Application of 3D printing in assessment and demonstration of stab injuries.
In stabbing related fatalities, the forensic pathologist has to assess the direction of wound track (thus, the direction of the stabbing) and the weapon's possible characteristics by examining the stab wound. The determination of these characteristics can be made only with a high level of uncertainty, and the precise direction of the stabbing is often difficult to assess if only soft tissues are injured. Previously reported techniques used for the assessment of these wound characteristics have substantial limitations. This manuscript presents a method using today's easily accessible three-dimensional (3D) printing technology for blade-wound comparison and wound track determination. Scanning and 3D printing of knives is a useful method to identify weapons and determine the precise stabbing direction in a stabbing incident without compromising the trace evidence or the autopsy results. Ballistic gel experiment, and dynamic stabbing test experiments prove the method can be applied in safety, without compromising the autopsy results. Identification of the exact knife is not possible with complete certainty but excluding certain knives will decrease the number of necessary DNA examinations, hence it can lower the burden on forensic genetic laboratories. The method addresses many of the shortcomings of previously used methods of probe insertion or post-mortem CT. Insertion of the printed knife into the wound gives a good visual demonstration of the stabbing direction, thus easing the forensic reconstruction of the stabbing incident. After combining the 3D printing with photogrammetry, the achieved 3D visualization is useful for courtroom demonstration and educational purposes.


Radiographic characteristics of colonic "mucosal bridges": sequelae of inflammatory bowel disease.
Colonic mucosal bridges are a relatively unusual entity occurring in patients with inflammatory disease of the colon. The authors describe two cases in which the pattern of multiple long, linear band-like defects may be easily misinterpreted as thickened mucosal folds, mucous strands, or foreign matter. The possibility of mucosal bridges should be considered if this radiographic pattern is demonstrated, and the patient's history is compatible with their formation.


Making light work of enzyme catalysis: protochlorophyllide oxidoreductase.
In the chlorophyll biosynthetic pathway, the enzyme protochlorophyllide oxidoreductase (POR) catalyses a key light-driven reaction that triggers a profound transformation in plant development. Because POR is activated by light, it can provide information on the way in which light energy can be harnessed to power enzyme reactions and it presents us with a unique opportunity to study catalysis at low temperatures and on ultrafast timescales that are not accessible for most analyses of enzyme function. Recent advances in our understanding of the catalytic mechanism of POR illustrate why it is an important generic model for studying enzyme catalysis and reaction dynamics.


Tissue distribution and molecular heterogeneity of bovine thiol:protein-disulphide oxidoreductase (disulphide interchange enzyme).
1. The distribution of thiol:protein-disulphide oxidoreductase (disulphide interchange enzyme) in 17 bovine tissue extracts was determined by rocket immunoelectrophoresis and by measuring the reductive cleavage of insulin. 2. The relative concentration (per mg total protein) was found to be in the order: Pancreas greater than liver greater than lymph node greater than testes, fat tissue greater than parotid gland, brain, spleen, lung greater than small intestine, spinal cord, large intestine, kidney greater than paunch, aorta greater than skeletal muscle greater than heart. 3. The distribution of specific activity showed a similar pattern, irrespectively of whether glutathione or L-cysteine was used as cosubstrate. 4. The concentration varied 200-fold and the specific activity 400-fold between pancreas and heart muscle, respectively. 5. Crossed immunoelectrophoresis demonstrated that a fast-migrating form of the enzyme was the only one present in almost all tissues, but 15% of the enzyme in liver was a slow-migrating form and 50% in heart muscle a medium-migrating form. 6. The lung contains a species having partial immunological identity to the enzyme. 7. Purified enzyme from bovine liver has a somewhat lower mobility than the fast-migrating form in extract. 8. The results seem to support the general view that the enzyme is involved in synthesis of disulphide-bonded extracellular proteins, although the presence of the enzyme in tissues like fat, brain, spinal cord, skeletal muscle and heart indicates other cellular functions as well.


Finding cancer biomarkers from mass spectrometry data by decision lists.
Finding accurate biomarkers is key to early diagnosis and successful treatment of many otherwise incurable diseases. In this work, we study the problem of finding biomarkers through mass spectrometry (SELDI-TOF) spectra from cancerous and normal tissues. In contrast to the common practice of using vague methods such as genetic algorithms, or uninterpretable methods such as Support Vector Machines, we look for a method that is simple, intuitive, interpretable, usable, and more accurate. We introduce decision lists to this domain. Our experiments on clinical cancer datasets demonstrate that decision lists can achieve more accurate results than other methods. More interestingly, the resulting decision lists are more interpretable for possible causal relationship between cancer and differentially expressed proteins, and directly usable in clinical biomarker design. In particular, our approach is capable of finding multiple biomarkers with high sensitivity and specificity. Such a feature will provide clues for medical experts to thoroughly investigate the roles of protein in cancer development and progression.


Perinatal intimate partner violence and postpartum contraception timing among currently married women in Southern Ethiopia: A multilevel Weibull regression modeling.
Adopting contraception on time is a critical intervention for postpartum women, but violence exposure around pregnancy may interfere with postpartum contraceptive use behaviors. Hence, this study aimed to investigate the time duration of the first modern contraceptive adoption and its individual-and community-level predictors among postpartum women in the Wolaita zone, South Ethiopia. A community-based prospective follow-up study was conducted among 1,292 postpartum women nested in 38 "Kebles" (clusters) using multistage-clustered sampling techniques. A multilevel Weibull regression model was employed to investigate predictors of time-to-method initiation after childbirth using STATA Version 14. Kaplan-Meier curve and Wilcoxon log-rank test were used to estimate time-to-modern contraceptive use across different variables. All variables with p-values <0.05 were considered for multivariate analysis. Adjusted time ratios (ATR) with 95 % CI were computed using Weibull accelerated failure time models. Of the respondents, 62% (95% CI: 59.1-64.5) had started the first modern contraception within a year after childbirth. The restricted mean survival time-to-postpartum modern contraceptive use was 6.28 months. Being a rural dweller (aTR: 1.44; 95% CI: 1.06-1.99) and living in the middle household wealth quintiles (aTR: 1.10; 95% CI: 1.02-1.19) predicted longer time duration to adopt first modern contraception by 44 and 10%, respectively. The women from the community with a high early marriage (aTR: 1.14; 95% CI: 1.01-1.28) took longer time to initiate modern postpartum methods. Furthermore, women who had no history of perinatal abuse took less time than those who had a history of abuse to start postpartum contraception (aTR: 0.71; 95% CI: 0.66-0.78). Rural residence, poor household wealth status, history of perinatal abuse, and a high rate of early marriage in the community are predicted to lengthen the time duration to start modern postpartum contraception. Thus, community-level women's empowerment, particularly among rural women and integration of intimate partner violence screening into family planning counseling throughout the continuum of care will likely to improve postpartum contraception timing.


Intraperitoneal adenovirus-mediated suicide gene therapy in combination with either topotecan or paclitaxel in nude mice with human ovarian cancer.
A mouse model of human ovarian cancer was used to investigate the effect of adenovirus-mediated thymidine kinase gene therapy (gt) in combination with chemotherapy. One hundred sixty female CD-1 nu/nu mice were injected intraperitoneally with Ov-ca-2774 cells. Onset of intraperitoneal treatment with either topotecan (6 or 12 mg/kg) or paclitaxel (18 or 36 mg/kg) was on day 4 or 8 and was repeated once after 4 days. Animals scheduled for gt received intraperitoneal application of adv/rsv-tk 1 day prior to chemotherapy and were subsequently treated with ganciclovir (gcv; 10 mg/kg, every 12 hours for 6 days). Survival was chosen as study endpoint. Whereas tumor burden had hardly any effect on survival, the lower dose of either cytotoxic agent was seen to be more effective than the higher one. In the topotecan group, an interaction between topotecan and gt was present. Survival was best for animals treated with low dose of topotecan only, the addition of gt reduced survival time significantly. With the higher dose, gt did not affect survival time. With paclitaxel, only slight effects of gt on the survival times were seen. Due to treatment toxicity, this animal model may be problematic for the evaluation of gt and chemotherapy combinations. The effect of dose varied strongly with time. Mice treated with high-dose chemotherapy had a substantially increased risk of dying in the time period following application, whereas this advantage of the lower dose disappeared later.


A new SPRING in lipid metabolism.
The SREBP transcription factors are master regulators of lipid homeostasis owing to their role in controlling cholesterol and fatty acid metabolism. The core machinery required to promote their trafficking and proteolytic activation has been established close to 20 years ago. In this review, we summarize the current understanding of a newly identified regulator of SREBP signaling, SPRING (formerly C12ORF49), its proposed mechanism of action, and its role in lipid metabolism. Using whole-genome functional genetic screens we, and others, have recently identified SPRING as a novel regulator of SREBP signaling. SPRING is a Golgi-resident single-pass transmembrane protein that is required for proteolytic activation of SREBPs in this compartment. Mechanistic studies identified regulation of S1P, the protease that cleaves SREBPs, and control of retrograde trafficking of the SREBP chaperone SCAP from the Golgi to the ER as processes requiring SPRING. Emerging studies suggest an important role for SPRING in regulating circulating and hepatic lipid levels in mice and potentially in humans. Current studies support the notion that SPRING is a novel component of the core SREBP-activating machinery. Additional studies are warranted to elucidate its role in cellular and systemic lipid metabolism.


