Minimal hepatic glucose-6-phosphatase-α activity required to sustain survival and prevent hepatocellular adenoma formation in murine glycogen storage disease type Ia.
Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA), is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC) activity. In a previous 70-90 week-study, we showed that a recombinant adeno-associated virus (rAAV) vector-mediated gene transfer that restores more than 3% of wild-type hepatic G6Pase-α activity in G6pc (-/-) mice corrects hepatic G6Pase-α deficiency with no evidence of HCA. We now examine the minimal hepatic G6Pase-α activity required to confer therapeutic efficacy. We show that rAAV-treated G6pc (-/-) mice expressing 0.2% of wild-type hepatic G6Pase-α activity suffered from frequent hypoglycemic seizures at age 63-65 weeks but mice expressing 0.5-1.3% of wild-type hepatic G6Pase-α activity (AAV-LL mice) sustain 4-6 h of fast and grow normally to age 75-90 weeks. Despite marked increases in hepatic glycogen accumulation, the AAV-LL mice display no evidence of hepatic abnormalities, hepatic steatosis, or HCA. Interprandial glucose homeostasis is maintained by the G6Pase-α/glucose-6-phosphate transporter (G6PT) complex, and G6PT-mediated microsomal G6P uptake is the rate-limiting step in endogenous glucose production. We show that hepatic G6PT activity is increased in AAV-LL mice. These findings are encouraging for clinical studies of G6Pase-α gene-based therapy for GSD-Ia.


Urinary hydroxyproline, creatinine and urea excretion during the growth of five siblings.
Urinary excretions of hydroxyproline, creatine and urea in 24 h specimens from 5 siblings have been determined monthly from 1971 to 1976 together with the measurements of body height and body weight. Changes with age in the urinary levels of these substances are in good agreement with those from cross-sectional studies in various age groups of children. Wide fluctuations of excretion levels occurred. The creatinine coefficients did not remain constant even over short periods. Menarche was observed shortly after the peak of hydroxyproline excretion at puberty. The hydroxyproline excretion pattern is similar to that of hydroxyproline index proposed by Whitehead, and it is quite different from that of hydroxyproline ratio.


Is phrenic nerve dysfunction after cardiac surgery related to internal mammary harvesting?
Although many surgeons feel that internal mammary artery (IMA) harvesting is a risk factor for phrenic nerve dysfunction (PND) following coronary artery bypass grafting surgery (CABG), objective data confirming this are lacking. We sought to compare two groups of cardiac surgical patients to determine if an association exists between IMA harvesting and PND following CABG. Using inpatient medical records and chest radiographs, we performed a retrospective analysis of 25 consecutive CABG patients and 25 consecutive valve procedure patients in order to compare the incidence of PND following cardiac surgery with and without IMA harvesting. Two patients were excluded. Thirty-one patients underwent IMA harvesting as part of their procedure, of whom 42% had PND evidenced on postextubation chest X-ray. Seventeen patients did not have IMA harvesting, and the incidence of PND in this group was 12% (p = 0.05). Both groups were similar in preoperative variables and operative techniques. This study suggests IMA harvesting is indeed a risk factor for PND following CABG.


Intracerebral hemorrhage and hematoma in Behçet's disease: case report.
The authors describe a patient with Behçet's disease who suffered from intracerebral hemorrhage 2 1/2 years after the initial diagnosis. There is strong evidence that this situation is not merely a coincidence; rather, these two abnormalities have a cause and effect relationship.


Multi-drug-resistant Acinetobacter baumannii intra-abdominal abscess.
Multi-drug-resistant bacteria are rarely isolated from patients with acute appendicitis. Case report and literature review. We report an unusual case of post-appendectomy intra-abdominal abscess with intra- operative cultures that grew multi-drug-resistant Acinetobacter baumannii. An 11-year-old boy underwent open appendectomy for perforated appendicitis. He developed a superficial surgical site infection at the Penrose drain site on the seventh postoperative day; cultures grew multi-drug-resistant Acinetobacter baumannii. A computed tomography scan revealed an intra- abdominal abscess. Open drainage was performed, and intra-operative cultures grew the same multi-drug-resistant A. baumannii along with Escherichia coli. Post-operative therapy with ceftriaxone may have predisposed the patient to nosocomial infection caused by multi-drug-resistant A. baumannii.


Military sexual trauma.
Nurses' awareness of MST as a specific type of sexual assault within the military culture and sensitivity to the physical and psychological symptoms are important aspects of care. Nurses must treat the physical and emotional components of sexual assault in all settings; however, referral to the veterans administration programs and resources is key for the woman veteran to receive the specialized care developed by the healthcare system. Women veterans who have PTSD from MST and combat exposure are prone to depression, suicide and substance use/abuse. Nurses must not fear asking the woman if she is having suicidal thoughts or has a plan and intent to follow through with the plan. MST and PTSD may result in internalized anger, shame, self-blame, helplessness, hopelessness and powerlessness. Patient safety is of utmost importance. Assessing Patients for Sexual Violence, A Guide for Health Care Providers (2009) is a useful resource for nurses. The National Center for PTSD (2009) newsletter on the topic of MST includes a list of research studies. The work of Benedict (2007) and Corbett (2007) provide additional personal accounts of women soldiers who were in the Middle East conflicts. The nurse's referral to specialized services to treat MST and PTSD with evidence-based therapies is a crucial first step in the resiliency and well-being of these brave women who have served in all branches of the U.S. military.


No evidence of parvovirus B19, Chlamydia pneumoniae or human herpes virus infection in temporal artery biopsies in patients with giant cell arteritis.
Recent studies have suggested that infective agents may be involved in the pathogenesis of giant cell arteritis (GCA), in particular Chlamydia pneumoniae and parvovirus B19. We investigated temporal arteries from patients with GCA for these infections as well as human herpes viruses using the polymerase chain reaction (PCR). Thirty temporal artery biopsies from 30 patients suspected of having GCA within a period of 1 yr were examined. Thirteen patients had classical GCA, two had biopsy-negative GCA, 10 patients had polymyalgia rheumatica and five patients had other conditions. DNA was extracted from frozen biopsies and PCR was used to amplify genes from Chlamydia pneumoniae, parvovirus B19 and each of the eight human herpes viruses: herpes simplex viruses HSV-1 and 2, Epstein-Barr virus, cytomegalovirus, varicella zoster virus and human herpes viruses HHV-6, -7 and -8. In all 30 biopsies, PCR was negative for DNAs of parvovirus B19, each of the eight human herpes viruses and C. pneumoniae. We found no evidence of DNA from parvovirus B19, human herpes virus or C. pneumoniae in any of the temporal arteries. These agents do not seem to play a unique or dominant role in the pathogenesis of GCA.


Reduction in the intracellular cAMP level triggers initiation of sexual development in fission yeast.
Schizosaccharomyces pombe initiates sexual development in response to nutritional starvation. The level of cAMP in S. pombe cells changed during the transition from exponential growth to stationary phase. It also changed in response to a shift from nitrogen-rich medium to nitrogen-free medium. A decrease of approximately 50% was observed in either case, suggesting that S. pombe cells contain less cAMP when they initiate sexual development. S. pombe cells that expressed the catalytic domain of Saccharomyces cerevisiae adenylyl cyclase from the S. pombe adh1 promoter contained 5 times as much cAMP as the wild type and could not initiate mating and meiosis. These observations, together with previous findings that exogenously added cAMP inhibits mating and meiosis and that cells with little cAMP are highly derepressed for sexual development, strongly suggest that cAMP functions as a key regulator of sexual development in S. pombe. The pde1 gene, which encodes a protein homologous to S. cerevisiae cAMP phosphodiesterase I, was isolated as a multicopy suppressor of the sterility caused by a high cAMP level. Disruption of pde1 made S. pombe cells partially sterile and meiosis-deficient, indicating that this cAMP phosphodiesterase plays an important role in balancing the cAMP level in vivo.


Toward automatic evaluation of medical abstracts: The current value of sentiment analysis and machine learning for classification of the importance of PubMed abstracts of randomized trials for stroke.
Text mining with automatic extraction of key features is gaining increasing importance in science and particularly medicine due to the rapidly increasing number of publications. Here we evaluate the current potential of sentiment analysis and machine learning to extract the importance of the reported results and conclusions of randomized trials on stroke. PubMed abstracts of 200 recent reports of randomized trials were reviewed and manually classified according to the estimated importance of the studies. Importance of the papers was classified as "game changer", "suggestive", "maybe" "negative result". Algorithmic sentiment analysis was subsequently used on both the "Results" and the "Conclusions" paragraphs, resulting in a numerical output for polarity and subjectivity. The result of the human assessment was then compared to polarity and subjectivity. In addition, a neural network using the Keras platform built on Tensorflow and Python was trained to map the "Results" and "Conclusions" to the dichotomized human assessment (1: "game changer" or "suggestive"; 0:"maybe" or "negative", or no results reported). 120 abstracts were used as the training set and 80 as the test set. 9 out of the 200 reports were classified manually as "game changer", 40 as "suggestive", 73 as "maybe" and 32 and "negative"; 46 abstracts did not contain any results. Polarity was generally higher for the "Conclusions" than for the "Results". Polarity was highest for the "Conclusions" classified as "suggestive". Subjectivity was also higher in the classes "suggestive" and "maybe" than in the classes "game changer" and "negative". The trained neural network provided a correct dichotomized output with an accuracy of 71% based on the "Results" and 73% based on "Conclusions" . Current statistical approaches to text analysis can grasp the impact of scientific medical abstracts to a certain degree. Sentiment analysis showed that mediocre results are apparently written in more enthusiastic words than clearly positive or negative results.


A 3D linear solvation energy model to quantify the affinity of flavonoid derivatives toward P-glycoprotein.
P-glycoprotein (Pgp/ABCB1) both accounts for multidrug resistance (MDR) in chemotherapy and contributes to reduce oral bioavailability and brain distribution of drugs. Flavonoids, reported as potent Pgp inhibitors, are able to bind to the cytosolic ATP-binding site and a vicinal hydrophobic pocket. In order to explore the interaction forces governing the affinity of flavonoids towards Pgp, the 3D quantitative structure-activity relationship (QSAR) approach was used to analyze a set of flavonoid derivatives. The variation of affinity towards Pgp was investigated by VolSurf descriptors of Molecular Interaction Fields (MIFs) related to hydrophobic interaction forces, polarizability, and hydrogen-bonding capacity. The 3D linear solvation energy VolSurf model developed here identifies shape parameters and hydrophobicity as the major physicochemical parameters responsible for the affinity of flavonoid derivatives towards Pgp and hydrogen-bonding capacities as minor modulators of this activity. Furthermore, this predictive model (q(2) of 0.71) was also validated by use of an external set of 10 flavones.


