Cholesterol content in brains of suicide completers.
An association between low levels of serum cholesterol and violent or suicidal behaviour has frequently been reported, but it remains unclear how cholesterol in the peripheral system might be related to the brain functions involved in mediating suicidal behaviour. To our knowledge, there have been no previous studies aimed at answering the important question of whether there are differences in cholesterol within the brains of suicide completers. In the present study, cholesterol content was measured in cortical and subcortical tissue of brains from 41 male suicide completers and 21 male controls that died of sudden causes with no direct influence on brain tissue. No significant differences in cholesterol content were found between suicides and controls in the frontal cortex, amygdala or hippocampus. However, when the suicide completers were stratified into violent (n=31) or non-violent (n=10) groups based on the method of death, violent suicides were found to have lower grey-matter cholesterol content overall compared to non-violent suicides [F(1,111)=4.75, p=0.03], specifically in the frontal cortex (t=-4.16, d.f.=37, p<0.0005). Further exploration of the frontal cortex revealed that violent suicides had lower cholesterol content compared to non-violent suicides in the orbitofrontal cortex (t=-2.01, d.f.=36, p=0.05) and the ventral prefrontal cortex (t=-2.49, d.f.=37, p=0.02). This study represents the first direct examination of cholesterol content in brain tissue from suicide completers, and the present findings provide added support for the relationship between low cholesterol and violent or suicidal behaviour.


Influence of freeze-drying and γ-irradiation in preclinical studies of flurbiprofen polymeric nanoparticles for ocular delivery using d-(+)-trehalose and polyethylene glycol.
This study investigated the suspension of poly(ε-caprolactone) nanoparticles as an ocular delivery system for flurbiprofen (FB-PεCL-NPs) in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-PεCL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5%) and submitted individually for freeze-drying and γ-irradiation with polyethylene glycol 3350 (PEG3350) and d-(+)-trehalose (TRE). Both formulations satisfied criteria according to all physicochemical parameters required for ocular pharmaceuticals. The FB-PεCL-NP formulations showed non-Newtonian behavior and sustained drug release. Ex vivo permeation analysis using isolated ocular pig tissues suggested that the presence of PEG3350 results in a reduction of FB transcorneal permeation. Moreover, TRE improved the penetration of FB across the cornea, especially after γ-irradiation. In addition, both formulations did not show a significant affinity in increasing FB transscleral permeation. Both formulations were classified as nonirritating, safe products for ophthalmic administration according to hen's egg test-chorioallantoic membrane and Draize eye test. Furthermore, an in vivo anti-inflammatory efficacy test showed that irradiated FB-PεCL-NPs prepared with PEG3350 (IR-NPsPEG) have longer anti-inflammatory effects than those presented with irradiated FB-PεCL-NPs prepared with TRE (IR-NPsTRE). IR-NPsPEG showed a suitable physical stability after an aqueous reconstitution over >30 days. This study concludes that both formulations meet the Goldman's criteria and demonstrate how irradiated nanoparticles, with innovative permeation characteristics, could be used as a feasible alternative to a flurbiprofen solution for ocular application in clinical trials.


Macrophages at the skeletal tissue-device interface of loosened prosthetic devices express bone-related genes and their products.
Aseptic loosening of prosthetic arthroplasty is the most common reason for implant failure in adult orthopaedic reconstruction. At the interface of aseptic loosened prostheses, there is an abundance of particle-activated macrophages and other inflammatory cells. The role of these particle-laden macrophages in the osteogenic arm of the remodeling skeleton in this pathological condition is poorly understood. Molecular signaling by mesenchymal cells and mononuclear inflammatory cells residing in the interfacial tissues between bone and cement or prosthetic material of aseptically loosened joint prostheses was studied using in situ hybridization and immunohistochemical techniques. We found that a range of collagenous and noncollagenous matrix proteins, including osteopontin, osteocalcin, bone sialoprotein, and type I collagen, were produced in the periprosthetic tissue by foamy macrophages, as well as nearby osteogenic cells. The former accumulated in profusion in the three zones of interfacial tissues: pseudomembranous, fibrous, and osseous. Spindle mesenchymal cells in the fibrous zone failed to express any of the osteogenic mRNAs or proteins sought. The expression of bone-related genes and proteins by foamy macrophages at the interface of an aseptic loosened prosthesis may contribute to the disturbance of bone remodeling at this site.


[Our childhood cases with intussusception and pneumatic reduction].
Intussusception is defined as telescopic insertion of the terminal ileum in to the colon after the cecum and colon. The aim of this study was to present our experience in pneumatic reduction of intussusception. In our study, 118 intussusception cases treated between 1996 and 2008 were analyzed. Age, gender, admission time, diagnostic/treatment methods, types of intussusception including leading point, and postoperative complications were evaluated. Of these patients, 76 (64%) were male and 42 (36%) were female. Mean age was 25 +/- 34 months (3-180 months). The most common clinical presentations were vomiting, abdominal pain/irritable crying and bloody stools. Intussusceptions were ileocolic in 109 (92.3%) patients, ileoileal in 7 (6%) patients, and colocolic in 2 (1.7%) patients. No mortality was noted. Fifty-three patients (45%) were treated by nonoperative reduction whereas the remainder were treated surgically. Among 65 patients operated, 13 leading points were detected. Pneumatic reduction success rate was 86%. Age significantly reduced the pneumatic reduction success rate; however, the duration between the beginning of symptoms and hospital admission and bloody stool were not effective. Intussusception can be treated by non-operative methods when diagnosed early. Our results suggest that pneumatic reduction of intussusception in the pediatric population should be considered as a first choice.


[Abortive myxovirus infection in Ehrlich's ascitic carcinoma cells. Further study of the nature of the virus-specific structures produced by heterokaryons].
Fowl plague virus-infected cells of Ehrlich ascitic carcinoma produce a noninfectious virus which is defective in fragility of its membranes. An attempt has been made to produce nondefective virus by fusion of infected Ehrlich cells with permissive cells: infected and non-infected chicken fibroblasts. The fusion of FPV-infected and 3H-uridine labeled Ehrlich ascitic carcinoma cells with infected unlabeled chicken fibroblasts using inactivated Sendai virus resulted in production of two types of labeled virus particles: with a buoyant density in cesium chloride gradient of 1.29 g/cm3 characteristic of particles produced by infected Ehrlich cells and buoyant density 1.22 g/cm3 typical of standard influenza virus. Both types of particles has infectious activity which was greater in the virus with the density of 1.22 g/cm3. However, particles with the density of 1.22 g/cm3 are not found upon the fusion of infected Ehrlich cells with uninfected chicken fibroblasts, with chicken fibroblasts early after infection, or with chicken fibroblasts treated with actinomycin D before infection. Infected chicken fibroblasts in hybrids were shown not to use the radioactive pool of Ehrlich cells and, accordingly, the virus with the density of 1.22 g/cm3 if formed from components pre-existing in Ehrlich cells. It is suggested that the standard virus buds on the areas of membranes of permissive cells which are parts of the hybrids.


Schwannoma: A surgical epidemiology.
To identify the surgical incidence and prevalence of schwannoma in our region and quantify the demographic, surgical, neoplastic, and outcome characteristics of the patients diagnosed with schwannoma.. A retrospective cross-sectional study was conducted from January 1 to December 31, 2019. Enrolled were 32 of the highest volume neurosurgical centres in Pakistan. Patients with a histopathological diagnosis of schwannoma and radiological imaging were included in the study. Medical records were reviewed for data, and SPSS version 25 was used for statistical analysis. Patients were followed up for one year, which was the duration of the study. From 2750 patients diagnosed with brain tumours, 148 patients had schwannomas. Out of these, 84 (56.8%) patients were male, and 64 (43.2%) patients were female. The mean age of the patients was 39 ± 14 years. The socioeconomic statuses of the enrolled patients were lower in 72 (53.3%) patients, middle in 57 (42.2%) patients, and upper middle to upper in 6 (4.4%) patients. All patients underwent surgery, 14 patients received radiotherapy, and two patients received chemotherapy. In our cohort, 115 (77.7%) patients presented to public sector hospitals, with only 33 (22.3%) patients presenting to private hospitals. At the end of the study period, 60 (40.5%) patients had been lost to follow-up. Of the remaining 88 patients, 75 (85.2%) were alive. The mortality rate on a one-year follow-up was 14.8%. Schwannoma comprises a larger percentage of the brain tumours in our regions than reported in the literature. The high mortality rate is of particular concern and warrants further investigation to improve patient care and outcomes.


Trimethoprim and sulfamethoxazole transmembrane clearance during modeled continuous renal replacement therapy.
There is limited data regarding trimethoprim (TMP)/sulfamethoxazole (SMX) continuous renal replacement therapy (CRRT) dosing. We aimed to estimate TMP/SMX transmembrane clearance (CLtm) during continuous hemofiltration (CH) and continuous hemodialysis (CD) to guide dosing. Using an in vitro model, TMP/SMX sieving coefficients (SC) and saturation coefficients (SA) were determined with high-flux polyarylethersulfone and polyacrylonitrile-sodium methallyl sulfonate copolymer hemodiafilters at ultrafiltration/dialysate rates of 1, 2, 3, and 6 l/h. TMP/SMX CLtm was calculated using measured SC and SA. TMP/SMX CRRT doses were modeled using CLtm and published TMP/SMX pharmacokinetic parameters. TMP SC/SA during CH/CD were significantly higher than SMX SC/SA. During modeling, TMP 10 mg/kg/day and its corresponding SMX dose, 50 mg/kg/day, resulted in steady state TMP/SMX peak concentrations associated with efficacy against Pneumocystis jirovecii. CRRT resulted in greater TMP CLtm than SMX. TMP 10 mg/kg/day divided q12h may be an appropriate initial dose to consider in patients undergoing CRRT.