Bilateral ocular shotgun injury.
We retrospectively studied 14 patients with bilateral ocular shotgun injury in order to determine overall visual prognosis and factors affecting individual prognosis. Although only eight of 28 eyes (29%) in this series recovered visual acuity of 20/100 or better, six of 14 patients (43%) recovered at least 20/100 and eight of 14 patients (57%) recovered visual acuity of at least 20/400. Tissue destruction in the form of severe ocular disorganization or direct injury of optic nerve or macula was the primary limiting factor to visual recovery in 16 of 20 eyes (80%) not recovering to 20/100, while retinal detachment was the limiting factor in only four of these 20 eyes (20%). While extensive ocular disorganization, direct optic nerve or macular injury, no light perception on initial examination, and multiple pellet injuries were predictive of poor outcome, retinal detachment and double perforating injury were not.


Energy Metabolism during Anaerobic Methane Oxidation in ANME Archaea.
Anaerobic methane oxidation in archaea is often presented to operate via a pathway of "reverse methanogenesis". However, if the cumulative reactions of a methanogen are run in reverse there is no apparent way to conserve energy. Recent findings suggest that chemiosmotic coupling enzymes known from their use in methylotrophic and acetoclastic methanogens-in addition to unique terminal reductases-biochemically facilitate energy conservation during complete CH4 oxidation to CO2. The apparent enzyme modularity of these organisms highlights how microbes can arrange their energy metabolisms to accommodate diverse chemical potentials in various ecological niches, even in the extreme case of utilizing "reverse" thermodynamic potentials.


Prolonged-efficacy of bisphosphonate in postmenopausal women with osteoporosis and chronic liver disease.
Osteoporosis is present often in postmenopausal women. The aim of this retrospective cohort study is to assess the cumulative appearance incidence and predictive factors for bone fracture in postmenopausal women with osteoporosis and chronic liver disease. The patients were 80 postmenopausal women with osteoporosis and chronic liver disease due to hepatitis virus B or C. These patients were given cyclic etidronate therapy within 3 months after diagnosis of osteoporosis (etidronate-group). Another 400 postmenopausal women with osteoporosis and chronic liver disease were selected as controls (control group). Patients in control group were matched 1:5 with etidronate-group for age. Patients in control group were not given any drugs after diagnosis of postmenopausal osteoporosis. The mean observation period was 8.1 years. Four patients in the etidronate-group and 46 in control group developed bone fracture. The 10th year cumulative appearance rates of bone fracture were 4.9% in etidronate-group and 13.8% in control group. Cox regression model showed that the appearance rate of bone fracture decreased with statistical significance in the following cases: (1) patients <65 years (P<0.001), (2) patients with serum albumin level of >or=3.5 g/dl (P=0.003), and (3) patients treated with etidronate (P=0.020). The cumulative survival rate after bone fracture was 82.2% at the second year, and 57.6% at the fifth year. The present study suggests that a serum albumin level of >or=3.5 g/dl and cyclic etidronate treatment reduce the appearance of bone fracture.


A two-year prospective follow-up study of the outcome after surgery in patients with slipped lumbar disk operated upon for the first time.
57 patients who were operated upon for the first time for slipped lumbar disk have been investigated in a prospective blind follow-up design. In both the preoperative and postoperative evaluation objective as well as subjective conditions have been considered, and the surgeons have not re-examined the patients. There is a 100% follow-up of the patients. We found that the following preoperative conditions are associated with surgical outcome, 6 and 24 months postoperatively: Medical parameters like statement of pain and surgical findings; social parameters such as being employed, duration of education, and whether you get sufficient social support from family and friends; duration of sick-leave, actions for damages, and number of life events. Psychological parameters such as pain drawing and the MMPI-scales: F, K, Hs, D, Hy, Pa, Pt, Sc, Ma, and Ad. In the statistical analysis multiple linear regression analysis is used, which allows evaluation of the different parameters compared with each other. It is found that conditions such as being employed, increase of the MMPI-scale Ad, alone could explain the 42% difference in surgical outcome. Good outcome is correctly predicted in 88% of the cases with observed good outcome. Poor outcome is correctly predicted in 54% of the cases with observed poor outcome.


Label-Free Quantitative Proteomics in Plant.
Label-free quantitation (LFQ) proteomics, mainly based on the extraction of the peptide (precursor) intensity at the MS1 (mass spectrum 1) level, enables to quantify the relative amount of the proteins among samples. In an LFQ proteomics study, all samples are scanned individually on an advanced mass spectrometer and the chromatographic features of each run are extracted to generate consensus patterns among various runs in the experiment. Here, we describe the LFQ proteomics experimental protocol adapted for plant research, such as plant iron homeostasis.


[Attention-deficit hyperactivity disorder: risk factors, protective factors, health supply, quality of life. A brief review].
Attention-deficit hyperactivity disorder (ADHD) is a chronic behavioural disorder diagnosed in 4.8 % of German children and adolescents. Although many studies indicate primarily a neurobiological etiology, the disorder cannot be diagnosed on the basis of specific markers. The principal aspect of diagnosis is the experienced clinician who must also take the differentiation of other behavioural disorders into account. In addition to inheritance, other known risk factors are nicotine exposition in pregnancy, adverse psychosocial conditions and birth complications. Protective factors are cognitive abilities, positive social contacts, and early treatment. The necessary structures in community support are developing; however, substantial enhancement is needed. Studies on quality of life indicate that ADHD should not be reduced to core symptoms since affected children are impaired in almost all areas of daily life.


Withdrawal of hospital outpatient treatments in severe diseases due to unacceptable toxicity: A retrospective study from the register of patients and treatments.
To retrospectively analyse hospital outpatient treatment (HOT) withdrawal due to unacceptable toxicity at our hospital. Information regarding unacceptable toxicity leading to treatment withdrawal was recorded. HOT interruptions because of unacceptable toxicity were identified from the Register of Patients and Treatments (RPT) (January 2014 to December 2017). Information regarding the demographic and clinical characteristics of patients, adverse drug reactions (ADRs) and drug treatments was retrieved from electronic health records. Causality and previous knowledge of ADRs were assessed according to the Spanish Pharmacovigilance System algorithm. Information regarding HOT risk management plans (RMPs) and their classification as inverted black triangle medicines was obtained from the European Medicines Agency (EMA). HOTs were withdrawn due to unacceptable toxicity in 136 (1.5%) registries corresponding to 135 (1.7%) patients. Fifty-one different HOTs (38.6% of those registered) were involved in 240 ADR/HOT pairs: 24 (47%) were additional monitoring medicines and 37 (72.5%) were EMA RMPs. The most frequent medicines involved in ADRs were lenalidomide (30, 12.5%) (mainly neutropenia, thrombocytopenia and bicytopenia), bevacizumab (19, 7.9%) (mainly venous and pulmonary thromboembolism) and sunitinib (13, 5.4%) (mainly thromboembolic events, diarrhoea and worsening of chronic renal failure). Cytopenia (40, 17.3%), diarrhoea (15, 6.5%), asthenia (9, 3.9%) and neuropathy (6, 2.6%) were the most frequent ADRs. All ADRs were severe, 10 (6 patients) had been poorly described or were unknown and only 9 (5 patients) had been reported by spontaneous notification. Valuable information regarding severe and unknown ADRs was obtained from the RPT. Such registers are useful tools to complement spontaneous ADR notifications.


Overall treatment time in advanced cervical carcinomas: a critical parameter in treatment outcome.
To search for possible influence of overall treatment time on the clinical outcome of advanced cervical carcinomas treated with radiation alone. Three hundred and eighty-six patients with Stage IIB and III cervical carcinomas treated with external radiation and intracavitary curietherapy between 1973 and 1983 were entered in the study. A multivariate analysis was carried out on data concerning these patients to determine whether overall treatment time was a prognostic factor. Overall treatment time and blood transfusions during treatment were the two most highly significant factors in the multivariate analysis. Loss of local control and overall survival, when treatment exceeded 52 days, was approximately 1% per day in both cases. These results suggest that overall treatment time might be a highly significant prognostic factor in the treatment outcome of advanced cervical carcinomas. Prospective randomized studies are strongly warranted to confirm this hypothesis.