Aberrantly regulated dysadherin and B-cell lymphoma 2/B-cell lymphoma 2-associated X enhances tumorigenesis and DNA targeting drug resistance of liver cancer stem cells.
Cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) are frequently resistant to current therapeutic regimens and therefore responsible for tumor recurrence. Previous studies have reported that expression levels of dysadherin in CSCs may be used as a prognostic indicator, which is also responsible for treatment failure and poor survival rates. The present study analyzed the association of enhanced dysadherin levels with drug resistance and evasion of apoptosis in human HCC SP cells. An SP of 3.7% was isolated from human HCC cells using fluorescence‑activated cell sorting. These SP cells displayed elevated levels of dysadherin and stemness proteins as well as high resistance to chemotherapeutic drugs and apoptosis. In order to reveal the possible link between dysadherin levels and tumorigenesis of SP cells, small interfering RNA technology was used to knockdown the expression of dysadherin in SP cells. Of note, the siRNA‑transfected SP cells showed significantly reduced levels of stemness proteins, and were more sensitive to DNA‑targeting drugs and apoptotic cell death as compared to non‑transfected cells. Furthermore, in vivo experiments in NON/SCID mice indicated that dysadherin‑expressing SP cells were highly tumorigenic, as they were able to induce tumor growth. The SP cell‑derived tumor tissues in turn showed elevated dysadherin levels. The results of the present study therefore suggested that knockdown of dysadherin suppressed the tumorigenic properties of cancer stem-like SP cells. Hence, dysadherin is a valuable potential target for the development of novel anti-cancer drugs.


Spectroscopic and catalytic properties of Rhus vernicifera laccase depleted in type 2 copper.
1. The type 2 copper in Rhus vernicifera laccase was completely removed without loss of other types of copper. The properties of this protein derivative and the role of type 2 copper in the catalytic action of laccase was investigated. 2. The molar extinction coefficient at 614 nm of the blue chromophore decreases from 5700 to 4700 cm-1 on removal of type 2 copper. There are no apparent absorption changes at other wavelengths in the visible or near ultraviolet region when this copper is taken away. The electron-paramagnetic-resonance (epr) parameter A parallel and the linewidth of type 1 Cu2+ decreases on removal of type 2 copper. 3. The rate of reduction of type 1 Cu2+ is not affected by removal of type 2 copper but the reduction of the two-electron acceptor is greatly impaired. These results strongly support the idea that type 1 Cu2+ is the primary site for electron transfer between substrate and enzyme and that the two-electron acceptor in the native enzyme is reduced by simultaneous electron transfer from reduced types 1 and 2 copper. 4. Reoxidation of types 1 and 3 copper and the formation of the oxygen intermediate are the same processes in native and type-2-depleted enzyme. These observations suggests that type 2 copper is not involved in the formation and rapid decay of the oxygen intermediate and that it is not necessary for the stabilization of this intermediate. 5. Two new epr signals are observed on reoxidation of reduced type-2-depleted laccase. One is temporarily formed on re-reduction of reoxidized enzyme and it is suggested that it might arise from copper, possibly type 3 copper. The other one is stable for hours and it is proposed that it might come from a modified oxygen intermediate.


Pretreatment of Rho kinase inhibitor inhibits systemic inflammation and prevents endotoxin-induced acute lung injury in mice.
Systemic inflammatory mediators play an important role in the development of sepsis. In this study, we analyzed the role of Rho kinase in the activation of immune response and acute lung injury in a mouse model of sepsis. C57BL/6J mice were randomly divided into three groups: control, LPS, and LPS+fasudil. We used a mouse model of endotoxemia that consists of intraperitoneal injection of a high dose of LPS (30 mg/kg); a Rho kinase inhibitor, fasudil (10 mg/kg), dissolved in sterile saline (1 μL/g body weight) was applied by intraperitoneal injection at 18 and 1 h before injection of LPS (LPS+fasudil group). The control mice received vehicle sterile saline only. Blood was collected and lungs were harvested at 3 and/or 6 h for analysis. At 3 and 6 h, the increased TNF-α and IL-1β levels in plasma and MPO activity in lung tissue by LPS could be significantly inhibited by fasudil. In addition, LPS-induced histologic changes in the lungs at 6 h could be effectively reversed by fasudil pretreatment. Furthermore, pretreatment of mice with fasudil inhibited LPS-induced increasing of TNF-α, IL-1β mRNA expression (3 and 6 h) and AP-1/DNA binding activity (3 h) in blood cells. In survival studies, fasudil (10 mg/kg), which was administered 18 and 1 h before the application of LPS, conferred a protection against lethality induced by LPS (30 mg/kg). These results suggest that Rho kinase may play a role in the pathology of systemic inflammation during early phase of sepsis, and the potential mechanism of action may be partly through the adjustment of AP-1 pathway.


Accounting for Pharmacokinetic Variability of Certolizumab Pegol in Patients with Crohn's Disease.
Certolizumab pegol is an effective biologic for patients with Crohn's disease (CD). Individual differences in certolizumab pegol apparent clearance (CL/F) affect exposure and possibly efficacy. A previously developed population pharmacokinetic (PK) model did not account for dynamic changes in clinical parameters during therapy. The aim of this study was to refine the existing PK model to capture the time-varying influence of covariates. Data collected from 2157 Crohn's disease patients in nine studies were analyzed using nonlinear mixed-effects modeling software (NONMEM). Certolizumab pegol concentration-time data were described by a one-compartment PK model with first-order absorption, and one-compartment disposition with linear, time-dependent elimination using antidrug antibody (ADAb) concentration as a continuous variable. The final dataset consisted of 12,926 analyzable records. Parameter estimates were absorption rate constant 1.83/day, CL/F 0.527 L/day, and apparent volume of distribution (V/F) 8.33 L. ADAb concentration (2.5-214 units/mL) increased the median CL/F by 142-174%. For a typical patient, body weight (46.8-100.5 kg) increased the median CL/F and V/F from 82 to 120%. Albumin (32-48 g/L) decreased and C-reactive protein (0.5-54.0 mg/L) increased the median CL/F from 123 to 85% and from 83 to 113%, respectively. Between-patient variability of CL/F was 19.6%. By incorporating time-varying covariates, this population PK model reduces between-patient variability on CL/F estimates, and the relative influence of ADAb can now be assessed. As Crohn's disease patient covariates are often time-dependent, this model is more reflective of patient drug exposure with sustained treatment.


Transferrin as a thermosensitizer in radiofrequency hyperthermia for cancer treatment.
One of the main characteristics of cancer tissues is poor development of neovascularization that results in a limited blood circulation. Because of this phenomenon, it is harder for cancer tissues to diffuse their elevated heat into other parts of the body. The scientific principle of radiofrequency hyperthermia relies on this quality of cancer tissues which with higher temperature becomes more apparent. Despite the obvious necessity to selectively heat the cancer tissue for radiofrequency hyperthermia, a proper thermosensitizer has not been developed until now. Here, we show that transferrin containing ferric ion could be an ideal thermosensitizer for the increased efficiency of radiofrequency hyperthermia. In our result, the ferric ion-enriched cancer tissues dramatically react with 13.56 MHz radiofrequency wave to cause cancer-selective dielectric temperature increment. The overall anticancer efficacy of a 13.56 MHz radiofrequency hyperthermia using transferrin as a thermosensitizer was much higher than the oncotherapeutic efficacy of paclitaxel, successfully eradicating cancer in a tumor-xenografted mouse experiment.


Effect of age and environmental factors on semen quality, glutathione peroxidase activity and oxidative parameters in Simmental bulls.
Taking into account that semen quality depends on animal age and climate conditions and that oxidative stress has been reported to be a common cause of infertility, the objective of this study was to monitor indicators of oxidative stress and antioxidant protection during four seasonal periods in service bulls of various age to get better insight into the significance of these factors upon evaluating service bull semen. The research was conducted over a year on 19 Simmental service bulls. Animals were divided into two groups according to age; Group I consisted of younger bulls aged two to four yrs (n=9), and Group II was comprised of older bulls aged five to ten yrs (n=10). Semen samples were obtained once in the middle of every seasonal period and blood samples for biochemical analysis were collected by jugular venipuncture immediately after ejaculate collection. The activity of total glutathione peroxidase (T-GSH-Px), selenium-dependent glutathione peroxidase (Se-GSH-Px) and selenium-independent glutathione peroxidase (non-Se-GSH-Px), together with the intensity of lipid peroxidation (thiobarbituric acid reactive substances; TBARS) and oxidative protein damage (protein carbonyl content (PCC)) were measured in seminal plasma. In samples of spermatozoa and blood serum, the activity of Se-GSH-Px and TBARS and PCC concentrations were determined. Older service bulls had significantly higher ejaculate volume in summer in comparison with younger bulls, whereas the number of spermatozoa and progressive motility percentage did not significantly vary with age. Younger animals had lower progressive motility percentage during summer than in spring, with more intensive oxidative processes observed in seminal plasma (TBARS) and spermatozoa (TBARS and PCC). Based on the results presented here, it can be concluded that younger bulls are more sensitive to elevated ambient temperatures during the summer, when intensified prooxidative processes in semen plasma and spermatozoa eventually led to decreased sperm progressive motility with consequential semen quality deterioration.


Prognostic value of endoanal ultrasound for fistula-in-ano: a retrospective analysis.
This study was designed to assess whether preoperative endoanal ultrasound plays a prognostic role in the surgical outcome of anal fistula. A retrospective review was conducted at a single institution. Sixty-nine patients underwent 83 studies. Indications for endoanal ultrasound included complex fistulas and tracts, multiple external openings, recurrent fistulas, and/or failed previous surgical intervention. Mean age was 51.7 years. Fifty-three patients (77 percent) were men. Mean duration of symptoms was 3.1 years. Forty-nine patients (71 percent) had undergone previous surgical intervention to eradicate sepsis or fistula. Sixty patients (87 percent) underwent surgical interventions and were divided into two groups: Group A (73.3 percent), concordance with ultrasound findings; and Group B (26.7 percent), nonconcordance. Mean follow-up in the surgical group was 15.6 months. Measured outcome was total number of operations per patient and failure rate of primary surgical intervention. No difference was noted in mean total number of operations between Group A (1.57) and Group B (1.69) (P = 0.71). There was a statistically nonsignificant trend toward a higher failure rate of the primary intervention in the nonconcordance group [failure rate 18.2 percent in Group A vs. 25 percent in Group B (P = 0.72)]. The findings and accuracy of preoperative endoanal ultrasound did not influence postoperative outcome.


