in situ. Thus, the morphogenetic programme of dendrite development can ensure the in vitro formation of neurons of a certain morphological phenotype. One of the possible prerequisites of the programme realization appears to be the inductive influence of afferent nervous fibers which reach hippocampal neurons in situ in the pre-cultivation period.


Minimally-invasive dentistry via dual-function novel bioactive low-shrinkage-stress flowable nanocomposites.
The objectives of this in vitro study were to develop a novel low-shrinkage-stress flowable nanocomposite with antibacterial properties through the incorporation of dimethylaminohexadecyl methacrylate (DMAHDM) and nanoparticles of amorphous calcium phosphate (NACP), and investigate the mechanical and oral biofilm properties, to be used in minimally-invasive techniques. The light-cured low-shrinkage-stress flowable resin was formulated by mixing urethane dimethacrylate (UDMA) and triethylene glycol divinylbenzyl ether (TEG-DVBE) at a 1:1 mass ratio. Different mass fractions of glass, and either 5% DMAHDM or 20%NACP or both were incorporated. Paste flowability, ultimate micro tensile strength and surface roughness were evaluated. The antibacterial response of DMAHDM resin was assessed by using biofilms of human saliva-derived microcosm model. Virtuoso flowable composite was used as a control. (45% resin+5% DMAHDM+20% NACP+30% glass) formula yielded the needed outcomes. It had flow rate within the range of ISO requirement. The micro tensile strength was (39.1 ± 4.3) MPa, similar to (40.1 ± 4.0) MPa for commercial control (p > 0.05). The surface roughness values of the novel composite (0.079 ± 0.01) µm similar to commercial composite (0.09 ± 0.02) µm (p > 0.05). Salivary microcosm biofilm colony forming unit values were reduced by 5-6 logs (p < 0.05). Biofilm metabolic activity was also substantially reduced, compared to control composite (p < 0.05). The novel bioactive flowable nanocomposite achieved strong antibacterial activities without compromising the mechanical properties. It is promising to be used as pit and fissure sealants, and as fillings in conservative cavities to inhibit recurrent caries and increase restoration longevity.


Analysis of the safety and immunogenicity profile of an azoximer bromide polymer-adjuvanted subunit influenza vaccine.
A systematic review of clinical trials conducted with a low-dose inactivated influenza vaccine adjuvanted by azoximer bromide (AZB, Polyoxidonium), was performed to compare vaccine reactogenicity against non-adjuvant vaccines. We also assessed whether lower amounts of antigen per viral strain in AZB-adjuvanted vaccines affected antibody responses. A robust search strategy identified scientific publications reporting 30 clinical trials, comprising data on 11,736 participants and 86 trial arms, for inclusion in the analysis. Local reaction rates (R lr) appeared to be lower in AZB-adjuvanted vaccine treatment arms versus comparator vaccine treatment arms. Post-vaccination geometric mean titres in those exposed to AZB-adjuvanted vaccine and comparator vaccine treatment arms were similar in both children and adults aged 18-60 years, implying an antigen-sparing effect by AZB. Meta‑regression analysis based on a literature search of records or reports of clinical trials featuring AZB and the inactivated subunit of influenza published between 1998-2018 was conducted online in January 2019 and updated in August 2019. This search covered trials performed between 1993 and 2016 and suggested that AZB did not contribute to vaccine reactogenicity.


An investigation into the potential action of polyphenols against human Islet Amyloid Polypeptide aggregation in type 2 diabetes.
Type 2 diabetes (T2D), a chronic metabolic disease characterized by hyperglycemia, results in significant disease burden and financial costs globally. Whilst the majority of T2D cases seem to have a genetic basis, non-genetic modifiable and non-modifiable risk factors for T2D include obesity, diet, physical activity and lifestyle, smoking, age, ethnicity, and mental stress. In healthy individuals, insulin secretion from pancreatic islet β-cells is responsible for keeping blood glucose levels within normal ranges. T2D patients suffer from multifactorial onset of β-cell dysfunction and/or loss of β-cell mass owing to reactive oxygen species (ROS) production, mitochondrial dysfunction, autophagy, and endoplasmic reticulum (ER) stress. Most predominantly however, and the focus of this review, it is the aggregation and misfolding of human Islet Amyloid Polypeptide (hIAPP, also known as amylin), which is detrimental to β-cell function and health. Whilst hIAPP is found in healthy individuals, its misfolded version is cytotoxic and able to induce β-cell dysfunction and/or death through various mechanisms including membrane changes in β-cell causing influx of calcium ions, arresting complete granule membrane recovery and ER stress. There are several existing therapeutics for T2D. However, there is a need for alternative or adjunct therapies for T2D with milder adverse effects and greater availability. Foremost among the potential natural therapeutics are polyphenols. Extensive data from studies evaluating the potential of polyphenols to inhibit hIAPP aggregation and disassemble aggregated hIAPP are promising. Moreover, in-vivo, and in-silico studies also highlight the potential effects of polyphenols against hIAPP aggregation and mitigation of larger pathological effects of T2D. Whilst there have been some promising clinical studies on the therapeutic potential of polyphenols, extensive further clinical studies and in-vitro studies evaluating the mechanisms of action and ideal doses for many of these compounds are required. The need for these studies is made more important by the postulated link between Alzheimer's disease (AD) and T2D pathophysiology given the similar aggregation process of their respective amyloid proteins, which evokes thoughts of cross-reactive polyphenols which can be effective for both AD and T2D patients.


