Users' Preferred Characteristics of Vaginal Rings for HIV Prevention: A Qualitative Analysis of Two Phase I Trials.
Vaginal rings address a critical need for an independently initiated, long-acting HIV prevention method, but their design must be acceptable to promote uptake and adherence. Human-centered design (HCD) may help address design preference questions. In two Phase I studies of vaginal rings for HIV prevention conducted in the United States, we used qualitative interviews to assess participants' perceptions and opinions of the physical characteristics of the ring they used and of a ring's physical characteristics after comparing four ring designs presented via a visual tool. Users were found to prefer ring designs that appear easy to use, are physically comfortable, that function well, and are aesthetically pleasing. The parameters for these features varied widely. Product developers and marketers should consider marketing messages in which the target users feel this product is made to meet their needs and desires. Product developers are encouraged to design using HCD early in ring development (Clinical Trial Registration number: NCT03234400 and NCT03670355).


Brachytherapy in Gynecologic Cancers: Why Is It Underused?
Despite its established efficacy, brachytherapy is underused in the management of cervical and vaginal cancers in some parts of the world. Possible reasons for the underutilization of brachytherapy include the adoption of less invasive techniques, such as intensity-modulated radiotherapy; reimbursement policies favoring these techniques over brachytherapy; poor physician or patient access to brachytherapy; inadequate maintenance of brachytherapy skills among practicing radiation oncologists; transitioning to high-dose-rate (HDR) brachytherapy with increased time requirements; and insufficient training of radiation oncology residents.


Validation of real-time PCR technique for detection of Mycobacterium bovis and Brucella abortus in bovine raw milk.
Brucellosis and tuberculosis are diseases of great economic impact in cattle herds and are controlled by governmental programs in many countries. The validation of a diagnostic technique is fundamental for its application in official control programs of these diseases. The aim of the present study was to validate a polymerase chain reaction in real time (qPCR) for detection of Mycobacterium bovis and Brucella abortus in samples of artificially contaminated raw milk. The technique was evaluated using tests of analytical sensitivity and specificity, repeatability, internal reproducibility, and robustness. Initially, five DNA extraction methodologies were tested, and the DNeasy Mericon Food Kit-Qiagen and the Maxwell® 16 Tissue DNA Purification Kit-Promega presented the best analytical specificity of all the commercial kits tested and were used exclusively in subsequent tests. The lowest limits of detection obtained in the qPCR were 2.3 pg for M. bovis DNA and 20.7 fg for B. abortus DNA. The repeatability and reproducibility associated with the robustness indicate that the evaluated methods are applicable as rapid tools for the official in vivo diagnosis of bovine tuberculosis and brucellosis in raw milk from dairy herds in Brazil.


Evaluation of the Central Effects of Systemic Lentiviral-Mediated Leptin Delivery in Streptozotocin-Induced Diabetic Rats.
Type 1 diabetes (T1D) is characterized by hyperphagia, hyperglycemia and activation of the hypothalamic-pituitary-adrenal (HPA) axis. We have reported previously that daily leptin injections help to alleviate these symptoms. Therefore, we hypothesized that leptin gene therapy could help to normalize the neuroendocrine dysfunction seen in T1D. Adult male Sprague Dawley rats were injected i.v. with a lentiviral vector containing the leptin gene or green fluorescent protein. Ten days later, they were injected with the vehicle or streptozotocin (STZ). HPA function was assessed by measuring norepinephrine (NE) levels in the paraventricular nucleus (PVN) and serum corticosterone (CS). Treatment with the leptin lentiviral vector (Lepvv) increased leptin and insulin levels in non-diabetic rats, but not in diabetic animals. There was a significant reduction in blood glucose levels in diabetic rats due to Lepvv treatment. Both NE levels in the PVN and serum CS were reduced in diabetic rats treated with Lepvv. Results from this study provide evidence that leptin gene therapy in STZ-induced diabetic rats was able to partially normalize some of the neuroendocrine abnormalities, but studies with higher doses of the Lepvv are needed to develop this into a viable option for treating T1D.


Identification of early response genes to roughness and fluoride modification of titanium implants in human osteoblasts.
Tissue response after implantation determines the success of the healing process. This response is not only dependent on the chemical properties of the implant surface but also by the surface topography or its roughness. Although in vitro and in vivo studies show improved results with rough- and fluoride-modified implants, the mechanisms behind these findings are still unknown. Here, we have used a two-step procedure to identify novel genes related to the early response of primary human osteoblasts to roughness and fluoride-modified titanium implants. Two hundred seventeen genes responding to roughness were identified by microarray analysis and 198 genes responding to fluoride, 33 genes were common. Those identified genes related to bone and mineralization were further investigated by real-time reverse-transcriptase polymerase chain reaction. After 1 day of culture, toll-like receptor 3, ankylosis-progressive homolog, decorin, osteocalcin, and runt-related transcription factor-2 were classified as responsive genes to roughness; Distal-less homeobox-2 and Tuftelin-1 as responsive genes to fluoride treatment. Responsive genes to both treatments were collagen type I, parathyroid hormone-like hormone, hairy and enhancer of split-1, follistatin, ectonucleotide pyrophosphatase/phosphodiesterase-1, and thyroid hormone receptor-alpha. Our strategy was useful for identifying novel genes that might be involved in the early response of osteoblasts to rough and fluoride-modified titanium implants.


Contact force ablation of accessory pathways in pediatric patients.
Contact force (CF) catheters provide feedback confirming adequate tissue contact for optimal lesion size and minimal complications. CF ablation catheters have resulted in decreased procedure times and improved outcomes for ablation of atrial fibrillation in adults. There is limited data evaluating CF use for accessory pathway (AP) ablation or in pediatric patients. The aim of our study was to compare a cohort who underwent AP ablation with a CF catheter to historical controls, evaluating for differences in procedure times, number of lesions, and outcomes. A retrospective chart review of CF ablation cases at Children's Wisconsin performed between June 2015 to April 2018 was compared to a historical control cohort of traditional radiofrequency (RF) ablations between June 2012 and June 2015. 43 patients with APs underwent 49 CF ablation procedures (18 males, 13.6 ± 3 years old) and a control cohort consisted of 77 procedures in 69 patients (38 males, 12.4 ± 4 years). The groups did not differ significantly on procedure time (CF 2.01 ± 0.48 h, control 1.53 ± 0.48 h, p = .37), or total lesions administered (CF and control 7 ± 6 lesions, p = .89). CF cases showed a trend toward improvement in acute success (98% CF, 90% controls, p = .15) though with increased recurrence compared to controls (13% CF, 4.3% controls, p = .16), neither being statistically significant. Our study suggests that ablation outcomes using CF are comparable to traditional RF ablation in pediatric patients with APs.


Prognostic value of the miR-200 family in bladder cancer: A systematic review and meta-analysis.
We aimed to evaluate the prognostic significance of high expression of the miR-200 family of microRNAs in bladder cancer. Studies on the correlation between the miR-200 family and prognosis in patients with bladder cancer were searched in databases. Combined hazard ratios (HRs) were calculated based on HRs and 95% confidence intervals (CIs) for overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS). Cochranes Q test and the I statistic were utilized to assess heterogeneity across the included studies. Potential publication bias was analyzed by Begg and Egger tests. The meta-analysis was conducted using RevMan 5.3 and Stata SE12.0. Data from a total of 1150 patients from 8 studies were extracted. The meta-analysis revealed that high expression of the miR-200 family was correlated with better OS (pooled hazard ratio: 0.50, 95% confidence interval: 0.40-0.62), CSS (pooled hazard ratio: 0.36, 95% confidence interval: 0.22-0.59) and RFS (pooled hazard ratio: 0.48, 95% confidence interval: 0.36-0.65). Both Begg test and Egger test verified no publication bias within the included cohorts. The high expression of the miR-200 family is strongly associated with better prognosis in bladder cancer patients, which will improve bladder cancer management in clinical practice.


The relative sensitivity of growth and reproduction in the springtail, Folsomia candida, exposed to xenobiotics in the laboratory: an indicator of soil toxicity.
The Folsomia candida reproduction test [ISO, 1998. Soil quality--Inhibition of reproduction of Collembola (Folsomia candida) by soil pollutants. International Standard Organization Report 11267, 1998, Geneva] is used to evaluate the ecotoxicological risks of contaminants in soils. The aim of this study was to compare the sensitivity of growth and reproduction of F. candida to four xenobiotics: two metals (Cd, Al), one metalloid (As), and one organic compound (pentachlorophenol). We showed that reproduction is a slightly more sensitive parameter than growth: EC(20) for reproduction was 1.25 microg/g dry soil for arsenic, 56 microg/g for cadmium, 97.5 microg/g for aluminum, and 41.7 microg/g for pentachlorophenol. The corresponding EC(20) values for growth were 2.8, 65, 630, and 94.6 microg/g. Keeping in mind that a growth test needs fewer juveniles and less time than a reproduction test, we conclude that the two parameters are complementary and could be used for a better ecotoxicological evaluation of contaminants. However, the relative growth and reproduction sensitivities should be tested with more chemicals before growth could be considered as a good alternative for a faster sublethal test.


The provision of preventive care for modifiable health risk behaviours by clinicians within substance use treatment settings: A systematic review.
People who use substances have a high prevalence of other modifiable health risk behaviours such as tobacco smoking which contribute to an increased mortality and morbidity. Preventive care can reduce the prevalence of such behaviours and is recommended by clinical practice guidelines. This review describes the prevalence of preventive care delivery by substance use treatment healthcare providers and examines differences by treatment setting. Five databases were searched for studies published between 2005 and 2017. Eligible studies reported levels of preventive care (assessment, brief advice and/or referral/follow-up) in substance use treatment services for tobacco smoking, nutrition or physical activity. Two reviewers independently conducted article screening, data extraction and methodological quality assessment. Sixteen studies were included and all except one investigated care provision for tobacco smoking only. Four studies reported care levels as a proportion and 12 studies reported care as a score-based mean. Client-reported receipt of smoking cessation care ranged from: 79-90% for assessment; 15-79% for brief advice; 0-30% for referral/follow-up. Meta-regression analyses of 12 studies found clinician-reported preventative care for tobacco smoking was more frequently reported in studies assessing care occurring across multiple substance use treatment settings, compared to studies reporting provision in inpatient only. This review indicated that, compared to smoking cessation care, little is known about the level of preventive care for nutrition or physical activity. Overall, the delivery of smoking cessation care reported was sub-optimal. High levels of assessment relative to brief advice and low levels of referral to ongoing assistance were indicated.


