Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk.
Approximately half of all patients with type 2 diabetes (T2D) develop a certain degree of renal impairment. In many of them, chronic kidney disease (CKD) progresses over time, eventually leading to end-stage kidney disease (ESKD) requiring dialysis and conveying a substantially increased risk of cardiovascular morbidity and mortality. Even with widespread use of renin-angiotensin system blockers and tight glycemic control, a substantial residual risk of nephropathy progression remains. Recent cardiovascular outcomes trials investigating sodium-glucose cotransporter 2 (SGLT2) inhibitors have suggested that these therapies have renoprotective effects distinct from their glucose-lowering action, including the potential to reduce the rates of ESKD and acute kidney injury. Although patients in most cardiovascular outcomes trials had higher prevalence of existing cardiovascular disease compared with those normally seen in clinical practice, the proportion of patients with renal impairment was similar to that observed in a real-world context. Patient cardiovascular risk profiles did not relevantly impact the renoprotective benefits observed in these studies. Benefits were observed in patients across a spectrum of renal risk, but were evident also in those without renal damage, suggesting a role for SGLT2 inhibition in the prevention of CKD in people with T2D. In addition, recent studies such as CREDENCE and DAPA-CKD offer a greater insight into the renoprotective effects of SGLT2 inhibitors in patients with moderate-to-severe CKD. This review outlines the evidence that SGLT2 inhibitors may prevent the development of CKD and prevent and delay the worsening of CKD in people with T2D at different levels of renal risk.


Improved health-related quality of life with semaglutide in people with non-alcoholic steatohepatitis: A randomised trial.
Non-alcoholic steatohepatitis (NASH) can adversely affect health-related quality of life (HRQoL). This double-blind, placebo-controlled, phase 2 trial aimed to report the effects of the glucagon-like peptide-1 receptor agonist, semaglutide, on HRQoL in patients with NASH as a secondary endpoint. Adults with biopsy-proven NASH and stage 1-3 fibrosis were randomised (3:3:3:1:1:1) to once-daily subcutaneous semaglutide 0.1, 0.2 or 0.4 mg, or placebo, for 72 weeks. Patients were invited to complete the Short Form-36 version 2.0 questionnaire at weeks 0, 28, 52 and 72. Between January 2017 and September 2018, 320 patients were enrolled. At 72 weeks, semaglutide was associated with significant improvements in physical component summary (PCS) score (estimated treatment difference [ETD] 4.26; 95% confidence interval [CI]: 1.96-6.55; p = 0.0003); bodily pain (ETD 5.07; 95% CI: 2.15-7.99; p = 0.0007); physical functioning (ETD 3.51; 95% CI: 1.16-5.86; p = 0.0034); role limitations due to physical health problems (ETD 2.80; 95% CI: 0.28-5.33; p = 0.0294); social functioning (ETD 3.16; 95% CI: 0.53-5.78; p = 0.0183) and vitality (ETD 4.47; 95% CI: 1.63-7.32; p = 0.0021). There was no significant difference in the mental component summary score (ETD 1.02; 95% CI: -1.59 to 3.62; p = 0.4441). After 72 weeks, improvements in PCS scores were significantly greater in patients (pooled semaglutide and placebo) with NASH resolution than without (p = 0.014). Treatment with semaglutide is associated with improvements in the physical components of HRQoL in patients with biopsy-proven NASH and fibrosis compared with placebo. gov: NCT02970942.


Nanoindentation study of human premolars subjected to bleaching agent.
Bleaching of teeth is gaining popularity due to cosmetic reasons. However, the effect it has on teeth is still largely unknown. This paper seeks to evaluate the effect of a bleaching agent, 30% hydrogen peroxide, on the nanomechanical properties of dentin and enamel using the nanoindentation technique. The Young's modulus and hardness obtained from nanoindentation before and after bleaching were compared. Five newly extracted human premolars were used. Nanoindentation was first done on the sliced enamel and dentin regions to determine their mechanical properties. One batch of samples was kept in Hank's balanced salt solution as control while the other was bleached in 30% hydrogen peroxide for 24h. The same number of nanoindentations was then done near the previously indented regions for both the control and bleached samples and the results compared. Using paired sample t-tests with alpha=0.05, it was found that there were no significant differences in both the Young's modulus and hardness of dentin and enamel kept in control. However, the mechanical properties of the bleached dentin were significantly decreased. For intertubular dentin, the mean hardness decreased by 29-55% and the mean Young's modulus decreased by 19-43%. For enamel, the mean hardness decreased by 13-32% while the mean Young's modulus decreased by 18-32%. The exact mechanism by which hydrogen peroxide affects the dentin and enamel has yet to be fully elucidated. However, it is observed to have an undermining effect on the nanomechanical properties of teeth.


Exposure of breastfed infants to quercetin after consumption of a single meal rich in quercetin by their mothers.
The exposure to quercetin (Q) has not been studied in breastfed infants whose mothers were consuming a Q-rich diet. The objective of the study was to determine whether plant-origin antioxidant-Q passes from the mother's diet to her milk and to calculate the pharmacokinetic parameters of this phenomenon. Eleven breastfeeding women were included in this controlled case study. Volunteers followed a Q-restricted diet for 5 consecutive days with the exception of the 3rd day when they received a single meal providing 1 mg of Q per kg of body weight. Urine analysis showed the presence of Q already in the first collected samples after the test (1.5-4 h), which indicated its rapid absorption from the meal. The Cmax = 68 ± 8.44 nmol/L concentration of Q in the milk was calculated for Tmax = 11.89 ± 3.37 h. It was significantly different (p = 0.007) from 40 nmol/L and (p = 0.016) from 42 nmol/L of Q concentration before and 48 h after the test, respectively. Q was shown to be a component of human milk at the nmol/L level. Infants breastfed by mothers consuming a diet rich in Q are exposed to a dose of approximately 0.01 mg of Q daily.


Surgical and Endoscopic Resection of Duodenal Neuroendocrine Tumors Have Similar Disease-Specific Survival Outcome.
Duodenal neuroendocrine tumors (dNETs) are rare, and their management is not well-defined. National Comprehensive Cancer Network (NCCN) guidelines recommend surgical resection of large dNETs (> 2 cm) and endoscopic resection of small tumors (< 2 cm). We compared the survival outcomes between surgical and endoscopic resection in various dNET sizes. A retrospective cohort study was conducted using patient data from Surveillance, Epidemiology, and End Results Program (SEER) database. Variables analyzed included age, tumor size, grade, stage, and lymph node status. Disease-specific survival (DSS) was compared for endoscopic and surgical groups in dNET size strata: 0-0.5, 0.5-1, 1-2, 2-3, and > 3 cm. Kaplan-Meier and multivariable Cox proportional hazards models were used for survival analysis. The study included 465 patients, with 124 (26.7%) undergoing surgical resection. The average age was 61.9 years, and tumor sizes ranged from 0.1 to 10.5 cm. Endoscopic resection had 40.5% of tumors between 0 and 0.5 cm, while surgery had only 21% (p < 0.001). In the surgical cohort, 79.8% had grade 1 tumors compared to 88.3% in the endoscopy group (P = 0.024). Among surgically resected cases, 48.4% (60 patients) had lymph node involvement. Age, tumor size, grade, and stage did not significantly predict survival after surgical resection. Stratified by tumor size, no difference in DSS was observed between surgery and endoscopy groups. Endoscopic resection demonstrated similar survival outcomes to surgical resection across dNET sizes in this national analysis. Given the risks and the lack of survival benefits for surgery, endoscopic resection may be beneficial for both small and large tumors. Further studies are warranted to validate the current NCCN guidelines.


Knowledge and attitude of dental professionals toward COVID-19 in Riyadh, Saudi Arabia: a cross-sectional survey.
Coronavirus disease-2019 (COVID-19) is a life-threatening global pandemic. The dental profession is considered a high-risk group in the transmission of the responsible virus. To assess the knowledge and attitude among dental professionals in response to the COVID-19 pandemic. We conducted a cross-sectional study of dental graduates, interns, postgraduates, and dental faculty from May to July 2020. A standardized questionnaire was developed to assess knowledge and attitude of 650 participants. The questionnaire comprised 14 questions to assess general knowledge about COVID-19, 11 questions regarding knowledge about prevention of COVID-19 in dental practice, and 10 questions regarding the attitude toward preventing COVID-19. Among the study population, only 376 (57.8%) knew the causative virus for COVID-19. Only 425 (65.3%) knew about rinsing the mouth with an antimicrobial solution or 1% hydrogen peroxide before the dental procedure. Regarding the hand hygiene guidelines, 357 (54.9%) had knowledge of the Centers for Disease Control and Prevention (CDC) and 377 (58.0%) about World Health Organization (WHO) guidelines. At the time of our survey, 72% of the participants showed sufficient knowledge, while 28% had low or insufficient knowledge about COVID-19. While there was a lack of knowledge among dental professionals in Riyadh, Saudi Arabia about COVID-19, there was an excellent positive attitude toward preventing disease. Greater awareness is needed to control the spread of this disease.


Venous thromboembolism in hematopoietic stem cell transplantation: A narrative review.
Venous thromboembolism (VTE) is a common complication of hematopoietic stem cell transplantation (HSCT) and its treatment has significant effects on morbidity and non-relapse mortality. There is a complex interplay on balancing the risk for thrombosis and bleeding in these patients, making treatment decisions particularly challenging. Despite this, there are currently no validated risk assessment models or guidelines to aid clinical decision making on thromboprophylaxis and VTE treatment in this population of patients. Herein, we review the many risk factors for VTE in HSCT patients, categorized into patient, disease, catheter, treatment, laboratory, and transplant-related variables. This review also discusses current thromboprophylaxis and VTE management strategies in HSCT patients, with scope into the development of risk assessment models that allow for identification of high-risk subgroups who may benefit from targeted intervention.


Tilting dependence and anisotropy of anomaly-related magnetoconductance in type-II Weyl semimetals.
We theoretically study chiral magnetic effect in type-II Weyl semimetals based on a concise formalism for the magnetoconductance in the semiclassical limit. Using the formula, we find that the anomaly-related current is generally dominated by the contribution from the Weyl nodes when the Fermi level is sufficiently close to the nodes. This is related to the fact that the current is proportional to the square of the Berry curvature, which enhances the contribution from the electrons around the Weyl nodes. The increase and the anisotropy of magnetoconductance induced by the tilting is also explained in a comprehensive way.