Promoting Diversity, Equity, and Inclusion for Psoriatic Diseases.
There is increasing evidence of racial and ethnic disparities in the evaluation and treatment of people with psoriasis (PsO) and psoriatic arthritis, and inadequate racial/ethnic diversity in psoriatic disease (PsD) research. At the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2021 annual meeting, a program focusing on diversity, equity, and inclusion (DEI) was presented to highlight known health and healthcare disparities in PsD. There is limited understanding of the prevalence and severity of PsD and how it affects quality of life among racial/ethnic minorities with PsD. Educational gaps and lack of diversity in our dermatology workforce may be contributing to challenges in appropriately diagnosing and treating PsO in darker skin types. Racial/ethnic minorities are also inadequately represented in clinical research, including trial recruitment and participation, for PsD. A panel of patient research partners, researchers, and clinicians ended the session with a broad discussion on how GRAPPA can better ensure racial/ethnic DEI in their educational, research, and clinical missions.


Electrochemically assisted microbial production of hydrogen from acetate.
Hydrogen production via bacterial fermentation is currently limited to a maximum of 4 moles of hydrogen per mole of glucose, and under these conditions results in a fermentation end product (acetate; 2 mol/mol glucose) that bacteria are unable to further convert to hydrogen. It is shown here that this biochemical barrier can be circumvented by generating hydrogen gas from acetate using a completely anaerobic microbial fuel cell (MFC). By augmenting the electrochemical potential achieved by bacteria in this MFC with an additional voltage of 250 mV or more, it was possible to produce hydrogen at the cathode directly from the oxidized organic matter. More than 90% of the protons and electrons produced by the bacteria from the oxidation of acetate were recovered as hydrogen gas, with an overall Coulombic efficiency (total recovery of electrons from acetate) of 60-78%. This is equivalent to an overall yield of 2.9 mol H2/mol acetate (assuming 78% Coulombic efficiency and 92% recovery of electrons as hydrogen). This bio-electrochemically assisted microbial system, if combined with hydrogen fermentation that produces 2-3 mol H2/mol glucose, has the potential to produce ca. 8-9 mol H2/mol glucose at an energy cost equivalent to 1.2 mol H2/mol glucose. Production of hydrogen by this anaerobic MFC process is not limited to carbohydrates, as in a fermentation process, as any biodegradable dissolved organic matter can theoretically be used in this process to generate hydrogen from the complete oxidation of organic matter.


What can Europeans learn from Americans?
In a wide-ranging look at many aspects of health care financing and delivery, the concepts of glasnost and perestroika are used as a framework for presenting ideas from the American system that may have value for European health care planners. These include more uniform approaches to data collection and cost reporting, patient outcome studies, evaluation of service and access standards, publication of information, quality assurance review, decentralization and independent institutions, prepaid group practice, demonstrations and experiments, and managed competition. Suggestions are offered for making health care systems on both sides of the Atlantic more manageable, efficient, and responsive.


A placebo for the pain: a medico-legal case analysis.
The objectives of this medico-legal case report are to consider the current status of the use of placebos in pain medicine from clinical, ethical, and legal perspectives. The focus of the analysis is a particular case in which the deceptive use of placebo pain therapy on an adolescent gave rise to professional grievances filed by the patient's mother against the physician who ordered and several nurses who administered the placebo. The medical board declined to take disciplinary action against the physician, and disciplinary action by the board of registered nursing against the nurses was successfully challenged by two of the charged nurses in an administrative review. While there is a growing literature that challenges the need for or justification of the deceptive use of placebos, the practice continues and, as the case under consideration indicates, retains some influential supporters. This is a case report from a community hospital. The patient, referred to here as KC, was an adolescent with migraine headaches. The substitution of a placebo (saline solution) for an opioid analgesic (morphine) was made during KC's treatment. The patient's pain subsided sufficiently following the administration of a placebo to permit his discharge from the hospital. The subsequent discovery by the patient's mother of the deceptive use of a placebo prompted her to file charges of professional misconduct against the treating physician and three nurses with their respective professional licensing boards. The medical board declined to take disciplinary action against the physician, and the disciplinary action by the board of registered nursing was successfully challenged in a ruling by an administrative law judge following a hearing in which expert witnesses took conflicting positions on the acceptability of the deceptive use of a placebo. While there is a developing literature that challenges the ethical legitimacy of the deceptive use of placebos in pain medicine, that literature has yet to be recognized as unqualifiedly setting the standard of care or of professionalism in medicine and nursing.


Characterization and evaluation of a novel anti-MUC-1 monoclonal antibody: induction of the idiotypic network in experimental mice.
To investigate the anti-idiotypic effect induced by a monoclonal antibody. A conventional fusion method was used to obtain hybridoma cells producing monoclonal antibody, which were detected by flow cytometry. ELISA were used to detect the humoral response induced by the antibody in mice. Cytotoxic and proliferation experiments were used to detect the cellular response induced by the antibody in mice. CS20 is a MUC-1 specific monoclonal antibody that strongly reacts with MUC-1 antigen expressed on the cell surface of breast cancer cells. The antibody could not kill tumor cells directly through complement-dependent cytotoxicity or antibody-dependent cell-mediated cytotoxicity. However, after 6 administrations of mAb CS20-KLH (keyhole limpet hemocyanin) conjugated to BALB/c mice (n = 5) at a dose of 50 micro g/mouse, anti-idiotypic antibodies and anti-anti-idiotypic antibodies were induced. T cells derived from CS20-KLH-immunized mice responded to mAb CS20, indicating the existence of idiotype-specific T cells. These data indicated the possibility of using MUC-1 specific antibody for active immunotherapy of breast cancer.


Impact of environmental parameters on marathon running performance.
The objectives of this study were to describe the distribution of all runners' performances in the largest marathons worldwide and to determine which environmental parameters have the maximal impact. We analysed the results of six European (Paris, London, Berlin) and American (Boston, Chicago, New York) marathon races from 2001 to 2010 through 1,791,972 participants' performances (all finishers per year and race). Four environmental factors were gathered for each of the 60 races: temperature (°C), humidity (%), dew point (°C), and the atmospheric pressure at sea level (hPA); as well as the concentrations of four atmospheric pollutants: NO(2)-SO(2)-O(3) and PM(10) (μg x m(-3)). All performances per year and race are normally distributed with distribution parameters (mean and standard deviation) that differ according to environmental factors. Air temperature and performance are significantly correlated through a quadratic model. The optimal temperatures for maximal mean speed of all runners vary depending on the performance level. When temperature increases above these optima, running speed decreases and withdrawal rates increase. Ozone also impacts performance but its effect might be linked to temperature. The other environmental parameters do not have any significant impact. The large amount of data analyzed and the model developed in this study highlight the major influence of air temperature above all other climatic parameter on human running capacity and adaptation to race conditions.


Zero delay synchronization of chaos in coupled map lattices.
We show that two coupled map lattices that are mutually coupled to one another with a delay can display zero delay synchronization if they are driven by a third coupled map lattice. We analytically estimate the parametric regimes that lead to synchronization and show that the presence of mutual delays enhances synchronization to some extent. The zero delay or isochronal synchronization is reasonably robust against mismatches in the internal parameters of the coupled map lattices, and we analytically estimate the synchronization error bounds.


[The role of nonsporulating anaerobic bacteria in the etiology of postabortion and postpartal endometritis].
As the result of the study carried out by the authors, a conclusion has been made on the leading role of polymicrobial aerobic-anaerobic complexes, capable of producing a synergic effect, in the etiology of endometritis, anaerobic microorganisms prevailing in their importance. In the etiology of endometritis the most important organisms are bacteroids and peptostreptococci among anaerobes, enterobacteria and group D streptococci among aerobes. Anaerobic bacteria causing endometritis are most sensitive to dalacin and lincomycin, least sensitive to benzylpenicillin, resistant to aminoglycosides. The amounts of aerobic and anaerobic microflora contaminating the uterine cavity correlate with the severity of endometritis.


Single-Cell in Situ RNA Analysis With Switchable Fluorescent Oligonucleotides.
Comprehensive RNA analyses in individual cells in their native spatial contexts promise to transform our understanding of normal physiology and disease pathogenesis. Here we report a single-cell in situ RNA analysis approach using switchable fluorescent oligonucleotides (SFO). In this method, transcripts are first hybridized by pre-decoding oligonucleotides. These oligonucleotides subsequently recruit SFO to stain their corresponding RNA targets. After fluorescence imaging, all the SFO in the whole specimen are simultaneously removed by DNA strand displacement reactions. Through continuous cycles of target staining, fluorescence imaging, and SFO removal, a large number of different transcripts can be identified by unique fluorophore sequences and visualized at the optical resolution. To demonstrate the feasibility of this approach, we show that the hybridized SFO can be efficiently stripped by strand displacement reactions within 30 min. We also demonstrate that this SFO removal process maintains the integrity of the RNA targets and the pre-decoding oligonucleotides, and keeps them hybridized. Applying this approach, we show that transcripts can be restained in at least eight hybridization cycles with high analysis accuracy, which theoretically would enable the whole transcriptome to be quantified at the single molecule sensitivity in individual cells. This in situ RNA analysis technology will have wide applications in systems biology, molecular diagnosis, and targeted therapies.


Nephrologists' reported attitudes about factors influencing recommendations to initiate or withdraw dialysis.
A nationwide survey of nephrologists was performed to learn which patient factors and characteristics of nephrology fellowship training they reported as influencing their decisions to start or stop dialysis. One hundred seventy-four of 482 responses were received. Most respondents were men in private practice living in large communities (41% in communities over 1,000,000 population). Most had completed a 2-yr fellowship (88%) at a medical school hospital (75%). Few (9%) received formal instruction in medical ethics during fellowship training, and only one quarter had informally discussed life-sustaining treatments during training. Neurological status was the most, and age the least, important patient factor reported to influence decisions to start or stop dialysis. No respondent demographic factors correlated with ranking of patient factors in decisions to initiate or forego dialysis. Family wishes and preexisting medical conditions were significantly more important considerations in initiating than in stopping dialysis. Insights about the factors practicing nephrologists reportedly weigh most heavily in making the difficult decisions to withhold or withdraw dialysis are provided by this study. Additional study of the actual practices of nephrologists in decisions to initiate or withdraw dialysis and the factors influencing those decisions are needed. Formal instruction in these and other ethical problems confronting nephrologists should perhaps be included in fellowship programs.