Removal of Haemonchus contortus, Ostertagia circumcincta and Trichostrongylus spp. from goats, by morantel citrate, levamisole hydrochloride, fenbendazole, and oxfendazole.
Young feral goats harbouring 3, 7 and 36 day old experimental infections of strains of gastrointestinal nematodes, known to be susceptible to anthelmintics in sheep, were dosed orally with commercially available anthelmintics at the manufacturers' recommended rates for sheep. The drugs and overall removals of Ostertagia circumcincta and Trichostrongylus spp. (T. colubriformis and T. vitrinus) respectively were: morantel citrate 69% and 68%; levamisole hydrochloride 55% and >99%; fenbendazole 98.5% and >99%; oxfendazole >99% and >99%. Results for Haemonchus contortus, while not inconsistent with high efficacy for all four drugs, must be interpreted with caution, in view of the erratic establishment of this worm in the controls.


Alteration of flavonoid accumulation patterns in transparent testa mutants disturbs auxin transport, gravity responses, and imparts long-term effects on root and shoot architecture.
Flavonoids have broad cross-kingdom biological activity. In Arabidopsis, flavonoid accumulation in specific tissues, notably the root elongation zone and root/shoot junction modulate auxin transport, affect root gravitropism, and influence overall plant architecture. The relative contribution made by aglycones and their glycosides remains undetermined, and the longer-term phenotypic effects of altered flavonoid accumulation are not fully assessed. We tested Arabidopsis thaliana mutants that accumulate different flavonoids to determine which flavonoids were causing these affects. Tandem mass spectrometry and in situ fluorescence localisation were used to determine the in vivo levels of aglycones in specific tissues of 11 transparent testa mutants. We measured rootward and shootward auxin transport, gravitropic responses, and identified the long-term changes to root and shoot architecture. Unexpected aglycone species accumulated in vivo in several flavonoid-pathway mutants, and lower aglycone levels occurred in transcription factor mutants. Mutants accumulating more quercetin and quercetin-glycosides changed the greatest in auxin transport, gravitropism, and aerial tissue growth. Early flavonoid-pathway mutants showed aberrant lateral root initiation patterns including clustered lateral root initiations at a single site. Transcription factor mutants had multiple phenotypes including shallow root systems. These results confirm that aglycones are present at very low levels, show that lateral root initiation is perturbed in early flavonoid-pathway mutants, and indicate that altered flavonoid accumulation affects multiple aspects of plant architecture.


Semi-quantitative assessment of ischemia with rubidium-82 PET myocardial perfusion imaging.
Semi-quantitative scores can be used as an adjunct to visual assessment in rubidium-82 positron emission tomography (82Rb PET). The semi-quantitative cut-off values used in 82Rb PET are derived from single-photon emission computed tomography (SPECT). It is unknown whether these cut-off values can be extrapolated to 82Rb PET. We compared the semi-quantitative with the visual assessment of ischemia and determined which summed difference score (SDS) score predicts ischemia best. We included 108 patients who underwent 82Rb PET imaging and performed visual and semi-quantitative assessment. A scan with a SDS ≥ 2 and a summed stress score (SSS) ≥ 4 was considered to demonstrate ischemia. We compared the semi-quantitative with the visual assessment. 41 (38%) Normal scans, and 67 (62%) scans with ischemia and/or an irreversible defect were included. The semi-quantitative assessment showed ischemia more often than the visual assessment (51% vs 29%, P < .001). Patients with a low or intermediate pre-test probability of coronary artery disease (CAD) and a SDS < 4 did not demonstrate ischemia by visual assessment. Semi-quantitative assessment in 82Rb PET imaging clearly demonstrates the presence of ischemia. Ischemia is unlikely in patients with low and intermediate pre-test probability of CAD and a SDS < 4.


Depiction of a postoperative pseudomeningocele with digital subtraction myelography.
Digital subtraction myelography is described for its utility in the detection of dural leaks associated with pseudomeningoceles. Although myelography, CT, and MR imaging have been described as effective means for diagnosing pseudomeningocele, this complicated entity can be difficult to diagnose.


Relative importance of genetic effects in rheumatoid arthritis: historical cohort study of Danish nationwide twin population.
To determine the relative importance of environmental and genetic effects in the development of rheumatoid arthritis. Historical cohort study with record linkage between a twin registry and the Danish discharge registry as well as the Danish national registry of deaths used to estimate completeness. Two population based nationwide twin birth cohorts. 37 338 twins were sent a questionnaire about rheumatic diseases. Self reported rheumatoid arthritis was verified by clinical examination and from medical records. The probandwise concordance rate of rheumatoid arthritis in monozygotic and dizygotic twins. The response rate was 84.7%. Rheumatoid arthritis was verified in 13 monozygotic and 36 dizygotic twins. There were no concordant monozygotic twin pairs and two concordant dizygotic twin pairs. Based on capture-recapture methods the probability of ascertainment was 78.3%. The probandwise concordance rate was 0 (95% confidence interval 0 to 24.7) in monozygotic twins and 8.8 (1.9 to 23.7) in dizygotic twins. Genes are of minor importance in the development of rheumatoid arthritis.


Use of an in vitro model for studying the eradication of catheter colonisation by Staphylococcus epidermidis.
Silicone rubber catheters were experimentally colonised with three different strains of Staphylococcus epidermidis sensu stricto. The catheters were then perfused with brain-heart infusion broth by means of an in vitro apparatus which simulates the pharmacokinetics of intraventricular administration of antimicrobial agents. When colonisation was established, vancomycin was administered to the dosing chamber three times daily so as to give peak concentrations of 16, 32, 64 and 128 mg/l. Each experiment was performed in triplicate. Samples of fluid taken from each catheter were cultured before treatment and at intervals thereafter during perfusion for 4 weeks or until recolonisation became apparent. Those catheters not showing evidence of recolonisation were examined by scanning electron microscopy for the presence of organisms. Colonisation was eradicated (as judged by cultural examination) in 37% catheters but eradication did not bear any clear relationship to drug concentrations. Electron microscopical examination of all catheters showing eradication by cultural means revealed the presence of organisms.


Effects of matrix elasticity and cell density on human mesenchymal stem cells differentiation.
Human mesenchymal stem cells (hMSCs) can differentiate into various cell types, including osteogenic and chondrogenic cells. The matrix elasticity and cell seeding density are important factors in hMSCs differentiation. We cultured hMSCs at different seeding densities on polyacrylamide hydrogels with different stiffness corresponding to Young's moduli of 1.6 ± 0.3 and 40 ± 3.6 kPa. The promotion of osteogenic marker expression by hard gel is overridden by a high seeding density. Cell seeding density, however, did not influence the chondrogenic marker expressions induced by soft gel. These findings suggest that interplays between cell-matrix and cell-cell interactions contribute to hMSCs differentiation. The promotion of osteogenic differentiation on hard matrix was shown to be mediated through the Ras pathway. Inhibition of Ras (RasN17) significantly decreased ERK, Smad1/5/8 and AKT activation, and osteogenic markers expression. However, constitutively active Ras (RasV12) had little effect on osteogenic marker expression, suggesting that the Ras pathways are necessary but not sufficient for osteogenesis. Taken together, our results indicate that matrix elasticity and cell density are important microenvironmental cues driving hMSCs proliferation and differentiation.


[Evidence-based emergency medicine].
Evidence Based (Emergency) Medicine (EB(E)M is a term referring to the application into daily clinical practice of only those methods, procedures, medications etc. which are based on scientific evidence. Where diagnostic and therapeutic principles have not been validated on a prospective, controlled randomised basis, this should be tried out at a later time, if at all possible. This concept may allow to bridge the gap between research and clinical practice, and represents the major goal of EB(E)M. Protagonists of EBEM are at times confronted with criticism that EBEM does not constitute the only but one out of several possible approaches to quality controlled medical care. The fact that more than 50% of all emergency procedures are not evidence based give rise to the question as to whether the performance of randomised controlled studies is ethically justifiable, if control groups are included whose treatment leaves out generally recommended and recognised (though not evidence based) therapeutic and/or diagnostic principles. The following examples may enumerate some of the procedures, methods or medications, respectively, without proven scientific evidence: Medication for resuscitation of cardiac arrest victims. Medication for acute asthmatic attacks Initial treatment of uncontrolled haemorrhagic shock. Endotracheal intubation in VF/VT. The principle need for initial ventilation and the volumes of ventilation in cardiac arrest patients. Effectiveness of ACD- and VEST-CPR. A few typical examples are presented to illustrate the requirements of current study designs which have to be met before results of an evaluation are accepted by the EBEM scientists to obtain approval for application of a procedure, method or medication in clinical practice (large patient numbers, power calculations, ethical issues) as well as their benefits and drawbacks.


Additive damage in the thromboxane related vasoconstriction and bradykinin relaxation of intramural coronary resistance arterioles in a rodent model of andropausal hypertension.
Hypertension and andropause both accelerate age-related vascular deterioration. We aimed to evaluate the effects of angiotensin-II induced hypertension and deficiency of testosterone combined regarding the resistance coronaries found intramurally. Four male groups were formed from the animals: control group (Co, n = 10); the group that underwenr orchidectomy (ORC, n = 13), those that received an infusion of angiotensin-II (AII, n = 10) and a grous that received AII infusion and were also surgically orchidectomized (AII + ORC, n = 8). AII and AII + ORC animals were infused with infusing angiotensin-II (100 ng/min/kg) using osmotic minipumps. Orchidectomy was perfomed in the ORC and the AII + ORC groupsto establish deficiency regarding testosterone. Following four weeks of treatment, pressure-arteriography was performed in vitro, and the tone induced by administration of thromboxane-agonist (U46619) and bradykinin during analysis of the intramural coronaries (well-known to be resistance arterioles) was studied. U46619-induced vasoconstriction poved to be significantly decreased in the ORC and AII + ORC groups when compared with Co and AII animals. In ORC and AII + ORC groups, the bradykinin-induced relaxation was also significantly reduced to a greater extent compared to Co and AII rats. Following orchidectomy, the vasocontraction and vasodilatation capacity of blood vessels is reduced. The effect of testosterone deficiency on constrictor tone and relaxation remains pronounced even in AII hypertension: testosterone deficiency further narrows adaptation range in the double noxa (AII + ORC) group. Our studies suggest that vascular changes caused by high blood pressure and testosterone deficiency together may significantly increase age-related cardiovascular risk.