Failure to obtain positive MEM tests in either cell-mediated immune conditions in the guinea-pig or in human cancer.
The macrophage electrophoretic mobility test described by Caspary and Field (1971) and modified by Pritchard et al. (1973) was investigated in various models of cell-mediated immune conditions in the guinea-pig and in cancer in man. No positive results were obtained in 92 guinea-pig experiments. Only 17 of 154 experiments on 74 patients gave definite positives in experiments with human cancer and a few positive results were obtained with normal healthy subjects.


Evaluation of Punarnavadi Mandura for haematinic activity against mercuric chloride-induced anemia in albino rats.
Punarnavadi Mandura, a compound Ayurvedic formulation, is one of the most commonly used medicine in the treatment of anemia (Pandu) in Ayurveda. The safety profile of this formulation is well established; however, no pharmacological study has been reported to provide the scientific basis for its use in the treatment of anemia. To evaluate the hematinic effect of Punarnavadi Mandura against mercuric chloride-induced anemia in albino rats. The test drug (Punarnavadi Mandura) was suspended in distilled water and administered orally in a dose of 450 mg/kg for 30 days in rats. Anemia was induced by simultaneous administration of mercuric chloride (9 mg/kg) for 30 consecutive days. Body weight was noted for each animals. At the end, haematological parameters, anaemia markers like serum iron, ferritin, and total iron binding capacity (TIBC), as well as relative weight of organs and histopathology investigation, were examined. Exposure of mercuric chloride to rats for 30 days resulted in a significant decrease of body weight, an increase in the weight of the liver and kidney and a decrease in hemoglobin content. It also decreased serum ferritin to a significant extent and increased serum TIBC. Histopathology of the liver shows macro fatty changes, vacuolization, marked necrosis, and severe degenerative changes, while the kidney shows cell infiltration. All these changes were significantly attenuated by the administration of Punarnavadi Mandura. The present data indicate that Punarnavadi Mandura has possessing marked cytoprotective activity, significantly attenuated the HgCl2-induced adverse changes on red blood cell related parameters, and showing hematinic activity in albino rats.


Management for the case of twice ruptured anterior communicating artery aneurysm: from nursing perspective.
The anterior communicating artery (ACoA) is the most common site of cerebral aneurysms, accounting for as much as 36% of aneurysms. Microsurgical clipping and coil embolization are treatment modalities for ruptured and nonruptured cerebral aneurysms. Compared with surgical clipping, coil embolization has a relatively lower mortality and incidence of cognitive impairment in patients. However, successful management of the patient with twice ruptured ACoA aneurysm is facing critical challenges.This article has described a case of twice ruptured aneurysm with the first rupture occurring when the patient was admitted and the second rupture occurring during coil embolization. Perioperative nursing assessment, monitoring, intervention, patient teaching, and the nurse's role are discussed from a nursing perspective.


Biomimetic nanoparticle synchronizing pyroptosis induction and mitophagy inhibition for anti-tumor therapy.
Inducing pyroptosis in cancer cells can result in a strong anti-tumor immune response. Our preliminary study indicates that pyroptosis can be temporarily strengthened by disrupting mitochondria, but ultimately diminished by defensive mitophagy. Here, this study reports a nano-system camouflaged with hybrid membranes consisting of homologous cell membrane and corresponding mitochondrial membrane, which is used to deliver a drug complex Ca@GOx consisting of calcium phosphate and glucose oxidase. By taking advantage of the homing effects of cell membrane and the orientated fusion mechanism of subcellular membrane, the nano-system is able to deliver Ca@GOx to mitochondria, induce mitochondrial Ca2+ overload and generate significant levels of ROS, thus leading to pyroptosis. However, it's found that this system exhibits limited anti-tumor effects in vivo due to the compensatory activation of mitophagy serving as negative feedback to pyroptosis. To address this issue, mitophagy-inhibiting chloroquine is loaded into nanoparticles to intensify pyroptosis. As a result, the combination significantly promotes tumor infiltration of CD8+T cells and improves anti-tumor effects. Together, this study establishes a rational combination of targeted mitochondria disruption and mitophagy blockage for effective pyroptosis-based therapy.


Microbial growth inhibition caused by Zn/Ag-Y zeolite materials with different amounts of silver.
Different loadings of silver exchanged on bimetallic Zn/Ag-NaY zeolite materials were studied for antimicrobial properties against four reference microorganisms. The sensitive indicator strains used were two bacteria (Escherichia coli and Bacillus subtilis) and two yeast species (Saccharomyces cerevisiae and Candida albicans). The bimetallic materials were compared with the monometallic materials prepared with the same concentrations of silver. A synergistic effect between the two metals, zinc and silver, was evidenced on the antimicrobial activity of the materials. All mono and bimetallic materials showed strong efficacy against bacteria and yeasts, although the later overall displayed lower MIC values. The results of X-ray photoelectron spectroscopy (XPS) confirm the presence of silver and zinc as ions, not homogeneously distributed throughout the zeolite framework, which implies that the metal ions are located in different sites of the faujasite structure.


Tetrameric manganese superoxide dismutases from anaerobic Actinomyces.
Superoxide dismutase was isolated from each of the anaerobically grown organisms Actinomyces naeslundii, Actinomyces strain E1S.25D, and Actinomyces odontolyticus. The enzymes were 100,000-110,000 mol wt acidic proteins (pI 4.3-4.6) and contained Mn and Zn, but no detectable Fe. The Mn and Zn content varied with the enzyme source. A. naeslundii superoxide dismutase, specific activity 2200 U/mg, contained 2.3 g atoms Mn and 1.4 g atoms Zn per mole tetramer whereas A. odontolyticus SOD, specific activity 700 U/mg, contained 1.4 g atoms Mn and 1.8 g atoms Zn per mole tetramer. Actinomyces strain E1S.25D, specific activity 1300 U/mg, contained 1.8 g atoms Mn and 1.2 g atoms Zn per mole tetramer. The amino acid compositions of the enzymes were comparable except for arginine, lysine, and tryptophan content. The enzymatic activity of each enzyme was stable in 5 mM H2O2 at 23 degrees C for 2 h. The enzymes were only modestly inhibited by 20 mM NaN3. The enzymatic activity was increased at low ionic strength but was markedly decreased at increased ionic strength with each salt tested except sodium perchlorate, which caused marked inhibition even at low ionic strength. Polyclonal antibodies to A. naeslundii and Actinomyces strain E1S.25D precipitated and inactivated their respective antigens whereas the precipitated A. odontolyticus superoxide dismutase-antibody complex retained virtually full catalytic activity. Immunological studies revealed that the native A. naeslundii and Actinomyces strain E1S.25D MnSODs share common epitopes and cross-reacted with precipitin lines of complete identity in Ouchterlony double diffusion gels. Antibody to the A. odontolyticus enzyme displayed only partial cross-reactivity with superoxide dismutase from the two other Actinomyces. Western blotting of the denatured antigens revealed reactivities of the antibodies that differed only slightly from the results of the Ouchterlony gels.


Characterization of temperature-sensitive mutants of bacteriophage PM2: membrane mutants.
In an effort to understand the genetic regulation of membrane morphogenesis, twenty-nine temperature-sensitive mutants of the membrane-containing bacteriophage PM2 were isolated. Characterization at restrictive temperature revealed groups showing no lysis (Groups I--IV), partial lysis (Groups V--VIII), and full lysis (groups IX--XII) of the host Pseudomonas BAL-31. When the cell lysis data are considered in conjunction with data on stimulation of viral DNA synthesis, at least six mutant groups are defined. Analysis by gel electrophoresis of the pattern of viral proteins synthesized under restrictive conditions further divides the mutants into twelve groups. Temperature shift experiments delineate early, intermediate and late mutants. Complementation data support some of these groupings. The observed low levels of complementation and recombination are discussed in terms of gene product/genome restriction, bound to the membrane at the site of infection. It is of particular interest to membrane morphogenesis that under restrictive conditions late mutants in Groups II, III and IV make empty-appearing vesicles inside the cell that are the size of virus membranes as seen in thin sections of cells in the electron microscope. Mutants ts 1 (Group II) and ts 12 (Group III) show defects in their ability to incorporate into membranes viral structural proteins sp 13 and sp 6.6. The possibility is discussed that either of these proteins control the size and shape of the viral membrane.


Study of hypocaloric peripheral parenteral nutrition in postoperative patients (European project).
The objective of this study is to ascertain whether or not the supply of a low-calorie amino acids (AA) parenteral solution is useful in postoperative patients, by assessing a series of parameters that indicate nutritional status. 75 postoperative patients who met at least 2 of the 3 criteria: 1) albumin less than 3 g/dl; 2)prealbumin less than 21 mg/dl; 3) body weight less than 95% of ideal weight, were studied. Patients were divided into 4 groups: control group, 15 patients receiving conventional infusion therapy; group I, 20 patients receiving glucose + AA; group II, 20 patients receiving glycerol + AA; and group III, 20 patients receiving sorbitol-xylitol + AA. The most significant findings were a prompt recovery of short half-life proteins (prealbumin and retinol binding protein), a less negative nitrogen balance, a greater decrease in urinary 3-methylhistidine and a marked increase in most AAs when hypocaloric peripheral parenteral nutrition (HPPN) was used. As regards complications, suture dehiscence occurred in a greater percentage of control patients than in the active therapy groups (13.3% versus 5%) and, in contrast, a greater number of cases of infusion phlebitis was observed in the HPPN groups. Clinical data were not statistically significant. We conclude that HPPN is a valid means for providing nutritional support but, at present, there are few randomized, controlled studies that show that its use is clearly beneficial.


Gut microbiota modulation by prednisolone in a rat kindling model of pentylenetetrazol (PTZ)-induced seizure.
The gut microbiota is a complex community composed by several microorganisms that interact in the maintenance of homeostasis and contribute to physiological processes, including brain function. The relationship of the taxonomic composition of the gut microbiota with neurological diseases such as autism, Parkinson's, Alzheimer's, anxiety, and depression is widely recognized. The immune system is an important intermediary between the gut microbiota and the central nervous system, being one of the communication routes of the gut-brain axis. Although the complexity of the relationship between inflammation and epilepsy has not yet been elucidated, inflammatory processes are similar in many ways to the consequences of dysbiosis and contribute to disease progression. This study aimed to analyze the taxonomic composition of the gut microbiota of rats treated with prednisolone in a kindling model of epilepsy. Male Wistar rats (90 days, n = 24) divided into four experimental groups: sodium chloride solution 0.9 g%, diazepam 2 mg/kg, prednisolone 1 mg/kg, and prednisolone 5 mg/kg administered intraperitoneally (i.p.) for 14 days. The kindling model was induced by pentylenetetrazole (PTZ) 25 mg/kg i.p. on alternate days. The taxonomic profile was established by applying metagenomic DNA sequencing. There was no change in alpha diversity, and the composition of the gut microbiota between prednisolone and diazepam was similar. The significant increase in Verrucomicrobia, Saccharibacteria, and Actinobacteria may be related to the protective activity against seizures and inflammatory processes that cause some cases of epilepsy. Further studies are needed to investigate the functional influence that these species have on epilepsy and the inflammatory processes that trigger it.