Stimulus-response coupling in FMLP-stimulated U937 monocytes: effect of differentiation on Gi2 expression.
The effect of differentiation on FMLP-stimulated InsP production and G-protein expression was investigated in U937 monocytes. FMLP (0.01-10 microM) stimulated [3H]InsP production in dimethyl sulphoxide-differentiated, but not in immature, U937 cells. Ionomycin (1 and 10 microM) stimulated [3H]InsP production equally well in both cell types. The FMLP response was blocked by pertussis toxin (100 ng/ml for 4 h) which catalysed [32P]ADP ribosylation of a 40 kDa 'Gi-like' G-protein alpha subunit in these cells. This protein was also identified immunologically using anti-peptide antibodies that detect 'Gi-like' alpha subunits (SG2) or Gi2 alpha specifically (LE2). With LE2 a 5-fold increase in Gi2 alpha levels was seen following differentiation of the cells, suggesting that FMLP receptor expression is accompanied by an increase in the G-protein with which these receptors interact.


Impact of hydrothermal pre-treatment on the anaerobic digestion of different solid-liquid ratio sludges and kinetic analysis.
This study is an assessment of hydrothermal pre-treatment (HTP) of different solid-liquid ratio (SLR) sewage sludge for enhancement of biogas production by anaerobic digestion. Anaerobic digestion efficacy was investigated by biochemical methane potential (BMP) tests and kinetic analyses. The results indicated that the solid-liquid ratio (SLR) of sludge could influence the COD solubilization and the concentration of volatile fatty acids (VFAs) after HTP. BMP tests revealed that HTP could improve the final methane yield. For the different solid-liquid ratios (5%, 8%, 10%, 12% and 15%) of sludge after HTP, the methane contents were found to be 64%, 66%, 62%, 61% and 60%, respectively. The optimum solid-liquid ratio was found to be 8%, and its cumulative biogas yield was 425.57 N ml g-1 VS. The modified Gompertz model and Logistic model were used for kinetic study of biogas production. Kinetic study results showed that the experimental data could be fitted with the two models and the modified Gompertz model was better fitted with the experimental data than the Logistic model. These findings proved that choosing an appropriate solid-liquid ratio for HTP could effectively improve the anaerobic digestion process of sewage sludge.


Comparative analysis of hydrogen bonding with participation of the nitrogen, oxygen and sulfur atoms in the 2(2'-heteroaryl)pyrroles and their trifluoroacetyl derivatives based on the 1H, 13C, 15N spectroscopy and DFT calculations.
The N-H...X (X = N,O,S) intramolecular hydrogen bond in the series of 2(2'-heteroaryl)pyrroles and their trifluoroacetyl derivatives is examined by the (1)H, (13)C, (15)N spectroscopy and density functional theory (DFT) calculations. The influence of the hydrogen bond on coupling and shielding constants is considered. It is shown that the N-H...N intramolecular hydrogen bond causes a larger increase in the absolute size of the (1)J(N,H) coupling constant and a larger deshielding of the bridge proton than the N-H...O hydrogen bond. The effect of the N-H...S interaction on the (1)J(N,H) coupling constant and the shielding of the bridge proton is small. The NMR parameter changes in the series of the 2(2'-heteroaryl)pyrroles due to N-H...X hydrogen bond and the series of the 1-vinyl-2-(2'-heteroaryl)-pyrroles due to C-H...X hydrogen bond have the same order. The proximity of the nitrogen, oxygen or sulfur lone pair to the F...H hydrogen bridge quenches the trans-hydrogen bond spin-spin couplings (1h)J(F,H-1) and (2h)J(F,N).


The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP.
Inhibition of vascular smooth muscle cell (VSMC) proliferation by intracellular cAMP prevents excessive neointima formation and hence angioplasty restenosis and vein-graft failure. These protective effects are mediated via actin-cytoskeleton remodelling and subsequent regulation of gene expression by mechanisms that are incompletely understood. Here we investigated the role of components of the growth-regulatory Hippo pathway, specifically the transcription factor TEAD and its co-factors YAP and TAZ in VSMC. Elevation of cAMP using forskolin, dibutyryl-cAMP or the physiological agonists, Cicaprost or adenosine, significantly increased phosphorylation and nuclear export YAP and TAZ and inhibited TEAD-luciferase report gene activity. Similar effects were obtained by inhibiting RhoA activity with C3-transferase, its downstream kinase, ROCK, with Y27632, or actin-polymerisation with Latrunculin-B. Conversely, expression of constitutively-active RhoA reversed the inhibitory effects of forskolin on TEAD-luciferase. Forskolin significantly inhibited the mRNA expression of the pro-mitogenic genes, CCN1, CTGF, c-MYC and TGFB2 and this was reversed by expression of constitutively-active YAP or TAZ phospho-mutants. Inhibition of YAP and TAZ function with RNAi or Verteporfin significantly reduced VSMC proliferation. Furthermore, the anti-mitogenic effects of forskolin were reversed by overexpression of constitutively-active YAP or TAZ. Taken together, these data demonstrate that cAMP-induced actin-cytoskeleton remodelling inhibits YAP/TAZ-TEAD dependent expression of pro-mitogenic genes in VSMC. This mechanism contributes novel insight into the anti-mitogenic effects of cAMP in VSMC and suggests a new target for intervention.


Urban effluents affect the early development stages of Brazilian fish species with implications for their population dynamics.
The pollution from urban effluents discharged into natural waters is a major cause of aquatic biodiversity loss. Ecotoxicological testing contributes significantly to understand the risk of exposure to the biota and to establish conservation policies. The objective of the current study was to assess the toxicity of a river highly influenced by urban effluents (Atuba River, Curitiba city, Southern Brazil) to the early stages of development in four South American native fish species, investigating the consequences at the population level through mathematical modelling. The species chosen were Salminus brasiliensis, Prochilodus lineatus, Rhamdia quelen, and Pseudoplatystoma corruscans, ecologically important species encompassing different conservation statuses and vulnerability. The embryos were exposed from 8 to 96 h post fertilization to the Atuba River water, collected downstream of the largest wastewater treatment plant in the Metropolitan Region of Curitiba, and their survival rates and deformities were registered. The species S. brasiliensis and P. lineatus presented the highest mortality rates, showing high sensitivity to the pollutants present in the water. According to the individual-based mathematical model, these species showed high vulnerability and risk of extinction under the tested experimental conditions, even when different sensitivity scenarios of juveniles and adults were considered. The other two species, R. quelen and P. corruscans, showed a more resistant condition to mortality, but also presented high frequency and severity of deformities. These results emphasize the importance of testing the sensitivity of different Brazilian native species for the conservation of biodiversity and the application of models to predict the effects of pollutants at the population level.


BDE209-promoted Dio2 degradation in H4 glioma cells through the autophagy pathway, resulting in hypothyroidism and leading to neurotoxicity.
Decabromodiphenyl ether (BDE209), the homologue with the highest number of brominates in polybrominated diphenyl ethers (PBDEs), is one of the most widespread environmental persistent organic pollutants (POPs) due to its mass production and extensive application in recent decades. BDE209 is neurotoxic, possibly related to its interference with the thyroid hormone (TH) system. However, the underlying molecular mechanisms of BDE209-induced TH interference and neurobehavioral disorders remains unknown. Here, we explored how BDE209 manipulated the major enzyme, human type II iodothyronine deiodinase (Dio2), that is most important in regulating local cerebral TH equilibrium by neuroglial cells, using an in vitro model of human glioma H4 cells. Clonogenic cell survival assay and LC/MS/MS analysis showed that BDE209 could induce chronic neurotoxicity by inducing TH interference. Co-IP assay, RT-qPCR and confocal assay identified that BDE209 destroyed the stability of Dio2 without affecting its expression, and promoted its binding to p62, thereby enhancing its autophagic degradation, thus causing TH metabolism disorder and neurotoxicity. Furthermore, molecular docking studies predicted that BDE209 could effectively suppress Dio2 activity by competing with tetraiodothyronine (T4). Collectively, our study demonstrates that BDE209-induced Dio2 degradation and loss of its enzymatic activity in neuroglial cells are the fundamental pathogenic basis for BDE209-mediated cerebral TH disequilibrium and neurotoxicity, providing a target of interest for further investigation using glial/neuronal cell co-culture system and in vivo models.


Is enteral nutrition optimally used in hospitalized patients? A study of the practice of nutrition in a Swedish hospital.
Thirty patients with parenteral nutrition were studied in order to evaluate if they could be given enteral nutrition instead. Based upon absolute and relative contraindications for enteral nutrition, we calculated that 80% of the patients were possible candidates for enteral nutrition. Long-term use of parenteral nutrition may cause complications. Besides metabolic and other advantages when enteral nutrition is used, economical gains are also important. We have calculated an estimated annual net profit of US$ 357,000 in our hospital, if enteral instead of parenteral feeding is used in patients suitable for the former type of feeding. This implies that it is really cost-beneficial to consider enteral nutrition in hospitalized patients. Although parenteral nutrition will continue to have its place in the management of different occasions, increased use of enteral nutrition may result in improved patient outcomes and improved cost-effectiveness.


Comprehensive analysis of clinical and laboratory features of 440 published cases of Sjögren's syndrome and renal tubular acidosis.
To describe the clinical and laboratory features of Sjögren's syndrome (SS) with renal tubular acidosis (RTA) from published literature. A systematic search of indexed publications in all languages till December 2021 identified cases of SS with RTA (SS-RTA) and were included if either antibody (anti-SSA/anti-SSB) or salivary gland histopathology were positive. There were 440 cases of SS-RTA (63.9% from Asia, 95.5% women). The median (range) age was 37 (6-78) years. Only 7.7% had a previous diagnosis of SS. Oral or ocular sicca symptoms were present in 63.7%. Positive ocular tests, oral tests, anti-SSA, anti-SSB and salivary gland histopathology were reported in 256/331 (77.3%), 123/128 (96%), 382/407 (93.9%), 298/379 (78.6%), and 246/268 (91.8%), respectively. Hypokalemic paralysis (HP) was the presenting feature in 63.6%; 25% had multiple episodes of HP and 8.4% had respiratory paralysis. Type 1, type 2, combined type 1 & 2, and type 4 RTA was seen in 388, 8, 38, and 3 patients, respectively. Proximal dysfunction and RTA complications were infrequently evaluated. Fanconi syndrome, nephrogenic diabetes insipidus, proteinuria, and low estimated glomerular filtration rate were found in 45, 21, 178, and 157, respectively. Nephrocalcinosis, renal stones, and osteomalacia were reported in 92, 79, and 72, respectively. Tubulointerstitial nephritis was found in 142 out of 152 renal biopsies. SS-RTA is an early manifestation of SS characterized by younger age and subclinical sicca symptoms. Although evaluated less frequently, oral sicca signs and salivary gland biopsy have a high positive yield. HP is the most common presentation. RTA is mostly distal; proximal dysfunction and complications were infrequently assessed.