MR-guided biopsies of lesions in the retroperitoneal space: technique and results.
The purpose of this study was to evaluate the safety and precision of MRI-guided biopsies of retroperitoneal space-occupying tumors in an open low-field system. In 30 patients with indistinct retroperitoneal tumors [paraaortic lesion (n=20), kidney (n=2), suprarenal gland (n=3) and pancreas (n=5)] MR-guided biopsies were performed using a low-field system (0.2 T, Magnetom Concerto, Siemens, Germany). For the monitoring of the biopsies T1-weighted FLASH sequences (TR/TE=160/5 ms; 90 degrees ) were used in all patients and modified FLASH sequences (TR/TE=160/13 ms; 90 degrees ) in ten patients. After positioning of the needle in the tumors 114 biopsy specimens were acquired in coaxial technique with 16-gauge cutting needles (Somatex, Germany). The biopsies were successfully performed in all patients without vascular or organ injuries. The visualization of the aortic blood flow with MRI facilitated the biopsy procedures of paraaortic lesions. The size of the lesions ranged from 1.6 to 7.5 cm. The median distance of the biopsy access path was 10.4 cm. Adequate specimens were obtained in 28 cases (93.3%) resulting in a correct histological classification of 27 lesions (90%). In conclusion, MR-guided biopsies of retroperitoneal lesions using an open low-field system can be performed safely and accurately and is an alternative to CT-guided biopsies.


The slow force response to stretch in atrial and ventricular myocardium from human heart: functional relevance and subcellular mechanisms.
Mechanical load is an important regulator of cardiac force. Stretching human atrial and ventricular trabeculae elicited a biphasic force increase: an immediate increase (Frank-Starling mechanism) followed by a further slow increase (slow force response, SFR). In ventricle, the SFR was unaffected by AT- and ET-receptor antagonism, by inhibition of protein-kinase-C, PI-3-kinase, and NO-synthase, but attenuated by inhibition of Na+/H+- (NHE) and Na+/Ca2+ exchange (NCX). In atrium, however, neither NHE- nor NCX-inhibition affected the SFR. Stretch elicited a large NHE-dependent [Na+]i increase in ventricle but only a small, NHE-independent [Na+]i increase in atrium. Stretch-activated non-selective cation channels contributed to basal force development in atrium but not ventricle and were not involved in the SFR in either tissue. Interestingly, inhibition of AT receptors or pre-application of angiotensin II or endothelin-1 reduced the atrial SFR. Furthermore, stretch increased phosphorylation of atrial myosin light chain 2 (MLC2) and inhibition of myosin light chain kinase (MLCK) attenuated the SFR in atrium and ventricle. Thus, in human heart both atrial and ventricular myocardium exhibit a stretch-dependent SFR that might serve to adjust cardiac output to increased workload. In ventricle, there is a robust NHE-dependent (but angiotensin II- and endothelin-1-independent) [Na+]i increase that is translated into a [Ca2+]i and force increase via NCX. In atrium, on the other hand, there is an angiotensin II- and endothelin-dependent (but NHE- and NCX-independent) force increase. Increased myofilament Ca2+ sensitivity through MLCK-induced phosphorylation of MLC2 is a novel mechanism contributing to the SFR in both atrium and ventricle.


Morphological recovery of hippocampal pyramidal neurons in the adult rat exposed in utero to ethanol.
Reduced numbers of dendritic spines on the secondary apical dendritic branches and basilar dendrites of CA1 and CA3 pyramidal neurons were observed in ethanol-treated rats during embryonic life aged 15 days when compared with age-matched controls. However, differences were no longer present at the age of 90 days. These results suggest that recovery of some morphological parameters of pyramidal hippocampal neurons may occur in rats exposed in utero to ethanol.


Intracardiac ultrasonic suture welding for knotless mitral valve replacement.
The difficulty in tying multiple knots with endoscopic instruments constitutes a technical obstacle to the development of closed-chest valve surgery. The following set of experiments was undertaken to ascertain the in-vivo feasibility of using an intracardiac ultrasonic welding device for knotless suture fixation during mitral valve replacement (MVR). Five adult sheep weighing 48-52 kg underwent MVR with a commercially available mechanical prosthesis, using pledgetted interrupted polypropylene sutures. An ultrasonic suture welder designed for intracardiac use was used to adjust suture tension and fuse strands together without knots. Echocardiographic assessment of the mitral prosthesis was carried out at baseline and after maintenance of supraphysiologic arterial pressures for 60 min. Subsequently, the animals' explanted hearts were assessed under sustained left ventricular (LV) pressurization to 180 mmHg in an ex-vivo pressure-loop system. MVR was successfully performed in all animals and welds reliably completed in less than 1 s. One sheep could not successfully be weaned off cardiopulmonary bypass; however, a normal prosthetic valve implant was confirmed at post-mortem examination. Echocardiographic assessment prior to and during LV pressurization revealed normal seating and function of the prosthesis in all cases. At post-mortem examination all valves were adequately implanted, suture tails laid flat on the surface of the prosthesis' sewing ring, welded suture strands were intact and accurately point-fused together, and no evidence of perivalvular leak was found around any of the prostheses despite sustained LV pressurization. This new modality proved reliable in an acute sheep model of MVR and could constitute a promising avenue towards facilitation of total endoscopic valve procedures in humans.


Constructing conformational library for amyloid-β42 dimers as the smallest toxic oligomers using two CHARMM force fields.
The study of amyloid-β (Aβ) dimers as the smallest toxic aggregates in the human brain suffering from Alzheimer's disease is of great interest. The structural characterization of the dimers, which is important to rationally design inhibitors for Aβ dimerization, is limited by the low stability of these species and their high tendency to aggregate into protofibrils and amyloid fibrils. Therefore, an efficient sampling method is needed for the computational study of the Aβ dimers. In this regard, we build a conformational library of the Aβ42 dimers by a new computational protocol; the blockwise excursion sampling (BES); with the CHARMM27 and CHARMM36m force fields. The CHARMM27 overestimates helix content and underestimates β-sheet content, while secondary structure content for the dimers sampled by the CHARMM36m force field is in reasonably consistent with the circular dichroism data. The CHARMM36m force field also generates more Aβ42 dimers in line with experimentally measured collision cross sections values relative to the CHARMM27 force field. Our results demonstrate that the BES is an efficient protocol for fast generating a heterogeneous conformational library of the Aβ42 dimers in agreement with experimental data. Having a reliable structural library for the Aβ42 dimers is very important to identify binding "hot spots" of the dimers versus potential drug candidates using ensemble docking approach.


Graves' disease presenting as bi-ventricular heart failure with severe pulmonary hypertension and pre-eclampsia in pregnancy--a case report and review of the literature.
Graves' disease, a well-known cause of hyperthyroidism, is an autoimmune disease with multi-system involvement. More prevalent among young women, it appears as an uncommon cardiovascular complication during pregnancy, posing a diagnostic challenge, largely owing to difficulty in detecting the complication, as a result of a low index of suspicion of Graves' disease presenting during pregnancy. Globally, cardiovascular disease is an important factor for pregnancy-related morbidity and mortality. Here, we report a case of Graves' disease detected for the first time in pregnancy, in a patient presenting with bi- ventricular heart failure, severe pulmonary hypertension and pre- eclampsia. Emphasis is placed on the spectrum of clinical presentations of Graves' disease, and the importance of considering this thyroid disorder as a possible aetiological factor for such a presentation in pregnancy. A 30-year-old Bangladeshi-Bengali woman, in her 28th week of pregnancy presented with severe systemic hypertension, bi-ventricular heart failure and severe pulmonary hypertension with a moderately enlarged thyroid gland. She improved following the administration of high dose intravenous diuretics, and delivered a premature female baby of low birth weight per vaginally, twenty four hours later. Pre-eclampsia was diagnosed on the basis of hypertension first detected in the third trimester, 3+ oedema and mild proteinuria. Electrocardiography revealed sinus tachycardia with incomplete right bundle branch block and echocardiography showed severe pulmonary hypertension with an estimated pulmonary arterial systolic pressure of 73 mm Hg, septal and anterior wall hypokinesia with an ejection fraction of 51%, grade I mitral and tricuspid regurgitation. Thyroid function tests revealed a biochemically hyperthyroid state and positive anti- thyroid peroxidase antibodies was found. (99m)Technetium pertechnetate thyroid scans demonstrated diffuse toxic goiter as evidenced by an enlarged thyroid gland with intense radiotracer concentration all over the gland. The clinical and biochemical findings confirmed the diagnosis of Graves' disease. Graves' disease is an uncommon cause of bi-ventricular heart failure and severe pulmonary hypertension in pregnancy, and a high index of clinical suspicion is paramount to its effective diagnosis and treatment.


Percutaneous absorption, blood levels, and urinary excretion of resorcinol applied topically in humans.
The absorption and metabolic disposition of 2% resorcinol applied topically in a hydroalcoholic vehicle was determined in three human subjects. The drug penetrated the skin at a rate of 0.37 micrograms/cm2/hour. After 2 weeks of bid application of 800 mg resorcinol to about 30% of body surface of each subject, an average of 1.64% of the dosage was being excreted in 24-hour urine specimens as the glucuronide or as the sulfate conjugate. There was no resorcinol in blood drawn at weeks 1, 2, 3, and 4, or nor were there any abnormalities in thyroid function or blood chemistries at weeks 2, 3, and 4. Resorcinol (2%) appears safe for topical use in humans.


Cutaneous rhinosporidiosis in a patient of lepromatous leprosy--a case report.
A rare coincidence of cutaneous Rhinosporidiosis and Lepromatous leprosy is reported. The clinical course of the cutaneous nodules simulated the feature of certain histoid nodule with ulceration.