Anesthetic Management of Successful Extracorporeal Resuscitation After Six Hours of Cardiac Arrest Due to Severe Accidental Hypothermia.
Accidental hypothermia (AH) in Mediterranean countries often is underestimated. AH should be suspected in patients also in moderate climates throughout all seasons. Compared with other countries, the mortality rate due to AH in Spain is low, and hypothermia rarely is recognized and treated. The case of a patient who experienced cardiac arrest due to severe AH and was resuscitated for more than six hours using extracorporeal life support recently was published. Herein that case is reviewed, with the anesthetic management during cannulation detailed. In addition, the authors highlight how the application of extracorporeal cardiopulmonary resuscitation guidelines is different in AH patients, how in-hospital (HOPE score) triage criteria should be applied, and how the establishment of clear standard operating procedures and education strategies should be promoted.


Three-dimensional characterization of human ventricular myofiber architecture by ultrasonic backscatter.
Normal human left ventricular architecture comprises a highly aligned array of cardiac myofibers whose orientation depends on transmural location. This study was designed to determine whether measurement of integrated backscatter could be used detect the progressive transmural shift of myofiber alignment that occurs from epicardium to endocardium in human ventricular wall segments. Integrated backscatter was measured at 32 transmural levels in seven cylindrical biopsy specimens (1.4 cm diam) sampled from normal regions of six explanted fixed human hearts by insonification of samples at 180 independent angles in 2 degrees steps around their entire circumference with a 5-MHz broadband piezoelectric transducer. Histologic analysis was performed to determine fiber orientation. Integrated backscatter varied approximately as a sinusoidal function of the angle of insonification at each transmural level. Greater integrated backscatter was observed for insonification perpendicular as compared with parallel to fibers (difference = 14.5 +/- 0.6 dB). Ultrasonic analysis revealed a progressive transmural shift in fiber orientation of approximately 9.2 +/- 0.7 degrees/mm of tissue. Histologic analysis revealed a concordant shift in fiber orientation of 7.9 +/- 0.8 degrees/mm of tissue. Thus, human myocardium manifests anisotropy of ultrasonic scattering that may be useful for characterization of the intramural fiber alignment and overall three-dimensional organization of cardiac myofibers.


Assessment of two commercial susceptibility test methods for determination of daptomycin MICs.
Daptomycin is a lipopeptide antibiotic with activity against several important gram-positive bacterial pathogens, including drug-resistant staphylococci and enterococci. Because the mechanism of action of daptomycin is calcium-dependent depolarization of the cell membrane, susceptibility testing requires medium supplemented with a physiological level of calcium. This study assessed two Food and Drug Administration-cleared commercial test devices for determination of daptomycin MICs, Etest and JustOne. A collection of 220 selected isolates, including Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, E. faecium, E. avium, E. durans, E. casseliflavus, and E. gallinarum, were tested by both methods. Included in the collection were 22 S. aureus and 14 Enterococcus sp. isolates that were recovered from patients and were nonsusceptible on the basis of the daptomycin MICs. As the reference method for comparison, all isolates were tested by the Clinical and Laboratory Standards Institute broth microdilution method incorporating cation-adjusted Mueller-Hinton broth with 50 microg/ml calcium. Daptomycin MICs agreed, within 1 twofold dilution, for 97% of the isolates by Etest and for 100% by JustOne. However, daptomycin MICs determined by Etest were 1 dilution lower than the reference MICs for 65% of the Enterococcus sp. isolates tested. This resulted in 28.5% very major (VM) errors (4/14) with enterococci (all E. faecium) but none (0/22) with staphylococci. Use of JustOne yielded MICs that were 1 dilution lower than the reference MICs for 69% of the staphylococci and 25% of the enterococci. This resulted in 13.6% VM errors (3/22) with staphylococci and 14.3% VM errors (2/14) with enterococci. The manufacturer-recommended JustOne inoculum preparation resulted in mean colony counts of only 5 x 10(4) to 1 x 10(5) CFU/ml in the wells of the strip. Increasing the inoculum to 3 x 10(5) to 4 x 10(5) CFU/ml eliminated two of five VM errors upon retesting. No major interpretive errors occurred with either device. In summary, daptomycin MICs generated by the Etest or JustOne method generally agreed within 1 dilution of the reference daptomycin MICs. However, both devices produced slightly lower MICs that resulted in some VM errors.


Effect of progressive incremental exercise and beta-adrenergic blockade on erythrocyte ion concentrations.
Ion concentrations in whole blood, plasma, and erythrocytes from arterialized venous blood were examined in eight healthy males performing incremental exercise tests to fatigue on an electrically braked cycle ergometer. Exercise was performed during control and low dose (LD) and high dose (HD) of propranolol (beta-blockade). The LD and HD resulted in a significant decrease in peak heart rate compared with control, while peak oxygen uptake during HD was significantly less than either control or LD. Plasma potassium concentration ([K+]) increased significantly during exercise for control, LD, and HD, while LD and HD plasma [K+] were both significantly greater than control. Erythrocyte [K+] increased significantly for control to 119.2 +/- 1.3 mmol/L, for LD to 116.9 +/- 2.0 mmol/L, and for HD to 117.7 +/- 1.2 mmol/L. Plasma lactate concentration ([Lac-]) increased significantly during exercise for control, LD, and HD. Erythrocyte [Lac-] increased significantly for control to 6.4 +/- 0.8 mmol/L, for LD to 6.4 +/- 0.6 mmol/L, and for HD to 5.0 +/- 0.5 mmol/L, with HD [Lac-] less than either control or LD. beta-Blockade did not significantly alter the percent change in mean corpuscular volume (% delta MCV) during exercise. The results indicate that incremental exercise produces an increase in erythrocyte [Lac-] and [K+]. Although beta-blockade increased plasma [K+] at peak exercise, there was no alteration in erythrocyte [K+] response. The treatment did not impair the ability of the erythrocyte to maintain MCV.


Tumor MET Expression and Gene Amplification in Chinese Patients with Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer.
MET and its sole ligand, hepatocyte growth factor (HGF), are promising targets in gastric and gastroesophageal junction cancer. We evaluated whether MET protein expression or MET gene amplification is prognostic for overall survival (OS) in Chinese patients with advanced gastric or gastroesophageal junction cancer. Archival formalin-fixed, paraffin-embedded tumor samples from patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancer enrolled in clinical trials at Peking University Cancer Hospital from 2008 to 2010 were assessed for MET and phospho-MET (p-MET) expression by immunohistochemistry and MET amplification by FISH. MET-positive expression was defined as membrane protein staining in ≥25% of tumor cells. MET amplification was defined as MET:centromere 7 ratio >2.0. We tested the association of MET status with clinical characteristics and OS, and also evaluated the association between expression and amplification. One hundred sixty-eight patients were eligible. Of the evaluable samples, 53 of 137 (39%) were MET positive, eight of 134 (6%) were p-MET positive, and eight of 113 (7%) were MET amplified. Neither MET expression nor MET amplification were associated with clinical characteristics, except Lauren classification (P = 0.04); MET amplification was associated with diffuse type. No significant OS difference was observed between MET-positive and MET-negative populations, regardless of first-line chemotherapy received. In 95 evaluable patients, MET expression was significantly associated with MET amplification (P < 0.001); all MET-amplified tumor samples showed some MET expression. In 96 evaluable patients, p-MET positivity was significantly associated with MET amplification (P < 0.001). Further evaluation in larger and independent sample sets is warranted to confirm our findings.


Corrosion of five different dental amalgams.
The purpose of this study was to determine the gamma-2 presence in two South African amalgams (Amalgaphase and Silvalloy) and to compare this data with that obtained from tests on a well-known gamma-2 containing amalgam (Amalcap) and on two products with a reportedly low gamma-2 content (Dispersalloy and Permite-C). Samples were prepared according to standard ISO procedures in special sample holders. The rotating disc electrode technique (similar to the technique described by Gal-Or, Bruckenstein and Carter, 1978) was used to determine the presence of gamma-2. All samples were evaluated after one and again after nine days. Results indicated that only Dispersalloy displayed no reaction at day one; in other words no gamma-2 could be detected after 24 hours. All other amalgams showed a definite peak on the polarization plot between -200 and -250 mV indicating electrochemical activity (corrosion) in that region. On day nine, only Amalcap (the gamma-2 containing amalgam) still exhibited a reaction peak. Thorough clinical studies will have to be undertaken to evaluate the durability of the South African products.


Effect of neutrase, alcalase, and papain hydrolysis of whey protein concentrates on iron uptake by Caco-2 cells.
Effects of enzymatic hydrolysates of whey protein concentrates (WPC) on iron absorption were studied using in vitro digestion combined with Caco-2 cell models for improved iron absorption. Neutrase- and papain-treated WPC could improve iron absorption; especially hydrolysates by Neutrase could significantly increase iron absorption to 12.8% compared to 3.8% in the control. Hydrolysates by alcalase had negative effects to the lowest at 0.57%. Two new bands at molecular weights (MW) around and below 10 kDa occurred at tricine-SDS-PAGE of hydrolysates by Neutrase, and one new band at MW below 10 kDa occurred in hydrolysates by papain. No new band was observed in hydrolysates by alcalase. Concentration of free amino acids indicated that, except for tyrosine and phenylalanine, amino acids in papain-treated hydrolysates were higher than that of alcalase, and no cysteine and proline were found in hydrolysates by alcalase. The results suggested that hydrolysate by Neutrase-treated WPC is a promising facilitator for iron absorption. Peptides of MW around and lower than 10 kDa and aspartic acid, serine, glutamic acid, glycin, cysteine, histidine, and proline may be contributors to enhancement.


Brief rhythmic discharges in neonates: a marker for seizures.
Brief rhythmic discharges (BRDs) are paroxysms of rhythmic electrographic activity with an amplitude of >2 μV and a duration of <10 seconds. Although BRDs are reported in neonates, this electrographic activity contrasts the accepted definition of neonatal seizures (duration of >10 seconds). BRDs are associated with background EEG abnormalities as well as increased morbidity and mortality (Oliveira et al., 2000, Nagarajan et al., 2011), and appear to be more closely related to formal neonatal seizures than post-neonatal epilepsy (Nagarajan et al., 2011). Most neonatal units are restricted to one-hour recordings, and if BRDs are observed without any accompanying electrographic seizures, then the neonate should be regarded as being at high risk of seizures and repeat recordings should be considered.