PEGylating poly(p-phenylene vinylene)-based bioimaging nanoprobes.
Conjugated polymer nanoparticles (CNPs) have attracted considerable attention within bioimaging due to their excellent optical properties and biocompatibility. However, unspecific adsorption of proteins hampers their effective use as advanced bioimaging probes. Controlled methodologies made possible tailor-made functional poly(p-phenylene vinylene), enabling one-pot synthesis of CNPs containing functional surface groups. Hence, it should be feasible to PEGylate these CNPs to tune the uptake by cell lines representative for the brain without imparting their optical properties. CNPs consisting of the statistical copolymer 2-(5'-methoxycarbonylpentyloxy)-5-methoxy-1,4-phenylenevinylene and poly(2-methoxy-5-(3',7'-dimethoxyoctyloxy)-1,4-phenylenevinylene) were fabricated by miniemulsion solvent evaporation technique. Surface carboxylic acid groups were used to covalently attach amine-terminated polyethylene glycol (PEG) of different molecular weights. We investigated the effect of grafting CNPs with PEG chains on their intrinsic optical properties, protein adsorption behavior and uptake by representative brain cell lines. PEGylation did not affect the optical properties and biocompatibility of our CNPs. Moreover, a significant decrease in protein corona formation and unspecific uptake in central nervous system cell lines, depending on PEG chain length, was observed. This is the first report indicating that PEGylation does not affect the CNPs role as excellent bioimaging tools and can be adapted to tune biological interactions with brain cells.


Measurement of serum progesterone by isotope dilution liquid chromatography tandem mass spectrometry: a candidate reference method and its application to evaluating immunoassays.
Measurement of serum progesterone is important in determining ovarian function. Most progesterone measurements are performed with immunoassays and results are often variable. Standardization of the measurements requires a reliable reference method. An isotope dilution liquid chromatography tandem mass spectrometry (ID-LC/MS/MS) method for the measurement of serum progesterone was developed. Serum samples were spiked with 13C3-progesterone, extracted with a three-step liquid-liquid extraction, and analyzed by LC/MS/MS. A bracketing calibration was used for the analysis and samples were prepared gravimetrically. The developed method showed intra-run and total relative standard deviations (RSDs) of 0.50~0.58% and 0.71~1.33%, respectively. The analytical recoveries were 99.08~101.50%. Measurement results on certified reference materials obtained with this method agreed with the certified values within the stated measurement uncertainties. The method was applied to evaluate immunoassays through split-sample comparisons. A panel of 48 fresh frozen individual samples were measured with the ID-LC/MS/MS method, and six immunoassays and results were compared. Significant calibration biases and sample-specific deviations were observed on some of the immunoassays.


Cancer of the neovagina.
Cancer of the neovagina has been documented, and found to occur at younger ages than cancer of the native vagina. A review of the world literature was performed to evaluate risk based on type of tissue used for replacement or reconstruction of the vagina, as well as signs and symptoms of tumor occurrence and follow-up possibilities for early detection/screening for cancer and precancerous changes. Comprehensive review of relevant published literature. Creation of a neovagina is infrequently performed with no established follow-up pattern. Neovaginal construction uses a variety of tissues: bowel, skin graft, vulvar skin flaps, rectus abdominus (myocutaneous) flaps, inverted penile skin. When exogenous tissue is used, tissue dysplasia can be expected because the tissue is suddenly subjected to new contacts/stresses. Pathological criteria of abnormality in epithelium transplanted to a vaginal location are not well established. Case reports suggest that squamous cell cancers occur in skin-graft vaginal constructions and adenocarcinomas occur in vaginas constructed of bowel. Clear or bloody discharge and postcoital bleeding are the most frequent first symptoms. Endoscopy and biopsy are needed for diagnosis. Although considered rare, many cases of cancer of the neovagina are documented in the literature. Careful follow up of patients who have undergone neovagina construction is important.


Viral nucleic acid synthesis in HSV infected neural cells.
HSV-1 replication and synthesis of viral DNA and RNA have been examined in gliomas of human (COX) and rat origin (C6) and in mouse neuroblastomas (D2). COX cells fully support HSV-1 replication and show patterns of viral DNA and RNA synthesis similar to those seen in continuous line cells. HSV-1 also grows to high titers in D2 cells but without concomitant high levels of viral DNA and RNA synthesis in the infected cells. Finally, HSV-1 established a persistent infection in C6 cells. Viral mRNA and DNA synthesis could not be detected in these cultures. At cycles of approximately 15--20 days, the persistently infected cultures exhibited massive CPE and relatively high production of infectious HSV.


[Retroperitoneal liposarcoma--contribution to differential diagnostic problems of primary retroperitoneal tumors].
The primary retroperitoneal tumours-a rare, but histologically very extensive group of above all malignant tumours-only late appear with their symptoms. Though with the help of the modern radiological investigation methods the proof of a tumour is frequently successful, so in special cases a coordination to organs may make great difficulties also when the total diagnostic spectre is used. These problems shall be shown by the demonstration of a case report.


The impact of head position on the cuff and tube tip position of preformed oral tracheal tubes in young children.
Head and neck movements affect both the length of the trachea and the position of tracheal tubes. This is of relevance when using cuffed tubes because changes in the position of the tube tip may not be equal to changes in the position of the cuff. The aim of the study was to assess the impact of head and neck movement on the position of the tube tip and the cuff of newly designed, oral preformed tracheal tubes in children. The tracheas of 128 children aged 1-8 years were intubated with preformed oral tubes. The distances 'carina-to-tracheal tube tip' and 'vocal cords-to-tube tip' were measured endoscopically. These measurements were performed with the head and neck in a functional neutral position (110 degrees ), during neck flexion (80 degrees ) and neck extension (130 degrees ). Tracheal length was dependent on head and neck position: neck extension elongated the trachea (p < 0.0001), and neck flexion shortened the trachea (p < 0.0001). Neck flexion moved the tube inward and resulted in endobronchial displacement in two patients. Neck extension moved the tube outwards. While no cuff was positioned between the vocal cords, cuff movement to the cricoid area occurred frequently. Complex interactions during head and neck movement along with the fixed insertion depth of preformed tubes often cause inadvertent malpositioning of the tube tip and cuff. Further changes to tube and cuff lengths might improve the safety of oral preformed tubes in children.


Ethical issues arising from the performance of pelvic examinations by medical students on anesthetized patients.
Anesthetized women are frequently examined by medical students before gynecologic surgery is performed. We argue that the key element in determining the appropriateness of such examinations is whether there is benefit to the patient as a result. Because every member of a surgical team needs a clear understanding of the nature, goals, and technical steps to be used in carrying out any operation, it is appropriate for a medical student to examine those patients in whose surgery he or she is going to participate as an active member of the surgical team. However, if pelvic examinations are carried out "solely for educational purposes" by students who are not actual members of the operating team, such actions are not appropriate unless specific permission has been obtained from the patient by the surgeon in charge of the case.


Timely Endoscopic Recognition of Aortoesophageal Fistula With Successful Treatment.
Aortoesophageal fistula (AEF) is a devastating cause of upper gastrointestinal bleeding that occurs because of pathologic communication of the esophagus with the aorta. Bleeding AEF has high mortality even with appropriate interventions. In this study, we present a case of a 52-year-old man who presented with hematemesis, which was found to be due to an actively bleeding AEF. Prompt identification of the fistula led to multiple endoscopic interventions that stabilized the patient and allowed him to undergo emergent endovascular aortic stent placement with successful bleeding control.


Structural Insights into the Assembly of the Adeno-associated Virus Type 2 Rep68 Protein on the Integration Site AAVS1.
Adeno-associated virus (AAV) is the only eukaryotic virus with the property of establishing latency by integrating site-specifically into the human genome. The integration site known as AAVS1 is located in chromosome 19 and contains multiple GCTC repeats that are recognized by the AAV non-structural Rep proteins. These proteins are multifunctional, with an N-terminal origin-binding domain (OBD) and a helicase domain joined together by a short linker. As a first step to understand the process of site-specific integration, we proceeded to characterize the recognition and assembly of Rep68 onto the AAVS1 site. We first determined the x-ray structure of AAV-2 Rep68 OBD in complex with the AAVS1 DNA site. Specificity is achieved through the interaction of a glycine-rich loop that binds the major groove and an α-helix that interacts with a downstream minor groove on the same face of the DNA. Although the structure shows a complex with three OBD molecules bound to the AAVS1 site, we show by using analytical centrifugation and electron microscopy that the full-length Rep68 forms a heptameric complex. Moreover, we determined that a minimum of two direct repeats is required to form a stable complex and to melt DNA. Finally, we show that although the individual domains bind DNA poorly, complex assembly requires oligomerization and cooperation between its OBD, helicase, and the linker domains.


A comparative study to determine the effects of breed and feed restriction on glucose metabolism of chickens.
The glucose metabolism of poultry draws wide attention as they have nearly twice the fasting blood glucose than that of mammals. To define the relationship between glucose metabolism and breed of chicken, the outcomes from different growth rate chickens showed that Arbor Acres (AA) broilers, a well-known fast-growing breed, had a lower fasting blood glucose concentration and glucose clearance rate when compared to Silky chickens, a Chinese traditional medicinal chicken with black skin and a slow growth rate. Moreover, AA broilers had a relatively slow rise in blood glucose in response to oral glucose solution than the Silky chickens on 21 and 42 d (P < 0.05), which is probably attributed to downregulated expression of pancreatic insulin (INS), and upregulated transcription of phosphoenolpyruvate carboxy kinase 1 (PCK1) and glucose transporter 2 (GLUT2) in the liver of AA broilers (P < 0.05). In response to feeding restriction from 7 to 21 d, both the fasting blood glucose and the response speed of AA broilers to oral glucose were increased on d 21 (P < 0.05), and the serum glucose concentrations after 3 weeks compensatory growth were improved by early feed restriction in AA broilers. Feed restriction could also upregulate the mRNA level of pancreatic INS on d 21 and 42, as well as decrease the expressions of PCK1, glucose-6-phosphatase catalytic (G6PC), and GLUT2 in the liver on d 21 (P < 0.05) when compared to the free feeding group. These results revealed that Silky chickens have a stronger capability to regulate glucose homeostasis than AA broilers, and feed restriction could improve the fasting blood glucose and the response to oral glucose of AA broilers.