Identification of oxadiazoles as new drug leads for the control of schistosomiasis.
Treatment for schistosomiasis, which is responsible for more than 280,000 deaths annually, depends almost exclusively on praziquantel. Millions of people are treated annually with praziquantel, and drug-resistant parasites thus are likely to evolve. Phosphinic amides and oxadiazole 2-oxides, identified from a quantitative high-throughput screen, were shown to inhibit a parasite enzyme, thioredoxin glutathione reductase (TGR), with activities in the low micromolar to low nanomolar range. Incubation of parasites with these compounds led to rapid inhibition of TGR activity and parasite death. The activity of the oxadiazole 2-oxides was associated with a donation of nitric oxide. Treatment of schistosome-infected mice with 4-phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide led to marked reductions in worm burdens from treatments against multiple parasite stages and egg-associated pathologies. The compound was active against the three major schistosome species infecting humans. These protective effects exceed benchmark activity criteria set by the World Health Organization for lead compound development for schistosomiasis.


Gene regulation: a tale of germline mRNA tails.
Gene regulation often plays by different rules in the germline compared to the soma. In Caenorhabditis elegans, the spatial and temporal expression of germline genes is controlled post-transcriptionally via the 3' UTR rather than transcriptionally via the promoter.


Results from APMP comparisons on radioactivity measurements of 58Co, 88Y and 166mHo.
International comparisons on radioactivity measurements of 55Co, 88Y and 166mHo were carried out within the framework of the Asia-Pacific Metrology Programme. Radioactive sources were also sent to the International Reference System (SIR) at the Bureau International des Poids et Mesures (BIPM) in order to link the results of these regional comparisons to the BIPM key comparison-reference values. The arithmetic mean for the activity results of 166mHo was in good agreement with the SIR reference value, but some disagreements were found for 58Co and 88Y results. The mean values for 58Co and 88Y were both higher than the existing SIR values by about 1.5% and 0.9%, respectively. Although there were some disagreements, it was successfully demonstrated that these regional comparisons could be linked to other international key comparisons through the SIR. The present results were also evaluated to estimate a reasonable uncertainty level for each laboratory, which is very important in the establishment of an adequate traceability scheme for radioactivity standards.


CHD chromatin remodelling enzymes and the DNA damage response.
The protein and DNA complex known as chromatin is a dynamic structure, adapting to alter the spatial arrangement of genetic information within the nucleus to meet the ever changing demands of life. Following decades of research, a dizzying array of regulatory factors is now known to control the architecture of chromatin at nearly every level. Amongst these, ATP-dependent chromatin remodelling enzymes play a key role, required for the establishment, maintenance and re-organization of chromatin through their ability to adjust the contact points between DNA and histones, the spacing between individual nucleosomes and the over-arching chromatin superstructure. Utilizing energy from ATP hydrolysis, these enzymes serve as the gatekeepers of genomic access and are essential for transcriptional regulation, DNA replication and cell division. In recent years, a vital role in DNA Double Strand Break (DSB) repair has emerged, particularly within complex chromatin environments such as heterochromatin, or regions undergoing energetic transactions such as transcription or DNA replication. Here, we will provide an overview of what is understood about ATP-dependent chromatin remodelling enzymes in the context of the DNA damage response. We will first touch upon all four major chromatin remodelling enzyme families and then focus chiefly on the nine members of the Chromodomain, Helicase, DNA-binding (CHD) family, particularly CHD3, CHD4, CHD5 and CHD6. These four proteins have established and emerging roles in DNA repair, the oxidative stress response, the maintenance of genomic stability and/or cancer prevention.