Covid-19 and rural landscape: The case of Italy.
Throughout the covid-19 emergency, health authorities have presented contagion data divided by administrative regions with no reference to the type of landscape, environment or development model. This study has been conducted to understand whether there is a correlation between the number of infections and the different rural landscapes of the country. Italy's rural landscape can be classified in four types, according to the intensity of energy inputs used in the agricultural process, socioeconomic and environmental features. Type A includes areas of periurban agriculture surrounding the metropolitan cities, type B areas of intensive agriculture with high concentration of agroindustry, type C hilly areas with highly diversified agriculture and valuable landscape, and type D high hills and mountains with forests and protected areas. Areas A and B are located in the plains, covering 21% of the territory and accounting for 57% of the population. They produce most of the added value, consume high levels of energy and represent the main source of pollution. Areas C and D cover 79% of the territory and 43% of the population. We find that provinces with 10% more type C and D areas exhibit on average 10% fewer cases of contagion. The result is statistically significant, after controlling for demographic, economic and environmental characteristics of the provinces. The pollution produced in more energy-intensive landscape has triggered an intense debate of how to ensure the economic competitiveness of Italian agriculture, without compromising environmental integrity or public health. Our findings speak to this debate, by suggesting that planning for more rural territory with lower energy inputs may come with the added benefit of new development opportunities and decreasing the exposure of the population to covid-19. Cost benefit-analyses should take into account that policies aimed at revitalizing more rural areas may reduce the economic impact of covid-19 and of potential future pandemics.


Organizational heterogeneity of vertebrate genomes.
Genomes of higher eukaryotes are mosaics of segments with various structural, functional, and evolutionary properties. The availability of whole-genome sequences allows the investigation of their structure as "texts" using different statistical and computational methods. One such method, referred to as Compositional Spectra (CS) analysis, is based on scoring the occurrences of fixed-length oligonucleotides (k-mers) in the target DNA sequence. CS analysis allows generating species- or region-specific characteristics of the genome, regardless of their length and the presence of coding DNA. In this study, we consider the heterogeneity of vertebrate genomes as a joint effect of regional variation in sequence organization superimposed on the differences in nucleotide composition. We estimated compositional and organizational heterogeneity of genome and chromosome sequences separately and found that both heterogeneity types vary widely among genomes as well as among chromosomes in all investigated taxonomic groups. The high correspondence of heterogeneity scores obtained on three genome fractions, coding, repetitive, and the remaining part of the noncoding DNA (the genome dark matter--GDM) allows the assumption that CS-heterogeneity may have functional relevance to genome regulation. Of special interest for such interpretation is the fact that natural GDM sequences display the highest deviation from the corresponding reshuffled sequences.


Mucinosis of the mammary areolae and mycosis fungoides.
We present a patient with cutaneous mucinosis of the mammary areolae who developed multiple erythematous macules with clearly defined, geographical edges 1 year after diagnosis. These lesions demonstrated mycosis fungoides on histology. We discuss a possible association between the mucinosis and the mycosis fungoides.


Genetic heterogeneity among patients with methylcobalamin deficiency. Definition of two complementation groups, cblE and cblG.
A number of patients with megaloblastic anemia and homocystinuria associated with low levels of methylcobalamin synthesis in cultured cells have been recognized. Methionine biosynthesis by intact cells, as determined by incorporation of label from 5-[14C]methyl-tetrahydrofolate into acid-precipitable material, was deficient in cultured skin fibroblasts that were derived from all of these patients. In one group of patients, activity of the methylcobalamin-dependent enzyme, methionine synthase, in cell extracts was within the normal range when the enzyme was assayed under standard conditions. In a second group of patients, methionine synthase activity was decreased under the same assay conditions. Genetic complementation analysis demonstrated the existence of two complementation classes that corresponded to these two groups of patients. The designation cblE has previously been proposed for normal methionine synthase activity. We propose the designation cblG for the mutation in those patients with methylcobalamin deficiency and decreased synthase activity. The results of these studies suggest that the products of at least two loci are required for cobalamin-dependent methionine biosynthesis in mammalian cells.


Preponderance of bacterial isolates in urine of HIV-positive malaria-infected pregnant women with urinary tract infection.
This study examined HIV and malaria co-infection as a risk factor for urinary tract infections (UTIs) in pregnancy. The study group included 74 pregnant women, 20 to 42 years of age, who attended the antenatal clinic at the Specialist Hospital at Akure, Ondo State, Nigeria. Forty-four of the pregnant women were either HIV seropositive with malaria infection (HIV+Mal+) or HIV seropositive without malaria (HIV+Mal-). The remaining thirty pregnant women served as controls and included women HIV seronegative but with malaria (HIV-Mal+) and women HIV seronegative without malaria. UTI was indicated by a bacterial colony count of greater than 10⁵/mL of urine, using cysteine lactose electrolyte deficient medium (CLED) as the primary isolation medium. Bacterial isolates were characterized using convectional bacteriological methods, and antibiotics sensitivity tests were carried out using the disk diffusion method. A total of 246 bacterial isolates were recovered from the cultures, with a mean of 3.53 isolates per subject. Women who were HIV+Mal+ had the most diverse group of bacterial isolates and the highest frequency of UTIs. The bacterial isolates from the HIV+Mal+ women also showed the highest degree of antibiotic resistance. While pregnancy and HIV infection may each represent a risk factor for UTI, HIV and malaria co-infection may increase its frequency in pregnancy. The higher frequency of multiple antibiotic resistance observed among the isolates, particularly isolates from HIV+Mal+ subjects, poses a serious public health concern as these strains may aggravate the prognosis of both UTI and HIV infection.


Neurturin and GDNF promote proliferation and survival of enteric neuron and glial progenitors in vitro.
Signaling through the c-Ret tyrosine kinase and the endothelin B receptor pathways is known to be critical for development of the enteric nervous system. To clarify the role of these receptors in enteric nervous system development, the effect of ligands for these receptors was examined on rat enteric neuron precursors in fully defined medium in primary culture. In this culture system, dividing Ret-positive cells differentiate, cluster into ganglia containing neurons and enteric glia, and create extensive networks reminiscent of the enteric plexus established in vivo. Glial cell-line-derived neurotrophic factor (GDNF) and neurturin both potently support survival and proliferation of enteric neuron precursors in this system. Addition of either neurturin or GDNF to these cultures increased the number of both neurons and enteric glia. Persephin, a third GDNF family member, shares many properties with neurturin and GDNF in the central nervous system and in kidney development. By contrast, persephin does not promote enteric neuron precursor proliferation or survival in these cultures. Endothelin-3 also does not increase the number of enteric neurons or glia in these cultures.


Salt and skin.
The introduction of salt as a therapeutic agent in dermatological disorders has been in use since ancient times. This ubiquitous agent is the most underrated substance after the advent of modern medicine. Though a commonly used agent in both traditional and modern medicine, it is important to understand its relationship to the skin to further enhance the comprehensive benefit. The complex history of the evolution of medicine and its skewed distribution among the countries of the world led to inclusion of locally available and economical agents into therapeutics as it becomes almost an inevitable need. Moreover, an inadequate knowledge about the harmful effects of chronic salt exposure led salt to have a unique role in occupational dermatoses. There is no adequate literature on both detrimental and therapeutic effects of salt and its relation to skin. Hence, a genuine attempt was made to summarize the known and the lesser known facts of this particular common seasoning agent.


The pattern of micro-organisms and the efficacy of new macrolide in acute lower respiratory tract infections.
Lower respiratory tract infection (LRTI) is one of the major health problems in developing countries such as Indonesia. According to the National Household Health Survey conducted by the Ministry of Health in 1992, LRTIs still rank fourth as the main cause of death in Indonesia. The problem of LRTIs could be simply managed as long as the causative organism can be identified and the proper antibiotic known. In some occasions, it is not quite so easy to identify the causative micro-organism, especially in lower tract infections. There are several methods of obtaining specimens from LRTIs for cultures. The easiest, most simple way is to collect expectorated sputum. Unfortunately, because of the high rate of contamination by upper respiratory tract flora, this method is not reliable. Recognizing the difficulties with routine expectorated sputum cultures, two alternative approaches have been suggested. One approach is to bypass potential expectorated sputum 'contaminants' in the oropharynx by transtracheal aspiration or transthoracic aspiration. The second approach is to modify the usual technique of processing expectorated sputum by either washing techniques or by quantitative cultures. Azithromycin and clarithromycin are chemically related to macrolide erithromycin. Both antibiotics retain the traditional macrolide spectrum of activity against gram-positive and atypical pneumonia pathogens, while demonstrating improved activity against gram-negative bacteria. The American Thoracic Society (ATS) recommended the use of macrolide for outpatients with community-acquired pneumonia, without comorbidity and 60 years of age or younger. A total of 34 outpatients with acute LRTIs were open-comparative, randomly allocated to treatment with the new macrolide in Persahabatan Hospital, Jakarta, 1996. The purposes of this study were: (i) to identify the causative micro-organisms; and (ii) to evaluate the clinical efficacy of the new macrolide in these infections. Azithromycin 500 mg was given orally once a day for 3 days and was administered 1 h before or 2 h after every meal. Clarithromycin 500 mg was given orally every 12 h for 10 days. The diagnosis of the patients were: 16 with pneumonia, 10 with acute bronchitis and 8 with acute exacerbation of chronic bronchitis. In this study of 34 patients, the sputum specimens were washed with N acetylcysteine before culture and we could only detect micro-organisms in one patient. Before treatment, we found 47 strains in 33 (97.05%) patients and after treatment we found five strains. From serological examination, only four (11.76%) atypical bacterial were detected. The most frequently found microorganisms were 23 strains of Klebsiella pneumoniae (40.42%), 10 of Streptococcus alpha haemolyticus (21.26%), five of Streptococcus pneumoniae (10.63%) and five of Staphylococcus aureus (10.63%). The atypical bacterial were: two Legionella pneumophila, one Mycoplasma pneumoniae and one Chlamydia pneumoniae. The clinical efficacy of new macrolides were 100% and the bacteriological responses with eradication of 94.12% vs 70.59% of isolates in the azithromycin and clarithromycin groups are shown in Table 1. There were no adverse reactions detected in the two treatment groups until the end of the study.