Aerobic training improves bone fragility by reducing the inflammatory microenvironment in bone tissue in type 2 diabetes.
Aerobic training (AT) is indicated in type 2 diabetes mellitus (T2DM) to control hyperglycaemia and inflammation. AT improves bone microarchitecture and resistance to fracture. The intensity of AT and the mechanisms that lead to the improvement in bone quality are still unknown. Using a mouse model of T2DM, we evaluated the effects of two intensities of forced AT. We divided mice into: sedentary (SED), T2DM-SED, low runners (LOW), T2DM-LOW, high runners (HIGH) and T2DM-HIGH. The AT for low was 8 m/minute (m/min); 5° slope or high 18 m/min; 15° slope for 2 months. We measured metabolic parameters, the serum cytokines concentration, lipocalin-2 (LCN-2) and adiponectin; and the tibial concentrations of LCN-2, tumour necrosis factor alpha (TNF-α) and protein carbonylation (CO). We evaluated femur morphometry and biomechanical properties. We performed multiple correlation analysis. The T2DM-LOW versus T2DM-SED group, shown an increase of interleukin (IL)-10 (417 ± 90 vs 102 ± 25 pg/mL) and improved trabecular bone (BV/TV: 31.8 ± 2.3 vs 19.25 ± 1.4%; Tb.Sp.: 1.62 ± 0.02 vs 2.0 ± 0.07 mm), by a decrease bone CO (3.4 ± 0.1 vs 6.0 ± 0.5 nmol/mg), bone TNF-α (84 ± 4 vs 239 ± 13 pg/mL) and LCN-2 (2887 ± 23 vs 3418 ± 105 pg/mL). The T2DM-HIGH versus T2DM-SED group showed a greater hypoglycaemic effect (228 ± 10 vs 408 ± 5 mg/dL), with improved cortical bone density (0.26 ± 0.012 vs 0.21 ± 0.007 mm) and fracture resistance (102 ± 8 vs 78 ± 5 MPa), by a reduction of bone TNF-α (77 ± 34 vs 239 ± 13 pg/mL); LCN-2 (2768 ± 20 vs 3418 ± 105 pg/mL) and CO (4.8 ± 0.5 vs 6.0 ± 0.5 nmol/mg). In conclusion, AT improves bone morphometry and biomechanical properties by reducing the bone inflammatory microenvironment.


Clinical update on K-Ras targeted therapy in gastrointestinal cancers.
KRAS mutations are common in pancreatic and colorectal cancers and are associated with lack of response to anti-epidermal growth factor receptor therapy. Ras is an established therapeutic target that has long eluded efforts to develop specific inhibitors, while targeting downstream signaling pathways has proven largely ineffective, highlighting a need for rational combination strategies to overcome resistance. Recently, renewed interest in directly targeting Ras has led to the development of several small-molecule inhibitors that bind directly to K-Ras or its effector proteins, downregulation of K-Ras expression using therapeutic antisense oligonucleotides or siRNAs, and targeting scaffold proteins such as kinase suppressor of Ras. Indirect approaches to inhibiting K-Ras include combining inhibitors of the mitogen-activated protein kinase pathway with novel targeted agents. Immunotherapy in early studies has also shown clinical promise. This review summarizes the current evidence for each of these approaches.


Chemokines as Regulators of Neutrophils: Focus on Tumors, Therapeutic Targeting, and Immunotherapy.
Neutrophils are an important component of the tumor microenvironment, and their infiltration has been associated with a poor prognosis for most human tumors. However, neutrophils have been shown to be endowed with both protumor and antitumor activities, reflecting their heterogeneity and plasticity in cancer. A growing body of studies has demonstrated that chemokines and chemokine receptors, which are fundamental regulators of neutrophils trafficking, can affect neutrophil maturation and effector functions. Here, we review human and mouse data suggesting that targeting chemokines or chemokine receptors can modulate neutrophil activity and improve their antitumor properties and the efficiency of immunotherapy.


Vertical flux of microplastic, a case study in the Southern Ocean, South Georgia.
Estimated plastic debris floating at the ocean surface varies depending on modelling approaches, with some suggesting unaccounted sinks for marine plastic debris due to mismatches between plastic predicted to enter the ocean and that accounted for at the surface. A major knowledge gap relates to the vertical sinking of oceanic plastic. We used an array of floating sediment traps combined with optical microscopy and Raman spectroscopy to measure the microplastic flux between 50 and 150 m water depth over 24 h within a natural harbour of the sub-Antarctic island of South Georgia. This region is influenced by fishing, tourism, and research activity. We found a 69 % decrease in microplastic flux from 50 m (306 pieces/m2/day) to 150 m (94pieces/m2/day). Our study confirms the occurrence of a vertical flux of microplastic in the upper water column of the Southern Ocean, which may influence zooplankton microplastic consumption and the carbon cycle.


Comparing strategies for prehospital transport to specialty care after cardiac arrest.
Outcomes are better when patients resuscitated from out-of-hospital cardiac arrest (OHCA) are treated at specialty centers. The best strategy to transport patients from the scene of resuscitation to specialty care is unknown. We performed a retrospective cohort study. We identified patients treated at a single specialty center after OHCA from 2010 to 2021 and used OHCA geolocations to develop a catchment area using a convex hull. Within this area, we identified short term acute care hospitals, OHCA receiving centers, adult population by census block group, and helicopter landing zones. We determined population-level times to specialty care via: (1) direct ground transport; (2) transport to the nearest hospital followed by air interfacility transfer; and (3) ground transport to air ambulance. We used an instrumental variable (IV) adjusted probit regression to estimate the causal effect of transport strategy on functionally favorable survival to hospital discharge. Direct transport to specialty care by ground to air ambulance had the shortest population-level times from OHCA to specialty care (median 56 [IQR 47-66] minutes). There were 1,861 patients included in IV regression of whom 395 (21%) had functionally favorable survival. Most (n = 1,221, 66%) were transported to the nearest hospital by ground EMS then to specialty care by air. Patient outcomes did not differ across transport strategies in our IV analysis. We did not find strong evidence in favor of a particular strategy for transport to specialty care after OHCA. Population level time to specialty care was shortest with ground ambulance transport to the nearest helicopter landing zone.


Cortisol, obesity, and the metabolic syndrome: a cross-sectional study of obese subjects and review of the literature.
Circulating cortisol and psychosocial stress may contribute to the pathogenesis of obesity and metabolic syndrome (MS). To evaluate these relationships, a cross-sectional study of 369 overweight and obese subjects and 60 healthy volunteers was performed and reviewed the previous literature. Overweight and obese subjects had at least two other features of Cushing's syndrome. They underwent measurements representing cortisol dynamics (24 h urine cortisol excretion (UFC), bedtime salivary cortisol, 1 mg dexamethasone suppression test) and metabolic parameters (BMI, blood pressure (BP); fasting serum triglycerides, HDL, insulin, and glucose). Subjects also completed the Perceived Stress Scale (PSS). UFC, salivary cortisol, and weight from 60 healthy volunteers were analyzed. No subject had Cushing's syndrome. UFC and dexamethasone responses were not associated with BMI or weight. However, salivary cortisol showed a trend to increase as BMI increased (P < 0.0001), and correlated with waist circumference (WC) in men (rs = 0.28, P = 0.02) and systolic BP in women (rs = 0.24, P = 0.0008). Post-dexamethasone cortisol levels were weak to moderately correlated with fasting insulin (rs = -0.31, P = 0.01) and HOMA-IR (rs = -0.31, P = 0.01) in men and systolic (rs = 0.18, P = 0.02) and diastolic BP (rs = 0.20, P = 0.009) in women. PSS results were higher in obese subjects than controls, but were not associated with cortisol or metabolic parameters. As expected, WC correlated with fasting insulin, HOMA-IR, and systolic BP (adjusted for BMI and gender; P < 0.01). Literature showed inconsistent relationships between cortisol and metabolic parameters. Taken together, these data do not support a strong relationship between systemic cortisol or stress and obesity or MS.


LOX-1 deletion decreases collagen accumulation in atherosclerotic plaque in low-density lipoprotein receptor knockout mice fed a high-cholesterol diet.
Collagen, as a component of the extracellular matrix, has been linked to atherosclerotic plaque formation and stability. Activation of LOX-1, a lectin-like oxidized low-density lipoprotein (LDL) receptor-1, exerts a significant role in collagen formation. We examine the hypothesis that LOX-1 deletion may inhibit collagen accumulation in atherosclerotic arteries in LDL receptor (LDLR) knockout (KO) mice. We generated LOX-1 KO and LOX-1/LDLR double KO mice on a C57BL/6 (wild-type mice) background and fed a 4% cholesterol/10% cocoa butter diet for 18 weeks. Vessel wall collagen accumulation was increased in association with atherogenesis in the LDLR KO mice (P < 0.01 vs. wild-type mice), but much less so in the double KO mice (P < 0.01 vs. LDLR KO mice). Collagen accumulation data were corroborated with pro-collagen I measurements. Expression/activity of osteopontin, fibronectin, and matrix metalloproteinases (MMP-2 and MMP-9) was also increased in the LDLR KO mice (P < 0.01 vs. wild-type mice), but not in the mice with LOX-1 deletion (P < 0.01 vs. LDLR KO mice). The expression of NADPH oxidase (p47(phox), p22(phox), gp91(phox), and Nox-4 subunits) and nitrotyrosine was increased in the LDLR KO mice (P < 0.01 vs. wild-type mice) and not in mice with LOX-1 deletion (P < 0.01 vs. LDLR KO mice). Phosphorylation of Akt-1 and endothelial nitric oxide synthase and expression of haem-oxygenase-1 were found to be reduced in the LDLR KO mice (P < 0.01 vs. wild-type mice), but not in the mice with LOX-1 deletion (P < 0.01 vs. LDLR KO mice). LOX-1 deletion reduces enhanced collagen deposition and MMP expression in atherosclerotic regions via inhibition of pro-oxidant signals.


Warm ischemia lung protection with pinacidil: an ATP regulated potassium channel opener.
Ischemia/reperfusion injury remains a limiting factor in lung transplantation. Traditional hyperkalemic preservation solutions are associated with a host of metabolic derangements. ATP-regulated potassium channel openers (PCOs) may provide an attractive alternative to traditional solutions by utilizing inherent mechanisms of ischemic preconditioning. The purpose of this study was to assess warm ischemia graft protection with pinacidil, a nonspecific PCO. An isolated recirculating blood perfused ventilated rabbit lung model was used (n = 15). No ischemia control lungs underwent immediate reperfusion (n = 5). Warm ischemia control lungs were flushed with lactated Ringers (LR), stored at 37 degrees C for 2.5 hours and then reperfused for 2 hours (n = 5). PCO protected lungs were flushed with LR + 100 micromol/L pinacidil, stored, and then reperfused (n = 5). Intermittent blood gases were taken from the pulmonary artery and left atria. Every 30 minutes, graft function was assessed with a 10-minute 100% fractional inspired oxygen concentration challenge to measure maximal gas exchange. Lung samples were graded for histologic injury and assayed for myeloperoxidase activity. A mixed-models repeated measures ANOVA demonstrated a significant difference between groups. Tukey's honestly significant difference multiple comparison test demonstrated significantly improved graft function and reduced histologic injury with pinacidil protection compared with the warm ischemia controls. There was no significant difference in graft function or pathology grade between the pinacidil protected lungs and the no ischemia controls. A similar trend, although not significant, was seen in myeloperoxdiase activity. Potassium channel openers with pinacidil can provide pulmonary protection against warm ischemia reperfusion injury.