[Correction of protein and water-electrolyte metabolism disorders in patients with unformed fistulas of the small intestine].
When treating 25 patients with the non-formed small intestinal fistulas, the use of alvesin "Novy" in the parenteral nutrition contributed to more intensive and effective correction of disorders in the protein and water-electrolyte metabolism as compared to that with the use of protein hydrolysates.


Safety and effectiveness of a Patient Blood Management (PBM) program in surgical patients--the study design for a multi-centre prospective epidemiologic non-inferiority trial.
Preoperative and hospital-acquired anaemia is common among surgical patients. It is associated with an increased risk of morbidity and mortality and a strong risk factor for allogeneic blood transfusions with their own inherent risks. Patient Blood Management (PBM) concepts aim to increase and preserve autologous erythrocyte volume and to optimise haemotherapy. They thus have great potential to benefit patients. This prospective, multi-centre clinical trial tests the hypothesis that PBM programs are safe and effective in the care of adult surgical patients. Primary outcome is a composite endpoint of adverse events and in-hospital mortality. This trial will determine whether the implementation of a PBM program is safe and effective in terms of clinical outcome compared to a pre-implementation cohort. This trial is registered at www.clinicaltrials.gov (NCT01820949).


Efficacy and Safety of a Topical Botanical in Female Androgenetic Alopecia: A Randomized, Single-Blinded, Vehicle-Controlled Study.
Androgenetic alopecia (AGA) in females is a difficult to treat skin disorder. A novel topical botanical lotion has been approved for its treatment. It acts by increasing Bcl-2, perifollicular Langerhans and mast cells, and perifollicular collagen. The aim of this study was to evaluate the efficacy and safety of this lotion in females. Forty women with AGA were randomized to apply the active lotion or placebo, twice daily for 24 weeks. Subjects were evaluated at 0, 12, and 24 weeks by clinical examination, photographic documentation, quality of life evaluation (DLQI), and trichogram (anagen to telogen ratio). The clinical evaluation demonstrated an increased hair density in the intervention group (great improvement in 7.7$, moderate in 88.5$, and stable in 3.8$). The self-assessment score increased from 4.5 to 6.0 (24 weeks), and the DLQI improved from 4 to 3 in the intervention group (p < 0.001). The mean anagen to telogen ratio in the intervention group was 2.1, 3.9, and 6.0 at 0, 12, and 24 weeks, respectively, whereas in the control group it was 2.2, 3.8, and 3.3, respectively. The new topical botanical lotion showed remarkable efficacy, with a high degree of patient satisfaction and improvement of their quality of life.


Chemical bases for medicinal plant use in Oaxaca, Mexico.
Fifty-eight medicinal plants used for the management of reproduction and the treatment of women's reproductive health problems in an indigenous community in southern Mexico are described. The efficacy of these plants is assessed according to both community members' understandings of the therapeutic effects they seek and the standards of conventional Western medicine. The majority of the plants contain chemicals which would appear to enable them to accomplish their intended effects in either or both the popular and the conventional medical systems.


Light-induced movement of magnesium ions in intact chloroplasts. Spectroscopic determination with Eriochrome Blue SE.
The metallochromic indicator Eriochrome Blue SE was used to measure light-induced internal movement of Mg2+ in intact chloroplasts. By dual-wave-length spectroscopy (measuring wavelength 554 nm, reference 592 nm) a light-induced, dark-reversible absorbance increase of Eriochrome Blue in samples of isolated intact chloroplasts was observed. The light/dark difference spectrum of Eriochrome Blue between 550 and 590 nm (reference wavelength 562 nm) indicated that this absorbance increase was caused by an increased concentration of free Mg2+ in a neutral or slightly alkaline chloroplast compartment. The signal was seen only with intact, but not with broken, envelope-free chloroplasts, which had lost most of their divalent cations. This is interpreted to show that the indicator responds to an increase of Mg2+ concentration in the chloroplast stroma, which represents an efflux of Mg2+ from the intra-thylakoid space caused by light-dependent proton pumping. As calculated from corrected values of the absorbance increase of Eriochrome Blue, the light-induced internal release of Mg2+ was close to 100 nequiv per mg chlorophyll at pH 7.6 and 250 nequiv at pH 7.1. This corresponds to a light-dependent increase in the concentration of free Mg2+ in the stroma of about 2 and 5 mM, respectively.


Direct identification of Leishmania species in biopsies from patients with American tegumentary leishmaniasis.
Accurate identification of Leishmania species is important for monitoring clinical outcome, adequately targeting treatment, and evaluation of epidemiological risk in tegumentary leishmaniasis. This is especially the case in regions where several species coexist and for travel medicine where the geographical source of infection is not always obvious. Species identification presently depends on parasite isolation, which is not very sensitive and not necessarily representative of parasites actually present in human tissues. We evaluated a polymerase chain reaction (PCR) assay combining amplification of the gp63 genes and restriction fragment length polymorphism (RFLP) analysis (gp63 PCR-RFLP) for direct Leishmania species-identification in tissues collected from Peruvian patients in 1999. By comparison with a kinetoplast DNA-based PCR, our PCR assay showed a detection sensitivity of 85%. Three species were encountered among patient samples, Leishmania (Viannia) braziliensis, L. (V.) peruviana and L. (V.) guyanensis, and their frequency and geographical distribution corresponded to earlier epidemiological studies of leishmaniasis in Peru. However, unexpected results raised questions about (i) the contribution of human migration to the emergence of new foci of given species, (ii) the pathogenicity of some species, and (iii) the frequency of mixed or hybrid infections.


Combined use of anterior and posterior surgery for adult scoliosis.
The two-staged anteroposterior approach is the indicated surgical procedure for many patients with adult spine deformities as described in this article. These surgeries are not easily performed. The surgeon must have excellent knowledge of anatomy as well as expertise in performing these procedures in order to obtain maximum correction, stabilization of the spine, and minimize complications.


Inspiratory muscle training to reduce risk of pulmonary complications after coronary artery bypass grafting: a systematic review and meta-analysis.
Pulmonary complications occur in a substantial proportion of patients who undergo coronary artery bypass grafting. Inspiratory muscle training (IMT), a simple, well-tolerated physical therapy, has been proposed to reduce the risk of complications, but its efficacy remains controversial. Randomized controlled trials (RCTs) examining the influence of IMT on the risk of pulmonary complications after coronary artery bypass grafting were identified from PubMed, Embase, CENTRAL, CINAL, and Web of Science through March 2023. Data were meta-analyzed for the primary outcomes of pulmonary complications, defined as pneumonia, pleural effusion, and atelectasis; and in terms of the secondary outcomes of maximum inspiratory pressure, maximum expiratory pressure, length of hospitalization, 6 min walk test, and peak expiratory flow and other outcomes. Risk of bias and quality of evidence assessments were carried out using the RoB 2.0 and Grading of Recommendations Assessment, Development and Evaluation (GRADE) applied to primary outcomes of pulmonary complications. Data from eight RCTs involving 755 patients were meta-analyzed. IMT was associated with a significantly lower risk of postoperative pneumonia [relative risk (RR) 0.39, 95% confidence interval (CI) 0.25-0.62, P < 0.0001] and atelectasis (RR 0.43, 95% CI 0.27-0.67, P = 0.0002), but not pleural effusion (RR 1.09, 95% CI 0.62-1.93, P = 0.76). IMT was associated with significantly better maximum inspiratory pressure (preoperative: mean difference (MD) 16.55 cmH2O, 95% CI 13.86-19.24, P < 0.00001; postoperative: mean difference (MD) 8.99 cmH2O, 95% CI 2.39-15.60, P = 0.008) and maximum expiratory pressure (MD 7.15 cmH2O, 95% CI: 1.52-12.79, P = 0.01), and with significantly shorter hospitalization (MD -1.71 days, 95% CI -2.56 to -0.87, P < 0.001). IMT did not significantly affect peak expiratory flow or distance traveled during the 6 min walk test. The available evidence from medium and high quality trials suggests that IMT can significantly decrease the risk of pneumonia and atelectasis after coronary artery bypass grafting while shortening hospitalization and improving the strength of respiratory muscles. https://www.crd.york.ac.uk/prospero/, identifier: CRD42023415817.


Smoking and malignancy in sinonasal inverted papilloma.
The authors investigated clinical features of squamous cell carcinomas (SCC) arising in sinonasal inverted papillomas (IP) and risk factors responsible for their malignant transformation. Retrospective analysis. In total, 162 patients diagnosed with sinonasal IP and treated between 1998 and 2009 at Pusan National University Hospital were enrolled. Their demographic data, information about previous surgery, smoking history, treatment modalities, follow-up duration, recurrence, and presence of malignancy were reviewed retrospectively. Seventeen patients (10.5%) were diagnosed with SCC arising in sinonasal IPs. Among them, nine (9/162, 5.6%; 9/17, 52.9%) were diagnosed with synchronous malignancies and three (3/162, 1.8%; 3/17, 17.6%) were diagnosed with metachronous malignancies. In five cases (5/162, 3.1%; 5/17, 29.4%), we could not determine whether their malignancies were synchronous or metachronous. Among 53 smokers, 14 (26.4%) had malignant transformation, while only three (2.8%) in 109 nonsmokers had malignant transformation (Odds ratio = 12.7; P < .001). The mean follow-up in the 17 patients with malignancy was 47.0 months. Three patients did not receive surgical treatment and died of progression of SCC. Among the other 14 patients who underwent curative surgeries, four (28.6%) had recurrences, and their mean period to cancer recurrence was 6.3 months. Two of them died of progression of the cancer. Mean survival of the five patients who died was 14.0 months. They all belonged to T4 stage. Smoking history is associated with malignant transformation of sinonasal IP. It suggests that close follow-up be required in smokers with sinonasal IP in order not to overlook the malignant transformation. 2b.