Failing Homeostasis of Quadriceps Muscle Energy- and pH Balance During Bicycling in a Young Patient With a Fontan Circulation.
Aims: Patients with a congenital heart condition palliated with a Fontan circulation generally present with decreased exercise capacity due to impaired cardiopulmonary function. Recently, a study in patients with a Fontan circulation reported evidence for abnormal vascular endothelial function in leg muscle. We investigated if abnormal skeletal muscle hemodynamics during exercise play a role in the limited exercise tolerance of Fontan patients. If so, abnormalities in intramuscular energy metabolism would be expected both during exercise as well as during post-exercise metabolic recovery. Methods: In a young patient with a Fontan circulation and his healthy twin brother we studied the in vivo dynamics of energy- and pH-balance in quadriceps muscle during and after a maximal in-magnet bicycling exercise challenge using 31-phosphorus magnetic resonance spectroscopy. An unrelated age-matched boy was also included as independent control. Results: Quadriceps phosphocreatine (PCr) depletion during progressive exercise was more extensive in the Fontan patient than in both controls (95% vs. 80%, respectively). Importantly, it failed to reach an intermittent plateau phase observed in both controls. Quadriceps pH during exercise in the Fontan patient fell 0.3 units at low to moderate workloads, dropping to pH 6.6 at exhaustion. In both controls quadriceps acidification during exercise was absent but for the maximal workload in the twin brother (pH 6.8). Post-exercise, the rate of metabolic recovery in the Fontan patient and both controls was identical (time constant of PCr recovery 32 ± 4, 31 ± 2, and 28 ± 4 s, respectively). Conclusion: Homeostasis of quadriceps energy- and pH-balance during a maximal exercise test failed in the Fontan patient in comparison to his healthy twin brother and an age-matched independent control. Post-exercise metabolic recovery was normal which does not support the contribution of significant endothelial dysfunction affecting adequate delivery of oxidative substrates to the muscle to the lower exercise capacity in this particular Fontan patient. These results suggest that mitochondrial ATP synthetic capacity of the quadriceps muscle was intact but cardiac output to the leg muscles during exercise was insufficient to meet the muscular demand for oxygen. Therefore, improving cardiac output remains the main therapeutic target to improve exercise capacity in patients with a Fontan circulation.


Toward the Value Sensitive Design of eHealth Technologies to Support Self-management of Cardiovascular Diseases: Content Analysis.
eHealth can revolutionize the way self-management support is offered to chronically ill individuals such as those with a cardiovascular disease (CVD). However, patients' fluctuating motivation to actually perform self-management is an important factor for which to account. Tailoring and personalizing eHealth to fit with the values of individuals promises to be an effective motivational strategy. Nevertheless, how specific eHealth technologies and design features could potentially contribute to values of individuals with a CVD has not been explicitly studied before. This study sought to connect a set of empirically validated, health-related values of individuals with a CVD with existing eHealth technologies and their design features. The study searched for potential connections between design features and values with the goal to advance knowledge about how eHealth technologies can actually be more meaningful and motivating for end users. Undertaking a technical investigation that fits with the value sensitive design framework, a content analysis of existing eHealth technologies was conducted. We matched 11 empirically validated values of CVD patients with 70 design features from 10 eHealth technologies that were previously identified in a systematic review. The analysis consisted mainly of a deductive coding stage performed independently by 3 members of the study team. In addition, researchers and developers of 6 of the 10 reviewed technologies provided input about potential feature-value connections. In total, 98 connections were made between eHealth design features and patient values. This meant that some design features could contribute to multiple values. Importantly, some values were more often addressed than others. CVD patients' values most often addressed were related to (1) having or maintaining a healthy lifestyle, (2) having an overview of personal health data, (3) having reliable information and advice, (4) having extrinsic motivators to accomplish goals or health-related activities, and (5) receiving personalized care. In contrast, values less often addressed concerned (6) perceiving low thresholds to access health care, (7) receiving social support, (8) preserving a sense of autonomy over life, and (9) not feeling fear, anxiety, or insecurity about health. Last, 2 largely unaddressed values were related to (10) having confidence and self-efficacy in the treatment or ability to achieve goals and (11) desiring to be seen as a person rather than a patient. Positively, existing eHealth technologies could be connected with CVD patients' values, largely through design features that relate to educational support, self-monitoring support, behavior change support, feedback, and motivational incentives. Other design features such as reminders, prompts or cues, peer-based or expert-based human support, and general system personalization were also connected with values but in narrower ways. In future studies, the inferred feature-value connections must be validated with empirical data from individuals with a CVD or similar chronic conditions.


Multiple bur hole surgery for the treatment of moyamoya disease in children.
The authors' aim in this study was to review their experience in the use of indirect revascularization alone in a series of 14 children with moyamoya disease, in which numerous bur holes and arachnoid openings were made over each affected hemisphere. Revascularization through multiple bur holes and arachnoid openings was performed in 14 children (mean age at diagnosis 6.5 years [range 3-15 years]) who suffered from progressive moyamoya disease. The authors performed surgery in a total of 24 hemispheres during 18 procedures. Ten children underwent bilateral multiple bur hole procedures, three underwent a unilateral procedure in the more severely affected hemisphere, and one child had previously undergone an encephaloduroarteriomyosynangiosis on the contralateral side. Ten to 24 bur holes were made in the frontotemporoparietooccipital area of each hemisphere, depending on the site and extent of the disease. Early postoperative perfusion magnetic resonance imaging studies, performed in the five most recent cases, showed restoration of cortical perfusion as early as 3 months, which was confirmed on subsequent angiography studies (performed between 8 and 12 months postoperatively) that showed excellent revascularization of the ischemic brain by external carotid artery collateral vessels. None of the children sustained further ischemic attacks postoperatively. Motor improvement was noted in those who had presented with paresis. A single seizure episode occurred in two patients at 2 weeks and 5 months after surgery; both children had presented with epilepsy. There were no postoperative deaths, and only one complication (an infected lumbar shunt in the patient who required cerebrospinal fluid [CSF] drainage). Five of the 18 procedures were complicated by subcutaneous CSF collections, which resolved with tapping and compressive head dressings; a transient lumbar drain was necessary in one case. The results obtained in this series suggest that in children with moyamoya disease this simple technique is both effective and safe. Furthermore, it is effective as a sole treatment without supplementary revascularization procedures.


Cellular mechanisms for developmental toxicity of chlorpyrifos: targeting the adenylyl cyclase signaling cascade.
Developmental neurotoxicity caused by chlorpyrifos exposure is generally thought to target cholinesterase but chlorpyrifos may also act on cellular intermediates, such as adenylyl cyclase, that serve global functions in the coordination of cell development. In the current study, neonatal rats were exposed to apparently subtoxic doses of chlorpyrifos (no weight loss, no mortality) either on Postnatal Days 1-4 or on Postnatal Days 11-14, and the effects on components of the adenylyl cyclase cascade were evaluated in brain regions that are enriched (forebrain) or sparse (cerebellum) in cholinergic innervation, as well as in a nonneural tissue (heart). In all three, chlorpyrifos evoked deficits in multiple components of the adenylyl cyclase cascade: expression and activity of adenylyl cyclase itself, functioning of G-proteins that link neurotransmitter and hormone receptors to cyclase activity, and expression of neurotransmitter receptors that act through this cascade. Disruption of signaling function was not restricted to transduction of cholinergic signals but rather extended to adrenergic signals as well. In most cases, the adverse effects were not evident during the immediate period of chlorpyrifos administration, but appeared after a delay of several days. These results suggest that chlorpyrifos can affect cell development by altering the activity and reactivity of the adenylyl cyclase signaling cascade, a major control point for trophic regulation of cell differentiation. The effects are not restricted to cholinergic targets, nor even to the central nervous system. Hence, disruption of cell development by chlorpyrifos is likely to be more widespread than previously thought.


Veratridine modification of the purified sodium channel alpha-polypeptide from eel electroplax.
In the interest of continuing structure-function studies, highly purified sodium channel preparations from the eel electroplax were incorporated into planar lipid bilayers in the presence of veratridine. This lipoglycoprotein originates from muscle-derived tissue and consists of a single polypeptide. In this study it is shown to have properties analogous to sodium channels from another muscle tissue (Garber, S. S., and C. Miller. 1987. Journal of General Physiology. 89:459-480), which have an additional protein subunit. However, significant qualitative and quantitative differences were noted. Comparison of veratridine-modified with batrachotoxin-modified eel sodium channels revealed common properties. Tetrodotoxin blocked the channels in a voltage-dependent manner indistinguishable from that found for batrachotoxin-modified channels. Veratridine-modified channels exhibited a range of single-channel conductance and subconductance states. The selectivity of the veratridine-modified sodium channels for sodium vs. potassium ranged from 6-8 in reversal potential measurements, while conductance ratios ranged from 12-15. This is similar to BTX-modified eel channels, though the latter show a predominant single-channel conductance twice as large. In contrast to batrachotoxin-modified channels, the fractional open times of these channels had a shallow voltage dependence which, however, was similar to that of the slow interaction between veratridine and sodium channels in voltage-clamped biological membranes. Implications for sodium channel structure are discussed.


Iatrogenic arteriovenous fistula of the iliac artery after lumbar discectomy surgery: a systematic review of the last 18 years.
Patients with iatrogenic iliac arteriovenous fistulas (IAVFs) after lumbar discectomy surgeries (LDSs) from our hospital and the published literature were reviewed in order to better understand this clinical phenomenon. Literature from databases about iatrogenic IAVFs after LDSs were retrieved and a patient from our hospital was reviewed with emphasis placed upon the patient's clinical data. From 31 publications and studies of 44 individuals' data, the study revealed L4-L5 and/or L5-S1 intervertebral space levels were mostly involved (62.0%). Most of the patients underwent computed tomography angiography (CTA) and/or digital subtraction angiography (DSA) examinations to confirm the potential diagnosis and rule out other differential diagnosis (86.4%). Most of the patients (63.6%) developed features of high output heart failure months to years after the LDSs, and the majority of them (88.6%) were treated with endovascular repairs. An iatrogenic IAVF after an LDS is a rare occurrence; however, more attention should be paid to it for the purpose of obtaining accurate diagnosis and proper treatment.