Laparoscopic sacrocolpopexy as the mainstay management for significant apical pelvic organ prolapse (LAP) study.
The primary aim of this study was to assess the clinical feasibility of a policy where laparoscopic sacrocolpopexy (LSC) is the default procedure for the management of a significant apical pelvic organ prolapse (a-POP). As a secondary aim, we wanted to evaluate LSC outcomes in relation to women's preoperative assessment of their surgical fitness using the American Society of Anesthesiologists physical status (ASA-PS) categorization. Retrospective cohort study. A university affiliated urogynecology center. All women with symptomatic a-POP (C ≥ -1) who attended the urogynecology clinic between the 1st of January and the 31st of December 2016 and had their surgery by the 31st of May 2017 were included in the study. In our unit, routine follow-up appointments are arranged at 3 and 12 months post LSC. Perioperative and mesh-related complications were assessed based on the Dindo-Clavien and IUGA/ICS classifications respectively. The preoperative outcome measures included Pelvic Organ Prolapse Quantification (POP-Q) stage, Pelvic Floor Distress Inventory (PFDI) and ASA-PS score. At follow-up women were asked to complete a PFDI, Patient Global Impression of Improvement (PGI-I), had their POP-Q staging and ultrasonographic assessment of mesh position and placement. The above measures are routinely collected as part of our standard practice. A preoperative ASA-PS score of <3 was used as a cut-off to dichotomies participants into low and high risk. A total of 220 women attended our center during the study period because of POP. Of these, 146 women were diagnosed with a significant a-POP and 142 (97.2 %) women opted for a surgical repair. Of the 142 women, 128 (90.1 %) were deemed suitable for a type of LSC and 121 had their surgery before the 31st of May 2017. There were no statistically significant differences in any of our collected perioperative, clinical, patient reported or ultrasonographic outcome measures when comparing women with ASA-PS scores of <3 or ≥3. In a specialized urogynecology healthcare setting, it is feasible and safe to rely on LSC as the mainstay surgical procedure for the repair of a significant a-POP. However, it is imperative to ensure that technical skills and equipment requirements are fulfilled and maintained.


Family's role in long-term care-A qualitative study of Finnish family members' experiences on supporting the functional ability of an older relative.
Family members are important providers of care for older people. In residential long-term care, however, their role is not always simple and straightforward: responsibility for care provision rests officially with staff members, but in practice family members often contribute to providing care. The main reason for admission to long-term care is functional decline. At the same time, the maintenance of functional ability is a central goal in long-term care. It is therefore reasonable to assume that functional ability is also an important factor in the relationship between family members and long-term care residents. This study aims to explore how family members experience their role in supporting the functional ability of older relatives in residential long-term care. With the approval of the local hospital district's ethics committee, we conducted semi-structured interviews with family members (n = 16) in Finland in 2016. Thematic data analysis showed that family members supported the functional ability of their older parent or spouse by organising and monitoring care and by bringing forth their relative's personal needs and wishes. They often saw their role alongside staff members as ambiguous, and their understanding of the scope of support for functioning extended beyond physical everyday tasks. In their talk, family members broadened the concept of functional ability from daily chores and independence to meaningful social relations and acknowledgement of person's individual background and preferences. Family members' views offer valuable insights into residents' personal needs, values and preferences and in doing so help care workers to support their functional ability with a person-centred care approach.


The effects of climatic pattern on lichen productivity: Cetraria cucullata (Bell.) Ach. in the arctic tundra of northern Alaska.
The climatic control of productivity for two populations of the lichen Cetraria cucullata (Bell.) Ach. growing in the arctic tundra of northern Alaska (70°28'N, 157°23'W) was examined. Respiratory losses of carbon vary with tissue temperature, tissue water content, and time since wetting. Potential net photosynthetic gains of carbon are affected by photon flux density, tissue temperature, and water content. The net CO2 exchange responses of populations growing on ridge tundra and on upland tundra differ and these differences reflect possible adaptation to the normal environmental regimes in the two habitats. Simulation of the lichen's net carbon balance using continuous hourly records of photon flux density, temperature, and water content for the unusually dry period June 28 through July 17, 1977 show that lichen biomass is actually lost during climatic regimes leading to frequent but short periods of lichen metabolic activity. This result is confirmed by the negative relative growth rates measured for C. cucullata over the same monitoring period. This observed loss of biomass may be attributable to depletion of carbon reserves to reactivate dormant metabolism without sufficiently long periods favorable for net photosynthetic activity to replenish the lost reserves. These results illustrate that environmental limits exist on the success of the dormancy strategy characteristic of lichen and moss carbon metabolism.


Construct validity of the childbirth trauma index for adolescents.
The potentially traumatic nature of childbirth for adult mothers has been confirmed in research; however, adolescent childbirth trauma is unexplored. This article presents research on the construct validity of the Childbirth Trauma Index by providing a conceptual analysis of psychological childbirth trauma, factor validity of the Childbirth Trauma Index, and discussion of testing the Childbirth Trauma Index via contrasted-groups approach. Childbirth trauma can result in an acute stress reaction or actual posttraumatic stress disorder. Using subjective reports, the Impact of Event Scale, and the Childbirth Trauma Index, an appraisal of birth trauma, trauma impact, and indicators associated with childbirth trauma were revealed among 112 adolescents. Clinical implications and research recommendations are offered.


An enhanced incorporation of fatty acid into phosphatidyl choline that parallels histamine discharge in mast cells.
Purified rat peritoneal and pleural mast cells preincubated briefly with radioactively labeled fatty acid were treated with A23187, which bypasses primary receptors in stimulating exocytosis. An enhanced incorporation of fatty acid into phosphatidyl choline (PC) that occurred in parallel with histamine release at 24-25 degrees C was observed and was initially proportional to the total amount of histamine discharged. Enhanced PC labeling and histamine secretion were also proportional at temperatures ranging from 17-37 degrees C. Both radioactive linoleic and palmitic acids were incorporated selectively at the beta-position of the glycerol backbone of PC. PC labeling by [3H]choline was not detectably different in control and stimulated cells, and phosphatidic acid did not exhibit selectively enhanced beta-acylation. Thus, the stimulated labeling in A23187-treated cells may occur secondary to the action of a phospholipase A2 that favors PC as a substrate. Other peritoneal cell types exhibit a very similar A23187-stimulated selective labeling of PC. Therefore, autoradiography has been used to provide a direct demonstration that in purified preparations, mast cells are the principal cell type engaged in A23187-elicited incorporation of fatty acid into PC. The efficacy of this approach has relied on special procedures devised to obtain significantly different autoradiographic grain densities between control and stimulated preparations that can be attributed to differences in the level of [3H]palmitate-labeled PC. Preliminary tests using compound 48/80 as a secretory stimulus for mast cells have identified a similar selectively enhanced PC labeling. In either case, however, consideration of possible relationships between PC metabolism and the secretory process are premature since they have not been tested directly.


[Luminescence microscopy determination of the survival of yeasts after dehydration].
The technique of luminescent microscopy can be used to determine the survival rate of yeast organisms dehydrated by the convective method. If the cells were subjected to more severe extreme actions, the technique should be combined with the direct microscopy to follow the growth of reactivated organisms and to count the number of microcolonies being formed. The authors propose to classify the state of living organisms after the action of sublethal factors basing on the ability of cells to grow after reactivation.


Surgeon-read screening mammography: an analysis of 11,948 examinations.
Mammography was pioneered by surgeons but is now the domain of radiologists. With ever-increasing cost pressures it must be examined whether interpretation of mammography by clinicians and radiation technologists is comparable to that of breast radiologists. We present the largest series of surgeon-read screening mammography to date. All mammography performed between 2003 and 2009 at a comprehensive breast centre was recorded prospectively. First assessment was by a radiation technologist and consensus established after second reading by a breast surgeon, who took responsibility for the reading. Data recorded were: age, hormonal replacement therapy, prior breast surgery, indications for mammography and outcomes. Outcomes were classified based using the Breast Imaging Reporting and Data System (BIRADS). Indeterminate lesions were imaged further or underwent tissue acquisition. All BIRADS 5 lesions underwent tissue acquisition. Of 11,948 mammograms, 538 were reported as indeterminate/compatible with malignancy; 240 biopsies were performed, and 87 cancers diagnosed. In 40-49-year-old women (4,956 mammograms), the recall rate was 4.2%, the biopsy rate was 1.6%, the malignancy rate of biopsy was 23.7% and the cancer diagnosis rate was 3.6/1,000 examinations; for 50-69-year-old women these figures were 6,546, 4.7, 2.2, 44.1% and 10.0/1,000, respectively, and in women older than 70 years, they were 446, 5.6, 3.4, 33.3% and 11.2/1,000, respectively. Of all cancers, 32.2% were non-invasive; of invasive cancers, 49.1% were 10 mm or less in diameter and 75% were node negative. These results are similar to those in high-quality organized screening programs. The role of breast surgeons in mammography interpretation should be expanded.


Human Health Risks Associated with Metals from Urban Soil and Road Dust in an Oilfield Area of Southeastern Algeria.
Hassi Messaoud town is a recent city that is situated inside the oil field, which hosts an important petroleum extraction field and refinery. Large-scale and long-term oil refinery and corresponding industrial activities may contaminate the surrounding soil/dust and could lead to pollution levels that can affect human health. The soil and road dust samples were analysed for different trace elements: copper (Cu), manganese (Mn), nickel (Ni), lead (Pb), and zinc (Zn). Geo-accumulation index (I(geo)), pollution index (PI), and integrated pollution index (IPI) were calculated to evaluate the heavy metal contamination level of urban soil and road dust. The I(geo) values indicate unpolluted to moderate polluted of investigated metals in the soil samples. The assessment results of PI support the results of I(geo), and IPI indicates heavy metals in road dust polluted seriously. The noncarcinogenic health risk assessment shows that ingestion of soil/dust particles is the route for exposure to heavy metals, followed by dermal adsorption. The human exposure risk assessment based on different exposure pathways showed that the hazard index (HI) was <1.0 for all of the elements. The relative exposure risk (noncarcinogenic) was greater for toddlers. Although the overall risk was within the acceptable limit of 1.00, the HI of Pb from the soil (0.103) and road dust (0.132) was close to the threshold limits, which over the long-term may pose a health risk.