Expression and purification of intracrine human FGF 11 and study of its FGFR-dependent biological activity.
Fibroblast growth factor 11 (FGF11) is one of intracrine FGFs (iFGFs), which function within cells. Unlike canonical FGFs, FGF11 remains intracellularly and plays biological roles in FGF receptor (FGFR)-independent manner. Here, we established an expression system of recombinant FGF11 proteins in E. coli and investigated whether the extracellular administration of FGF11 can activate cellular signaling. Human FGF11 has two isoforms, FGF11a and FGF11b, depending on the presence of nuclear localization sequences (NLSs) in the N-terminus. Because these two isoforms are unstable, we prepared an FGF11a-Mut by substituting three cysteine residues in the NLS with serine and FGF11b-ΔC with C-terminal truncation. The introduction of mutation in the NLS improved the solubility of FGF11 prepared from E. coli. Exogenous addition of FGF11b and FGF11b-ΔC to BALB3T3 increased cell proliferation, while FGF11a-Mut exerted no effect. FGF11b-ΔC showed higher cell proliferation activity and FGFR signaling than FGF11b. The cell-proliferating activities of FGF11b and FGF11b-ΔC were blocked by an FGFR1 inhibitor or a recombinant FGFR1, confirming the FGFR1-dependent extracellular activity of FGF11b. The analysis of circular dichroism suggested that the C-terminus of FGF11 has an α-helical structure, which may affect its interaction with FGFR1. These results suggest that the N-and C-terminus of recombinant FGF11 are involved in the activation of FGFR1. The above results provide novel insights into the function and mechanism of FGF11 that may aid the development of useful ligands for FGFR regulation.


High-performance BiVO4 photoanodes cocatalyzed with bilayer metal-organic frameworks for photoelectrochemical application.
In this work, we modified a BiVO4 photoanode with bilayer Fe-MOF and Ni-MOF as cocatalysts for the first time and obtained a highly efficient BiVO4 composite photoanode whose photocurrent density was increased by 2.7 times. The optimized BiVO4/Fe-MOF/Ni-MOF photoanode demonstrated a photocurrent density of 1.80 mA/cm2 at 1.23 V vs. a reversible hydrogen electrode (RHE). The onset potential of the BiVO4/Fe-MOF/Ni-MOF photoanode markedly decreased from 0.9 V to 0.69 V in comparison with the pure BiVO4 photoanode. It is speculated that Fe-MOF and Ni-MOF led to more reactive oxygen evolution sites and that the bilayer cocatalysts synergistically promoted the separation of photogenerated electron-hole pairs, which may be the influencing factor for the photoelectrochemical performance of the BiVO4/Fe-MOF/Ni-MOF photoanode being distinctively enhanced. Thus, this work sheds some interesting new light on the construction of a high-efficiency photoanode for photoelectrochemical applications.


Spatial distribution of dissolved Pb, Hg, Cd, Cu and As in the Bohai Sea.
Characteristics of the spatial distribution of selected dissolved heavy metals were analyzed during large scale surveys from August 12 to 25, 2003 in the Bohai Sea. Dissolved Pb was the only element with average concentrations higher than the grade-one sea water quality standard of China. The spatial distribution of dissolved Pb in surface water was similar to those of Cd, Cu and As, where the isopleths generally indicated decreasing values from the bays to the central areas. Only for Hg did the high concentrations not only appear in Liaodong Bay, Bohai Bay and Laizhou Bay, but also in the Central Area, viz. not only in inshore but also in offshore areas. Vertical distributions of dissolved Pb, Cd, Cu and As were largely uniform, while that of dissolved Hg increased with depth. We infer that the input of pollutants from land was the main influencing factor for the detected distribution patterns of dissolved heavy metals, followed by the dynamics of sea water, release from bottom sediments and biochemical processes. Comparing with historical data, average concentrations of dissolved heavy metals appear to decline in recent years.


Phenylephrine induces early and late cardioprotection through mitochondrial permeability transition pore in the isolated rat heart.
The aim of this study was to investigate the role of mitochondrial permeability transition pore (mPTP) in cardioprotection afforded by phenylephrine pretreatment in early and late phases. Rat hearts were isolated and perfused with Krebs buffer in Langendorff preparation and subjected to 30 min regional ischemia followed by 60 min of reperfusion. Phenylephrine as a selective α1-adrenoceptor agonist and atractyloside as a specific opener of the mPTP were used. Seven groups (n = 6) of rats were randomly studied: (I) control: surgical procedure was performed with no ischemia/reperfusion, (II) ischemia/reperfusion: hearts underwent regional ischemia/reperfusion, (III) early phenylephrine: phenylephrine (50 μM) was perfused for 5 min prior to ischemia/reperfusion, (IV) late phenylephrine: rats were treated with phenylephrine (10 mg/kg, i.p) 24 h prior to ischemia/reperfusion, (V) early phenylephrine+atractyloside: hearts were perfused with phenylephrine as in group III and then atractyloside (20 mM) 5 min before reperfusion for 20 min, (VI) late phenylephrine+atractyloside: hearts were treated with phenylephrine as in group IV and then received atractyloside (20 mM), 5 min before reperfusion for 20 min, (VII) atractyloside-IR group: hearts were perfused with atractyloside (20 mM) 5 min before reperfusion for 20 min. Compared with ischemia/reperfusion group, perfusion of phenylephrine in early and late phases decreased myocardial infarct size (% of ischemia zone), reduced creatine kinase-MB (CK-MB) in the coronary effluent, and improved cardiac function. Administration of atractyloside abolished cardioprotective effects of phenylephrine in both early and late phases and returned infarct size, CK-MB and cardiac function to levels as seen in ischemia/reperfusion group. These results suggest that administration of atractyloside as a specific opener of the mPTP abolishes phenylephrine-induced early and late cardioprotection in the isolated rat hearts.


Nisin and pediocin production on mussel-processing waste supplemented with glucose and five nitrogen sources.
Optimization of bacteriocin production by L. lactis subsp. lactis CECT 539 and Ped. acidilactici NRRL B-5627 on mussel-processing wastes. The concentrations of glucose and five nitrogen sources that optimize nisin and pediocin production were determined using a second order orthogonal factorial design. NH4Cl, glycine and glutamic acid were poor nitrogen sources. Enhanced pediocin and nisin productions were achieved in a medium supplemented with yeast extract or Bacto casitone. Mussel-processing wastes could be successfully used as a culture medium for bacteriocin production at low production cost. Average optimization led to a threefold increase in pediocin production (from 322 to 934 BU ml(-1)) and in nisin production (from 32 to 100 BU ml(-1)) when compared with the unsupplemented medium. For this reason, mussel-processing waste warrants further investigation due to its potential use as a cheap culture medium for upscaling bacteriocin production.


Perspectives in interventional electrophysiology in children and those with congenital heart disease: electrophysiology in children.
Recent developments in paediatric pacing and ablation of arrhythmia substrate have been characterised by adoption and modification of techniques used in adults. Infants, small children and those of all ages with congenital heart disease are a patient group with a higher risk profile needing a special approach. Current success rates for catheter ablation are high and major complication rates are low. Important issues with respect to long-term outcome include questions about coronary injury, long-term effects of radiation exposure and late recurrence. Non-fluoroscopic electro-anatomical mapping systems (3D systems), cryo-ablation and remote navigation are techniques recently improved such that it is possible to potentially reduce fluoroscopy and complications. Pacing in young children and congenital heart disease often warrants an epicardial approach to avoid embolism, venous occlusion and lead failure related to growth. Defibrillator and resynchronisation therapy are increasingly important tools to reduce mortality, although the indications are not as clear as in adult patients without congenital heart disease.