Report of a meeting to discuss a National Centre for the Replacement of Animals in Experiments.
Following the publication of their joint proposal for a National Centre for the Replacement of Animals in Experiments in 2002, the Dr Hadwen Trust and the Lord Dowding Fund organised a meeting, held on 18 November 2003 at Portcullis House, Westminster, in London, in order to discuss the concept further. A one-page summary of their proposal is attached as an appendix, and full copies are available from the Lord Dowding Fund and the Dr Hadwen Trust. The meeting aimed to discuss the need to stimulate and promote research to replace animal experiments by means of a National Centre (a coordinating body), and how this should be established and funded. Participants, numbering about 80 in total, included politicians (national and European), government officials, scientists, funding bodies and animal welfare representatives. This report is a summary of the issues raised by speakers and other participants at the meeting.


Low correlation between biometric parameters, cardiovascular risk factors and aortic dimensions by computed tomography coronary angiography.
To analyze the relationship between aortic measures and biometric parameters in a large cohort of consecutive patients undergoing computed tomography coronary angiography.1170 patients (717 men/453 women) performing computed tomography coronary angiography for coronary evaluation were retrospectively evaluated. Aortic diameters and areas were measured at reproducible anatomic landmarks, perpendicular to the axis of vessel, at the level of the aortic root (AoR), the sinotubular junction (STJ), and the tubular ascending aorta (TAo). Biometric parameters and cardiovascular risk factors were recorded.The average values of AoR, STJ, and TAo were 35.63 ± 5.00 mm, 30.56 ± 4.82 mm, 35.07 ± 5.84 mm. Hypertension was significantly associated with aortic dimensions.Aortic measures were significantly different between men and women (37.56 ± 4.77 mm vs 32.58 ± 3.68 mm for AoR, 31.88 ± 4.84 mm vs 28.47 ± 3.98 mm for STJ and 35.93 ± 5.86 mm vs 33.70 ± 5.54 mm for TAo) (P < .001) and linearly increased with age. Low Spearman correlation coefficients were found and the correlation of TAo diameters with age displayed the highest values (ρ = 0.372 for male and ρ = 0.373 for female, P < .001). Multiple linear regression analysis models were compared by R. The best model used body surface area (BSA) and age as independent variables and TAo diameter as dependent variable (R = 0.29 for AoR; R = 0.21 for STJ, and R = 0.20 for TAo).In conclusion, in our population low correlation between aortic dimensions and biometric parameters highlights the difficulty of identifying normal ranges, as well as issues related to normalization using conventional biometric parameters.


Recombinant surfactant protein-D selectively increases apoptosis in eosinophils of allergic asthmatics and enhances uptake of apoptotic eosinophils by macrophages.
Pulmonary surfactant protein-D (SP-D) is a multifunctional, pattern recognition molecule involved in resistance to allergen challenge and pulmonary inflammation. In view of therapeutic effects of exogenous SP-D or recombinant fragment of human surfactant protein-D (rhSP-D) (composed of eight Gly-X-Y collagen repeat sequences, homotrimeric neck and lectin domains) in murine models of lung allergy and hypereosinophilic SP-D gene-deficient mice, we investigated the possibility of a direct interaction of purified rhSP-D with human eosinophils derived from allergic patients and healthy donors. rhSP-D showed a sugar- and calcium-dependent binding to human eosinophils, suggesting involvement of its carbohydrate recognition domain. While eosinophils from allergic patients showed a significant increase in apoptosis, oxidative burst and CD69 expression in presence of rhSP-D, eosinophils from healthy donors showed no significant change. However, these eosinophils from healthy donors when primed with IL-5 exhibited increase in apoptosis on incubation with rhSP-D. Apoptosis mediated by rhSP-D in primed eosinophils was not affected by the antioxidant, N-acetyl-L-cysteine. There was a manifold increase in binding of rhSP-D to apoptotic eosinophils than the normal eosinophils and rhSP-D induced a significant increase in uptake of apoptotic eosinophils by J774A.1 macrophage cells. The study suggests that rhSP-D mediated preferential increase of apoptosis of primed eosinophils while not affecting the normal eosinophils and increased phagocytosis of apoptotic eosinophils may be important mechanisms of rhSP-D and plausibly SP-D-mediated resolution of allergic eosinophilic inflammation in vivo.


Effects of large hiatal hernias on esophageal peristalsis.
Anatomic changes induced by large hiatal hernia may alter esophageal pressure topography measurements made during high-resolution manometry. Retrospective study. Single-institution tertiary hospital. Ninety patients with large (>5 cm) hiatal hernias on endoscopy were compared with a control group of 46 patients without hernia selected from the same database of 2000 consecutive clinical high-resolution manometry studies. High-resolution manometry with at least 7 evaluable swallows for analysis. Esophageal pressure topography was analyzed for lower esophageal sphincter pressure, distal contractile integral, contraction amplitude, contractile front velocity, and distal latency time. Esophageal length was measured on esophageal pressure topography from the distal border of the upper esophageal sphincter to the proximal border of the lower esophageal sphincter. Esophageal pressure topography diagnosis was based on the Chicago Classification. The manometry catheter was coiled in the hernia and did not traverse the diaphragm in 44 patients (49%) with large hernia. Patients with large hernias had lower average lower esophageal sphincter pressures, a lower distal contractile integral, slower contractile front velocity, and shorter distal latency time than patients without hernia. They also exhibited a shorter mean esophageal length. However, the distribution of peristaltic abnormalities was not different in patients with and without large hernia. Patients with large hernias had an alteration of esophageal pressure topography measurements and a shortened esophagus. However, the distribution of peristaltic disorders was unaffected by the presence of hernia.


Regorafenib in the treatment of metastatic colorectal cancer.
Regorafenib is an orally available multikinase inhibitor, currently approved in metastatic chemorefractory colorectal cancer patients. The results of two large randomized Phase III trials are available, providing significant results in overall and progression-free survival in this situation. Its use requires a special attention regarding patient selection, dosing schedule and management of adverse events. Identifying patients who will tolerate and have benefit from regorafenib is a challenge for clinicians. Therapeutic monitoring (especially cfDNA), predictive biomarkers and specific perfusion-based imaging techniques will may be result in optimizing regorafenib treatment.


[New aspects in surgery of the thyroid gland with intraoperative monitoring of the recurrent laryngeal nerve].
A method for electrophysiological monitoring of the recurrent laryngeal nerve during thyroid surgery is described. An electromyographic record from the muscles of the vocal folds is obtained using two fine needle electrodes. The electrodes are placed endoscopically. The nerve is identified by electrical stimulation, and the electromyographic activity is registered using a Nerve Integrity Monitor NIM-2 (Xomed-Treace). Our experience with this method in 43 patients is described. The safety of the integrity of the recurrent laryngeal nerve is increased using intraoperative monitoring. This has led to a modification of the operative concept in thyroid surgery. Electrophysiological monitoring is mandatory in surgery of large goitres, retrotracheal and substernal extension, for re-operations and malignant diseases of the thyroid gland.


Similar Outcomes of Standard Radiotherapy and Hypofractionated Radiotherapy Following Breast-Conserving Surgery.
Adjuvant radiation therapy is commonly administered to breast cancer patients who received breast-conserving surgery. However, lengthy treatment times of standard radiotherapy pose certain challenges. Here, we performed a prospective controlled study comparing standard radiation to hypofractionated radiotherapy in terms of efficacy and outcome. Eighty breast cancer patients (tumor stage pT1-2N0-1M0) who had undergone breast-conservation surgery were randomly divided into 2 groups (40 patients/group). The experimental group received 43.2 Gy to the whole breast in 18 fractions for 24 days with a concomitant boost (50.4 Gy) to the tumor bed. The control group received 45 Gy to the whole breast in 25 fractions for 44 days with a boost to the tumor bed of 59 Gy. Survival, locoregional recurrence, adverse effects, and aesthetic results were all considered for analysis. The following criteria were included as part of study follow-up: local control, survival, adverse skin reactions, cosmetic outcome, and hematological toxicity. At a median follow-up of 27 months (follow-up rate 100%), there were no statistical differences in any of the categories between the 2 groups. The 2-year survival rate of both groups was 100% without any locoregional recurrence. Although there was some skin toxicity, these instances were not severe and they cleared on their own within 6 weeks. The most common problems encountered by patients were breast fibrosis and altered pigmentation. A shortened whole-breast hypofractionated irradiation schedule with a concomitant boost is as effective as standard radiation and may be a reasonable alternative following breast conservation surgery.


Sulfur in Mesoporous Tungsten Nitride Foam Blocks: A Rational Lithium Polysulfide Confinement Experimental Design Strategy Augmented by Theoretical Predictions.
To enhance the utilization of sulfur in lithium-sulfur batteries, three-dimensional tungsten nitride (WN) mesoporous foam blocks are designed to spatially localize the soluble Li2S6 and Li2S4 within the pore spaces. Meanwhile, the chemisorption behaviors of polysulfides and the capability of WN as an effective confiner are systematically investigated through density functional theory calculations and experimental studies. The theoretical calculations reveal a decrease in chemisorption strength between WN and the soluble polysulfides (Li2S8 > Li2S6 > Li2S4), while the interactions between WN and the insoluble Li2S2/Li2S show a high chemisorption strength of ca. 3 eV. Validating theoretical insights through electrochemical measurements further manifest that the assembled battery configurations with sulfur cathode confined in the thickest WN blocks exhibit the best rate capabilities (1090 and 510 mAh g-1 at 0.5C and 5C, respectively) with the highest initial Coulombic efficiency of 90.5%. Moreover, a reversible capacity of 358 mAh g-1 is maintained with a high Coulombic efficiency approaching to 100%, even after 500 cycles at 2C. As guided by in silico design, this work not only provides an effective strategy to improve the retentivity of polysulfides but also underpins that properly architectured WN can be effective retainers of polysulfides.