Patterns of care and outcomes among triple-negative early breast cancer patients in South Western Sydney.
Triple-negative breast cancer (TNBC) represents 12-24% of all breast cancer and carries a poor prognosis upon recurrence. Little is known of the treatment, or timing and frequency of recurrences outside of a clinical trial. We describe the patterns of care and outcomes of women with TNBC treated at two cancer centres in Sydney, NSW, Australia, to help oncologists talk to women with this subtype of breast cancer about their likely prognosis. We searched the electronic medical record for women with stages I-III TNBC diagnosed from 2006 to 2014. For each woman, we recorded demographics, tumour characteristics, treatment details, recurrences and survival using the Kaplan-Meier method. We identified 137 women with a median age of 55 years (interquartile range (IQR) 44-63). The median tumour size was 25 mm (IQR 16-35). Most women had grade 3 (92%) and ductal carcinomas (89%), and 35% were node positive; 113 (82%) patients received (neo)adjuvant chemotherapy. The most prescribed regimens for node-negative tumours were: fluorouracil, epirubicin and cyclophosphamide (FEC) × 6 (23pts, 35%), and for node-positive tumours, FEC-Docetaxel (18pts, 40%). Adjuvant radiotherapy was delivered to 114 (83%) patients. After a median follow up of 40 months, 17 patients (12%) had a recurrence. All but one recurrence (94%) occurred within 3 years of diagnosis. Twelve women received palliative chemotherapy, and 14 women have died. The median survival from the time of recurrence was 18 months (IQR 5-26). Seven women (5%) had a documented BRCA1 mutation, and four women (3%) had a documented BRCA2 mutation. TNBC affects women at a relatively young age and tends to recur early. Survival following metastatic disease is short, and more effective therapies are needed.


Esophageal carcinoma presenting as a primary renal tumor.
A patient with esophageal carcinoma presenting with hematuria is described. Initial studies confirmed the presence of a renal mass that was thought to be a primary renal neoplasm. Further studies to evaluate anemia before a renal operation led to the discovery of an unsuspected esophageal carcinoma. Although metastases to the kidneys are relatively common it is uncommon for these lesions to be clinically apparent or responsible for producing initial symptomatology. Only after discovery of the esophageal lesion was the possibility of a secondary renal neoplasm considered. Intractable hematuria was treated successfully by embolizing the renal artery of the bleeding kidney with gelatin sponge fragments.


Clenbuterol, a beta 2-adrenergic agonist, reverses muscle wasting due to scald injury in the rat.
The effects of clenbuterol, a beta 2-adrenergic agonist, on body weight, tissue masses, and protein and RNA contents were studied following scald injury (30 per cent TBSA) in the rat. While the masses of heart, liver and epididymal fat pads remained unaffected, significant reductions in gastrocnemius, plantaris and soleus muscle masses (approximately 11 per cent; P < 0.01) were observed following injury, none of which were mimicked by pair-feeding or could be attributed to dehydration. This muscle wasting was accompanied by significant reductions in protein and/or RNA content. Oral administration of clenbuterol (4 mg/kg diet) had no anabolic effects, either in the scalded animals or their pair-fed controls. While clenbuterol (12 mg/kg diet) did not affect the masses of heart and fat pads, increases in the wet weights (approximately 20 per cent), RNA (approximately 30 per cent) and protein content (approximately 20 per cent) of the gastrocnemius and plantaris muscles were observed in all animals; the magnitude of these effects was greater (P < 0.05) in the scalded animals than in their pair-fed controls. Clenbuterol had no effect on body weight but increased (P < 0.001) carcass water content. These data indicate that there is a selective mobilization of muscle protein and sparing of fat in the early phase following burn injury, and that beta 2-adrenergic agonists, such as clenbuterol, may be of therapeutic value in inhibiting or reversing muscle atrophy associated with thermal injury.