From payments for ecosystem services to eco-compensation: Conceptual change or paradigm shift?
Payments for ecosystem services (PES) is an effective policy in conserving ecosystem services and is increasingly applied globally. The concept of PES was firstly defined in 2005, researches with various terminologies, concepts, and practices emerged since then. This paper analyzed the research patterns of PES studies through bibliometric methods, with a special focus on the trends of terminology, location (geographical research hotspot), types of PES, and PES effectiveness evaluation based on author keywords analysis. The results showed that PES started to receive considerable academic attentions from 2005, and the number of PES publications have relatively kept an increasing trend since then. The most influential journal, country, research organization, and author were Ecological Economics, USA, Chinese Academy of Sciences (CAS, China), and Dr. Wunder. Further analysis revealed that there were various terminologies in PES studies, notably "ecological compensation" and "eco-compensation" (EC) were primarily adapted by Chinese research community. China was the geographical research hotspot and developing countries (Vietnam, Mexico, and Brazil) have received growing academic interests in last decade. "Forest and Carbon" PES was the most concerned types of PES in last five years. There were 125 articles evaluated the effectiveness of empirical PES initiatives, and the majority focused on the social aspect. We proposed two suggestions for future research: (1) adapting EC as an alternative term for PES studies because of its inclusiveness and representation of empirical practices; (2) enhancing integrated evaluation of PES programs to achieve multiple benefits.


Epidemiology and pathogenesis of osteoporosis.
Osteoporosis is likely to become the most common disorder of our aging population. An understanding of factors that affect the incidence of osteoporosis is critical if we are to successfully minimize the impact of this disorder on morbidity, mortality, and the cost of health care. This article will provide an overview of the frequency, distribution, and consequences of the various types of osteoporotic fractures in different populations. We will discuss the major risk factors, emphasizing those that are reversible. Fracture risk not only involves abnormalities of bone mass and architecture, but also factors that affect the incidence of falls. The racial, ethnic, and geographic differences in fracture incidence are associated with parallel differences in bone mineral density (BMD), but the differences are often relatively small, suggesting that other architectural or metabolic differences in the skeleton make an important contribution. On the other hand, when combined with low BMD, multiple risk factors and comorbid conditions increase the risk of fracture as well as morbidity and mortality from fracture. Osteoporosis can result pathogenetically from inadequate peak bone mass, excessive bone resorption, or impaired bone formation. These can be affected by genetics, nutrition, lifestyle, systemic hormones, and local factors. The relative importance of these mechanisms is not fully understood and may differ among patients. Nevertheless, our current understanding of epidemiology and pathogenesis can help clinicians to develop the optimal approach to diagnosis and management.


Electron microscopic analysis of in vitro transcriptional complexes: mapping of promoters of the coliphage T5 genome.
Transcriptional complexes formed in vitro with coliphage T5 DNA as template were analyzed by electron microscopy and the number and location of starting sites utilized by E. coli RNA polymerase were determined. Of the 40 promoters characterized in this way, 6 map in the two terminal "pre-early" regions, 29 in the "early" and 5 in the "late" region. The direction of transcription within the different regions determined in this study agrees with earlier findings derived from RNA synthesized in vivo.


Differential MRI diagnosis between brain abscesses and necrotic or cystic brain tumors using the apparent diffusion coefficient and normalized diffusion-weighted images.
Magnetic Resonance Diffusion-Weighted Imaging (DWI) has been reported to be helpful for the differential diagnosis between abscesses and cystic/necrotic brain tumors. However the number of patients is still limited, and the sensitivity and specificity of the method remain to be confirmed. The primary purpose of this study was to investigate a larger sample of patients, all investigated under the same experimental conditions, in order to obtain statistically significant data. Moreover, there is no consensus about the appropriate values of b required to use to make an accurate diagnosis from DWI. The secondary purpose of this study was to determine the discriminating threshold b values for raw diffusion-weighted images and for normalized diffusion-weighted images. On the basis of 14 abscesses, 10 high-grade gliomas and 2 metastases, we show that the calculation of accurate Apparent Diffusion Coefficient (ADC) values gives a specificity rate of 100%. Without ADC calculation, we show that image normalization is required to make an accurate differential diagnosis, and we highlight the ability of DWI to discriminate between brain abscesses and cystic/necrotic brain tumors using normalized signal intensity at lower b values (503 s/mm(2)) than usual.


Immunogenetic basis of HIV-1 infection, transmission and disease progression.
Susceptibility to HIV-1 infection and rate of disease progression to AIDS are complex traits modulated by environmental and genetic factors. Studies on large AIDS cohorts and their meta-analyses have identified numerous AIDS restriction genes that regulate HIV cell entry (particularly chemokine co-receptors and their ligands), acquired and innate immunity (major histocompatibility complex (MHC), killer immunoglobulin-like receptors (KIRs), and cytokines) and others that influence outcome of HIV infection. However, vast inter-individual variability is often observed and some rare individuals like 'long-term non-progressors (LTNPs) or exposed uninfected' (EUs) appear to be protected due to natural resistance. A better understanding of genetic basis of such a 'natural resistance' to infection would bear important implications in designing therapeutic vaccine designs. The genetic variants that could limit AIDS vary in different populations. We have studied genetic variations in the MHC, cytokines and CCR2-CCR5 loci in the Asian-Indian HIV-infected population and compared with other global populations.


Absolute band neutrophils count is a predictor of overall survival in advanced uterine cervical cancer.
Neutrophils play a role during the oncogenic process, and their count can be a prognostic marker. The objective was to evaluate the association of band and segmented neutrophils with prognostic factors, overall survival, and disease-free survival in advanced uterine cervical cancer (IIB to IVB staging). This study evaluated 88 patients diagnosed with uterine cervical cancer staging IIB to IVB. The recorded data from medical records were age, parity, staging, histological type, absolute count of total neutrophils, band neutrophils and segmented neutrophils, disease-free survival, and overall survival. Receiver-operating characteristic (ROC) curve was used to obtain the area under the curve (AUC) and determine the best cut-off values for each parameter. Survival was verified by the Kaplan-Meier method, and multivariate analysis was performed by Cox regression. The level of significance was ≤ 0.05. Regarding the total neutrophils, band, and segmented neutrophils count, a cut-off value of 6187/mm3, 273 mm3 and 6062/mm3 were found, respectively. Overall survival was shorter in patients with total neutrophils greater than 6187/mm3 (p = 0.012), band neutrophils greater than 273/mm3 (p = 0.001), and segmented neutrophils greater than 6062/mm3 (p = 0.013). After multivariate analysis considering the two types of neutrophils, only band neutrophils greater than 273/mm3 remained as an independent factor for shorter overall survival. The absolute count of band neutrophils greater than 273/mm3 was a potential predictor of shorter overall survival in women with invasive cervical cancer. This count can be of great clinical use, in addition to being inexpensive, less invasive, and easy to perform.


Umpolung reactivity of difluoroenol silyl ethers with amines and amino alcohols. application to the synthesis of enantiopure alpha-difluoromethyl amines and amino acids.
Difluoroenol silyl ethers, produced in situ from acylsilanes and CF3TMS, react as electrophiles with amines to give difluoroimines, via the corresponding hemiaminal adduct, as evidenced by 19F NMR spectroscopy. Reaction with (R)-phenylglycinol led to 2-difluoromethyloxazolidines. After separation of the diastereomers, reduction with LAH and Strecker-type synthesis gave enantiopure alpha-difluoromethylamines and alpha-difluoromethyl-alpha-amino acids, respectively.


Advancements in CAD/CAM technology: Options for practical implementation.
The purpose of this review is to present a comprehensive review of the current published literature investigating the various methods and techniques for scanning, designing, and fabrication of CAD/CAM generated restorations along with detailing the new classifications of CAD/CAM technology. I performed a review of a PubMed using the following search terms "CAD/CAM, 3D printing, scanner, digital impression, and zirconia". The articles were screened for further relevant investigations. The search was limited to articles written in English, published from 2001 to 2015. In addition, a manual search was also conducted through articles and reference lists retrieved from the electronic search and peer-reviewed journals. CAD/CAM technology has advantages including digital impressions and models, and use of virtual articulators. However, the implementation of this technology is still considered expensive and requires highly trained personnel. Currently, the design software has more applications including complete dentures and removable partial denture frameworks. The accuracy of restoration fabrication can be best attained with 5 axes milling units. The 3D printing technology has been incorporated into dentistry, but does not include ceramics and is limited to polymers. In the future, optical impressions will be replaced with ultrasound impressions using ultrasonic waves, which have the capability to penetrate the gingiva non-invasively without retraction cords and not be affected by fluids. The coming trend for most practitioners will be the use of an acquisition camera attached to a computer with the appropriate software and the capability of forwarding the image to the laboratory.


3-(3-Nitro-phen-yl)-1-[4-(prop-2-yn-yloxy)phen-yl]prop-2-en-1-one.
The structure of the title compound, C18H13NO4, shows that the whole mol-ecule is almost planar but with a dihedral angle between the two phenyl rings of 19.22 (5)°. The mol-ecules are linked by C-H⋯O inter-actions, forming sheets in the (21) plane.


Genus Suaeda: Advances in phytology, chemistry, pharmacology and clinical application (1895 - 2021).
More than 100 species of annual herb genus Suaeda widely distribute (Asia, North America, northern Africa and Europe), are rich in resources (about hundreds of millions of tons/Y) and have a long historical application. Most of them are mainly used for traditional food, feed and medicine. Recently, they have been employed to repair saline-alkali land and beautify the environment. So far, only 27 species have been reported on the bioactivity diversity, broad spectrum and effectiveness in clinical practice. Therefore, the in-depth and extensive research of Suaeda has become a research hotspot around the world. However, only one review summarized the nutritional, chemical and biological values of Suaeda. By searching the international authoritative databases (ACS Publications, ScienceDirect, PubMed, Springer, web of Science and Bing International etc.) and collecting 103 literatures closely related to Suaeda (1895-2021), herewith a comprehensive and systematic review was conducted on the phytology, chemistry, pharmacology and clinical application, enveloping the classification evolution between Amaranthaceae and Chenopodiaceae, distribution and common botanical characteristics; involving 9 chemical categories of 163 derivatives covering 14 new and 6 first-isolated ones, and appraising the content determination of 6 categories of components; mainly including the pharmacology of 13 species in vivo and vitro; estimating the clinical application of 16 species cured the related diseases of eight human physiological system except for the motor system. It is expected that this paper will provide forward-looking scientific ideas and literature support for the further modern research, development and utilization of the genus.