European Reference Network for Rare Vascular Diseases (VASCERN) position statement on cerebral screening in adults and children with hereditary haemorrhagic telangiectasia (HHT).
Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia inherited as an autosomal dominant trait. Approximately 10 % of patients have cerebral vascular malformations, a proportion being cerebral arteriovenous malformations (AVMs) and fistulae that may lead to potentially devastating consequences in case of rupture. On the other hand, detection and treatment related-risks are not negligible, and immediate. While successful treatment can be undertaken in individual cases, current data do not support the treatment of unruptured AVMs, which also present a low risk of bleeding in HHT patients. Screening for these AVMs is therefore controversial.Structured discussions, distinctions of different cerebrovascular abnormalities commonly grouped into an "AVM" bracket, and clear guidance by neurosurgical and neurointerventional radiology colleagues enabled the European Reference Network for Rare Vascular Disorders (VASCERN-HHT) to develop the following agreed Position Statement on cerebral screening:1) First, we emphasise that neurological symptoms suggestive of cerebral AVMs in HHT patients should be investigated as in general neurological and emergency care practice. Similarly, if an AVM is found accidentally, management approaches should rely on expert discussions on a case-by-case basis and individual risk-benefit evaluation of all therapeutic possibilities for a specific lesion.2) The current evidence base does not favour the treatment of unruptured cerebral AVMs, and therefore cannot be used to support widespread screening of asymptomatic HHT patients.3) Individual situations encompass a wide range of personal, cultural and clinical states. In order to enable informed patient choice, and avoid conflicting advice, particularly arising from non-neurovascular interpretations of the evidence base, we suggest that all HHT patients should have the opportunity to discuss knowingly brain screening issues with their healthcare provider.4) Any screening discussions in asymptomatic individuals should be preceded by informed pre-test review of the latest evidence regarding preventative and therapeutic efficacies of any interventions. The possibility of harm due to detection of, or intervention on, a vascular malformation that would not have necessarily caused any consequence in later life should be stated explicitly.We consider this nuanced Position Statement provides a helpful, evidence-based framework for informed discussions between healthcare providers and patients in an emotionally charged area.


Review: brain neurobiology of gambling disorder based on rodent models.
Different literature reviews of gambling disorder (GD) neurobiology have been focused on human studies, others have focused on rodents, and others combined human and rodent studies. The main question of this review was: which are the main neurotransmitters systems and brain structures relevant for GD based on recent rodent studies? This work aims to review the experimental findings regarding the rodent´s neurobiology of GD. A search in the Pub Med database was set (October 2012-October 2017) and 162 references were obtained. After screening, 121 references were excluded, and only 41 references remained from the initial output. More, other 25 references were added to complement (introduction section, neuroanatomical descriptions) the principal part of the work. At the end, a total of 66 references remained for the review. The main conclusions are: 1) according to studies that used noninvasive methods for drug administration, some of the neurotransmitters and receptors involved in behaviors related to GD are: muscarinic, N-methyl-D-aspartate (NMDA), cannabinoid receptor 1 (CB1), cannabinoid receptor 2 (CB2), dopamine 2 receptor (D2), dopamine 3 receptor (D3), and dopamine 4 receptor (D4); 2) moreover, there are other neurotransmitters and receptors involved in GD based on studies that use invasive methods of drug administration (eg, brain microinjection); example of these are: serotonin 1A receptor (5-HT1A), noradrenaline receptors, gamma-aminobutyric acid receptor A (GABAA), and gamma-aminobutyric acid receptor B (GABAB); 3) different brain structures are relevant to behaviors linked to GD, like: amygdala (including basolateral amygdala (BLA)), anterior cingulate cortex (ACC), hippocampus, infralimbic area, insular cortex (anterior and rostral agranular), nucleus accumbens (NAc), olfactory tubercle (island of Calleja), orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), prefrontal cortex (PFC) - subcortical network, striatum (ventral) and the subthalamic nucleus (STN); and 4) the search for GD treatments should consider this diversity of receptor/neurotransmitter systems and brain areas.


Decreasing the risk of sudden unexpected death in epilepsy: structured communication of risk factors for premature mortality in people with epilepsy.
Good practice guidelines highlight the importance of making people with epilepsy aware of the risk of premature mortality in epilepsy particularly due to sudden unexpected death in epilepsy (SUDEP). The SUDEP and Seizure Safety Checklist ('Checklist') is a structured risk communication tool used in UK clinics. It is not known if sharing structured information on risk factors allows individuals to reduce SUDEP and premature mortality risks. The aim of this study was to ascertain if the introduction of the Checklist in epilepsy clinics led to individual risk reduction. The Checklist was administered to 130 consecutive people with epilepsy attending a specialized epilepsy neurology clinic and 129 attending an epilepsy intellectual disability (ID) clinic within a 4-month period. At baseline, no attendees at the neurology clinic had received formal risk advice, whereas all those attending the ID clinic had received formal risk advice on multiple occasions for 6 years. The Checklist was readministered 1 year later to each group and scores were compared with baseline and between groups. Of 12 risk factors considered, there was an overall reduction in mean risk score for the general (P = 0.0049) but not for the ID (P = 0.322) population. Subanalysis of the 25% of people at most risk in both populations showed that both sets had a significant reduction in risk scores (P < 0.001). Structured discussion results in behavioural change that reduces individual risk factors. This impact seems to be higher in those who are at current higher risk. It is important that clinicians share risk information with individuals as a matter of public health and health promotion.


Synthesis of single-site copper catalysts for methane partial oxidation.
Cu-Exchanged zeolites are known as active materials for methane oxidation to methanol. However, understanding of the formation of Cu active species during synthesis, dehydration and activation is fragmented and rudimentary. We show here how a synthesis protocol guided by insight in the ion exchange elementary steps leads to highly uniform Cu species in mordenite (MOR).


Beckwith Wiedemann syndrome: A population-based study on prevalence, prenatal diagnosis, associated anomalies and survival in Europe.
Beckwith Wiedemann syndrome is a complex developmental disorder characterized by somatic overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycemia, and predisposition to embryonal tumors. We present epidemiological and clinical aspects of patients with Beckwith Wiedemann syndrome diagnosed prenatally or in the early years of life, using data from EUROCAT (European Surveillance of Congenital Anomalies) registries. The study population consisted of 371 cases identified between January 1990 and December 2015 in 34 registries from 16 European countries. There were 15 (4.0%) terminations of pregnancy after prenatal detection of severe anomaly/anomalies, 10 fetal deaths (2.7%), and 346 (93.3%) live-births. Twelve (3.6%) of the 330 live-births with available information on survival died in the first week of life, of those eleven (91.6%) were preterm. First-year survival rate was 90.9%. Prematurity was present in 40.6% of males and 33.9% of females. Macrosomia was found in 49.2% and 43.3% of preterm males and females, respectively. Of term newborns, 41.1% of males and 24% of females were macrosomic. Out of 353 cases with known time of diagnosis, 39.9% were suspected prenatally, 36.3% at birth, 7.6% were diagnosed in the first week of life, and 16.2% in the first year of life. The mean gestational age at prenatal diagnosis by obstetric ultrasound was 19.8 ± 6.2 (11-39) gestational weeks. The mean prenatal diagnosis of cases where parents opted for termination of pregnancy was 15.3 ± 2.4 (11-22) gestational weeks, and the mean gestational age at termination was 19.3 ± 4.1 (13-26) gestational weeks. The prenatal detection rate was 64.1% (141/220) with no significant change over time. There were 12.7% of familial cases. The study confirmed the association of assisted reproductive technologies with Beckwith Wiedemann syndrome, as 7.2% (13/181) of patients were conceived by one of the methods of assisted reproductive technologies, which was three times higher compared to the general population of the countries included in the study. Twin pregnancies of undetermined zygosity were recorded in 5.7% (21/365) cases, and were on average three to four times more common than in European countries that participated in the study. The estimated mean prevalence of classical Beckwith Wiedemann syndrome in Europe was 3.8 per 100,000 births or 1:26,000 births.


Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson's disease.
An inversion polymorphism of approximately 900 kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene defines two haplotype clades, H1 and H2. Several small case-control studies have observed a marginally significant excess of the H1/H1 diplotype among patients with Parkinson's disease (PD), and one reported refining the association to a region spanning exons 1 to 4 of MAPT. We sought to replicate these findings. We genotyped 1,762 PD patients and 2,010 control subjects for a single nucleotide polymorphism (SNP) that differentiates the H1 and H2 clades. We also analyzed four SNPs that define subhaplotypes within H1 previously reported to associate with PD or other neurodegenerative disorders. After adjusting for age, sex, and site, we observed a robust association between the H1/H1 diplotype and PD risk (odds ratio for H1/H1 vs H1/H2 and H2/H2, 1.46; 95% confidence interval, 1.25-1.69; p = 8 x 10(-7)). The effect was evident in both familial and sporadic subgroups, men and women, and early- and late-onset disease. Within H1/H1 individuals, there was no significant difference between cases and control subjects in the overall frequency distribution of H1 subhaplotypes. Our data provide strong evidence that the H1 clade, which contains MAPT and several other genes, is a risk factor for PD. However, attributing this finding to variants within a specific region of MAPT is premature. Thorough fine-mapping of the H1 clade in large numbers of individuals is now needed to identify the underlying functional variant(s) that alter susceptibility for PD.


Shearing of a confined granular layer: tangential stress and dilatancy.
We study the behavior of a confined granular layer under shearing, in an annular cell, at low velocity. We give evidence that the response of the granular layer under shearing is described by characteristic length scales. The tangential stress reaches its steady state on the same length scale as the dilatancy. Stop-and-go experiments performed at several driving velocities show a logarithmic increase of the static friction coefficient with waiting time, followed by rejuvenation on a characteristic length of the order of the magnitude of a Hertz contact between adjacent grains. The dilatancy does not evolve during the stop, neither during the elastic reloading when the driving is resumed. There is a small variation when sliding sets anew, which corresponds to the rejuvenation of the layer, and this variation is independent of the waiting time. We argue that aging is due to the behavior of individual contacts between grains, not global evolution of the piling. Under an instantaneous increase of the velocity, the tangential stress reaches a new steady state, exhibiting velocity strengthening behavior. An increase of dilatancy is also observed. It is much larger than fluctuations in the steady state, variations in a stop and-go-experiment, but much less than for shearing of freshly poured grains. The dilatancy variation during a velocity jump is not due to structural rearrangements of the piling. The evolutions of tangential stress and dilatancy are logarithmic in the ratio of upper and lower velocities.