Nonoperative Treatment for Displaced Proximal Humeral Fractures in Elderly Patients: Correlation Between Deviations and Clinical Outcomes.
Objectives To describe the functional result of the conservative treatment of displaced proximal humerus fractures (PHF) using the American Shoulder and Elbow Surgeons (ASES) score after 12 months and assess whether the different initial classifications and radiographic measurements are related to clinical results. Methods Forty patients > 60 years old, with displaced PHUs submitted to conservative treatment were evaluated at standardized times (3, 6, and 12 months). The American Society of Shoulder and Elbow Surgeons (ASES), Constant-Murley and Single Assessment Numeric Evaluation (SANE) scales were used as clinical outcomes. Radiographic variables included the Neer and Resch classifications, the presence and displacement of tuberosity fracture, metaphyseal comminution, medial periosteal lesion, and angular and translational deviations of the head in the coronal and sagittal plane. Results The result of the ASES score was 77.7 ± 23.2 for the whole sample, the mean absolute values of the Constant-Murley score were 68.7 ± 16 and 82.6% for the scale relative to the contralateral side. The SANE scale at 12 months was 84.8 ± 19. We observed that the severity of the Neer classification and the coronal plane angular deviation (measured by the head-shaft angle) and the presence of fractures in both tuberosities negatively influenced the ASES score after 12 months of treatment. Conclusion Nonoperative treatment of displaced proximal humerus fractures in elderly patients results in good clinical results. Clinical results are negatively influenced by the angular deviation of the humeral head and the presence of fractures of the greater and lesser tubercles, as well as by the Neer classification.


The structure of a eukaryotic nicotinic acid phosphoribosyltransferase reveals structural heterogeneity among type II PRTases.
Nicotinamide adenine dinucleotide (NAD) is an essential cofactor for cellular redox reactions and can act as an important substrate in numerous biological processes. As a result, nature has evolved multiple biosynthetic pathways to meet this high chemical demand. In Saccharomyces cerevisiae, the NAD salvage pathway relies on the activity of nicotinic acid phosphoribosyltransferase (NAPRTase), a member of the phosphoribosyltransferase (PRTase) superfamily. Here, we report the structure of a eukaryotic (yeast) NAPRTase at 1.75 A resolution (locus name: YOR209C, gene name: NPT1). The structure reveals a two-domain fold that resembles the architecture of quinolinic acid phosphoribosyltransferases (QAPRTases), but with completely different dispositions that provide evidence for structural heterogeneity among the Type II PRTases. The identification of a third domain in NAPRTases provides a structural basis and possible mechanism for the functional modulation of this family of enzymes by ATP.


Development of The American Society of Colon and Rectal Surgeons' Rectal Cancer Surgery Checklist.
There is excellent evidence that surgical safety checklists contribute to decreased morbidity and mortality. The purpose of this study was to develop a surgical checklist composed of the key phases of care for patients with rectal cancer. A consensus-oriented decision-making model involving iterative input from subject matter experts under the auspices of The American Society of Colon and Rectal Surgeons was designed. The study was conducted through meetings and discussion to consensus. Patient data were extracted from an initial literature review. The checklist was measured by its ability to improve care in complex rectal surgery cases by reducing the possibility of omission through the division of treatment into 3 distinct phases. The process generated a 25-item checklist covering the spectrum of care for patients with rectal cancer who were undergoing surgery. The study was limited by its lack of prospective validation. The American Society of Colon and Rectal Surgeons rectal cancer surgery checklist is composed of the essential elements of preoperative, intraoperative, and postoperative care that must be addressed during the surgical treatment of patients with rectal cancer.


Theoretical frameworks and approaches used within the Reserve, Resilience and Protective Factors professional interest area of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment.
Reserve, resilience, maintenance, and related concepts are intensely debated in aging and Alzheimer's disease research. Through a short survey, we gathered information about theoretical concepts and methodologies used among research groups of the Reserve, Resilience, and Protective Factors Professional Interest Area of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment. Overall 53 research groups responded. Reserve and resilience were the most frequently used conceptual frameworks. Education, occupation, leisure, and social activities were frequently used as measures, as were longitudinal designs. Neuropsychological assessments were almost universal, and usage of imaging biomarkers was frequent. In observational-epidemiological study designs, resilience and reserve together (vs reserve alone) were commonly used as theoretical frameworks. We provide a first description of concepts and methodologies used among reserve and resilience researchers. This will inform initiatives aiming to reach consensus on terminology and applications to establish common definitions.


Correction: On demand modulation of lipid composition in an individual bilayer.
Correction for 'On demand modulation of lipid composition in an individual bilayer' by John S. H. Danial et al., Soft Matter, 2017, 13, 1788-1793.


Epidemiology of Bacteremia in Febrile Infants Aged 60 Days and Younger.
To describe the current epidemiology of bacteremia in febrile infants 60 days of age and younger in the Pediatric Emergency Care Applied Research Network (PECARN). We conducted a planned secondary analysis of a prospective observational study of febrile infants 60 days of age and younger presenting to any of 26 PECARN emergency departments (2008 to 2013) who had blood cultures obtained. We excluded infants with significant comorbidities or critically ill appearance. The primary outcome was prevalence of bacteremia. Of 7,335 screened infants, 4,778 (65.1%) had blood cultures and were enrolled. Of these patients, 84 had bacteremia (1.8%; 95% confidence interval [CI] 1.4% to 2.2%). The prevalence of bacteremia in infants aged 28 days or younger (47/1,515) was 3.1% (95% CI 2.3% to 4.1%); in infants aged 29 to 60 days (37/3,246), 1.1% (95% CI 0.8% to 1.6%). Prevalence differed by week of age for infants 28 days of age and younger (0 to 7 days: 4/156, 2.6%; 8 to 14 days: 19/356, 5.3%; 15 to 21 days: 15/449, 3.3%; and 22 to 28 days: 9/554, 1.6%). The most common pathogens were Escherichia coli (39.3%; 95% CI 29.5% to 50.0%) and group B streptococcus (23.8%; 95% CI 16.0% to 33.9%). Bacterial meningitis occurred in 19 of 1,515 infants 28 days of age and younger (1.3%; 95% CI 0.8% to 2.0%) and 5 of 3,246 infants aged 29 to 60 days (0.2%; 95% CI 0.1% to 0.4%). Of 84 infants with bacteremia, 36 (42.9%; 95% CI 32.8% to 53.5%) had urinary tract infections (E coli 83%); 11 (13.1%; 95% CI 7.5% to 21.9%) had bacterial meningitis. The prevalence of bacteremia and meningitis among febrile infants 28 days of age and younger is high and exceeds that observed in infants aged 29 to 60 days. E coli and group B streptococcus are the most common bacterial pathogens.


Comparison of intestinal flora between patients with chronic and advanced Schistosoma japonicum infection.
Schistosoma japonicum infection is an important public health problem, imposing heavy social and economic burdens in 78 countries worldwide. However, the mechanism of transition from chronic to advanced S. japonicum infection remains largely unknown. Evidences suggested that gut microbiota plays a role in the pathogenesis of S. japonicum infection. However, the composition of the gut microbiota in patients with chronic and advanced S. japonicum infection is not well defined. In this study, we compared the composition of the intestinal flora in patients with chronic and advanced S. japonicum infection. The feces of 24 patients with chronic S. japonicum infection and five patients with advanced S. japonicum infection from the same area were collected according to standard procedures, and 16S rRNA sequencing technology was used to analyze the intestinal microbial composition of the two groups of patients. We found that alteration occurs in the gut microbiota between the groups of patients with chronic and advanced S. japonicum infections. Analysis of alpha and beta diversity indicated that the diversity and abundance of intestinal flora in patients with advanced S. japonicum infection were lower than those in patients with chronic S. japonicum infection. Furthermore, Prevotella 9, Subdoligranulum, Ruminococcus torques, Megamonas and Fusicatenibacter seemed to have potential to discriminate different stages of S. japonicum infection and to act as biomarkers for diagnosis. Function prediction analysis revealed that microbiota function in the chronic group was focused on translation and cell growth and death, while that in the advanced group was concentrated on elevating metabolism-related functions. Our study demonstrated that alteration in gut microbiota in different stages of S. japonicum infection plays a potential role in the pathogenesis of transition from chronic to advanced S. japonicum infection. However, further validation in the clinic is needed, and the underlying mechanism requires further study.


Precision Approaches in the Management of Colorectal Cancer: Current Evidence and Latest Advancements Towards Individualizing the Treatment.
The genetic and molecular underpinnings of metastatic colorectal cancer have been studied for decades, and the applicability of these findings in clinical decision making continues to evolve. Advancements in translating molecular studies have provided a basis for tailoring chemotherapeutic regimens in metastatic colorectal cancer (mCRC) treatment, which have informed multiple practice guidelines. Various genetic and molecular pathways have been identified as clinically significant in the pathogenesis of metastatic colorectal cancer. These include rat sarcoma (RAS), epithelial growth factor receptor (EGFR), vascular endothelial growth factor VEGF, microsatellite instability, mismatch repair, and v-raf murine sarcoma viral oncogene homolog b1 (BRAF) with established clinical implications. RAS mutations and deficiencies in the mismatch repair pathway guide decisions regarding the administration of anti-EGFR-based therapies and immunotherapy, respectively. Furthermore, there are several emerging pathways and therapeutic modalities that have not entered mainstream use in mCRC treatment and are ripe for further investigation. The well-established data in the arena of targeted therapies provide evidence-based support for the use or avoidance of various therapeutic regimens in mCRC treatment, while the emerging pathways and platforms offer a glimpse into the future of transforming a precision approach into a personalized treatment.