Factors in the outcome of transsphenoidal surgery for prolactinoma and non-functioning pituitary tumour, including pre-operative bromocriptine therapy.
Radical transsphenoidal surgery in 58 patients with large non-functioning pituitary tumours relieved pressure symptoms and disconnection hyperprolactinaemia without loss of pituitary function, and verified the diagnosis. Pre-operative bromocriptine did not cause any shrinkage of non-functioning tumours (n = 8), even up to 48 weeks. Thirty-two patients not given postoperative radiotherapy are being followed-up, and although two show minor CT scan evidence of tumour regrowth, for the others the delay in radiotherapy is enabling reproduction where required. In 20 patients with non-invasive macroprolactinomas radical surgery caused no loss of pituitary function but cured eight, of whom one has relapsed; none of eight invasive prolactinomas was cured by surgery. Pre-operative bromocriptine caused marked size reduction in seven of seven macroprolactinomas, but if continued beyond 6 weeks induced tumour fibrosis and uneven shrinkage which made surgery dangerous and unproductive. Selective transsphenoidal surgery relieved hyperprolactinaemia in 70% of patients with meso- (n = 15) or microprolactinoma (n = 24) usually without loss of pituitary function: the relapse rate was 1 per 88 patient years of follow-up. Invasive prolactinomas, and macroprolactinomas showing uneven shrinkage with a short (up to 4 weeks) course of bromocriptine should have radiotherapy rather than surgery, while the patients most suited to surgery are those with mesoprolactinomas, or some macroprolactinomas with compact intrasellar shrinkage after short-term bromocriptine. Microprolactinomas generally did not benefit from surgery as compared to conservative therapy. In none of the tumour groups were the surgical findings an accurate predictor of postoperative pituitary function.


Tamoxifen augments the innate immune function of neutrophils through modulation of intracellular ceramide.
Tamoxifen is a selective oestrogen receptor modulator widely used for the treatment of breast cancer. In addition to its activity as an oestrogen receptor agonist/antagonist, tamoxifen also modulates sphingolipid biosynthesis, which has been shown to play an important role in the regulation of neutrophil activity. Here, we find that tamoxifen stimulation enhances several pro-inflammatory pathways in human neutrophils, including chemotaxis, phagocytosis and neutrophil extracellular trap (NET) formation. The enhancement of NET production occurs via a ceramide/PKCζ-mediated pathway, and treatment with synthetic ceramide is sufficient to promote NET formation. Pretreatment of human neutrophils with tamoxifen boosts neutrophil bactericidal capacity against a variety of pathogens in vitro and enhances clearance of the leading human pathogen methicillin-resistant Staphylococcus aureus in vivo. Our results suggest that tamoxifen, and the lipid signalling pathways it modulates, merit further exploration as targets for boosting host innate immune function.


Molecular characterisation and analysis of bovine rotavirus strains circulating in Ireland 2002-2004.
One hundred and two faecal samples were collected from calves diagnosed with rotavirus infection, in the southern region of Ireland, from 2002 to 2004. Ninety one percent (n=93) were confirmed positive for rotavirus, using latex agglutination and enzyme linked immunosorbent assay (ELISA) methods. Determination of the G- and P-types was carried out using nested reverse transcriptase polymerase chain reaction (nRT-PCR). G6 was the most prevalent genotype, accounting for 80.6% (75/93), G10 accounted for 6.5% (6/93) and G6G10 mixed types accounted for 9.7% (9/93) of the collection. Rotavirus in three of the samples (3.2%) could not be characterised with any of the five G-specific primers used in this study. A subset of the positive samples (n=54) was examined for their P-type specificities, P[5] and P[11] accounted for 77.8% (42/54), and 9.3% (5/54), respectively. One P[1] genotype (1.9%) was found in the collection. P[5] and P[11] mixed genotypes accounted for 11% (6/54) of the study. The genotypes corresponded to the UK-like strain (G6P[5]) 57.4%, KN4-like strain (G6[P11]) 7.4%, B223-like strain (G10P[11]) and NCDV-like strain (G6P[1]) 1.9% each. The unusual combination of G10P[5] accounted for 7.4%, with mixed infections G6+G10P[5] and G6P[5]+P[11] representing 13% and 11%, respectively. This is the first time that the G- and P-types of bovine rotaviruses (BRVs) have been determined in Ireland, and this study contributes to a better understanding of the epidemiology of such viruses circulating in Ireland.


Borderlands in the diagnosis of regional enteritis: trends in overdiagnosis and value of therapeutic trial.
Our regional experience in the state of Connecticut indicates that Crohn's disease is being overdiagnosed. Six patients with disorders mimicking regional enteritis are presented, one of whom had an atypical clinical course and the remainder had atypical therapeutic responses. The radiologist should be aware of clinical responses and make reassessments if necessary, in order not to overlook surgically treatable conditions.


Corrigendum: Relevance of RNA N6-methyladenosine regulators for pulmonary fibrosis: Implications for chronic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis.
[This corrects the article DOI: 10.3389/fgene.2022.939175.].


Operative technique for repair of tracheoinnominate artery fistula.
Tracheoinnominate artery fistula is a relatively rare but highly lethal complication for long-term tracheostomy patients that occurs with an estimated incidence of 1 out of every 150 tracheostomies performed. Appropriate operative technique during tracheostomy and meticulous postoperative care usually prevent this devastating lesion. When tracheoinnominate fistula is suspected, immediate evaluation under general anesthesia in the operating suite, followed by prompt thoracotomy and repair, is essential for the survival of these patients.


Settling on leaves or flowers: herbivore feeding site determines the outcome of indirect interactions between herbivores and pollinators.
Herbivore attack can alter plant interactions with pollinators, ranging from reduced to enhanced pollinator visitation. The direction and strength of effects of herbivory on pollinator visitation could be contingent on the type of plant tissue or organ attacked by herbivores, but this has seldom been tested experimentally. We investigated the effect of variation in feeding site of herbivorous insects on the visitation by insect pollinators on flowering Brassica nigra plants. We placed herbivores on either leaves or flowers, and recorded the responses of two pollinator species when visiting flowers. Our results show that variation in herbivore feeding site has profound impact on the outcome of herbivore-pollinator interactions. Herbivores feeding on flowers had consistent positive effects on pollinator visitation, whereas herbivores feeding on leaves did not. Herbivores themselves preferred to feed on flowers, and mostly performed best on flowers. We conclude that herbivore feeding site choice can profoundly affect herbivore-pollinator interactions and feeding site thereby makes for an important herbivore trait that can determine the linkage between antagonistic and mutualistic networks.


The causal association between genetically regulated 25OHD and chronic obstructive pulmonary disease: A meta-analysis and Mendelian randomization study.
Backgrounds and objectives: Chronic obstructive pulmonary disease (COPD) is a multifactorial disease under genetic control. We present a meta-analysis to examine the associations of vitamin D binding protein (VDBP) gene rs7041 polymorphism with the risk of COPD and changes in circulating 25OHD concentrations. Methods: A literature search, quality assessment, and data extraction were conducted independently by two investigators. Data are expressed as odds ratio (OR) or weighted mean difference (WMD) with a 95% confidence interval (CI). The inverse variance weighted method (IVW) in R (version 1.1.456) was applied to calculate the Mendelian randomization coefficient. Results: A total of 13 articles with 3,667 participants were meta-analyzed. The rs7041-GT genotype was associated with a 49% reduced COPD risk (OR: 0.51, 95% CI: 0.30 to 0.88, p = 0.014) compared to the rs7041-TT genotype. Carriers of the rs7041-GT genotype had significantly higher concentrations of circulating 25OHD than those with the rs7041-TT genotype (WMD: 0.32 ng/ml, 95% CI: 0.09 to 0.55, p = 0.006). Under the assumptions of Mendelian randomization, and assuming a linear logistic relationship between circulating 25OHD and COPD, an inverse association was noted after using VDBP gene rs7041 polymorphism as an instrument (WMD: -2.07, 95% CI: -3.72 to -0.41, p = 0.015). There was a low probability of publication bias. Conclusion: We observed significant associations of VDBP gene rs7041 polymorphism with the risk of COPD and changes in circulating 25OHD concentrations. Importantly, we found a causal relationship between genetically regulated 25OHD concentrations and COPD risk.


The effect of triamcinolone acetonide on plasma glucose and ketone concentration and on the total entry rate of glucose in twin pregnant hypoglycaemic ketotic sheep.
Hypoglycaemic ketosis clinically resembling pregnancy toxaemia was induced by starvation in Clun Forest sheep pregnant with twins. Total glucose entry was measured by the continuous infusion of trace amounts of (2-3H) glucose before and after the induction of ketosis and 24 h after the intramuscular injection of the ketotic sheep with triamcinolone acetonide (0.5 mg/kg). The concentration of glucose in plasma fell significantly after the induction of ketosis and rose significantly after the injection of steroid. The total entry rate of glucose fell significantly after the induction of ketosis and rose, but no significantly, after steroid injection. It is suggested that the dose of steroid which was used may inhibit glucose utilisation by peripheral tissues. The induction of ketosis significantly reduced the duration of pregnancy but the steroid injection did not produce a significant additional effect.


Ultrasound-guided regional anesthesia: learning with an optimized cadaver model.
To date, there have been few studies of the simulation of ultrasound-guided regional anesthesia for teaching purposes. The present study aimed to evaluate the visibility of nerves and their adjacent structures, and the feasibility of the use of ultrasound-guided blocks in specially prepared cadavers to develop a new teaching model. Nerves of the brachial, lumbar, and sacral plexus were examined, and their visibility evaluated in 12 specially embalmed cadavers. Thereafter a needle was advanced under direct ultrasound guidance to target nerves, and selected blocks were imitated using saline. The model was evaluated with standardized questionnaires in two international workshops with 124 participants. The selected nerves were successfully identified in all cadavers. The typical ultrasound appearance of nerves and their adjacent structures was very similar to the echotexture of the living, and the spread of injected saline around nerves was comparable to that of local anesthetics used in live patients. 79 % of the participants completed the questionnaire and confirmed the value of this optimized teaching model. This cadaver model is a promising teaching tool for practicing both the visualization of nerves and the needle manipulation. Moreover, it is possible to simulate the interventional application and the spread of local anesthetics using saline. With the aim of maximizing the effectiveness of teaching, it is hoped that we, and others, may be able to establish the use of this kind of tool as a valuable adjunct to other models of teaching regional anesthesia.