[Transforaminal lumbar interbody fusion: goals of the minimal invasive approach].
Transforaminal lumbar interbody fusion (TLIF) is an effective technique, which can achieve a fusion rate of up to 90%. The minimally invasive approach has become increasingly popular because it is able to minimize iatrogenic soft tissue and muscle injury. Although the minimally invasive TLIF technique has gained popularity, its effectiveness compared with open TLIF has yet to be established. The authors prospectively compared the outcomes of patients who underwent mini-open TLIF with patients who underwent open TLIF. Between 2007 and 2008, 50 patients underwent TLIF for grade 1 spondylolisthesis; 25 mini-open TLIF and 25 open TLIF. The mean age in each group was 48years, and there was no statistically significant difference between the groups. Data were collected perioperatively. Pain and functional disability were measured using a visual analogue scale (VAS) and the Oswestry disability index (ODI) at 3months, 6months, 1year and 2years. In addition, foraminal and disc height were measured at the same intervals and the fusion was evaluated at 1year on CT-scan. Soft tissue damage was evaluated by measuring the serum myoglobin and creatine phosphokinase activity. The mean VAS improved from 7 to 2.8 and the ODI decreased from 30/50 to 15/50 and fusion rate at 1 year was 98%. There was no statistical difference for the clinical and radiological outcomes between the groups. The mean operative time was 186min for the open group, 170min for the mini-open group (P<0.05) and the mean blood loss was 486mL for the open group and 148mL for the mini-open group (P<0.01). The mini-open TLIF procedure for symptomatic low grade spondylolisthesis is an effective option which achieves similar clinical and radiological outcomes and reduces perioperative morbidity as well as soft tissue damage.


Severe maternal morbidity and mortality during the COVID-19 pandemic: a cohort study in Rio de Janeiro.
To identify factors associated with adverse maternal outcomes during the coronavirus disease 2019 (COVID-19) pandemic. This was a single-centre prospective cohort study at a maternity department in a public general hospital in Rio de Janeiro. All pregnant women evaluated for emergency care, labour and delivery, respiratory symptoms, obstetric reasons or medical reasons between May 2020 and March 2022 at the study institution were invited to enrol in this study. The endpoint was maternal mortality or intensive care unit (ICU) admission. In total, 1609 pregnant women were enrolled in this study. Of these, 25.5% (n=410) were infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) based on reverse transcription polymerase chain reaction or an antigen test. There were 21 deaths and 67 ICU admissions in 4% of the cohort. The incidence of severe maternal morbidity and mortality was higher during the Gamma wave than during the Delta wave (P=0.003). Vaccination conferred protection against the endpoint [relative risk (RR) 0.4, 95% confidence interval (CI) 0.1-0.9; P=0.0169]. Factors associated with severe morbidity and mortality included caesarean section (RR 3.7, 95% CI 1.7-7.9; P=0.0008), SARS-CoV-2 infection in the third trimester (RR 2.4, 95% CI 1.1-5.6; P=0.0006) and comorbidities (RR 3, 95% CI 1.8-5.2; P<0.0001). COVID-19 was significantly associated with the risk of severe maternal morbidity and mortality. Immunization of pregnant women against COVID-19 was highly protective against adverse outcomes, and should be encouraged during pregnancy.


An unusual case of posttransplant peritoneal primary effusion lymphoma with T-cell phenotype in a HIV-negative female, not associated with HHV-8.
Primary effusion lymphoma (PEL) is a recently individualized form of non-Hodgkin's lymphoma (WHO classification) that mainly develops in HIV infected males, more frequently in homosexuals and advanced stages of the disease (total CD4+ lymphocyte count below 100-200/microL). Occasionally, it appears in other immunodepressive states (such as solid organs transplant period) and even, although very rarely, in immunocompetent patients. From a pathogenetic point of view, PEL has been related to Kaposi's sarcoma associated herpes virus (also named human herpesvirus 8, HHV-8), an etiological factor of Kaposi's sarcoma. The relative infrequency of this disease, the absence of wide casuistics allowing a better characterization, and its unfavorable outcome support the need of a deeper knowledge. We present here the clinical-biological findings of a patient, HIV seronegative, who was diagnosed with peritoneal PEL of T-cell origin, and not HHV-8-associated, five years after renal transplantation.


Immunohistochemical study of distribution of estrogen receptors in corpus and cervix uteri.
An immunohistochemical assay based on monoclonal antiestrophilin antibodies has been used to localize estrogen receptor (ER) in frozen sections of normal human endometrial, myometrial and cervical tissues from menstruating, hormonally treated, pregnant and postmenopausal women. Specific staining was confined to the cellular nuclei. In proliferative phase endometrium, postmenopausal emdometrium, and endometrium from patients treated with hormone ERs were easily detected in most glandular and stromal cells. After ovulation and in early pregnancy a quick and distinct decrease of ER expression was noted. This was especially the case with the more superficial layers of endometrium (endometrium functionalis), the majority of whose cells had either weak localization of ER or none at all. In the endometrium basalis, however, the reduction of ER localization turned out to be more moderate. More then half of the epithelial and stromal cells displayed nuclear staining, partly strong. The myometrium of the corpus uteri showed a similar ER localization and dependence on hormonal stage when compared with the endometrium functionalis. The endocervical mucosa displayed a high degree of ER expression in the proliferative phase, in postmenopausal women and in women who had been treated with hormones. Unlike the endometrium and myometrium, the endocervical glands underwent minimal changes in nuclear ER content during the menstrual cycle. Although the endocervical stroma showed cyclic alterations in ER levels, their reduction after ovulation was less marked than in the corresponding endometria. In cervical squamous epithelium ER localization was predominantly confined to the basal layers. In the course of cellular maturation, specific nuclear staining vanished. In the proliferative phase, after the menopause and in early pregnancy, the basal, parabasal and intermediate cells were specifically stained. In the postovulatory phase, However, nuclear staining was confined to the basal and parabasal cells. Hormonally treated squamous epithelia almost completely lacked nuclear ER localization.


Effects of glycated albumin on mesangial cells: evidence for a role in diabetic nephropathy.
Nonenzymatically glycated proteins are preferentially transported across the glomerular filtration barrier, and the glomerular mesangium in diabetes is bathed with serum containing increased concentrations of glycated albumin. We investigated effects of glycated albumin on mesangial cells, which are involved in diabetic nephropathy. [3H]-thymidine incorporation was significantly inhibited when murine mesangial cells were grown in culture media containing human serum that had been nonenzymatically glycated by incubation for 4 days with 28 mM glucose. This inhibition was reversed when monoclonal antibodies that selectively react with Amadori products of glycated albumin were added to the culture media. Purified glycated albumin containing Amadori adducts of the glycation reaction induced significant inhibition of thymidine incorporation and stimulation of Type IV collagen secretion compared with cells cultured in the presence of purified nonglycated albumin. These changes were prevented when monoclonal antibodies specifically reactive with fructosyl-lysine epitopes in glycated albumin were added to the cultures. The antibodies had no effect on growth or collagen production in the presence of nonglycated albumin. The results provide the first evidence directly implicating Amadori adducts in glycated albumin in the pathogenesis of diabetic nephropathy, which is characterized by decreased cellularity in association with expansion of the mesangial matrix.


Clock-drawing performance predicts inpatient rehabilitation outcomes after traumatic brain injury.
The authors used clock-drawing performance to assess cognition and predict inpatient rehabilitation outcomes among persons with traumatic brain injury. Clock-drawing performance, as assessed with the Clock Drawing Interpretation Scale, predicts rehabilitation length of stay as well as Functional Independence Measure scores at the time of neurobehavioral assessment and rehabilitation discharge.


Melatonin: a potent candidate in the regulation of fish oocyte growth and maturation.
Recent studies on several fish species, especially carp, implicated pineal hormone melatonin (N-acetyl-5-methoxytryptamine) as a potent candidate in the regulatory mechanism of seasonal reproduction. Under natural conditions, the temporal pattern of serum melatonin varied with daily light-dark cycle and the reproductive status of the fish as well. Carefully controlled study revealed that exogenous administration of melatonin may result in stimulation or inhibition or no influences at all on the gonadal functions depending on the reproductive status of fish. Cross-talk between the melatonin and ovarian steroid has been evident from in vitro study, in which melatonin accelerated the action of 17α,20β-dihydroxy-4-pregnen-3-one or maturation inducing hormone (MIH) on meiotic cell cycle resumption in carp oocytes by formation of maturation promoting factor (MPF) - a complex of two proteins, cyclin B and cyclin dependant kinase Cdk1. While several lines of evidence suggest melatonin effects on hypothalamo-hypophyseal-gonadal axis, localization and dynamics of a 37-kDa melatonin receptor protein in carp oocytes argued in favor of extra-hypothalamic direct action of melatonin on fish reproduction. A recent study in carp indicated that influences of an identical regimen of photoperiods in different parts of annual cycle on ovarian functions vary in relation to the profiles of serum melatonin, but not to any rhythm parameters of MT1 or MT2 receptors on the gonad or brain. The purpose of this short review is to bring together the current knowledge on the biological effects of melatonin on fish reproduction mainly focusing the recent findings on carp.


Consultations for Foreign Bodies in Aerodigestive Tract: Assessment of Diagnostic Modalities.
To evaluate test characteristics of various diagnostic modalities in the workup of foreign body (FB) sensation in the aerodigestive tract. Database containing all inpatient otolaryngology consultations between 2008 and 2020 was used. Cases of FB sensation were identified by documented encounter diagnosis or hospital problem of FB or globus sensation. Variables including basic patient demographics, clinical presentations, diagnostic imaging modalities, procedures, and outpatient follow-up were collected. One hundred and six patients were included in the study. A FB was visualized in 55 patients (52%) and removed in 52 patients (49%); 3 patients had a FB that was visualized initially but not found in the operating room. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were found to be 41%, 50%, 58%, and 33%, respectively, for X-ray (XR); 91%, 61%, 70%, and 87%, respectively, for computed tomography (CT). Sensitivity and NPV were 25% and 57%, respectively, for flexible fiberoptic laryngoscopy (FFL). Seventy-one of 106 patients (67%) underwent invasive interventions during their workup for FBs. Ten out of 11 (91%) chicken bones were found in the digestive tract compared to 7 out of 19 (37%) fishbones (p = 0.0046). In patients with history of FB ingestion, CT may be more beneficial than XR as a screening tool for locating foreign bodies and guiding further management. FFL alone is inadequate for ruling out a FB in the aerodigestive tract given FB's high likelihood of being in the esophagus or buried in soft tissue or mucosa. 3 Laryngoscope, 133:1361-1366, 2023.