Diltiazem pharmacokinetics in the rat and relationship between its serum concentration and uterine and cardiovascular effects.
1 The kinetics of diltiazem were investigated in ovariectomized (ovx) non-pregnant and intact late pregnant anaesthetized rats following a bolus i.v. injection (2 mg kg-1) and during a 180 min i.v. infusion (50 micrograms kg-1 min-1 and 100 micrograms kg-1 min-1). Uterine contractions, mean blood pressure and heart rate were measured in the non-pregnant rats. 2 Measurement of serum diltiazem concentrations after bolus i.v. injection in ovx non-pregnant rats showed a biexponential decay with time from which the following parameters were calculated: volume of distribution area (V(area)) - 256 +/- 46 ml; rate constants k12 - 0.46 +/- 0.10 min-1; k21 - 0.09 +/- 0.01 min-1; kel - 0.13 +/- 0.03 min-1; elimination clearance - 3.2 +/- 0.3 ml min-1; distribution t1/2 (t1/2) - 1.4 +/- 0.3 min; elimination t1/2 (t1/2 beta) - 61.2 +/- 13.0 min. In pregnant rats, a biexponential decay was also observed with similar parameters to those in non-pregnant animals except for markedly increased V(area) - 1004 +/- 184 ml; kel - 0.54 +/- 0.16 min-1 and elimination clearance - 14.8 +/- 2.3 ml min-1. 3 Measurement of serum diltiazem concentrations during infusion yielded the following parameters in non-pregnant ovx rats: V(ss)--79 +/- 10 ml; rate constants k12 - 1.02 +/- 0.21 min-1; k21 - 0.03 +/- 0.01 min-1; kel - 0.39 +/- 0.06 min-1; elimination clearance - 7.8 +/- 1.2 ml min-1. In pregnant rats a marked increase was observed in kel - 1.25 +/- 0.38 min-1 and elimination clearance - 36.4 +/- 13.8 ml min-1. 4 An immediate reduction in uterine contractions, mean blood pressure and heart rate was observed after bolus i.v. injection of diltiazem with a return towards control values as serum diltiazem concentrations declined. There were significant correlations between the inhibition of the 3 parameters and the log serum concentrations of diltiazem. Serum concentration-response curves indicated IC50 values of 0.5 microgram ml-1 for inhibition of uterine contractions, 0.7 microgram ml-1 for reduction in blood pressure and 1.2 micrograms ml-1 for reduction in heart rate. There were maintained reductions in the integral of uterine contractions, mean blood pressure and heart rate during infusion. 5 The metabolite desacetyldiltiazem was rarely detected after i.v. bolus injection and was not found in 5/13 rats infused with diltiazem, yet significant inhibition of uterine contractions was observed in all rats. Diltiazem was 3.2 fold more potent than desacetyldiltiazem as an inhibitor of contractions of the rat isolated uterus. 6 These findings indicate that the inhibition of uterine contractions is due to a direct action of diltiazem, and not the metabolite desacetyldiltiazem, and suggest only a slight selectivity for uterine inhibition compared to cardiovascular effects.


Risk scores for predicting mortality after surgical ventricular reconstruction for ischemic cardiomyopathy: results of a Japanese multicenter study.
Surgical ventricular reconstruction has been believed to be beneficial for those with ischemic cardiomyopathy. However, the effectiveness of surgical ventricular reconstruction was not proved by a large-scale trial, and no report has clearly demonstrated the exact indications and limitations of surgical ventricular reconstruction. The purpose of this study was to elucidate predictive factors of mortality after surgical ventricular reconstruction and to develop a prognostic model by calculating risk scores. The study subjects were 596 patients who underwent surgical ventricular reconstruction for chronic ischemic heart failure in 11 Japanese cardiovascular hospitals between 2000 and 2010. Potential predictors of postoperative mortality were assessed using the Cox proportional hazards model, and a risk score was calculated. Forty-one patients died before discharge, and 81 patients died during a mean follow-up time of 2.9 years. Four independent predictors of mortality were identified: age, Interagency Registry for Mechanically Assisted Circulatory Support profile, left ventricular ejection fraction, and severity of mitral regurgitation. Each variable was assigned a number of points proportional to its regression coefficient. A risk score was calculated using the point scores for each patient, and 3 risk groups were developed: a low-risk group (0-4 points), an intermediate-risk group (5-6 points), and a high-risk group (7-12 points). Their 3-year survivals were 93%, 81%, and 44%, respectively (log-rank P < .001). Harrell's C-index of the predictive model was 0.69. A simple prognostic model was developed to predict mortality after surgical ventricular reconstruction. It can be useful in clinical practice to select treatment options for ischemic heart failure.


The structure of an enzyme-product complex reveals the critical role of a terminal hydroxide nucleophile in the bacterial phosphotriesterase mechanism.
A detailed understanding of the catalytic mechanism of enzymes is an important step toward improving their activity for use in biotechnology. In this paper, crystal soaking experiments and X-ray crystallography were used to analyse the mechanism of the Agrobacterium radiobacter phosphotriesterase, OpdA, an enzyme capable of detoxifying a broad range of organophosphate pesticides. The structures of OpdA complexed with ethylene glycol and the product of dimethoate hydrolysis, dimethyl thiophosphate, provide new details of the catalytic mechanism. These structures suggest that the attacking nucleophile is a terminally bound hydroxide, consistent with the catalytic mechanism of other binuclear metallophosphoesterases. In addition, a crystal structure with the potential substrate trimethyl phosphate bound non-productively demonstrates the importance of the active site cavity in orienting the substrate into an approximation of the transition state.


Creative Contributory Contests to Spur Innovation in Sexual Health: 2 Cases and a Guide for Implementation.
Sexual health campaigns are often designed "top-down" by public health experts, failing to engage key populations. Using the power of crowdsourcing to shape a "bottom-up" approach, this note describes 2 creative contributory contests to enhance sexual health campaigns. We provide guidance for designing creative contributory contests to improve HIV and other sexually transmitted disease testing.


Incongruence between morphotypes and genetically delimited species in the coral genus Stylophora: phenotypic plasticity, morphological convergence, morphological stasis or interspecific hybridization?
Morphological data suggest that, unlike most other groups of marine organisms, scleractinian corals of the genus Stylophora are more diverse in the western Indian Ocean and in the Red Sea than in the central Indo-Pacific. However, the morphology of corals is often a poor predictor of their actual biodiversity: hence, we conducted a genetic survey of Stylophora corals collected in Madagascar, Okinawa, the Philippines and New Caledonia in an attempt to find out the true number of species in these various locations. A molecular phylogenetic analysis of the mitochondrial ORF and putative control region concurs with a haploweb analysis of nuclear ITS2 sequences in delimiting three species among our dataset: species A and B are found in Madagascar whereas species C occurs in Okinawa, the Philippines and New Caledonia. Comparison of ITS1 sequences from these three species with data available online suggests that species C is also found on the Great Barrier Reef, in Malaysia, in the South China Sea and in Taiwan, and that a distinct species D occurs in the Red Sea. Shallow-water morphs of species A correspond to the morphological description of Stylophora madagascarensis, species B presents the morphology of Stylophora mordax, whereas species C comprises various morphotypes including Stylophora pistillata and Stylophora mordax. Genetic analysis of the coral genus Stylophora reveals species boundaries that are not congruent with morphological traits. Of the four hypotheses that may explain such discrepancy (phenotypic plasticity, morphological stasis, morphological convergence, and interspecific hybridization), the first two appear likely to play a role but the fourth one is rejected since mitochondrial and nuclear markers yield congruent species delimitations. The position of the root in our molecular phylogenies suggests that the center of origin of Stylophora is located in the western Indian Ocean, which probably explains why this genus presents a higher biodiversity in the westernmost part of its area of distribution than in the "Coral Triangle".


Image statistics determine the integration of visual cues to motion-in-depth.
Motion-in-depth perception is critical in enabling animals to avoid hazards and respond to potential threats. For humans, important visual cues for motion-in-depth include changing disparity (CD) and changing image size (CS). The interpretation and integration of these cues depends upon multiple scene parameters, such as distance moved, object size and viewing distance, posing a significant computational challenge. We show that motion-in-depth cue integration depends upon sensitivity to the joint probabilities of the scene parameters determining these signals, and on the probability of CD and CS signals co-occurring. Models that took these factors into account predicted human performance in speed-in-depth and cue conflict discrimination tasks, where standard linear integration models could not. These results suggest that cue integration is affected by both the uncertainty of sensory signals and the mapping of those signals to real-world properties. Evidence of a role for such mappings demonstrates the importance of scene and image statistics to the processes underpinning cue integration and the perception of motion-in-depth.


Effects of freestall vs. bedded pack housing on growth performance, health status, and behavioral responses of weaned heifers.
This research evaluates the effect of two housing types, freestalls vs. bedded-pack, on growth performance, health scoring, and behavior of weaned heifers. Twenty-four heifers with no previous experience with freestalls (12 heifers/ treatment) were randomly assigned to the two treatments (freestalls vs. bedded-pack) at d 80 ± 3 of age. Heifers had free access to total mixed ration (TMR) and water throughout the experiment. The TMR intake and health score were recorded daily from d 80 to 110 of age. Body weight and skeletal growth of heifers were measured at the beginning (d 80) and the end (d110) of the experiment. Feeding behaviors were recorded for a period of 22 h and at the same time. Growth performance (ADG, structural growth, and final body weight), overall DMI, and health assessment (fecal score, general appearance, and rectal temperature) were similar between treatments. Behavioral patterns of eating, drinking, standing, lying, and rumination were also similar between treatments. However, in freestall-housed heifers, the proportion of time spent lying inside the stall increased by 8.1%, and time spent lying outside the stall decreased by 9.44% from the beginning to the end of the study (from 80 to 110 d). In summary, our results indicate that weaned heifers showed similar growth performance, behavior, and health when housed in freestall and bedded-pack housing. However, introducing weaned heifers to freestall housing at an early age will prepare them for using the facility.


Plant competition and disease in genetically diverse wheat populations.
The direct and indirect effects of plant genetic diversity on epidemics and the influence of disease on plant competition were investigated using the wheat (Triticum aestivum)/stripe rust (Puccinia striiformis) system. Replacement series consisting of a susceptible and a resistant wheat genotype or two wheat genotypes susceptible to different races of stripe rust were grown in the presence and absence of the pathogen. Stripe rust severity, number of seed heads, seed yield, and seed weight were determined separately for each wheat genotype in the mixtures and the pure stands. The frequency of susceptible genotypes in a mixture explained up to 67% of the variation in disease severity. However, competitive interactions among plant genotypes sometimes appeared to alter susceptibility and obscured the relationship. In pure stands of single genotypes, disease severity explained between 52 and 58% of the variation in seed yield. In mixtures, coefficients of determination were only 10 and 31%, suggesting a strong influence of plant-plant interactions on seed yield. These results suggest that host-parasite coevolutionary models need to account for the strong effect that specific plant genotype combinations may have on disease severity and plant reproduction.