Spatial localization of motion-defined and luminance-defined contours.
Thresholds for the vernier alignment of contours defined by luminance and coherent random-dot motion were measured. The luminance-defined contours were localized with a precision better than the receptor grain, while the motion-defined contours were localized more poorly than this limit. When motion-defined and luminance-defined targets were matched for dot density, vernier thresholds were equivalent at low densities. When the targets were also equated for perceived contrast, the vernier thresholds became equivalent at higher densities as well. These results suggest that the precision with which motion-defined contours are localized is contrast and sample limited. Next, the localization mechanism for motion-defined targets was investigated. Length summation limits were similar for motion-defined and luminance-defined targets, suggesting that these targets could be localized by a common mechanism. Vernier targets were then flanked by two additional bars. Motion-defined flanks interfered with the localization of motion-defined targets and luminance-defined flanks interfered with the localization of luminance-defined targets. However, motion-defined and luminance-defined bars did not interact to produce spatial interference. This result indicates that the mechanisms for localizing luminance-defined and motion-defined targets are independent. We suggest that parallel mechanisms govern the vernier localization of motion-defined and luminance-defined targets.


HIV prevention clinical trials' community engagement guidelines: inequality, and ethical conflicts.
In 2004 and 2005, the first clinical trials were launched to investigate the use of tenofovir for HIV prevention in Cambodia,Cameroon, Nigeria and Thailand. Controversies erupted over the ethical integrity of the research protocol. We reflect on the events that ledto the controversies and identified that scientific and ethical concerns raised by members of local communities at each of these sites wereerased by trialists, causing crisis that led to premature shut down the early PrEP trials. In the aftermath of these trials, the World HealthOrganisation, UNAIDS, and AVAC developed ethics guidelines intended to recognize the concerns as authentic, and developed guidelines toimprove researchers' engagement of communities in biomedical HIV prevention trial design and implementation. Our findings suggest thatthe ethics guidelines are limited in its ability to address power inequalities that leads to voice erasures and non-recognition of localcompetencies. Rather the ethical documents enabled trialists to gain a new sense of authority through the interpretations of ethical researchconduct enabling trialists regain power that can further entrench inequality and voice erasures. To address concerns with what seems anintractable problem, we suggested models of engagement for off-shored research may be the option.


Cell(s) of Origin of Langerhans Cell Histiocytosis.
Langerhans cell histiocytosis (LCH) is heterogeneous disease characterized by common histology of inflammatory lesions containing Langerin(+) (CD207) histiocytes. Emerging data support a model in which MAPK activation in self-renewing hematopoietic progenitors may drive disseminated high-risk disease, whereas MAPK activation in more differentiated committed myeloid populations may induce low-risk LCH. The heterogeneous clinical manifestations with shared histology may represent the final common pathway of an acquired defect of differentiation, initiated at more than one point. Implications of this model include re-definition of LCH as a myeloid neoplasia and re-focusing therapeutic strategies on the cells and lineages of origin.


Neighbourhood child population density as a proxy measure for exposure to respiratory infections in the first year of life: A validation study.
Assessing exposure to infections in early childhood is of interest in many epidemiological investigations. Because exposure to infections is difficult to measure directly, epidemiological studies have used surrogate measures available from routine data such as birth order and population density. However, the association between population density and exposure to infections is unclear. We assessed whether neighbourhood child population density is associated with respiratory infections in infants. With the Basel-Bern lung infant development study (BILD), a prospective Swiss cohort study of healthy neonates, respiratory symptoms and infections were assessed by weekly telephone interviews with the mother throughout the first year of life. Using population census data, we calculated neighbourhood child density as the number of children < 16 years of age living within a 250 m radius around the residence of each child. We used negative binomial regression models to assess associations between neighbourhood child density and the number of weeks with respiratory infections and adjusted for potential confounders including the number of older siblings, day-care attendance and duration of breastfeeding. We investigated possible interactions between neighbourhood child population density and older siblings assuming that older siblings mix with other children in the neighbourhood. The analyses included 487 infants. We found no evidence of an association between quintiles of neighbourhood child density and number of respiratory symptoms (p = 0.59, incidence rate ratios comparing highest to lowest quintile: 1.15, 95%-confidence interval: 0.90-1.47). There was no evidence of interaction with older siblings (p = 0.44). Results were similar in crude and in fully adjusted models. Our study suggests that in Switzerland neighbourhood child density is a poor proxy for exposure to infections in infancy.


Visual Acuity Improves in Children and Adolescents With Idiopathic Infantile Nystagmus.
Idiopathic infantile nystagmus is associated with reduced visual acuity. Recent work has linked extraocular muscle surgery to improvements in visual acuity through childhood but no work has reported long-term secular trends in visual acuity in infantile nystagmus. Our aim is to describe visual acuity changes for children and adolescents with idiopathic infantile nystagmus to allow comparison for future interventional studies. Retrospective chart review. Review of patients attending our center up to the age of 18 with a diagnosis of idiopathic infantile nystagmus and visual acuity measured using Snellen visual acuity. Patients provided informed consent. We observed improvements in best corrected visual acuity in 43 children and adolescents with idiopathic infantile nystagmus. Binocular best corrected visual acuity improved at a rate of -0.16 logarithm of the minimum angle of resolution (logMAR)/log year of age (P < 0.001), an improvement of 0.05 logMAR (half a Snellen line) as the age doubles. Intraclass correlation was 0.95 and interindividual correlation between visual acuity and age was significant (r = -0.24, P < 0.001). We describe a natural history of gradual improvement in binocular visual acuity in infantile nystagmus and provide a baseline against which future interventional work can be compared.


Feasibility and safety of ultra-fast track anesthesia for totally thoracoscopic closure of ventricular septal defect: A randomized controlled trial.
Ultra-fast channel anesthesia (UFTA) can reduce the dosage of opioid narcotic drugs, allow for a rapid postoperative extubation and reduce the harmful stress response during perioperative period. However, there has been limited information about the application of UFTA during thoracoscopic closure of ventricular septal defect (VSD). The aim of this study was to assess the feasibility and safety of UFTA technique in patients undergoing totally thoracoscopic closure of VSD. Seventy-eight patients were randomly divided into study (UFTA) and control (standard general anesthesia) group. Totally thoracoscopic closure of VSD was performed in all patients. Extubation in the study and control group was attempted in the operating room and the intensive care unit, respectively. All patients in the study group were extubated in the operating room immediately after surgery, but 2 (6.1%) required reintubation. All the control group patients were extubated after a period of mechanical ventilation (3.0 ± 3.7 h vs 0 h in the study group, p = 0.001) in the intensive care unit. The intensive care and hospital stays in the study group were shorter than in the control group (4.3 ± 2.5 vs 13.4 ± 4.4 h, p = 0.003, and 5.8 ± 0.8 vs 6.5 ± 1.2 d, p = 0.047). The total costs for the treatment in the study group was lower than in the control group (5264 ± 514 vs 4662 ± 461 US dollars, p = 0.02). UFTA and operating room extubation was feasible and safe in the majority of patients following totally thoracoscopic closure of VSD. This technique was associated with a shorter intensive care stay and lower overall costs for the surgical treatment.


A lesion of the patella: An unexpected location of Rosai-Dorfman disease: A case report.
Primary osseous Rosai-Dorfman disease (RDD) is a rare and benign disease that can pose diagnosis challenges. We report the case of a 29-year-old woman who presented with pain in her left patellar region for the past 6 months with no other clinical sign especially no lymphadenopathy associated. A surgical excision was done. Histopathology confirmed the diagnosis of a primary RDD patellar disease. The patient was followed up for 2 months without any recurrence. The aim of this study was to present a rare case of RDD in a patellar location and to review clinicopathological features, therapeutic modalities, evolutionary aspects and prognosis of a primary patellar RDD. The diagnosis of a primary osseous RDD without associated lymphadenopathy should be kept in mind when a sclero-lytic lesion is found. Excision of the lesion is the gold standard of the treatment.


Keratinophilic fungi isolated from the air at Pavia.
The presence of keratinophilic fungi was revealed by sampling the air of Pavia (Italy) from March 1981 to February 1982. The species isolated were: Chrysosporium indicum , Geomyces pannorum var. pannorum , Microsporum gypseum, Myceliophtora vellerea and Trichophyton terrestre . Several filamentous fungi tolerating high levels of cycloheximide were also recovered.