On the mechanism of dialkyltin-induced thymus involution.
In relation to the thymolytic activity of dialkyltin compounds, the effects of di-n-butyltin (DBTC) and di-n-octyltin dichloride (DOTC) on the ultrastructure of the rat thymus, the proliferation of bone marrow stem cells and their interference with growth hormone production are analyzed. Ultrastructurally, depletion of small lymphocytes in the thymic cortex, without signs of lymphocyte destruction or macrophage activation, was the most prominent feature of DOTC treatment. The thymus cortex was maximally depleted 96 h after a single i.p. injection of 1 mg DOTC/kg body weight. 120 h after DOTC treatment a repopulation of the cortex with small lymphocytes was noted together with the presence of many pale large nuclei of large lymphocytes, suggestive of active blast transformation. These thymus effects are probably not caused by a diminished input of bone marrow stem cells into the thymus, since neither the spontaneous blastogenesis nor the colony formation of bone marrow cells isolated from DBTC-treated animals were affected. An indirect mechanism of thymus involution induced by interference with the hormonal system is also very unlikely. A stress-related increase of glucocorticosteroids by dialkyltins has already been excluded (Seinen and Willems, 1976). An interference of dialkyltins with growth hormone production, as indicated in this study, did not occur. Application of growth hormone in amounts that reversed the hypophysectomy-induced thymus atrophy did not modify the thymus involution induced by DOTC treatment of rats. However, an interference with the production of thymic humoral factors cannot be excluded yet, although it is not supported by morphological changes in thymic reticular cells. Only an increased vacuolization of reticular epithelial cells is seen when the thymus is markedly involuted, but this is considered to be a consequence rather than a cause of thymus atrophy. Most probably the dialkyltin-induced thymus involution is caused by an antiproliferative activity, which is strongly supported by an inhibition of thymidine incorporation of thymocytes isolated from DBTC-treated rats.


Asymptomatic idiopathic intracranial hypertension in children.
To define characteristics of pediatric asymptomatic idiopathic intracranial hypertension (IIH). We retrospectively reviewed our Neuro-Ophthalmology database (2000-2006) for all cases of symptomatic and asymptomatic pediatric IIH. Out of 45 IIH cases, 14 (31.1%) were asymptomatic (incidental examination). When compared with children with symptomatic IIH, asymptomatic cases were younger [5.6 (1.8-15) vs 11.0 (5-17) years, P = 0.007], had lower percentage of obesity (14.3% vs 48.4%, P = 0.046), and had male predominance (71.4% vs 38.7%, P = 0.06). Asymptomatic cases required shorter duration of acetazolamide treatment [3 (0-8), vs 6 (0-20) months, P = 0.021], and resulted in complete resolution of swollen discs. We speculate that asymptomatic IIH may be more common in young children and could represent a milder form or a presymptomatic phase before evolving into classic symptomatic IIH. Further studies to assess the clinical significance of asymptomatic IIH are warranted.


Evaluation of nitrate reductase assay for rapid detection of resistance to second-line drugs in Mycobacterium tuberculosis in a tertiary care hospital.
The present study evaluated nitrate reductase assay (NRA) for rapid detection of resistance to 5 second-line drugs: kanamycin, ethionamide, ofloxacin, cycloserine, and para-aminosalicylic acid. Eighty-six multidrug-resistant clinical isolates of Mycobacterium tuberculosis were used to compare NRA with proportion method for rapid detection of resistance to second-line drugs. The sensitivity of the NRA for different drugs ranged from 86.4% to 100%, whereas the specificity ranged from 98.4% to 100%. Excellent agreement was found between the 2 tests with respect to their κ values. For 63% of the isolates, the results were available in 14 days (turnaround time). The NRA is a rapid, accurate, simple, and inexpensive method for detection resistance to second-line drugs. This method may become an appropriate alternative method, especially for the resource poor settings.


A Systematic Review of Cost-Utility Analyses in Chronic Limb-Threatening Ischemia.
To review and describe the available literature on cost-utility analysis of revascularization and non-revascularization treatment approaches in chronic limb-threatening ischemia. A systematic review was performed on cost-utility analysis studies evaluating revascularization (open surgery or endovascular), major lower extremity amputation, or conservative management in adult chronic limb-threatening ischemia patients. Six bibliographic databases and online registries were searched for English language articles up to August 2021. The outcome for cost-utility analysis was quality-adjusted in life years. Procedures were compared using incremental cost-effectiveness ratios which were converted to 2021 United States dollars. Study reporting quality was assessed using the 2022 Consolidated Health Economic Evaluation Reporting Standards statement. The study was registered in International Prospective Register of Systematic Reviews (CRD42021273602). Three trial-based and five model-based studies were included for review. Studies met between 14/28 and 20/28 criteria of the Consolidated Health Economic Evaluation Reporting Standards CHEERS statement. Only one study was written according to standardized reporting guidelines. Most studies evaluated infrainguinal disease, and adopted a health care provider perspective. There was a large variation in the incremental cost-effectiveness ratios presented across studies. Open surgical revascularization (incremental cost-effectiveness ratios: $3,678, $58,828, and $72,937), endovascular revascularization (incremental cost-effectiveness ratios: $52,036, $125,329, and $149,123), and mixed open or endovascular revascularization (incremental cost-effectiveness ratio: $8,094) maybe more cost-effective than conservative management. The application of cost-utility analyses in chronic limb-threatening ischemia is in its infancy. Revascularization in infrainguinal disease may be favored over major lower extremity amputation or conservative management. However, data is inadequate to support recommendations for a specific treatment. This review identifies short and long-term considerations to address the current state of evidence. Cost-utility analysis is an important tool in healthcare policy and should be encouraged amongst the vascular surgical community.


Metals bioavailability in surface sediments off Nile delta, Egypt: Application of acid leachable metals and sequential extraction techniques.
Surface sediments from Nile Delta coast were analyzed for texture, CaCO3, organic matter, fractionation, and acid leachable metals (Cr, Fe, Mn, Ni, Pb, and Zn). The distribution pattern of acid leachable heavy metals in the sediment follows the sequence: Fe>Mn>Pb>Zn>Ni>Cr. All the acid leachable metals didn't exceed the sediment quality guidelines values (effects range low (ERL) and effects range medium (ERM)) and therefore doesn't represent a danger to marine organisms. The correlation of acid leachable Fe, Ni, and Mn indicates a similarity in the association of metals of similar origin. The negative correlation of sand with acid leachable Cr, Fe, Ni, Pb, and Zn indicates that these elements can be easily released by ion exchange processes due to the electrostatic interaction of trace metals as they are weakly bound and is bioavailable to the liquid phase. The acid leachable Cr, Pb, and Zn indicate their association with the CaCO3, while acid leachable Fe, Mn, and Ni are hardly combined with carbonates. All the contents of acid leachable metals are negatively correlated or uncorrelated with OM, which indicates that the studied heavy metals are hardly combined with OM. The results of the partitioning study showed that the residual form was the dominant fraction of the Cr, Fe, and Ni among most of the studied locations. Among the non-lithogenic fractions, the Fe-Mn oxy-hydroxide is the main scavenger for all metals. In terms of risk assessment code (RAC) value, a decrease order in environmental risk by heavy metals was Pb>Mn>Zn>Ni>Cr>Fe. Although the results of the two techniques were not consistent with each other in terms of predicting the metals bioavailability, a combination of total metal concentrations, acid leachable metals, and sequential extraction analysis is necessary to acquire the comprehensive information on the baseline, anthropogenic input, and bioavailability of heavy metals.


Water flux and energy use in wild house mice (Mus domesticus) and the impact of seasonal aridity on breeding and population levels.
Water turnover rate (WTR), urine concentration and field metabolic rate (FMR) were examined in house mice, Mus domesticus, permanently inhabiting roadside verge areas and seasonally invading crops in semi-arid wheatlands in South Australia. FMR was approximately proportional to body mass0.5 and mean values varied from 4.8 ml CO2 g-1h-1 (2.9 kJ g-1d-1) in autumn and winter, to 7.0 ml CO2 g-1h-1 (4.2 kJ g-1d-1) in maturing crops during spring. WTR was independent of body mass, indicating that larger mice were selecting a diet containing moister foods. WTR was low in summer and high in winter, and in mice from crops varied from 165 ml l-1 body water d-1 (122 ml kg-1d-1) to 1000 ml l-1d-1 (725 ml kg-1d-1). Seasonal changes in WTR were less extreme on the roadside, where a greater diversity of food was available. In the crops, breeding occurred throughout summer during two of three years, but the population increased only in the one summer when mice had marginally higher WTR. On the roadside breeding and population growth were continuous during summer, except in a drought year. Avcrage urine concentration was inversely related to WTR, and varied from 2.0 to 4.8 Osm l-1. The data indicate that the water conserving abilities of mice equal those of many desert rodents. The water conserving abilities of mice living in crops during summer were fully extended, and in some years aridity limited breeding success and population levels. The degree of moisture stress to which mice are exposed during summer appears to depend not only on rainfall but also on other factors such as availability of food and shelter, and the level of weed infestation in crops.


Pharmacokinetics of nilvadipine in healthy volunteers.
The pharmacokinetics of nilvadipine, a new antihypertensive and antianginal drug, were examined in healthy male volunteers. In a Latin square, three-way crossover design with a one-day run-in period, six subjects in three groups of two each were given single 2-, 4-, or 6-mg oral doses of nilvadipine after overnight fasting. Nilvadipine plasma concentrations up to 32 hours after drug treatment were determined by capillary column gas chromatography-negative-ion chemical ionization mass spectrometry (detection limit, 0.01 ng/mL). Nilvadipine urinary concentrations were determined by capillary column gas chromatography with electron capture detector (detection limit, 0.5 ng/mL). Nilvadipine plasma concentrations declined in a bi- or triexponential pattern after reaching the maximum plasma concentrations. The mean +/- standard deviation maximum plasma concentrations of 1.48 +/- 0.47, 3.48 +/- 0.53, and 6.69 +/- 1.54 ng/mL were attained from 1.08 to 1.50 hours after doses of 2, 4, and 6 mg, respectively. The elimination half-life was dose-independent and averaged 11.0 +/- 2.3 hours. The area under the plasma concentration-time curve increased in proportion to the dose. Nilvadipine was not detected in the urine. The pharmacokinetics of nilvadipine were generally linear over the dosage range studied. Besides the above model-independent pharmacokinetic parameters, model-dependent parameters were also obtained by curve-fitting the plasma data to a bi- or triexponential equation with zero-order absorption. Nilvadipine decreased blood pressure slightly and in a dose-dependent fashion.