Unusually weak metal-hydrogen bonds in HV(CO)4(P-P) and their effectiveness as H(*) donors.
The V-H bonds in HV(CO)4(P-P) are unusually weak (55 to 58 kcal/mol). They transfer H* to styrene more rapidly than CpCr(CO)3H does and are effective stoichiometric reagents for the cyclization of appropriate 1,6-dienes.


Marrow transplantation for pancytopenia in dyskeratosis congenita.
A 33-year-old man with dyskeratosis congenita received a marrow transplant to treat severe pancytopenia. The graft was successful-, but the patient developed severe acute graft-versus-host-disease grade IV and died 51 days postgrafting. - The outcome of transplantation in dyskeratosis congenita is compared to that in Fanconi's anaemia due to the resemblance of both diseases in some aspects.


Intraocular pressure control and persistence on treatment in glaucoma and ocular hypertension.
The purpose of this study was to characterize current patterns of treatment of glaucoma and ocular hypertension and to examine the effect of those patterns on intraocular pressure (IOP) control and persistence on therapy. A retrospective chart review was conducted at 3 ophthalmology practices in Alberta. Data were collected for patients who had begun therapy for newly diagnosed primary open-angle glaucoma or ocular hypertension between May 1, 1998, and Sept. 30, 1999 (phase 1), and for patients who had begun second-line therapy after initial therapy with a beta-blocker had failed (phase 2). Data were collected for a minimum of 24 months for phase 1 and a minimum of 18 months for phase 2. We included 115 patient charts in phase 1 and 93 in phase 2. In each phase, the patients for whom latanoprost had been prescribed in unfixed combination with a beta-blocker had the greatest mean percentage reduction in IOP at month 24, and the patients for whom latanoprost had been prescribed alone or in combination with a beta-blocker were more likely to still be on initial therapy at month 24; the difference in persistence on therapy was statistically significant only in phase 1 (p = 0.001). The mean number of switches in therapy was smaller in phase 1 than in phase 2 in all therapy groups. Compared with other first- and second-line forms of therapy, treatment with latanoprost, alone or in combination with a beta-blocker, was associated with greater reductions in IOP, better therapeutic persistence, fewer therapy switches and fewer ophthalmologist visits over a 2-year period.


A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part II. Population pharmacokinetic and pharmacodynamic modeling and simulation.
A new benzodiazepine, remimazolam, which is rapidly metabolized by tissue esterases to an inactive metabolite, has been developed to permit a fast onset, a short, predictable duration of sedative action, and a more rapid recovery profile than currently available drugs. We report on modeling of the data and simulations of dosage regimens for future study. A phase I, single-center, double-blind, placebo and active controlled, randomized, single-dose escalation study was conducted. Fifty-four healthy subjects in 9 groups received a single 1-minute IV infusion of remimazolam (0.01-0.3 mg/kg). There were 18 control subjects taking midazolam and 9 placebos. Population pharmacokinetic and pharmacodynamic modeling of the data was undertaken and the parameters obtained were used for Monte-Carlo simulations of alternative dosing regimens. A 4-compartment mammillary pharmacokinetic model of midazolam and a physiologically based recirculation model of remimazolam were fitted to the observed plasma levels. The recirculation model of remimazolam explained the observed high venous, compared with arterial, concentrations at later time points. The 2 models were used to simulate the arterial concentrations required for the pharmacodynamic models of sedation (Bispectral Index and Modified Observer's Assessment of Alertness/Sedation [MOAA/S]) and gave population mean pharmacodynamic parameters as follows: Bispectral Index-IC(50): 0.26, 0.07 μg/mL; γ: 1.6, 8.6; k(e0): 0.14, 0.053 min(-1); I(MAX): 39, 19, and MOAA/S-IC(50): 0.4, 0.08 μg/mL; γ: 1.4, 3.4; k(e0): 0.25, 0.050 min(-1) for remimazolam and midazolam, respectively. Simulations to obtain >70% of the population with MOAA/S scores of 2 to 4 were developed. This criterion was achieved (95% confidence intervals: 67%-74%) with a 6-mg initial loading dose of remimazolam followed by 3-mg maintenance doses at >2-minute intervals. Recovery to a MOAA/S score of 5 is predicted to be within 16 minutes for 89% (95% confidence intervals: 87%-91%) of the treated population after this loading/maintenance dose regimen. Population pharmacokinetic and pharmacodynamic models developed for remimazolam and midazolam fitted the observed data well. Simulations based on these models show that remimazolam delivers extremely rapid sedation, with maximal effect being reached within 3 minutes of the start of treatment. This property will enable maintenance doses to be given more accurately than with slower-acting drugs. No covariate effects considered to be clinically relevant were observed, suggesting that dosing by body weight may offer no advantage over fixed doses in terms of consistency of exposure to remimazolam within the weight range studied (65-90 kg).


Oncolytic viruses in hematological malignancies: hijacking disease biology and fostering new promises for immune and cell-based therapies.
The increased tropism for malignant cells of some viruses has been highlighted in recent studies, prompting their use as a strategy to modify the transcriptional profile of those cells, while sparing the healthy ones. Likewise, they have been recognized as players modulating microenvironmental immunity, namely through an increase in antigen-presenting, natural-killer, and T CD8+ cytotoxic cells by a cross-priming mechanism elicited by tumor-associated antigens. The immunomodulatory role of the oncolytic virus seems relevant in hematological malignancies, which may relapse as a result of a proliferative burst elicited by an external stimulus in progenitor or neoplastic stem cells. By reprogramming the host cells and the surrounding environment, the potential of virotherapy ranges from the promise to eradicate the minimal measurable disease (in acute leukemia, for example), to the ex vivo purging of malignant progenitor cells in the setting of autologous bone marrow transplantation. In this review, we analyze the recent advances in virotherapy in hematological malignancies, either when administered alone or together with chemotherapeutic agents or other immunomodulators.


Metal-phenolic capsules with ROS scavenging reshape the oxidative microenvironment of atherosclerosis.
Arterial injury makes the tissue in a state of high oxidative stress. At the same time, abnormal lipid metabolism can further lead to bleeding and thrombosis. Therefore, the anti-inflammatory and anti-oxidant polyphenol, EGCG was organically complexed with Fe3+ to form a metal-phenolic framework carrier. And the antihyperlipidemic drug, atorvastatin (ATV) was loaded into the carrier to enhance the bioavailability, and simultaneously alleviate the oxidative stress of the inflammatory site and abnormal lipid metabolism. The results confirmed that the obtained material EGCG-Fe-ATV had good biocompatibility and biosafety effect. In addition, EGCG-Fe-ATV showed outstanding anti-inflammatory, anti-oxidant and lipid-lowering properties. These therapeutic outcomes of EGCG-Fe-ATV were achieved by reducing systemic and local oxidative stress and inflammation, alleviating inflammatory cell infiltration in plaques, and modulating lipid synthesis and transferase to alter cholesterol transport. In conclusion, the combination of metal-phenolic capsules with ATV provides a new strategy for reshaping the oxidative microenvironment of atherosclerosis.


A large outbreak of enteritis in goat flocks in Marmara, Turkey, by G8P[1] group A rotaviruses.
Group A rotaviruses are regarded as major enteric pathogens of large ruminants, while their impact on the health of small ruminants is not well documented. We report the detection of group A rotavirus from a large outbreak of enteritis that occurred in two goat flocks in the town of Kırklareli, Marmara Region, Turkey, in 2007. The disease was observed in young kids, with high morbidity and mortality rates, but not in adult animals. Rotavirus antigen was detected in the stools of the examined animals, and rotaviruses were isolated in MA104 cells. Upon sequencing of the VP4, VP6, VP7 and NSP4 genes, the strain (RVA/goat-tc/TUR/Kirklareli/2007/G8P[1]) was characterized as G8P[1], with E2 NSP4 and VP6 I2 genotype. These findings indicate that group A rotavirus should be included in the diagnostic algorithms for enteric disease in small ruminants.


Work above shoulder level and shoulder complaints: a systematic review.
To investigate the association and the exposure-response relationship between work above shoulder height and shoulder pain or disorders. A systematic search was performed in Medline, Embase, and Health and Safety Science Abstracts. Included were articles with prospective cohort, case-control, cross-sectional, or intervention study designs. Quality assessment was based on an evaluation scheme adjusted to study design and normalized to 100%. The cut-off for sufficient quality to include articles was above 40% and cut-off for high-quality articles was above 50% of maximal score. The level of strength of evidence for an association between exposure and effect was assessed according to the GRADE guidelines. Thirty-four articles were included. Articles that document large effects (higher risk estimates; OR ≥ 2) have higher quality score, include analyses of severe arm elevation, more often use clinical outcome, and report an exposure-response relationship compared to studies reporting lower risk estimates. The studies that reported large effects were all significant. An exposure-response relationship was found in many high-quality studies when relating exposure intensity of arm elevation (level of arm elevation, amplitude) as well as duration of arm elevation, especially > 90°. We conclude on a limited evidence for an association between arm elevation at work and shoulder disorders. Severe arm elevation with elbows above shoulder level (i.e., > 90°) shows a moderate evidence for an association with shoulder disorders.


Thai health care provider knowledge of neonatal male circumcision in reducing transmission of HIV and other STIs.
Male circumcision (MC) reduces the risk of female-to-male transmission of HIV and other sexually transmitted infections (STIs). MC has not been practiced as a disease prevention measure in Thailand probably because of low recognition of its benefits among stakeholders. Neonatal male circumcision (NMC) is simpler, safer and cheaper than adult MC. This study aimed to assess Thai health care provider knowledge of benefits implementing NMC in Thailand. Multi-stage sampling identified 16 government hospitals to represent various hospital sizes and regions of the country. Researchers administered a fixed choice questionnaire, developed by the research team based on a previous study, to physician administrators, practicing physicians, and nurses whose jobs involved NMC clinical procedures or oversight. The participants reviewed printed educational materials on the benefits of NMC during questionnaire completion. Data were analyzed using descriptive statistics, chi square tests, odds ratios, and logistic regression. One hundred thirty-three individuals participated in this quantitative study. Only 38% of the participants agreed that NMC reduced the risk of sexual transmission of HIV while 65% indicated that they knew that NMC prevented STIs. Most participants recognized the benefits of NMC on hygiene (96%) as well as cancer prevention (74%). Major concerns raised were potential trauma to the child, child rights and safety of NMC. After reviewing written information about the benefits of NMC, 59% of the participants agreed that NMC should be offered in their hospital. Physicians and nurses who had previous experience with circumcising patients of all ages were more reluctant to have NMC performed in their hospital. A clear policy advocating NMC, thorough preparation of health facilities, and staff training are needed before NMC could be used in Thailand as prevention strategy for HIV and other STIs.