Caring for adults with severe mental illness and physical health problems.
Emeritus Professor Alan Glasper, from the University of Southampton, discusses a recent report that reveals discrepancies in the management of physical health problems among people with severe mental illness.


Epidemiological Features and Management of Oral Cancer Patients: Experience from a Single Private Comprehensive Cancer Care Center in the State of Odisha.
Oral cancer is the most common cancer in India. Challenges in the management of oral cancer patients in India include, delay in the presentation with high volume of advanced disease to be handled, affordability of patients and lack economical support especially in the non-governmental institutions and lack of awareness among patients and their relatives. Present study, a retrospective analysis of a prospectively maintained data, portrays the epidemiological features and management of patients with oral cancer presented to a private comprehensive cancer care hospital in the state of Odisha, India. A total of 1049 patients were considered for the analyses, managed between January 2014 and December 2016. Among 1049 patients, 20% (n, 215) were females and 80% (n, 834) were males. Mean age among the present cohort of patients was 50 years with age group 40-55 years being most common. All the patients underwent resection with curative intent and a 1 cm gross resection margins with or without bone and skin. Margin negative resection could be achieved in 82% of patients. Nodal involvement was seen in 36% of patients in the final histopathological assessment. Management of oral cancer patients is a major oncological and reconstructive challenge in India due to the advanced nature of disease at presentation. Inspite of socioeconomic constraints, these patients can be managed even in a private cancer centers with optimum outcomes. This is possible through coordinated team efforts.


Vitamin B12 protects against DNA damage induced by hydrochlorothiazide.
DNA damage induced by hydrochlorothiazide was previously reported in cultured human lymphocytes. In this study, we aimed to investigate the harmful effects of hydrochlorothiazide on DNA by measuring the spontaneous frequency of sister chromatid exchanges (SCEs) in cultured human lymphocytes. We also aimed to investigate the possible protection of that damage by vitamin B12. The results showed that hydrochlorothiazide (5 µg/mL) significantly increased the frequency of sister chromatid exchanges (P < 0.001) in human lymphocytes in comparison with control. Additionally, the frequency of hydrochlorothiazide-induced SCEs was significantly decreased by co-treatment with vitamin B12 at concentration of 13.5 µg/mL (P < 0.001). In conclusion, hydrochlorothiazide is genotoxic to human lymphocytes and its toxicity is reduced by vitamin B12.


Comparison of surrogate and subject reports of dietary practices, smoking habits and weight among married couples in the Tecumseh Diet Methodology Study.
Agreement between surrogate and subject reports of current food frequencies and other eating habits, smoking behavior and weight was assessed in 1982-1983 for 180 husbands and wives, aged 45 through 64 years. Agreement was measured by per cent exact agreement and weighted kappa for frequencies of 30 itemized foods or food groups, and for surrogate- and subject-based quintiles of frequencies of eight broad food groups and of vitamin A and C consumption indexes. Surrogate and subject mean frequencies were generally similar, but at the individual level of analysis, agreement varied widely. Agreement was greatest, among the food items and groups, for alcoholic beverages, and among the other items, for smoking status. Extreme misclassification by quintile was very small, but only 40% of persons self-classified in either extreme quintile were similarly classified by their spouses. This level of misclassification may result in the dilution of real relationships between diet and health.


Ex vivo evaluation of high-intensity focused ultrasound with ultrasonic-induced cavitation bubbles.
In high-intensity focused ultrasound (HIFU) comprising high-intensity burst ultrasound (triggering pulse) and medium-intensity continuous wave ultrasound (heating wave), optimizing the effects of the triggering pulse conditions on the coagulated volume may help to reduce treatment times. HIFU combined with a triggering pulse was applied to chicken deep pectoral muscles. The acoustic power of the heating wave was set to 36, 54, or 72 W. Four different triggering pulse conditions were used: heating wave only; or pulse widths and pulse repetition frequencies of 30 μs and 1 kHz, 300 μs, and 100 Hz, or 3 ms and 10 Hz. Compared to the heating wave only condition, the coagulated volume was significantly larger under all conditions that included a triggering pulse. Significant differences were also observed in the ellipticity of the coagulated region between some conditions. HIFU combined with a triggering pulse may play an important role in reducing treatment times.


Determination of MICs of levofloxacin for Mycobacterium tuberculosis with gyrA mutations.
The purpose of the present study was to correlate gyrA mutations found in Mycobacterium tuberculosis isolates using the GenoType(®) MTBDRsl assay with minimum inhibitory concentrations of the fluoroquinolone levofloxacin (LVX). Of 123 archived clinical M. tuberculosis isolates evaluated, 93 isolates had an Ala90Val, Ser91Pro, Asp94Ala, Asn/Tyr, Gly or His mutation and 30 were wild-type. Phenotypically, gyrA mutations Ala90Val, Ser91Pro or Asp94Ala showed a low level of resistance to LVX, while Asp94Asn/Tyr, Asp94Gly or Asp94His mutations had high-level resistance.


Oral Health in Pregnancy.
Oral health is crucial to overall health. Because of normal physiologic changes, pregnancy is a time of particular vulnerability in terms of oral health. Pregnant women and their providers need more knowledge about the many changes that occur in the oral cavity during pregnancy. In this article we describe the importance of the recognition, prevention, and treatment of oral health problems in pregnant women. We offer educational strategies that integrate interprofessional oral health competencies.


Suppression of inspiratory fast rhythm, but not bilateral short-term synchronization, by morphine in anesthetized rabbit.
To better understand the involvement of opioid receptor systems in the respiratory control, effects of morphine on the high-frequency component of inspiratory nerve discharge were evaluated. The inspiratory fast rhythm in the bilateral phrenic nerve discharge of anesthetized and artificially ventilated rabbits was analyzed with power spectral and coherence functions. Morphine (0.625-10 mg/kg, i.v.) decreased the amplitude and frequency of the inspiratory fast rhythm in a dose-dependent manner via naloxone-sensitive mechanisms. In contrast, the bilateral short-time scale correlation of the phrenic fast rhythm was resistant to morphine even at a strong suppression of the respiratory activities. It is concluded that there is little influence of opioid receptor system to the neural connectivity underlying bilateral phrenic synchronization.


Changes in obstetric practice in our time.
In the years since 1939 there has been a marked change in the nature and results of obstetric practice at the Royal Women's Hospital, Melbourne. The noteworthy changes have been a reduction in the number of maternal deaths (from 12.2 per 1,000 in the 1940's to 0.2 per 1,000 in the 1980's), especially those due to septic abortion, and an increase in the Caesarean section rate (from 2% to 14%). The increase in the operative delivery rate has been matched by a decrease in mortality in patients thus delivered, the maternal and perinatal mortality rates changing from 5.5 and 88.9 per 1,000 to 0 and 7.6 per 1,000 respectively in the case of forceps delivery and from 24.7 and 162.5 per 1,000 to 0.15 and 10.6 per 1,000 respectively in the case of Caesarean delivery.


Methapyrilene hepatotoxicity is associated with oxidative stress, mitochondrial disfunction and is prevented by the Ca2+ channel blocker verapamil.
Methapyrilene (MP) is an unusual hepatotoxin in that it causes periportal necrosis in rats. The mechanism of acute methapyrilene hepatotoxicity has, therefore, been investigated in cultured male rat hepatocytes. Addition of methapyrilene to rat hepatocytes resulted in a time- and dose-dependent loss in cell viability between 4 and 8 h of incubation as judged by cellular enzyme leakage. The cytochrome P450 (CYP) inhibitor metyrapone protected against methapyrilene-mediated toxicity suggesting that MP is metabolised by CYP for toxicity. The concentration-dependent protection from methapyrilene toxicity afforded by metyrapone correlated with an inhibition of microsomal CYP2C11-associated androstenedione 16alpha hydroxylase activity, and hepatocytes prepared from hypophysectomised rats (containing reduced levels of microsomal immunodetectable CYP2C11 and associated androstenedione 16alpha hydroxylase activity) showed resistance to the toxic effects of methapyrilene. These data suggest that the toxicity of methapyrilene is predominantly dependent on the CYP2C11 isoform. Treatment of hepatocytes with a toxic concentration of MP caused oxidative stress as indicated by increases in NADP+ levels within 2 h and cellular thiol oxidation as evidenced by a reduction--but not complete loss--in glutathione levels. Methapyrilene hepatotoxicity was associated with an early loss in mitochondrial function, as indicated by mitochondrial swelling and significant losses in cellular ATP within 2 h. Co-incubation of methapyrilene-treated hepatocytes with inhibitors of inner mitochondrial transition permeability pore opening--cyclosporin A or the thiol reductant dithiothreitol--abrogated cell death suggesting that pore opening and loss of mitochondrial Ca2+ homeostasis play a significant role in methapyrilene-mediated cell death. Co-incubation of methapyrilene-treated hepatocytes with the phenylalkylamine calcium channel blocker verapamil--but not by treating cells in a nominally calcium-free medium--also abrogated cell death, suggesting that if Ca2+ is involved in cell killing then it is dependent on an intracellular Ca2+ pool. Pre-treatment of hepatocytes for 1 h with verapamil--to inhibit intracellular Ca2+ pool filling--increased the potency of verapamil protection against methapyrilene toxicity by approximately 100-fold. Taken together, these data indicate that methapyrilene intoxication leads to mitochondrial disfunction and suggest a critical role for a loss of mitochondrial Ca2+ homeostasis in this model of hepatocyte death.


Intraoperative motor evoked potential monitoring: overview and update.
Amidst controversy about methodology and safety, intraoperative neurophysiology has entered a new era of increasingly routine transcranial and direct electrical brain stimulation for motor evoked potential (MEP) monitoring. Based on literature review and illustrative clinical experience, this tutorial aims to present a balanced overview for experienced practitioners, surgeons and anesthesiologists as well as those new to the field. It details the physiologic basis, indications and methodology of current MEP monitoring techniques, evaluates their safety, explores interpretive controversies and outlines some applications and results, including aortic aneurysm, intramedullary spinal cord tumor, spinal deformity, posterior fossa tumor, intracranial aneurysm and peri-rolandic brain surgeries. The many advances in motor system assessment achieved in the last two decades undoubtedly improve monitoring efficacy without unduly compromising safety. Future studies and experience will likely clarify existing controversies and bring further advances.