Study on Zn relative concentration and state in sheep duodenum by XAFS.
Synchrotron-based X-ray absorption fine structure (XAFS) spectroscopy is not widely used in animal science. The objective of this study was to employ the XAFS technique to determine changes in zinc absorption and concentrations in the sheep interstinal sac using different zinc sources. Forty-eight sheep were slaughtered and their duodena were dissected. The duodena were randomly assigned to six zinc sources (ZnO, ZnSO(4), ZnMet, ZnLys, ZnSO(4) + methionine, ZnSO(4) + lysine). Ten centimeters of duodenal sac midpiece was incubated for 40 min in vitro using the everted intestinal sac technique in culture medium containing zinc from different sources. The amount of zinc present was normalized to 4 mg. XAFS was used to analyze the relative concentration and oxidation state of zinc, and atomic absorption spectrometry (AAS) was used to verify zinc concentration. The results showed that, for increasing zinc concentrations, organic zinc was a better source than inorganic zinc. In addition, the zinc concentration achieved using ZnMet was higher than that for ZnO and ZnSO(4) (P < 0.05) as measured by atomic absorption spectroscopy. The results using XAFS were consistent with that of AAS. The states of organic zinc and inorganic zinc were identical after being incubated for 40 min. As observed in these experiments, organic zinc was more easily absorbed than inorganic zinc. Our data demonstrate that organic zinc was dissociated into ions and then absorbed as inorganic zinc. In our experiments, we are the first investigators to use XAFS spectroscopy to determine zinc absorption in the sheep duodenal wall. We observed reduced absorption of inorganic zinc in the presence of methionine or lysine. Taken together, we postulate that the optimal molar ratio of inorganic zinc and ligand requires further study.


Peer advisers compared with specialist health professionals in delivering a training programme on self-management to people with diabetes: a randomized controlled trial.
To assess the effectiveness and acceptability of peer advisers in diabetes in delivering a programme of training on self-management for people with diabetes. Adults with diabetes were randomly allocated to an education programme delivered either by trained peer advisers or by specialist health professionals. The primary outcome measure was change in knowledge tested before and at the conclusion of the four courses, each consisting of six sessions. Glycated haemoglobin and Diabetes Care Profile were assessed at baseline and at 6 months. Sessional and end-of-course evaluation responses were analysed, as was the attendance record. Eighty-three patients were randomized. Of these, 14 failed to attend and two were excluded. Knowledge scores improved significantly in both groups, but there was no difference between the groups for any of the knowledge domains. No difference was noted in the Diabetes Care Profiles or in glycated haemoglobin. The attendance record was similar in both groups. In the post-sessional evaluations, both groups scored highly, with the health professionals significantly more so. The post-course questionnaire exploring patients' understanding and confidence in self-management of specific aspects of diabetes care revealed no difference between the groups. Trained patients are as effective in imparting knowledge to their peers as specialist health professionals. Both are also acceptable to patients as trainers. However, lay tutors require to be given appropriate training, specific to the education programme they would be expected to deliver.


Dynamic changes in ultrasound characteristics of nodules in cirrhotic liver and their implications in surveillance for malignancy.
To investigate whether there are ultrasound characteristics that can suggest HCC in ultrasound surveillance of nodules in cirrhotic liver. Data from 277 patients with hepatitis B virus-related nodules in cirrhotic liver undergoing ultrasound surveillance of the nodules for malignancy were reviewed. Size of the nodules ranged 6-23 mm. The nodules were followed by color Doppler ultrasound at 3- to 6-month intervals, with focus on size, shape, echogenicity, margin, halo sign, and vasculature. Suspicious malignant nodules underwent contrast-enhanced CT/MRI, and some indeterminate nodules underwent biopsy. Nodules in 189 patients were hypo/isoechoic/faint high echoic, 23 were hyperechoic, and 65 were both hypo/isoechoic/faint high echoic and hyperechoic. Forty-two patients developed hepatocellular carcinoma: 35 from nodules and 7 from background parenchyma. Fourteen nodules recessed (size >10 mm), 11 new nodules emerged (size >10 mm), and the total number of nodules increased over 5 years. All hepatocellular carcinomas developed from hypo/isoechoic/faint high echoic nodules, and no typical hyperechoic nodules developed into hepatocellular carcinomas. The size increased significantly when the nodules developed into hepatocellular carcinomas. No nodule presented an overt halo, seven hepatocellular carcinomas developed from nodules with a halo, and ill-defined margins of 16 nodules became well defined when they developed into hepatocellular carcinomas. No vasculature was detectable in the nodules, while it was detectable in eight hepatocellular carcinomas. No significant change occurred in nodules without malignancy. The characteristics for dynamic surveillance of nodules in cirrhotic liver for malignancy should include nodule growth, margin, halo, and vasculature. Apart from evident growth, an ill-defined margin becoming a well-defined margin, a newly emerged halo, and newly detectable vasculature are strongly suggestive of nodule malignancy.


Metabolic Disturbances in the Gut-brain Axis of a Mouse Model of MPTP-induced Parkinsonism Evaluated by Nuclear Magnetic Resonance.
Parkinson's Disease is a synucleinopathy that primarily affects the dopaminergic cells of the central nervous system, leading to motor and gastrointestinal disturbances. However, intestinal peripheral neurons undergo a similar neurodegeneration process, marked by α-synuclein (αSyn) accumulation and loss of mitochondrial homeostasis. We investigated the metabolic alterations in different biometrics that compose the gut-brain axis (blood, brain, large intestine, and feces) in an MPTP-induced mouse model of sporadic Parkinson's Disease. Animals received escalating administration of MPTP. Tissues and fecal pellets were collected, and the metabolites were identified through the untargeted Nuclear Magnetic Resonance spectroscopic (1H NMR) technique. We found differences in many metabolites from all the tissues evaluated. The differential expression of metabolites in these samples mainly reflects inflammatory aspects, cytotoxicity, and mitochondrial impairment (oxidative stress and energy metabolism) in the animal model used. The direct evaluation of fecal metabolites revealed changes in several classes of metabolites. This data reinforces previous studies showing that Parkinson's disease is associated with metabolic perturbation not only in brain-related tissues, but also in periphery structures such as the gut. In addition, the evaluation of the microbiome and metabolites from gut and feces emerge as promising sources of information for understanding the evolution and progression of sporadic Parkinson's Disease.


The role of FOXO1 in β-cell failure and type 2 diabetes mellitus.
Over the past two decades, insulin resistance has been considered essential to the aetiology of type 2 diabetes mellitus (T2DM). However, insulin resistance does not lead to T2DM unless it is accompanied by pancreatic β-cell dysfunction, because healthy β cells can compensate for insulin resistance by increasing in number and functional output. Furthermore, β-cell mass is decreased in patients with diabetes mellitus, suggesting a primary role for β-cell dysfunction in the pathogenesis of T2DM. The dysfunction of β cells can develop through various mechanisms, including oxidative, endoplasmic reticulum or hypoxic stress, as well as via induction of cytokines; these processes lead to apoptosis, uncontrolled autophagy and failure to proliferate. Transdifferentiation between β cells and α cells occurs under certain pathological conditions, and emerging evidence suggests that β-cell dedifferentiation or transdifferentiation might account for the reduction in β-cell mass observed in patients with severe T2DM. FOXO1, a key transcription factor in insulin signalling, is implicated in these mechanisms. This Review discusses advances in our understanding of the contribution of FOXO1 signalling to the development of β-cell failure in T2DM.


A crystallin mutant cataract with mineral deposits.
Connexin mutant mice develop cataracts containing calcium precipitates. To test whether pathologic mineralization is a general mechanism contributing to the disease, we characterized the lenses from a nonconnexin mutant mouse cataract model. By cosegregation of the phenotype with a satellite marker and genomic sequencing, we identified the mutant as a 5-bp duplication in the γC-crystallin gene (Crygcdup). Homozygous mice developed severe cataracts early, and heterozygous animals developed small cataracts later in life. Immunoblotting studies showed that the mutant lenses contained decreased levels of crystallins, connexin46, and connexin50 but increased levels of resident proteins of the nucleus, endoplasmic reticulum, and mitochondria. The reductions in fiber cell connexins were associated with a scarcity of gap junction punctae as detected by immunofluorescence and significant reductions in gap junction-mediated coupling between fiber cells in Crygcdup lenses. Particles that stained with the calcium deposit dye, Alizarin red, were abundant in the insoluble fraction from homozygous lenses but nearly absent in wild-type and heterozygous lens preparations. Whole-mount homozygous lenses were stained with Alizarin red in the cataract region. Mineralized material with a regional distribution similar to the cataract was detected in homozygous lenses (but not wild-type lenses) by micro-computed tomography. Attenuated total internal reflection Fourier-transform infrared microspectroscopy identified the mineral as apatite. These results are consistent with previous findings that loss of lens fiber cell gap junctional coupling leads to the formation of calcium precipitates. They also support the hypothesis that pathologic mineralization contributes to the formation of cataracts of different etiologies.


200 Gy sterilised Toxoplasma gondii tachyzoites maintain metabolic functions and mammalian cell invasion, eliciting cellular immunity and cytokine response similar to natural infection in mice.
200Gy gamma-irradiated Toxoplasma gondii RH tachyzoites failed to reproduce in vitro and in vivo. In short-term cultures, these parasites maintained a respiratory response, the ability to invade cells and preserved protein and nucleic acid synthesis. ELISA and Western blotting techniques demonstrated the similarity in humoral response between mice infected with gamma-irradiated tachyzoites and animals infected with naive parasites and treated with sulfadoxine, higher than mice immunised with formaldehyde-killed tachyzoites. Splenocyte stimulation by T. gondii antigen produced lymphoproliferative response and cytokine profile (IL-10, IL-12, IFN-gamma and TNF-alpha) similar to those produced by chronic natural infection. Mice immunised with irradiated tachyzoites had extended survival times after subsequent tachyzoite challenge, and displayed minimal cerebral pathology after cyst challenge. Irradiated tachyzoites lose their reproductive ability whilst maintaining metabolic function and may provide a novel tool for the study of toxoplasmosis and vaccine development.