Managing Pediatric Pain in the Emergency Department.
Far more attention is now given to pain management in children in the emergency department (ED). When a child arrives, pain must be recognized and evaluated using a pain scale that is appropriate to the child's development and regularly assessed to determine whether the pain intervention was effective. At triage, both analgesics and non-pharmacological strategies, such as distraction, immobilization, and dressing should be started. For mild pain, oral ibuprofen can be administered if the child has not received it at home, whereas ibuprofen and paracetamol are suitable for moderate pain. For patients who still require pain relief, oral opioids could be considered; however, many EDs have now replaced this with intranasal fentanyl, which allows faster onset of pain relief and can be administered on arrival pending either intravenous access or definitive care. Intravenous opioids are often required for severe pain, and paracetamol or ibuprofen can still be considered for their likely opioid-sparing effects. Specific treatment should be used for patients with migraine. In children requiring intravenous access or venipuncture, non-pharmacological and pharmacological strategies to decrease pain and anxiety associated with needle punctures are mandatory. These strategies can also be used for laceration repairs and other painful procedures. Despite the gaps in knowledge, pain should be treated with the most up-to-date evidence in children seen in EDs.


Transoral Robotic Excision of Paediatric Lingual Thyroglossal Duct Cyst.
Lingual thyroglossal duct cyst (TGDC) is a rare variant of TGDC that emerges within the tongue base. It presents a unique surgical challenge. There are different approaches to managing this condition. Transoral robotic surgery (TORS) has been successfully used for lesions of the tongue base in adults. This report presents a 7 year old boy with a cystic lesion in the base of tongue, which was diagnosed to be a lingual TGDC. The cyst was excised transorally using Da Vinci Robotic system. The surgery was performed in a short operating time with no complications or recurrence on follow up. TORS is an effective and reliable method of excision of lingual TGDC in the paediatric population. Lingual TGDC can be managed by simple excision of the cyst without excision of hyoid bone. Further studies are needed to confirm the safety and recurrence rates of this technique in paediatric population.


Novel HIV-protease inhibitors containing beta-hydroxyether and -thioether dipeptide isostere surrogates: modification of the P3 ligand.
Studies involving modifications to the P3 position of previously described HIV-protease inhibitors containing beta-hydroxyether and thioether dipeptide isostere replacements led to the discovery of pseudopeptides 8o and 8p with improved antiviral activities.


Video analysis of endoscopic cutting task performed by one versus two operators.
In the performance of complex laparoscopic tasks, one question is whether the task should be distributed between two operators or accomplished bimanually by one operator. The authors hypothesized that superior task performance results when two operators work collaboratively in a dyad team as opposed to one operator performing the task bimanually. Furthermore, in a visually misaligned condition, the performance of a team will be more robust than that of a single operator working alone. The suture-cutting task was performed by 24 right-handed subjects in a mock surgical setup using a laparoscopic grasper and a pair of laparoscopic scissors. The cutting task was performed by 8 subjects bimanually (using both limbs) and 16 paired subjects unimanually (using their preferred limbs). The image of the work plane was displayed either vertically or superimposed over the work plane. In half of the conditions, the camera was rotated 45 degrees, causing misalignment between the actual and displayed work planes. Movements were videotaped. Important movement events were identified and used to subdivide the task into subtasks. Durations of the subtasks and attempts for grasping and cutting were analyzed using a mixed-design multivariate analysis of variance (MANOVA). For a number of subtasks, the dyad group showed shorter durations than the bimanual group. The 45 degrees rotation of the camera degraded both bimanual and dyad performance, resulting in prolonged movement times for all subtasks. The learning process was facilitated by the superimposed display in that grasper and scissor reaching times improved over trials, as compared with the vertical display. The results indicate the superior role of team collaboration, as compared with the single operator, in a complex remote manipulation such as a laparoscopic cutting task. This enhanced task performance is achieved because of the larger capacity for information processing. These results may have some relevance for optimizing performance of endoscopic surgery.


SMaRT for Therapeutic Purposes.
Spliceosome-mediated mRNA trans-splicing (SMaRT) is a promising strategy for treatment of genetic diseases which cannot be targeted via classical therapy approaches. SMaRT utilizes an exogenous pre-mRNA trans-splicing molecule (PTM) to correct a diseased target pre-mRNA. This process relies on splicing of two separate pre-mRNA molecules in trans creating a mature chimeric mRNA molecule which consists of the protein coding sequence of the PTM as well as the endogenous mRNA. For therapeutic implications, the most critical step in SMaRT is to develop PTMs resulting in a high ratio of trans-splicing to regular cis-splicing.This protocol provides guidelines on how to design PTMs and describes a fast screening assay to test their efficiencies. To elucidate the therapeutic potential of the best candidates in a more native setting, these PTMs are tested further on mini genes.