Interventions for dialysis patients with hepatitis C virus (HCV) infection.
Hepatitis C virus (HCV) infection is common in chronic kidney disease (CKD) patients on dialysis, causes chronic liver disease, may increase the risk of death, and impacts kidney transplant outcomes. Direct-acting antivirals have replaced interferons because of better efficacy and tolerability. This is an update of a review first published in 2015. We aimed to look at the benefits and harms of interventions for HCV in CKD patients on dialysis: death, disease relapse, treatment response/discontinuation, time to recovery, quality of life (QoL), cost-effectiveness, and adverse events. We aimed to study comparisons of available interventions, compared with placebo, control, with each other and with newer treatments. We searched the Cochrane Kidney and Transplant's Specialised Register to 23 February 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE and EMBASE, handsearching conference proceedings, and searching the International Clinical Trials Register Portal (ICTRP) and ClinicalTrials.gov. Randomised controlled trials (RCTs), quasi-RCTs, first period of randomised cross-over studies on interventions for HCV in CKD on dialysis were considered. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Three studies were included in this update, therefore 13 studies (997 randomised participants) met our inclusion criteria. Overall, the risk of bias was judged low in seven studies, unclear in four, low to unclear in one, and high in one study. Interventions included standard interferon, pegylated (PEG) interferon, standard or PEG interferon plus ribavirin; direct-acting antivirals, and direct-acting antivirals plus PEG interferon plus ribavirin. Compared to placebo or control, standard interferon may make little or no difference to death (5 studies, 134 participants: RR 0.89, 95% CI 0.06 to 13.23) or relapse (low certainty evidence), probably improves end-of-treatment response (ETR) (5 studies, 132 participants: RR 8.62, 95% CI 3.03 to 24.55; I² = 0%) (moderate certainty evidence), and probably makes little or no difference to sustained virological response (SVR) (4 studies, 98 participants: RR 3.25, 95% CI 0.81 to 13.07; I² = 53%), treatment discontinuation (4 studies, 116 participants: RR 4.59, 95% CI 0.49 to 42.69; I² = 63%), and adverse events (5 studies, 143 participants: RR 3.56, 95% CI 0.98 to 13.01; I² = 25%) (moderate certainty evidence). In low certainty evidence, PEG interferon (1 study, 50 participants) may improve ETR (RR 1.53, 95% CI 1.09 to 2.15) but may make little or no difference to death (RR 0.33, 95% CI 0.01 to 7.81), SVR (RR 2.40, 95% CI 0.99 to 5.81), treatment discontinuation (RR 0.11, 95% CI 0.01 to 1.96), adverse events (RR 0.11, 95% CI 0.01 to 1.96) and relapses (21/38 relapsed) (RR 0.72, 95% CI 0.41 to 1.25) compared to standard interferon. In moderate certainty evidence, high-dose PEG interferon (alpha-2a and alpha-2b) may make little or no difference to death (2 studies, 97 participants: RR 4.30, 95% CI 0.76 to 24.33; I² = 0%), ETR (RR 1.42, 95% CI 0.51 to 3.90; I² = 20%), SVR (RR 1.19, 95% CI 0.68 to 2.07; I² = 0%), treatment discontinuation (RR 1.20, 95% CI 0.63 to 2.28; I² = 0%) or adverse events (RR 1.05, 95% CI 0.61 to 1.83; I² = 27%) compared to low-dose PEG interferon. High-dose PEG interferon may make little or no difference to relapses (1 study, 43 participants: RR 1.11, 95% CI 0.45 to 2.77; low certainty evidence). There were no significant subgroup differences. Standard interferon plus ribavirin may lead to higher treatment discontinuation (1 study, 52 participants: RR 2.97, 95% CI 1.19 to 7.36; low certainty evidence) compared to standard interferon alone. In low certainty evidence, PEG interferon plus ribavirin (1 study, 377 participants) may improve SVR (RR 1.80, 95% CI 1.46 to 2.21), reduce relapses (RR 0.33, 95% CI 0.23 to 0.48), slightly increase the number with adverse events (RR 1.10, 95% CI 1.01 to 1.19), and may make little or no difference to ETR (RR 1.01, 95% CI 0.94 to 1.09) compared to PEG interferon alone. The evidence is very uncertain about the effect of PEG interferon plus ribavirin on treatment discontinuation (RR 1.71, 95% CI 0.69 to 4.24) compared to PEG interferon alone. One study reported grazoprevir plus elbasvir improved ETR (173 participants: RR 174.99, 95% CI 11.03 to 2775.78; low certainty evidence) compared to placebo. It is uncertain whether telaprevir plus ribavirin (high versus low initial dose) plus PEG interferon for 24 versus 48 weeks (1 study, 35 participants) improves ETR (RR 1.02, 95% CI 0.67 to 1.56) or SVR (RR 1.02, 95% CI 0.67 to 1.56) because the certainty of the evidence is very low. Data on QoL, cost-effectiveness, cardiovascular outcomes and peritoneal dialysis were not available. In dialysis patients with HCV infection grazoprevir plus elbasvir probably improves ETR. There is no difference in ETR or SVR for combinations of telaprevir, ribavirin and PEG interferon given for different durations and doses. Though no longer in use, PEG interferon was more effective than standard interferon for ETR but not SVR. Increasing doses of PEG interferon did not improve responses. The addition of ribavirin to PEG interferon may result in fewer relapses, higher SVR, and higher numbers with adverse events.


CD4+CD25+ immunoregulatory T cells may not be involved in controlling autoimmune arthritis.
Accumulating evidence suggests that regulatory T cells play a crucial role in preventing autoimmunity. Recently, a naturally occurring CD4+CD25+ T-cell subset that is anergic and also suppressive has been shown to suppress autoimmunity in several animal models. We used proteoglycan-induced arthritis (PGIA) as a study model to investigate the role of the CD4+CD25+ regulatory T cells in autoimmune arthritis. There was no significant change in the percentage of CD4+CD25+ T cells during the immunization period when proteoglycan- or ovalbumin-immunized BALB/c and C57BL/6 mice were compared. An adoptive transfer study showed that the CD4+CD25+ T cells did not protect severe combined immunodeficient mice from arthritis when they were cotransferred with splenocytes from arthritic animals. Similarly, depletion of the CD4+CD25+ T cells did not enhance the onset of the disease or disease severity in severe combined immunodeficient mice. Moreover, CD28-deficient mice, which have very few CD4+CD25+ T cells, were highly resistant to PGIA. These findings indicate that the CD4+CD25+ regulatory T cells may not play a critical role in controlling PGIA.


Cancer stem cells and self-renewal.
The cancer stem cell (CSC) or cancer-initiating cancer (C-IC) model has garnered considerable attention over the past several years since Dick and colleagues published a seminal report showing that a hierarchy exists among leukemic cells. In more recent years, a similar hierarchical organization, at the apex of which exists the CSC, has been identified in a variety of solid tumors. Human CSCs are defined by their ability to: (i) generate a xenograft that histologically resembles the parent tumor from which it was derived, (ii) be serially transplanted in a xenograft assay thereby showing the ability to self-renew (regenerate), and (iii) generate daughter cells that possess some proliferative capacity but are unable to initiate or maintain the cancer because they lack intrinsic regenerative potential. The emerging complexity of the CSC phenotype and function is at times daunting and has led to some confusion in the field. However, at its core, the CSC model is about identifying and characterizing the cancer cells that possess the greatest capacity to regenerate all aspects of the tumor. It is becoming clear that cancer cells evolve as a result of their ability to hijack normal self-renewal pathways, a process that can drive malignant transformation. Studying self-renewal in the context of cancer and CSC maintenance will lead to a better understanding of the mechanisms driving tumor growth. This review will address some of the main controversies in the CSC field and emphasize the importance of focusing first and foremost on the defining feature of CSCs: dysregulated self-renewal capacity.


Hospital preparedness for disaster and mass casualty management in Pakistan: A cross-sectional evaluation study.
World Health Organization has advocated preemptive readiness of health systems to manage disas-trous events. Pakistan is known to be highly susceptible to disasters on the one hand and significantly lacking in coping ability on the other. Preparedness of health facilities in such locales is especially important, despite which there is little published evidence regarding hospitals' response capacity in Pakistan. From 12 most disaster prone districts of the country, a purposive sample of 20 hospitals was assessed us-ing 51 indicators, scored as fully (2), partially (1), or not prepared (0). Two domains, disaster preparedness and mass casualty management, and five subdomains, networking, planning, staff-readiness, materials, and safety, were evalu-ated. Proportions of maximum possible scores achieved by an entity were categorized as acceptable (≥66 percent), par-tial (35-65 percent), or inadequate (<35 percent). Out of the 20 hospitals, 14 (70 percent) were secondary and 3 tertiary level facilities (30 percent). Overall, hospitals were partially prepared with a score of 54.0 percent, 95 percent confidence interval [52.3 percent, 54.7 percent]. Disaster preparedness, 55.2 percent [54.0, 57.0], was significantly better prepared than mass casualty management, 49.2 percent [46.8, 51.6], p < 0.001. Overall, facility safety was the least prepared among the subdomains, 38.3 per-cent [31.8, 44.8], while materials were the best, 75.9 percent [72.6, 79.3]. The least prepared subdomains were staff-readiness in Punjab, 52.1 percent [47.5, 56.8], and facility safety in KP, 29.2 percent [22.1, 36.4]. Hospitals' preparedness for disaster and mass casualty management is deficient in these most vulner-able districts of Pakistan. Improvement initiatives commensurate with locale vulnerabilities should be instituted.


A food chain-based ecological risk assessment model for oil spills in the Arctic environment.
This paper investigates the linkage between the acute impacts on apex marine mammals with polar cod responses to an oil spill. It proposes a Bayesian network-based model to link these direct and indirect effects on the apex marine mammals. The model predicts a recruitment collapse (for the scenarios considered), causing a higher risk of mortality of polar bears, beluga whales, and Narwhals in the Arctic region. Whales (adult and calves) were predicted to be at higher risk when the spill was under thick ice, while adult polar bears were at higher risk when the spill occurred on thin ice. A spill over the thick ice caused the least risk to whale and adult polar bears. The spill's timing and location have a significant impact on the animals in the Arctic region due to its unique sea ice dynamics, simple food web, and short periods of food abundance.