Immunomodulation by filarial nematodes.
In order to chronically infect their hosts, filarial nematodes have generated a range of strategies to evade and down-modulate the host's immune system. The recent concept of suppression of immune responses by regulatory T cells has in part benefited from examinations in human and murine filariasis. Its further development in basic immunology animal models has in turn helped to better understand down-regulatory immune mechanisms in filariasis. Thus, filarial nematodes orchestrate down-regulation by inducing regulatory T cells and alternatively activated macrophages, which are able to suppress both Th1 and Th2 responses. Regulatory T cells can also induce the secretion of IgG4 from B cells as another arm of modulation. Dendritic cells are down-regulated upon first encounter with infective L3 larvae. Failure to respond to down-regulatory induction is based on genetic traits in hosts and leads to reduced parasite loads, albeit at the expense of pathology and disease. Since down-regulation in chronically and heavily infected hosts extends to third-party antigens, it is essential to analyse the impact of filarial infection for vaccination, allergy and important coinfections such as malaria, in order to foresee and avert potentially disastrous consequences of filariasis control programmes.


Does the human body produce a substance similar to caffeine?
The idea that the human body probably produces a substance similar to caffeine came to my mind after reviewing the literature on the "restless legs syndrome". This syndrome is a disorder in which the afflicted individual feels an irresistible urge to move the legs, generally when sitting or lying down, and especially in bed, at night, just prior to getting to sleep. The patient has an extremely unpleasant deep discomfort inside the calves, requiring that the legs be moved(1). The "restless legs syndrome" has been described in persons who consume a lot of caffeine(2,3), in patients with iron deficiency anemia(4), and in patients with chronic renal failure(5). Since this syndrome occurs in persons who indulge in caffeine consumption as well as in patients with iron deficiency and patients with chronic renal failure, it is tempting to postulate that the human body- in cases of iron deficiency and chronic renal failure -produces a substance similar to caffeine. The following discussion entertains the hypothetical route that might be involved in the formation of this substance.


[Nephroprotection--anaesthetic management of renal transplantation].
Kidney transplantation is a standard surgical procedure. Improvements of immunosuppressive therapy, donor management and surgical technique reduced perioperative complications and improved graft survival. In this review the authors discuss the anaesthetic management of kidney transplantation and nephroprotective strategies: reduction of ischemia-reperfusion injury, maintenance of optimal graft perfusion, avoidance of nephrotoxic agents and effective immunosuppression.


Correcting bias due to missing stage data in the non-parametric estimation of stage-specific net survival for colorectal cancer using multiple imputation.
Population-based net survival by tumour stage at diagnosis is a key measure in cancer surveillance. Unfortunately, data on tumour stage are often missing for a non-negligible proportion of patients and the mechanism giving rise to the missingness is usually anything but completely at random. In this setting, restricting analysis to the subset of complete records gives typically biased results. Multiple imputation is a promising practical approach to the issues raised by the missing data, but its use in conjunction with the Pohar-Perme method for estimating net survival has not been formally evaluated. We performed a resampling study using colorectal cancer population-based registry data to evaluate the ability of multiple imputation, used along with the Pohar-Perme method, to deliver unbiased estimates of stage-specific net survival and recover missing stage information. We created 1000 independent data sets, each containing 5000 patients. Stage data were then made missing at random under two scenarios (30% and 50% missingness). Complete records analysis showed substantial bias and poor confidence interval coverage. Across both scenarios our multiple imputation strategy virtually eliminated the bias and greatly improved confidence interval coverage. In the presence of missing stage data complete records analysis often gives severely biased results. We showed that combining multiple imputation with the Pohar-Perme estimator provides a valid practical approach for the estimation of stage-specific colorectal cancer net survival. As usual, when the percentage of missing data is high the results should be interpreted cautiously and sensitivity analyses are recommended.


Detection of a shared idiotope on two encephalomyocarditis virus neutralizing monoclonal antibodies by neutralization inhibition enzyme immunoassay.
Idiotypic cross-reactivity between encephalomyocarditis virus (EMCV) neutralizing monoclonal antibodies UM 21.1 (IgG2b) and UM 21.3 (IgG2a) was detected by neutralization inhibition enzyme immunoassay using polyclonal and monoclonal anti-idiotypic antibodies. One strongly cross-reactive anti-idiotypic monoclonal antibody, designated 21.1A5 (IgG2b), might recognize a recurrent idiotope on EMCV neutralizing antibodies but it did not induce EMCV neutralizing anti-anti-idiotypic antibodies in homologous BALB/c mice.


Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease.
The mechanism by which Helicobacter pylori predisposes to duodenal ulcers (DUs) remains unclear. The aim of this study was to investigate the effect of the infection on acid secretion. Acid output was examined basally and in response to gastrin-releasing peptide (GRP) and gastrin in healthy volunteers with and without H. pylori infection and in patients with DUs before and after eradication of the infection. Compared with H. pylori-negative healthy volunteers, patients with DUs with H. pylori had the following abnormalities of acid secretion: (1) threefold increase in basal acid output, (2) sixfold increase in acid response to GRP, (3) increased maximal acid response to exogenous gastrin, (4) increased ratio of basal acid output to maximal gastrin-stimulated output, and (5) increased ratio of maximal GRP-stimulated acid output to maximal gastrin-stimulated output. All of these abnormalities resolved fully after H. pylori eradication except for increased maximal acid output to gastrin, which was unchanged. Infected healthy volunteers showed a threefold increase in acid response to GRP that resolved after eradication of H. pylori infection. These disturbances in acid secretion caused by H. pylori infection are consistent with impaired inhibitory control and are likely to be relevant to the mechanism by which the infection predisposes to DU.


Parenting very low birth weight children at school age: maternal stress and coping.
To compare severity and determinants of stress and coping in mothers of 8-year-old very low birth weight (VLBW) and term children varying in medical and developmental risk. Three groups of mothers/infants were prospectively compared in a longitudinal study from birth to 8 years (110 high-risk VLBW, 80 low-risk VLBW, and 112 term). Maternal psychological distress, coping, parenting/marital stress, child health, and family impact were measured in the children at age 8 years. Mothers of VLBW children differed from term mothers, reporting less consensus with partners, more concern for their children's health, less parent-child conflict, and fewer years of education attained. Mothers of high-risk VLBW children experienced the greatest family and personal strains and used less denial and disengagement coping. The groups exhibited no differences in the sense of parenting competence, divorce rate, parenting/marital satisfaction, family cohesion, and psychological distress symptoms. Multiple birth, low socioeconomic status, and lower child IQ added to maternal stress. VLBW birth has long-term negative and positive impacts on maternal/family outcomes related to the infant's medical risk.


Analytical Method for Predicting Ferromagnetic Properties of Benzyl-Radical Polymers Based on NBMO Theory.
It has been demonstrated that the high-spin stability of benzyl radical oligomers can be predicted without any quantum chemical calculations. This method is composed of three steps: (1) predicting the shapes of nonbonding molecular orbitals (NBMOs), (2) counting up the mixings of NBMOs, and (3) formulating the mixings for the number of radical centers (N). This treatment enables us to predict the high-spin stability evaluated by ab initio MO calculations involving the post-Hartree-Fock method or the density functional theory (DFT) method.


Intravenous immunoglobulins: evolution of commercial IVIG preparations.
Since its first use in 1952, human immunoglobulin has been used to treat people who have inherited antibody deficiencies. This article summarizes IVIG clinical development in primary immunodeficient patients and manufacturing improvements introduced over time. Manufacturing improvements include purification procedures that have reduced the incidence of adverse events and improved clinical efficacy, as well as virus inactivation and removal steps that have increased safety from blood-borne infections. Current manufacturing procedures, IVIG production trends, and recent clinical trial results are also reviewed.


The effects of farmers' place attachment and identity on water conservation moral norms and intention.
Investment in the behavioral change projects would not be possible without knowing their prerequisites and determinants including intention, moral norms, identity, and place attachment. Therefore, this study aimed at the determination of the effects of place attachment (PAT) (place dependence (PDE), place identity (PID), and place affect (PAF)) and farmers' identity (conservationist identity (CONID) and productivist identity (PROID)) on the moral norms of water conservation (MNWC) as well as the intention of water conservation (IWC) of the Iranian farmers. This was a descriptive-correlational and causal-relational study. The instrument of the study was a questionnaire completed using a cross-sectional survey and face-to-face interviews. Hence, a stratified random sampling method along with a proportionate allocation was used to select 380 farmers. The research findings indicated that the PAT (PDE, PID, and PAF) and CONID had significant positive effects on the MNWC. In addition, MNWC and CONID had significant positive effects on the IWC. However, PROID had a significant negative effect on the MNWC and IWC. In general, it was found that independent variables (PDE, PID, PAF, PROID, and CONID) could predict 39% and 53% of the variance of the MNWC and IWC variables, respectively. Moreover, the social-psychological framework of the study provides practitioners, decision-makers, policymakers, researchers, and other stakeholders of the agricultural water management with useful practical and theoretical insights about the practices of behavior changes and social interventions. Finally, it is recommended that government decision-makers should further focus on the increased attractiveness of the rural and agricultural areas to increase PAT, MNWC, and IWC.


Biliary Epithelial Cells Are Not the Predominant Source of Hepatic CXCL12.
Hepatic expression levels of CXCL12, a chemokine important in inflammatory and stem cell recruitment, and its receptor, C-X-C chemokine receptor 4, are increased during all forms of liver injury. CXCL12 is expressed by both parenchymal and nonparenchymal hepatic cells, and on the basis of immunohistochemistry, biliary epithelial cells (BECs) are thought to be a predominant source of hepatic CXCL12, thereby promoting periportal recruitment of C-X-C chemokine receptor 4-expressing lymphocytes. Our study aims to show that BECs may, in fact, not be the predominant source of hepatic CXCL12. We measured CXCL12 secretion and expression from human and murine BECs using enzyme-linked immunosorbent assay and Western blot analysis from cell culture supernatants and whole cell lysates, respectively, whereas CXCL12 expression in murine livers was analyzed in a Cxcl12-Gfp reporter mouse. Cell culture supernatants and whole cell lysates from BECs failed to demonstrate their expression of CXCL12. Furthermore, we confirmed these results with a Cxcl12-Gfp reporter mouse in which green fluorescent protein expression is notably absent from BECs. Interestingly, on the basis of green fluorescent protein expression, we demonstrate a population of CXCL12-expressing cells within the portal tract that are distinct, yet intimately associated with BECs. These findings indicate that BECs are not a predominant source of CXCL12.