Polyhedral cobalt(II) and iron(II) siloxanes: synthesis and x-ray crystal structure of [(RSi(OH)O2)Co(OPMe3)]4 and [(RSiO3)2(RSi(OH)O2)4(mu3-OH)2Fe8(THF)4] (R = (2,6-iPr2C6H3)N(SiMe3)).
The cobalt(II) and iron(II) siloxane compounds were prepared by the reaction of lipophilic N-bonded silanetriol 1 with metal silylamides M[N(SiMe3)2]2 (M = Co (2), Fe (3)) in a 1:1 and 3:4 molar ratio, respectively. A plot of 1/chi versus temperature in the range of 2-300 K indicates the paramagnetic behavior of 2 and 3. The composition and molecular structures of 2 and 3 were fully determined by IR, elemental analysis, and X-ray crystal structural analyses. Compound 2 possesses a pseudo-4-fold (S4) symmetry, whereas 3 reveals an inversion center. Compound 2 represents a tetracobalt(II) drum while 3 exhibits an octairon(II) cage containing siloxane ligands.


[Clinical features and genetic analysis of a case with Perlman syndrome due to variant of DIS3L2 gene].
To analyze the clinical phenotype and genetic characteristics of a child with Perlman syndrome. Genomic DNA was extracted from peripheral blood samples from the patient and her parents. Whole exome sequencing (WES) was carried out to detect potential variant in the proband. Candidate variant was verified by Sanger sequencing. The pathogenicity of candidate variants was evaluated according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). The results of WES showed that the proband has harbored compound heterozygous variants of the DIS3L2 gene, namely c.2109delC and c.1829.c.1830insC, which were respectively inherited from her mother and father. The results were confirmed by Sanger sequencing. Based on the ACMG guidelines, the two novel variants were both predicted to be pathogenic (PVS1+PS2+PM2). The compound heterozygous variants of the DIS3L2 gene probably underlay the Perlman syndrome in this patient. Above finding has enriched the spectrum of DIS3L2 gene mutations.


Internet- and mobile-based intervention for depression in adults with chronic back pain: A health economic evaluation.
Depression and comorbid chronic back pain (CBP) lead to high personal and economic burden. Internet- and mobile-based interventions (IMI) might be a cost-effective adjunct to established interventions. A health economic evaluation was embedded into an observer-blinded, multicenter RCT (societal and health care perspective). We randomly assigned participants (≥18 years) with CBP and diagnosed depression from 82 orthopedic clinics across Germany to intervention (IG + treatment as usual [TAU]) or TAU control group (CG). The IG received a guided IMI. Primary outcomes were depression response and quality-adjusted life years (QALYs) at 6-months follow-up. Multiple imputation was used to address missing data. Incremental cost-effectiveness/cost-utility ratios (ICER/ICUR) and the probability of being cost-effective at different willingness-to-pay thresholds were calculated. Statistical uncertainty was estimated using bootstrapping techniques (N = 10,000). Between October 2015 and July 2017 210 participants were randomly assigned to IG (n = 105) and CG (n = 105). Depression response did not differ significantly between groups. QALYs were significantly higher in the IG compared to the CG. Taking the societal perspective and assuming a commonly used willingness-to-pay of €34,000/QALY, the intervention's likelihood of being cost-effective was 64%. The main limitation is that the study was powered to detect clinical but not health economic differences between groups. The IMI is considered cost-effective (vs. CG) for individuals with depression and CBP (societal perspective). These results are promising when considering the high individual and economic burden of this patient group. Further research is needed to adequately inform political decision makers before implementation into routine care.


Genetic component of autoimmune rheumatological diseases.
The purpose of this review is to present the main aspects of the genetic component of autoimmune rheumatic diseases, including the characteristics of the multifactorial or polygenic inheritance model, and its monogenic forms, as well as the main associated genes in both cases. The epigenetic changes involved, and the influence of the environment and sex that confer greater risk to women suffering from any of these diseases. Finally, to make known the advances that the study of omic sciences has allowed, opening the way to a new molecular classification of these diseases, aimed at personalized medicine. A review of the literature of the last 5 years, of English-language publications, in the PubMed database was performed and 28 review articles, and 19 original articles were included. Knowledge of the genetic factors involved in the aetiology of autoimmune rheumatic diseases, thanks to the availability of molecular studies, allows a better understanding of their pathophysiology and the possibility of diagnosis and treatment based on molecular markers in the future.


Inhibition of Hageman factor, plasma thromboplastin antecedent, thrombin and other clotting factors by phenylglyoxal hydrate (38500).
Exposure of purified Hageman factor (HF, Factor XII) to phenylglyoxal hydrate (PHG), an agent reacting with arginine residues in protein, inhibited its coagulant properties upon subsequent exposure of negatively charged agents. Once HF had been exposed to kaolin or ellagic acid, however, subsequent addition of PHG was much less inhibitory. PHG had no effect upon the ability of HF to bind to negatively charged surfaces. PGH also inhibited preparations of activated PTA (Factor XI) and thrombin, and, when incubated with plasma, reduced the titer of coagulable fibrinogen, PTA Christmas factor (Factor IX), antihemophilic factor (Factor VIII), Factor VII, Stuart factor (Factor X), proaccelerin (Factor V) and prothrombin (Factor II), and to a lesser degres, HF.


Comparison of microbial communities of activated sludge and membrane biofilm in 10 full-scale membrane bioreactors.
Operation of membrane bioreactors (MBRs) for wastewater treatment is hampered by the membrane biofouling resulting from microbial activities. However, the knowledge of the microbial ecology of both biofilm and activated sludge in MBRs has not been sufficient. In this study, we scrutinized microbial communities of biofilm and activated sludge from 10 full-scale MBR plants. Overall, Flavobacterium, Dechloromonas and Nitrospira were abundant in order of abundance in biofilm, whereas Dechloromonas, Flavobacterium and Haliscomenobacter in activated sludge. Community structure was analyzed in either biofilm or activated sludge. Among MBRs, as expected, not only diversity of microbial community but also its composition was different from one another (p < 0.05). Between the biofilm and activated sludge, community composition made significant difference, but its diversity measures (i.e., alpha diversity, e.g., richness, diversity and evenness) did not (p > 0.05). Effects of ten environmental factors on community change were investigated using Spearman correlation. MLSS, HRT, F/M ratio and SADm explained the variation of microbial composition in the biofilm, whereas only MLSS did in the activated sludge. Microbial networks were constructed with the 10 environmental factors. The network results revealed that there were different topological characteristics between the biofilm and activated sludge networks, in which each of the 4 factors had different associations with microbial nodes. These results indicated that the different microbial associations were responsible for the variation of community composition between the biofilm and activated sludge.


Visible light-induced oxidative coupling reaction: easy access to Mannich-type products.
An efficient methodology for the functionalization of sp(3) C-H bond adjacent to nitrogen has been developed utilizing visible light-induced photoredox catalysis. Through optimization of solvent and light source, the reaction can be rapidly achieved to provide the desired product under mild reaction conditions.


Deciphering Bitcoin Blockchain Data by Cohort Analysis.
Bitcoin is a peer-to-peer electronic payment system that has rapidly grown in popularity in recent years. Usually, the complete history of Bitcoin blockchain data must be queried to acquire variables with economic meaning. This task has recently become increasingly difficult, as there are over 1.6 billion historical transactions on the Bitcoin blockchain. It is thus important to query Bitcoin transaction data in a way that is more efficient and provides economic insights. We apply cohort analysis that interprets Bitcoin blockchain data using methods developed for population data in the social sciences. Specifically, we query and process the Bitcoin transaction input and output data within each daily cohort. This enables us to create datasets and visualizations for some key Bitcoin transaction indicators, including the daily lifespan distributions of spent transaction output (STXO) and the daily age distributions of the cumulative unspent transaction output (UTXO). We provide a computationally feasible approach for characterizing Bitcoin transactions that paves the way for future economic studies of Bitcoin.


Histochemistry of the forestomach epithelium of the reindeer calf.
Samples from the rumen, reticulum and omasum of 26 reindeer calves were taken during the winter season. Non-specific alkaline and acid phosphatases, cytochrome and amine oxidases as well as succinate, lactate and 3-hydroxybutyrate dehydrogenases were demonstrated in the epithelium histochemically. The phosphatases were usually present in all the epithelial layers, whereas the activities of the other enzymes decreased in the outer layers and could not be demonstrated in the stratum corneum. The activity of alkaline phosphatase seemed to be highest in the reticulum and lowest in the omasum. The reason for the higher activity of this enzyme in epithelial taps in the rumen and omasum and in the reticular and omasal papillae may be the greater need for effective vertical transcellular transport in these regions. There was a tendency for enzymes other than phosphatases to be more active in the rumen than in the other forestomachs, which probably reflects the higher metabolic activity of the ruminal epithelium. No clear differences between early and late winter could be demonstrated.


Rehearsal-based digital serious boardgame versus a game-free e-learning tool for anatomical education: Quasi-randomized controlled trial.
Serious games may resolve problems relating to low motivation in complex medical topics such as anatomy. However, they remain relatively novel introductions to the science of learning, and further research is required to ascertain their benefits. This study describes the overall development and testing of a digital serious boardgame designed to facilitate the rehearsal of musculoskeletal anatomy based on self-determination theory with considerations for the psychological state of Flow. It was hypothesized that students assigned to the intervention game condition would attain higher Flow scores, a measure of engagement and intrinsic motivation, than students assigned to the game-free control, and that the intervention condition would report either superior or non-superior, but not inferior, scores on a surprise recall test. A total of 36 second-year undergraduate medical students participated in the quasi-randomized controlled trial, where the intervention groups went first and randomly drew questions that were mirrored into the control groups. All students were administered an identical 10-question baseline assessment before their interventions, the Short Flow Scale immediately after, and a surprise test four-to-six weeks later. Independent samples t-tests indicated that students of both conditions were of similar baseline knowledge (t = 0.7, p = 0.47), significantly higher Flow scores in the game condition (t = 2.99, p = 0.01), and no significant differences between surprise test scores (t = -0.3, p = 0.75). The game appears to be an appropriate game-based tool for student rehearsal of anatomical education, stemming from a strong theoretical base that facilitates high engagement and intrinsic motivation.