Simple method of improving the quality of platelet concentrates and the importance of production control.
Some technical improvements of the method to prepare platelet concentrates (PC) have been developed. The contamination of the PC with red blood cells (RBC) and white blood cells (WBC) is thereby kept at a low level. A majority of routinely prepared PC did not show any visible RBC contamination which means that they contained less than 0.4 X 10(9) RBC per PC unit. None of the tested examples contained more than 1 X 10(9) RBC per PC unit. The WBC contamination was less than 0.1 X 10(9) cells per PC unit in 75 per cent of tested examples and did not exceed 0.6 X 10(9) cells per PC unit. Routine platelet counting by thrombocounter applied on samples from all PRPs was found to be a reasonably simple way to make routine PC quality control. By sufficient supervision of the details of the procedure the main yield can be maintained at about 100 X 10(9) cells per unit. By follow-up of the weekly yield any deterioration of production efficiency can easily be detected.


Sarcolemmal glucose transport in Ca2+-tolerant myocytes from adult rat heart. Calcium dependence of insulin action.
Cardiac myocytes were isolated from adult rat ventricles by a method which preserves their functional integrity, including long survival in physiological concentrations of Ca2+. Sarcolemmal glucose transport was assessed by measuring linear initial uptake rates of the nonmetabolized glucose analog 3-O-methyl-D-glucose. Transport was saturable and showed competition by D-glucose and other features of chemical and stereo-selectivity. Transport was stimulated by insulin in a dose-dependent manner, resulting in an almost 5-fold increase in Vmax, with little change in Km. Stimulation of 3-methylglucose transport by insulin was largely Ca2+-dependent. Omission of Ca2+ from the incubation medium caused a minor rise in basal 3-methylglucose uptake but the insulin-stimulated rise in Vmax was only 30%. The Ca2+ antagonist D600 also antagonized stimulation of hexose transport by insulin. In all the above respects, 3-methylglucose transport in myocytes is identical to that in intact heart muscle. In addition, the decrease in insulin response by Ca2+ omission was partially reversed by subsequent return to a Ca2+-containing medium. ATP levels remained stable in the absence of Ca2+, showing that the Ca2+ dependence did not reflect nonspecific cell damage.


Characterization of blast cells in chronic granulocytic leukaemia in transformation, acute myelofibrosis and undifferentiated leukaemia. II. Studies with monoclonal antibodies and terminal transferase.
A panel of 19 monoclonal antibodies (McAb) and the enzyme terminal transferase (TdT) have been applied to the characterization of poorly differentiated blasts from 50 patients with chronic granulocytic leukaemia (CGL) and myelofibrosis in blast crisis (BC), acute myelofibrosis and undifferentiated leukaemia. These cells were also extensively studied by transmission electron microscopy (TEM) (see Polli et al, 1985a). McAb against platelet glycoproteins (GP) showed a high specificity for megakaryoblasts, in particular those reactive with the GPIIb/IIIa complex (J15) and GPIIIa (C15 and C17), which were positive in a higher proportion of blasts than the McAb to GPIb (AN51 and FMC25). Findings with these anti-platelet McAb paralleled those of the platelet-peroxidase (PPO) reaction in 76% of cases studied simultaneously. The PPO reaction was always positive in cases in which two or more of the McAb were reactive with the blast cells. The differences observed suggest, nevertheless, that PPO is more sensitive for megakaryoblasts than the McAb and that this TEM technique should be reserved for cases which are negative with the platelet specific McAb. Of the McAb against myeloid antigens used in this series OKM1 was positive in 50% of cases but the others failed to demonstrate early features of differentiation in myeloblasts and monoblasts. In only three cases were erythroid precursors demonstrated by TEM and these were the only ones reactive with a McAb to glycophorin-A (LICR LON/R10). TdT and the McAb J5 helped in the identification of lymphoblasts which were seen as a 'pure' proliferation in 23% of CGL-BC and as part of blast cell mixtures in another 17% of cases. The McAb reactive to haemopoietic precursor cells (RFB1, FMC8 and OKIa), on the other hand, were of no practical value for the classification of blast cell types. The lineage specificity of several of the McAb used in this study, confirmed by TEM, suggest that these reagents are valuable tools for the characterization of immature blast cells.


O-GlcNAcylation of truncated NAC segment alters peptide-dependent effects on α-synuclein aggregation.
Numerous post-translational modifications (PTMs) of the Parkinson's disease (PD) associated α-synuclein (α-syn) protein have been recognised to play critical roles in disease aetiology. Indeed, dysregulated phosphorylation and proteolysis are thought to modulate α-syn aggregation and disease progression. Among the PTMs, enzymatic glycosylation with N-acetylglucosamine (GlcNAc) onto the protein's hydroxylated amino acid residues is reported to deliver protective effects against its pathogenic processing. This modification has been reported to alter its pathogenic self-assembly. As such, manipulation of the protein's O-GlcNAcylation status has been proposed to offer a PD therapeutic route. However, targeting upstream cellular processes can lead to mechanism-based toxicity as the enzymes governing O-GlcNAc cycling modify thousands of acceptor substrates. Small glycopeptides that couple the protective effects of O-GlcNAc with the selectivity of recognition sequences may prove useful tools to modulate protein aggregation. Here we discuss efforts to probe the effects of various O-GlcNAc modified peptides on wild-type α-synuclein aggregation.


Immunoglobulin G4-related disease presenting as bilateral ovarian masses and mimicking advanced ovarian cancer.
Immunoglobulin G4-related disease (IgG4-RD) is characterized by extensive infiltration of IgG4(+) plasma cells and fibrosis in various organs. However, the involvement of the ovary in IgG4-RD has never been reported. A 59-year-old woman presented with urinary retention. Magnetic resonance imaging and computed tomography revealed a huge multinodular pelvic mass and common iliac/para-aortic lymph node swelling. A laparotomy was performed under the suspicion of advanced ovarian cancer, and the pelvic mass was identified as ovary in origin. Histopathology of the excised tumor revealed massive lymphoplasmacytic infiltration (>90% were IgG4(+) plasma cells), storiform fibrosis, and obliterative phlebitis; thus leading to a diagnosis of IgG4-RD. We conclude that IgG4-RD can present as a bilateral ovarian mass along with lymphadenopathy, therefore mimicking ovarian cancer.


[Relation between histologic-bioptic findings in the synovial membrane and the clinical results of therapy in subsequent chemical synovectomy].
The histological findings in needle biopsy specimens from 35 patients suffering from chronic exudative synovitis of the knee were compared with the clinical data and with the results of chemical synovectomy carried out after the needle biopsy. The investigations suggest that in cases with the pronounced histological changes less improvement can be expected from chemical synovectomy than in cases with slighter histological changes.


Unmet mental health care needs in U.S. children with medical complexity, 2005-2010.
Children with special healthcare needs (CSHCN) are those who have or are at elevated risk for a chronic physical, developmental, behavioral or emotional condition and need healthcare services of a type or quantity beyond that required by children generally. Within CSHCN, a small group of children with medical complexity have medical vulnerability and intensive care needs that are not easily met by existing healthcare models. This study estimated the national prevalence of unmet mental healthcare needs among CSHCN with and without medical complexity. Secondary data analysis (N=80,965) based on the National Survey of CSHCN 2005-2006 and 2009-2010 waves. During 2005-2010, 7.66% of CSHCN in the U.S. were with medical complexity. The prevalence of unmet needs for mental healthcare services among CSHCN increased from 3.71% in 2005-2006 to 5.62% in 2009-2010. In 2005-2006 the prevalence of unmet mental healthcare needs among children with medical complexity was 9.92%, tripling the prevalence among CSHCN without medical complexity of 3.10%. The prevalence of unmet mental healthcare needs among children with medical complexity further increased to 13.71% in 2009-2010, whereas that among CSHCN without medical complexity increased to 5.07%. Among CSHCN with medical complexity, older children and children living in poorer households were more likely to have an unmet need for mental healthcare services. Substantial disparities in access to mental healthcare services between CSHCN with and without medical complexity were present, and the prevalence of unmet mental healthcare needs among both groups had noticeably increased during 2005-2010.


Pediatric Palliative Care: Insights into Assessment Tools andReview Instruments.
The proper assessment of needs and outcomes in pediatric palliative care (PPC) is imperativeto ensure the best possible service to patients and families. However, given the multidimensionalnature of PPC, the low number of patients in this setting, the heterogeneity of diseases, the presenceof cognitive impairment in many patients, and the physiological development of children, outcomescan be complex and difficult to measure. Consequently, in this context, the use of standardizedand validated tools to assess the needs of children and families, to assess symptom severity, andto estimate the quality of PPC service represent a current need. Even if efforts have been made tostandardize approaches and tools for palliative care in adults, to our knowledge, a similar comprehensiveassessment of PPC has not yet been conducted to date. This narrative review provides anoverview and discusses the evaluation of tools currently applied in PPC, with an educational intentfor healthcare providers. We found that several instruments are available to assess different dimensionsof PPC. We proposed a classification into eligibility tools, patient and family needs assessmenttools, and care assessment tools. At present, two main eligibility tools exist, the PaPaS Scale and theACCAPED Scale questionnaire. Most of the tools for patient and family needs assessment have notbeen specifically validated in the PPC setting, and many may be more readily applied in researchsettings rather than in daily practice. Similar considerations can be made for tools assessing QoL,while tools assessing PPC service quality seem to be easily applied. Efforts to develop new specifictools and validate existing ones are undoubtedly advocated. However, in the patient's best interest,PPC healthcare providers should start using available tools, regardless of their validation status.


New concepts of resistance in the treatment of Helicobacter pylori infections.
The prevalence of antimicrobial drug resistance is now so high that all patients infected with Helicobacter pylori should be considered as having resistant infections. Ideally, therapy should be based on pretreatment antibiotic-susceptibility testing but this strategy is not currently practical. At present, clarithromycin-containing triple therapies do not reliably produce a > or =80% cure rate on an intention-to-treat basis and are, therefore, no longer acceptable as empiric therapy. In this Review, we discuss concepts of resistance that have become part of mainstream thinking for other infectious diseases but have not yet become so with regard to H. pylori. We also put data on the pharmacokinetics and pharmacodynamics of the drugs used in H. pylori therapy and the effect of host cytochrome P450 genotypes in context with treatment outcomes. Our primary focus is to address the problem of H. pylori resistance from a novel perspective, which also attempts to anticipate the direction that research will need to take to provide clinicians with reliable approaches to this serious infection. We also discuss current therapies that provide acceptable cure rates when used empirically (i.e. sequential therapy; four-drug, three-antibiotic, non-bismuth-containing 'concomitant' therapy; and bismuth-containing quadruple therapy) and how they might be further improved.


Photoperiodic time measurement during the termination of photorefractoriness in the starling (Sturnus vulgaris L.).
Groups of photorefractory male European starlings have been kept under Nanda-Hamner LD schedules ranging from LD 6:6 to LD 6:54 for about 6 weeks. Subsequently, when transferred to LD 13:11, all birds of groups LD 6:18 and LD 6:42 went through a complete cycle of testicular growth and regression. Furthermore, they carried out a postnuptial molt, indicating that they have been able to terminate photorefractoriness under these LD schedules. In contrast, no positive responses could be detected in groups LD 6:6, LD 6:30, LD 6:36, and LD 6:54. Groups LD 6:12, LD 6:24, and LD 6:48 were intermediate in their reactions. Only part of these birds showed gonadal recrudescence when tested for photosensitivity. Changes in plasma testosterone levels were closely related to variations in testicular diameter. These results clearly suggest a strong circadian component in photoperiodic time measurement during the termination of photorefractoriness in the starling. Positive or negative responses were completely in line with predictions derived from the model of external coincidence. A comparison with the results of a similar experiment previously done with photosensitive birds failed to detect basic differences in the interpretation of the various LD cycles. These findings suggest that the same photoperiodic time measurement system is used at both phases of the starling's annual cycle.


Gene silencing using RNA interference in embryonic stem cells.
Pluripotent embryonic stem (ES) cells are an important model system to examine gene expression and lineage segregation during differentiation. One powerful approach to target and inhibit gene expression, RNAi, has been applied to ES cells with the goal of teasing out the cascades of gene expression/repression that shape the early embryo. In this chapter, we describe the current understanding of the mechanisms of gene silencing by small hairpin RNAs, as well as controls and caveats to using this approach in ES cells. A consideration of synthetic vs plasmid-based RNAi vectors, design of targeting constructs, transfection of ES cells, and flow sorting of targeted cells is followed by methods for the analysis of phenotype and behavior of targeted cell populations using immunohistochemistry, reverse transcriptase polymerase chain reaction, Western blotting, and scanning electron microscopy.


Distinct translation regulation by two alternative 5'UTRs of a stress-responsive protein--dPrx I.
Translation efficiency is often regulated in part by 5'-untranslated region (5'UTR). Sequence analysis of an evolutionarily conserved stress-responsive protein, Drosophila Peroxiredoxin I (dPrx I), found the transcript to have two alternative 5'UTRs that lead to an identical coding sequence: namely Ia and Ib. Although both isoforms coexisted in Drosophila cells, the Ia isoform appeared to be dominant. Furthermore, reporter assay found that Ia enhanced translation in steady-state cells while Ib increased translation in cells under oxidative stress. Together, our data suggest that the two alternative 5'UTRs of dPrx I may be involved in a translational regulatory mechanism that responds to cellular oxidative stress.


Modelling benzo[a]pyrene in air and vegetation for different land uses and assessment of increased health risk in the Iberian Peninsula.
The ability of the modelling system WRF + CHIMERE implemented with high spatial and temporal resolution over the Iberian Peninsula (IP) to represent the levels of benzo[a]pyrene (BaP) in air and vegetation was tested in areas where different land uses are observed. Biomonitoring data available on the levels of polycyclic aromatic hydrocarbons (PAHs) in pine needles from the IP were used to estimate the atmospheric concentrations of BaP and, at the same time, fuelled the comparison of the vegetation representations given by the model. A total of 70 sites were sampled, including urban, industrial, rural and remote locations, which revealed different performances of the method for air and vegetation concentrations of BaP. The validation of this chemistry transport model (CTM) was complemented with the data available from the European Monitoring and Evaluation Programme (EMEP) air sampling network. This, in association with a quantitative risk assessment (QRA) method, allowed the estimation of the increased risk of lung cancer due to exposure to BaPs in the IP for three target values set by the European Union.


The new histological system for the diagnosis of adrenocortical cancer.
Adrenocortical cancer (ACC) is a rare malignant tumor that originates in the adrenal cortex. Despite extensive molecular-genetic, pathomorphological, and clinical research, assessing the malignant potential of adrenal neoplasms in clinical practice remains a daunting task in histological diagnosis. Although the Weiss score is the most prevalent method for diagnosing ACC, its limitations necessitate additional algorithms for specific histological variants. Unequal diagnostic value, subjectivity in evaluation, and interpretation challenges contribute to a gray zone where the reliable assessment of a tumor's malignant potential is unattainable. In this study, we introduce a universal mathematical model for the differential diagnosis of all morphological types of ACC in adults. This model was developed by analyzing a retrospective sample of data from 143 patients who underwent histological and immunohistochemical examinations of surgically removed adrenal neoplasms. Statistical analysis was carried out on Python 3.1 in the Google Colab environment. The cutting point was chosen according to Youden's index. Scikit-learn 1.0.2 was used for building the multidimensional model for Python. Logistical regression analysis was executed with L1-regularization, which is an effective method for extracting the most significant features of the model. The new system we have developed is a diagnostically meaningful set of indicators that takes into account a smaller number of criteria from the currently used Weiss scale. To validate the obtained model, we divided the initial sample set into training and test sets in a 9:1 ratio, respectively. The diagnostic algorithm is highly accurate [overall accuracy 100% (95% CI: 96%-100%)]. Our method involves determining eight diagnostically significant indicators that enable the calculation of ACC development probability using specified formulas. This approach may potentially enhance diagnostic precision and facilitate improved clinical outcomes in ACC management.


Intralesional infiltration of corticosteroids in the treatment of localised langerhans' cell histiocytosis of the mandible Report of known cases and three new cases.
Langerhans' cell histiocytosis (LCH) can involve virtually any site and organ of the body, either as an isolated lesion or as a widespread systemic disease. Bone can be involved as a part of generalised disease or as a separate entity, formerly known as eosinophilic granuloma. The clinical cause of localised LCH (LLCH) to bone is generally benign. Solitary bone lesions may resolve spontaneously after diagnostic biopsy in a period of months to years. If treatment is indicated, as in larger lesions with pain, swelling and risk for spontaneous fracture, the disease can be controlled by chemotherapy or local measures such as surgical curettage, low-dose radiotherapy and intralesional injection of corticosteroids. There are no controlled studies in the literature comparing outcomes of these treatment modalities because of low incidence of the disease and general tendency to regress. Three patients (female, 28 months; male, 9 years; male, 15 years) with LLCH of the mandible were treated in an one stage procedure with intralesional injection of 80, 40 and 80 mg methylpredisolone succinate, respectively, as the primary form of treatment. Patients were seen for clinical and radiological evolution 1, 3, 6, 9 and 12 months after treatment, and yearly thereafter. The overall outcome was excellent. The lesions showed clinically and radiologically complete remission approximately 6 months after treatment. There were no complications nor morbidity of the treatment. After a follow-up period of 12 months, the patients are well with no evidence of residual disease on radiographs. Local injection of corticosteroids should be the initial choice of treatment of LLCH of the mandible, because of the favourable treatment outcome in this disease and possible complications and lasting effects of surgery, radiotherapy and chemotherapy.


Geographical distribution and conservation strategy of national key protected wild plants of China.
National key protected wild plants (NKPWPs) are considered flagship species for plant diversity conservation in China. Using data for 1101 species, we characterized NKPWPs distribution patterns in China and assessed conservation effectiveness and conservation gaps. In total, 4880 grid cells at a 20 × 20 km resolution were filled with occurrence records for NKPWPs. We identified 444 hotspot grid cells and 27 diversity hotspot regions, containing 92.37% of NKPWPs. However, 43.24% of these hotspot grid cells were fully or partially covered by national nature reserves (NNRs), where 70.21% of species were distributed. Approximately 61.49% of the NKPWPs species were protected by NNRs, but the populations or habitats of 963 species were partially or fully outside of NNRs. With global warming, the overall change in the extent of suitable habitats for NKPWPs is expected to be small, however, habitat quality in some areas with a high habitat suitability index will decrease.


Referral and use of heart failure clinics: what factors are related to use?
Heart failure (HF) clinics have been shown to reduce hospital readmissions and generally have favourable effects on quality of life, survival, and care costs. This study investigated the rates of referral and use of HF clinics and examined factors related to program use. This study represents a secondary analysis of a larger prospective cohort study conducted in Ontario. In hospital, 474 HF inpatients from 11 hospitals across Ontario completed a survey that examined predisposing, enabling, and need factors affecting HF clinic use. Then 1 year later, 271 HF patients completed a mailed survey that assessed referral to and use of HF clinics. Forty-one patients (15.2%) self-reported referral, and 35 (13%) self-reported attending an HF clinic. Generalized estimating equations showed that factors related to greater program use were having an HF clinic at the site of hospital recruitment (odds ratio [OR] = 8.40; P = 0.04), referral to other disease management programs (OR = 4.87; P = 0.04), higher education (OR = 4.61; P = 0.02), lower stress (OR = 0.93; P = 0.03), and lower functional status (OR = 0.97; P = 0.03). Similar to previous research, only one-seventh of HF patients were referred to and used an HF clinic. Both patient-level and health-system factors were related to HF clinic use. Given the benefits of HF clinics, more research examining how equitable access can be increased is needed. Also, the appropriateness and cost repercussions of use of multiple disease management programs should be investigated.


HER2 gene copy number and breast cancer-specific survival.
HER2 amplification occurs in 10-15% of breast cancers. It is associated with poor breast cancer-specific survival (BCSS) and is an important prognostic and predictive marker. While it has been accepted that the HER2:chromosome 17 centromere (CEP17) ratio determines HER2 status, recent guidelines acknowledge the significance of HER2 copy number alone. The aims of this study were to assess BCSS according to mean HER2 copy number and HER2 status expressed as a HER2:CEP17 ratio with and without increased CEP17 copy number. The study population comprised breast cancer patients treated with surgery only and with long-term follow-up. In situ hybridization for HER2:CEP17 was performed on tissue microarrays and was successful in 679 cases. These were included in the study. Kaplan-Meier methods were used to estimate BCSS. A total of 47 cases had ≥4 < 6 HER2 copies; 16 were HER2+ and 31 were HER2- by ratio. Eighty-five cases had ≥6 copies of HER2 and only two of these were HER2- by ratio. The risk of death from breast cancer was increased among those with ≥6 HER2 compared to cases with 0-3.9 HER2 signals [hazard ratio (HR): 2.05; confidence interval (CI): 1.49-2.82 (unadjusted)]. After adjusting for stage, there was increased risk of death from breast cancer during the first 5 years after diagnosis in cases that were HER2- by ratio but with ≥4 < 6 HER2 (HR: 2.38; CI: 1.23-4.60). Increased copy number of HER2 may confer an increased risk of death from breast cancer despite negative HER2 status by ratio.