A Problem in NIH and Federally Funded Prostate Cancer Interventional Clinical Trials.
Obesity, diagnosed in 41.1% of African American (AA) men, is a risk factor for prostate cancer (PCa) recurrence, progression, and increased mortality. Obesity is associated with aggressive PCa only in AA men and not White American (WA) men. The overall health of AA PCa patients is also more likely to be adversely affected by comorbid type 2 diabetes (T2D), often an outcome of obesity and a cause of reduced odds of PCa survival. This evidence suggests that preventing and controlling comorbid obesity and T2D in AA men diagnosed with PCa should be a research funding priority. The aim of this study is to determine if federally funded PCa clinical trials controlled T2D and obesity. Completed interventional PCa clinical trials conducted in the USA, funded by the NIH or other federal agency, which included males aged 18-64 years, and reported study protocols were included in the study. We examined the intervention modalities used in the trials to determine if any attempted to control obesity and T2D. Fifty-eight trials met the study inclusion criteria. Of these 11 were excluded from the analysis as they did not report AA men. A total of 5802 men participated in the remaining 47 trials. Of these, 917 (15.8%) were AA and 4885 (84.2%) were WA men. Forty (85.1%) trials used pharmaceutical medication therapies or other clinical procedures. None of the medications or clinical procedures used were indicated for treatment of obesity and T2D. 5 (10.6%) trials addressed treatment preferences, survivorship, coping, function, and incontinence among PCa patients. Only 2 (4.25%) trials examined weight loss and diet. None of the completed federally funded PCa clinical trials that included AA men used methods to control T2D. Only an insignificant number (4.25%) attempted to control obesity. This gap in therapeutic optimization to control these comorbid conditions indicates a critical area in need of federal funding priority.


The forkhead box O transcription factor regulates lipase and anti-microbial peptide expressions to promote lipid catabolism and improve innate immunity in the Eriocheir sinensis with hepatopancreatic necrosis disease.
Eriocheir sinensis is a crustacean with great economic value, but the occurrence of hepatopancreatic necrosis disease (HPND) severely restricts the development of crab aquaculture. Study on the survival mechanism of crabs with HPND is beneficial to provide new strategies for disease prevention and control. The Forkhead box O (FOXO) transcription factor family is involved in various key biological processes of organisms. In this study, a FOXO gene (named as EsFOXO) from E. sinensis was cloned. The full-length cDNA of EsFOXO is 2592 bp containing a 2133 bp open reading frame that encodes 710 amino acids. EsFOXO was widely distributed in multiple immune tissues. Further study found that the expression of EsFOXO in the intestine of crabs with HPND was significantly upregulated compared with that in the normal crabs. However, whether EsFOXO is involved in the immune and metabolic regulation of crabs remains unknown. RNA interference analysis showed that EsFOXO participates in the positive regulation of the expression of two pancreatic lipases, three anti-lipopolysaccharide factors, and three crustins. Results from our research suggest that two strategies are adopted by crabs with HPND for survival under starvation: on the one hand, the synthesis of antimicrobial peptides is increased to improve the innate immunity; on the other hand, the expression of enzymes correlated with lipid catabolism is up-regulated that mobilizes the fat in the crab, going through catabolism. Our study provides more evidence for an in-depth understanding of the survival mechanism of crabs with HPND.


Modified pressure cooker technique: An easier way to control onyx reflux.
The use of onyx enabled the treatment of various intracranial vascular diseases more effectively than cyanoacrylate. The pressure cooker technique allowed definitive control of reflux and was made possible via detachable microcatheters. We present a variation of this technique called the modified pressure cooker to make reflux control easier and more reproducible and thus simplifying the procedure. We also extended the application of the technique to other diseases beyond arteriovenous malformations including dural arteriovenous fistulas and hypervascular tumors.


Stress Factors as Possible Regulators of Pluripotent Stem Cell Survival and Differentiation.
In recent years, extensive research efforts have been directed toward pluripotent stem cells, primarily due to their remarkable capacity for pluripotency. This unique attribute empowers these cells to undergo self-renewal and differentiate into various cell types originating from the ectoderm, mesoderm, and endoderm germ layers. The delicate balance and precise regulation of self-renewal and differentiation are essential for the survival and functionality of these cells. Notably, exposure to specific environmental stressors can activate numerous transcription factors, initiating a diverse array of stress response pathways. These pathways play pivotal roles in regulating gene expression and protein synthesis, ultimately aiming to preserve cell survival and maintain cellular functions. Reactive oxygen species, heat shock, hypoxia, osmotic stress, DNA damage, endoplasmic reticulum stress, and mechanical stress are among the examples of such stressors. In this review, we comprehensively discuss the impact of environmental stressors on the growth of embryonic cells. Furthermore, we provide a summary of the distinct stress response pathways triggered when pluripotent stem cells are exposed to different environmental stressors. Additionally, we highlight recent discoveries regarding the role of such stressors in the generation, differentiation, and self-renewal of induced pluripotent stem cells.


How many long branch orders occur in Chelicerata? Opposing effects of Palpigradi and Opilioacariformes on phylogenetic stability.
Excepting a handful of nodes, phylogenetic relationships between chelicerate orders remain poorly resolved, due to both the incidence of long branch attraction artifacts and the limited sampling of key lineages. It has recently been shown that increasing representation of basal nodes plays an outsized role in resolving the higher-level placement of long-branch chelicerate orders. Two lineages have been consistently undersampled in chelicerate phylogeny. First, sampling of the miniaturized order Palpigradi has been restricted to a fragmentary transcriptome of a single species. Second, sampling of Opilioacariformes, a rarely encountered and key group of Parasitiformes, has been restricted to a single exemplar. These two lineages exhibit dissimilar properties with respect to branch length; Opilioacariformes shows relatively low evolutionary rate compared to other Parasitiformes, whereas Palpigradi possibly acts as another long-branch order (an effect that may be conflated with the degree of missing data). To assess these properties and their effects on tree stability, we constructed a phylogenomic dataset of Chelicerata wherein both lineages were sampled with three terminals, increasing the representation of these taxa per locus. We examined the effect of subsampling phylogenomic matrices using (1) taxon occupancy, (2) evolutionary rate, and (3) a principal components-based approach. We further explored the impact of taxon deletion experiments that mitigate the effect of long branches. Here, we show that Palpigradi constitutes a fourth long-branch chelicerate order (together with Acariformes, Parasitiformes, and Pseudoscorpiones), which further destabilizes the chelicerate backbone topology. By contrast, the slow-evolving Opilioacariformes were consistently recovered within Parasitiformes, with certain subsampling practices recovering their placement as the sister group to the remaining Parasitiformes. Whereas the inclusion of Opilioacariformes always resulted in the non-monophyly of Acari with support, deletion of Opilioacariformes from datasets consistently incurred the monophyly of Acari except in matrices constructed on the basis of evolutionary rate. Our results strongly suggest that Acari is an artifact of long- branch attraction.


[Primary and secondary arterial hypertension - update 2016].
In patients with hypertension without diabetes and with an increased risk of cardiovascular complications a blood pressure of below 130 mmHg should be targeted. Hypertensive patients with an age above 80 years should be treated in the same way as younger hypertensive patients if they are otherwise healthy and functionally independent. On the other hand frail elderly patients could have an increased morbidity and mortality with intensive blood pressure control. In patients with resistant hypertension spironolactone was the most effective drug when given in addition to their baseline drugs (ACE-inhibitor/angiotensin receptor antagonist, calcium channel blocker and thiazide diuretic).


Sub-lethal effects and bioconcentration of the human pharmaceutical clotrimazole in rainbow trout (Oncorhynchus mykiss).
The aim of this study was to characterize biomarker responses, haematological profiles, structural changes and uptake in juvenile rainbow trout exposed to clotrimazole (CLO) at three concentrations (0.01 - [lowest environmentally relevant concentration], 1.0 [highest environmentally relevant concentration] and 10 μg L(-1)) in a semi-static system over a period of 42 days. Antioxidant defence enzymes, which responded to CLO exposure, changed the oxidative stress status of cells, but no differences were observed in lipid peroxidation. Clotrimazole triggered a biphasic response of CYP3A-like activity in liver microsomes, which may indicate a detoxification process in the liver. Histopathological alterations were most pronounced in kidneys and testes in the group exposed to 10 μg L(-1). Structural changes in the kidney included tubulonephrosis and hyaline droplet degeneration in the tubular epithelial cells. The relative proportions of germ cells in testes were changed: The number of spermatozoa was reduced, and the spermatogonia and spermatocytes were increased. The highest CLO concentration was detected in fish liver (3710 ng per gram wet tissue) and kidney (4280 ng per gram wet tissue). Depuration half-life was estimated to be 72, 159, and 682 h in liver, muscle, and kidney, respectively. Taken together, these results provide valuable toxicological data on the effects of CLO on aquatic non-target organisms, which could be useful for further understanding of the potential risks in the real aquatic environment.


Morphometric Comparison of Tympanic Membrane in Unilateral Mucosal Chronic Otitis Media.
Previous studies of the middle ear in Chronic Otitis Media have focussed on radiological assessment of temporal bone; endoscopic studies were focussed on perforation size and location. The malleus handle (manubrium) is a constant ossicular feature visible on otoendoscopy. It's relative position may indicate the previously documented differences in ossicular chain and middle ear cleft development relative to the tympanic ring and inner ear capsule between affected ear and contralateral ear. descriptive. hospital based. 84 patients with unilateral mucosal chronic otitis media. each patient underwent Otoendoscopy and the findings were recorded through a camera connected to a laptop. Using image j software these images were analysed. Participants were of mean age of 35 years with left preponderance, and no gender preponderance was found. In our study, majority of the perforations were small sized perforations. The malleus handle foreshortening was about 92.6% compared to unaffected ear which was statistically insignificant. There was a significant inter group difference in the distance between the tip of the manubrium and the inferior annulus-which was decreased in affected ears and in the distance from the lateral process to the anterior tympanic ring-which was increased in affected ears. There was no difference in the malleo scutal angles. These differences were not dependent on the site or size of the perforation. The differences we found between ears were unexpected. The significance of the differences in the shape of the tympanic membrane between affected and unaffected ears in unilateral mucosal COM need further study. We did not find a statistically significant difference in the malleo-scutal angles between ears.


P-type Ca2+ channels trigger stimulus-evoked [3H]acetylcholine release from mammalian motor endplates.
In the present experiments it was tested whether omega-agatoxin-IVA, a peptide blocking P-type voltage-dependent Ca2+ channels, inhibits the evoked release of newly synthesized [3H]acetylcholine from the rat phrenic nerve. Release of [3H]acetylcholine was evoked by electrical stimulation of the isolated phrenic nerve (100 or 750 pulses at 5 Hz). omega-Agatoxin-IVA inhibited evoked [3H]acetylcholine release in a concentration-related manner; inhibition started at a concentration of 30 nM with complete block occurring at 500 nM. In conclusion, the present experiments demonstrate that omega-agatoxin-IVA-sensitive P-type Ca2+ channels are critically involved in the regulation of stimulus-induced transmitter release at mammalian motor endplates.


Acute effects of nasal salmon calcitonin on calcium and bone metabolism.
Effects of a single dose of 200 IU of nasal salmon calcitonin (SCT) on calcium metabolism and biochemical markers of bone turnover were investigated in 12 healthy male volunteers in a randomized, placebo-controlled, cross-over design. The nasal spray was given in the morning, and subsequently blood and urine samples were collected for 26 hours. There was a significant decrease in serum ionized calcium with a nadir 4 hours after administration of nasal SCT accompanied by a significant increase in serum parathyroid hormone (P = 0.01) and serum calcitriol (P = 0.04). Nasal SCT did not reduce urinary hydroxyproline/creatinine. Urinary deoxypyridinoline/creatinine was lowered significantly 2 hours after administration of nasal SCT and throughout the first 24 hours, but remained unchanged for the last 2 hours. On a 24-hour basis, urinary deoxypyridinoline/creatinine decreased from 14.1 (3.5) nmol/mmol to 11.7 (3.2) nmol/mmol after nasal SCT (P = 0.04). Nasal SCT did not change the serum levels of alkaline phosphatase, osteocalcin, and the carboxyterminal propeptide of type 1 procollagen. The results indicate that nasal SCT given as a single dose provokes a modest decrease in bone resorption lasting several hours, but leaves bone formation unaffected.


Hepatic hilar transection method for liver surgery (with video).
The procedure used to isolate the hepatic artery, the portal vein and the bile duct separately at the hepatic hilum was first reported in the 1940s, and remains significant as an essential technique for liver surgery in the era of more complicated liver surgery and liver transplantation. The anatomy of the vessels at the hepatic hilum is highly variable; therefore, preoperative imaging studies are indispensable for understanding the anatomy in each individual patient. The minimal extent of the transection should be defined according to the operative procedure, as excessive disruption of the blood flow and lymphatic vessels can induce postoperative complications. When isolating the vessels, gentle handling and appropriate ligation/division of the vessels are required to avoid bleeding and injuries to the vessels to be preserved. The bile duct is wrapped with perivascular connective tissue and is difficult to isolate separately. Therefore, the hilar plate should be divided together with the bile duct, under the guidance of intraoperative cholangiography.


The effects of pollen composition on fitness components in a neotropical herb.
Experimental pollinations of Costus allenii (Zingiberaceae) were conducted to assess the effects of pollen composition on fitness. Plants were selfed, outcrossed with the first nearest neighbor, and outcrossed with pollen mixtures obtained from the nearest 2, 3, and 5 plants. Cross type had a significant effect on seed production, seed weight and total-plant dry weight. Progeny from crosses with 3, and 5 parents grew significantly larger than selfed progeny, or those from 1-parent crosses. Competition experiments indicated the superiority of progeny from 3-, and 5-parent crosses over progeny from 1-parent crosses, but no differences in competitive ability were observed between progeny from 3-, and 5-parent crosses. Relative fitness, based on 1) seed production, 2) percent germination, and 3) dry weight, varied significantly among crosses, and was greatest for crosses with 3 parents and lowest for selfs. The relative fitness of progeny from 5-parent crosses was lower than that of all other outcrossed classes. We suggest that the significant effect of pollen composition on fitness results from variation in the genetic similarity of seed and pollen parents, which is a function of spatial distribution and population structure.


[The effect of lysine-enriched bread on the formation of N-nitrosamines from their precursors in the stomach of dogs].
Data are presented on nitrosamine (NA) formation in the stomach of dogs after per os intake of their precursors--morpholine (or diethylamine) and sodium nitrite. It has been shown that bread enriched with lysine given to dogs in combination with the precursors promotes a five-six-fold reduction of carcinogenic NA formation in the dog's stomach as compared to the control.


Prospective pilot evaluation of a new needle prototype for endoscopic ultrasonography-guided fine-needle aspiration: comparison of cytology and histology yield.
Endoscopic ultrasonography (EUS) with the adjunct of EUS-guided fine needle aspiration has become an important diagnostic modality in gastroenterologic oncology. EUS-guided fine needle aspiration mainly relies on cytology; data are scarce that compare cytology and histology. While testing a 22-gauge prototype needle, we prospectively compared the yield for both. Forty-two consecutive patients (27 male, 15 female; mean age 59.2 years, range: 17-90 years) were included. In each patient we aimed to make two needle passes, and if the material acquired appeared insufficient macroscopically (no in-room cytopathology was available), further passes were done. The material was sent for cytological and histological assessment. A median number of two passes (range: 2-3) were uneventfully performed for pancreatic lesions (n=30), mediastinal and other lymph nodes/masses (n=8) and various other lesions (n=4) and yielded adequate material for cytology, histology or at least one of the two investigations in 62, 67 and 74% of patients, respectively. No false positive results were found (specificity 100%). Sensitivities were 58.6 and 65.5%, respectively, for cytology and histology alone; combined assessment increased sensitivity to 79.3%. When adjusted values were calculated, based only on those cases with adequate material, sensitivity was 89.5% for cytology and 85.7% for histology, and increased to 100% with combined assessment. The new needle achieves sensitivities similar to those previously reported with no significant differences in sensitivity between cytology and histology. More effective tissue acquisition methods must be sought to improve overall results.


Phosphoinositide binding regulates alpha-actinin CH2 domain structure: analysis by hydrogen/deuterium exchange mass spectrometry.
alpha-Actinin is an actin bundling protein that regulates cell adhesion by directly linking actin filaments to integrin adhesion receptors. Phosphatidylinositol (4,5)-diphosphate (PtdIns (4,5)-P(2)) and phosphatidylinositol (3,4,5)-triphosphate (PtdIns (3,4,5)-P(3)) bind to the calponin homology 2 domain of alpha-actinin, regulating its interactions with actin filaments and integrin receptors. In this study, we examine the mechanism by which phosphoinositide binding regulates alpha-actinin function using mass spectrometry to monitor hydrogen-deuterium (H/D) exchange within the calponin homology 2 domain. The overall level of H/D exchange for the entire protein showed that PtdIns (3,4,5)-P(3) binding alters the structure of the calponin homology 2 domain increasing deuterium incorporation, whereas PtdIns (4,5)-P(2) induces changes in the structure decreasing deuterium incorporation. Analysis of peptic fragments from the calponin homology 2 domain showed decreased local H/D exchange within the loop region preceding helix F with both phosphoinositides. However, the binding of PtdIns (3,4,5)-P(3) also induced increased exchange within helix E. This suggests that the phosphate groups on the fourth and fifth position of the inositol head group of the phosphoinositides constrict the calponin homology 2 domain, thereby altering the orientation of actin binding sequence 3 and decreasing the affinity of alpha-actinin for filamentous actin. In contrast, the phosphate group on the third position of the inositol head group of PtdIns (3,4,5)-P(3) perturbs the calponin homology 2 domain, altering the interaction between the N and C terminus of the full-length alpha-actinin antiparallel homodimer, thereby disrupting bundling activity and interaction with integrin receptors.


Using Emergency Medical Services Data to Monitor Nonfatal Opioid Overdoses in Real Time : Development, Validation, and Use of a Case Definition, Rhode Island, 2018.
No case definition exists that allows public health authorities to accurately identify opioid overdoses using emergency medical services (EMS) data. We developed and evaluated a case definition for suspected nonfatal opioid overdoses in EMS data. To identify suspected opioid overdose-related EMS runs, in 2019 the Rhode Island Department of Health (RIDOH) developed a case definition using the primary impression, secondary impression, selection of naloxone in the dropdown field for medication given, indication of medication response in a dropdown field, and keyword search of the report narrative. We developed the case definition with input from EMS personnel and validated it using an iterative process of random medical record review. We used naloxone administration in consideration with other factors to avoid misclassification of opioid overdoses. In 2018, naloxone was administered during 2513 EMS runs in Rhode Island, of which 1501 met our case definition of a nonfatal opioid overdose. Based on a review of 400 randomly selected EMS runs in which naloxone was administered, the RIDOH case definition accurately identified 90.0% of opioid overdoses and accurately excluded 83.3% of non-opioid overdose-related EMS runs. Use of the case definition enabled analyses that identified key patterns in overdose locations, people who experienced repeat overdoses, and the creation of hotspot maps to inform outbreak detection and response. EMS data can be an effective tool for monitoring overdoses in real time and informing public health practice. To accurately identify opioid overdose-related EMS runs, the use of a comprehensive case definition is essential.


Biochemical markers of vasospastic coronary artery disease.
The risk factors for vasospastic angina pectoris (VSA) have not yet been well defined. We compared the plasma levels of lipids, apo(lipo)proteins, remnants of triglyceride (TG)-rich lipoproteins, oxidized low density lipoprotein (Ox-LDL), cholesteryl ester transfer protein (CETP) [which transfers esterified cholesterol (EC) from HDL to TG-rich lipoproteins and reduces plasma HDL levels], high-sensitivity C-reactive protein (hs-CRP), homocysteine and plasminogen-activator inhibitor (PAI)-1 in background-matched groups of controls, and patients with VSA or coronary atherosclerotic disease (CAD) (n=50 subjects each). The cholesterol levels of remnant-like particles (RLP), which are equivalent to the remnants of TG-rich lipoproteins, were measured using a precipitation method. Ox-LDL, CETP and PAI-1 were measured by means of sandwich ELISA; hs-CRP by means of nephelometry; and homocysteine by means of HPLC. Plasma LDL-C levels were high only in the CAD group, and plasma apo E and PAI-1 levels were high only in the VSA group. The plasma levels of TG, apo CII and RLP-C were highest in the VSA group, followed by the CAD group. The plasma levels of apoB, apo CIII, Ox-LDL, CETP, hs-CRP and homocysteine were equally increased in both the VSA and CAD groups. The increases in plasma RLP-C, CETP, hs-CRP and homocysteine were not significantly different between stable and unstable states of angina pectoris in either the VSA or CAD group. The increases in plasma TG-rich lipoproteins and their remnants were more significant markers of VSA than of CAD. The increases in plasma CETP, Ox-LDL, hs-CRP and homocysteine were equally important markers of VAS and CAD.