Sensitivity of chronically HIV-1 infected HeLa cells to electrical stimulation.
Use of combination anti-retroviral drug regimens including protease inhibitors dramatically decreased morbidity and mortality rates in HIV-1 infected individuals. However, such combination therapies appear to have many side effects, in addition to the emergence of resistant HIV-1 strains. Therefore, in this study we sought to elucidate novel therapeutic principles against HIV-1 infection. We examined the effects of electrical stimulation on both chronically HIV-1(LAI) infected HeLa cells (P6 HeLa/HIV-1(LAI)) and uninfected cells (P6 HeLa). Cells were cultured on an optically transparent electrode and application of potential at 1.0 V vs Ag/AgCl was performed over time periods ranging from 10 min to 60 min. Both P6 HeLa/HIV-1(LAI) and P6 HeLa cells were progressively damaged as the duration of electrical stimulation increased. However, P6 HeLa/HIV-1(LAl) cells were much more influenced by electrical stimulation than P6 HeLa cells. The difference in damage rate was most obvious at 30 min of electrical stimulation, with damaged cells accounting for about 87% and 4% of P6 HeLa/HIV-1(LAI) and P6 HeLa cells, respectively. After the application of potential for 20 min, the proliferation of P6 HeLa/HIV-1(LAI) cells was markedly inhibited, while the P6 HeLa cells proliferated to an extent similar to that of uninfected cells without application of potential. These results indicate that sensitivity to electrical stimulation is much higher in chronically HIV-1 infected cells than in uninfected cells. This could be considered as a useful new approach against HIV-1 infection.


Improved distal circulatory support for repair of descending thoracic aortic aneurysms.
Bleeding is a well-known problem when cardiopulmonary bypass with full systemic heparinization is used for distal support during aortic cross-clamping. The recent advent of heparin-coated cardiopulmonary bypass equipment prompted our review of 91 consecutive patients who underwent repair of descending thoracic and thoracoabdominal aortic aneurysms. Two different surgical techniques were used: 42 of 91 patients had simple aortic cross-clamping and rapid reanastomosis, whereas 49 of 91 had distal support using all heparin-coated perfusion equipment with low systemic heparinization (100 IU/kg body weight; activated coagulation time > 180 seconds). Baseline parameters, location (thoracoabdominal: 28/91; 31%), and type of aneurysm (ruptured: 14/91; 15%) were similar in both groups. Cross-clamp time was 37 +/- 22 minutes for support versus 29 +/- 13 minutes for simple clamping (p < 0.05). There were fewer revisions due to bleeding for support (1/49 patients; 2%) versus simple (4/42; 10%; p < 0.05) and fewer patients with impaired renal function requiring temporary hemofiltration for support (4/49 patients; 8%) versus simple (6/42; 14%). Hospital mortality was lower for support (5/49; 10%) versus simple (8/42; 19%). Transfusion requirements during operation were 3,732 +/- 3,458 mL for simple versus 3,392 +/- 2,058 mL for support (not significant). Chest tube drainage totaled 982 +/- 1,102 mL for simple versus 720 +/- 618 mL for support (not significant). The total volume requirements were 8,156 +/- 4,753 mL for simple versus 7,495 +/- 3,342 mL for support (not significant) during operation and 4,416 +/- 2,422 mL for simple versus 3,380 +/- 1,432 mL for support (p < 0.025) during the 24 hours after operation.(ABSTRACT TRUNCATED AT 250 WORDS)


The Safety and Efficacy of Mineralocorticoid Receptor Antagonists in Patients Who Require Dialysis: A Systematic Review and Meta-analysis.
Patients who require dialysis are at high risk for cardiovascular mortality, which may be improved by mineralocorticoid receptor antagonists (MRAs). Systematic review and meta-analysis of randomized controlled trials. Adults undergoing long-term hemodialysis or peritoneal dialysis with or without heart failure. Randomized controlled trials evaluating an MRA in dialysis and reported at least one outcome of interest. Spironolactone (8 trials) or eplerenone (1 trial) compared to placebo (7 trials) or standard of care (2 trials). Cardiovascular and all-cause mortality, hyperkalemia, serum potassium level, hypotension, change in blood pressure, and gynecomastia. We identified 9 trials including 829 patients. The overall quality of evidence was low due to methodologic limitations in most of the included trials. The relative risk (RR) for cardiovascular mortality was 0.34 (95% CI, 0.15-0.75) for MRA-treated compared with control patients. The RR for all-cause mortality was 0.40 (95% CI, 0.23-0.69). The RR for hyperkalemia for MRA treatment was 3.05 (95% CI, 1.21-7.70). Sensitivity analyses demonstrated wide variability in RRs for cardiovascular mortality, all-cause mortality, and hyperkalemia, suggesting further uncertainty in the confidence of the primary results. Trial quality and size insufficient to robustly and precisely identify a treatment effect. Given the uncertainty of both the benefits and harms of MRAs in dialysis, large high-quality trials are required.


Function-morphological investigations of fish inner ear otoliths as basis for interpretation of human space sickness.
In man, altered gravity may lead to a vestibular dysfunction causing space motion sickness. A hypothesis was developed, according to which asymmetric inner ear statoliths might be the morphological basis of space sickness. The animal model, fish, revealed further information: inner ear "stone" (otolith) growth is dependent on the amplitude and the direction of gravity, regulated by a negative feedback mechanism. The present study was focused on the question, where the regulation centre of adaptive otolith growth may be situated. Therefore, the vestibular nerve was unilaterally transected in neonate swordtail fish (Xiphophorus helleri). As growth marker, the calcium tracer alizarin-complexone was used. It was found that otolith growth had ceased on the operated head sides indicating that the brain is significantly involved in regulating otolith growth. About 2 weeks after nerve transection, otoliths had regained normal growth, probably due to nerve regeneration. Concerning fish, it has now to be tested, if this regeneration is affected by altered gravity, e.g. in a long-term experiment on the International Space Station. Regarding mammals, it has to be proved if asymmetric statoliths are the basis of kinetosis and whether or not the mammalian brain has an effect on statolith growth in the course of compensating altered gravity.


Application of a Small Molecule Radiopharmaceutical Concept to Improve Kinetics.
Recently, large molecules or nanoparticles are actively studied as radiopharmaceuticals. However, their kinetics is problematic because of a slow penetration through the capillaries and slow distribution to the target. To improve the kinetics, a two-step targeting method can be applied by using small molecules and very rapid copper-free click reaction. Although this method might have limitations such as internalization of the first targeted conjugate, it will provide high target-to-non-target ratio imaging of radiopharmaceuticals.


CERKL-Associated Retinal Dystrophy: Genetics, Phenotype, and Natural History.
To analyze the clinical characteristics, natural history, and genetics of CERKL-associated retinal dystrophy in the largest series to date. Multicenter retrospective cohort study. Forty-seven patients (37 families) with likely disease-causing CERKL variants. Review of clinical notes, ophthalmic images, and molecular diagnosis from 2 international centers. Visual function, retinal imaging, and characteristics were evaluated and correlated. The mean age at the first visit was 29.6 ± 13.9 years, and the mean follow-up time was 9.1 ± 7.4 years. The most frequent initial symptom was central vision loss (40%), and the most common retinal feature was well-demarcated areas of macular atrophy (57%). Seventy-seven percent of the participants had double-null genotypes, and 64% had electrophysiological assessment. Among the latter, 53% showed similar severity of rod and cone dysfunction, 27% revealed a rod-cone, 10% a cone-rod, and 10% a macular dystrophy dysfunction pattern. Patients without double-null genotypes tended to have fewer pigment deposits and included a higher proportion of older patients with a relatively mild electrophysiological phenotype. Longitudinal analysis showed that over half of the cohort lost 15 ETDRS letters or more in ≥ 1 eye during the first 5 years of follow-up. The phenotype of CERKL-retinal dystrophy is broad, encompassing isolated macular disease to severe retina-wide involvement, with a range of functional phenotypes, generally not fitting in the rod-cone/cone-rod dichotomy. Disease onset is often earlier, with more severe retinal degenerative changes and photoreceptor dysfunction, in nullizygous cases. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.


Converting case managers from MD/service to unit-based assignments: a before and after comparison.
An ongoing dilemma in acute care case management is whether to assign case managers to a unit or MD/Service-based assignment. There are strong logical arguments to be made on both sides of the decision. There are also strong political reasons why organizations opt for one or the other. This article describes one hospital's rationale and experience in converting from care manager assignments made on the basis of partnering with the MDs/Service, to serving both the point of care nursing unit and the physicians. Of note, the unit-based assignment structure has (1) saved 90 min a day in each care manager's time; (2) allowed care managers to help nursing better plan, pace, and trace care; (3) helped the hospital accommodate a 9% increase in admissions with an additional 140 more referrals to the Transitional Care Unit; and (4) ensured the consistent management of the observation level of care.


Interactions between tafenoquine and artemisinin-combination therapy partner drug in asexual and sexual stage Plasmodium falciparum.
The 8-aminoquinoline tafenoquine (TFQ), a primaquine derivative, is currently in late-stage clinical development for the radical cure of P. vivax. Here drug interactions between TFQ and chloroquine and six artemisinin-combination therapy (ACT) partner drugs in P. falciparum asexual stages and gametocytes were investigated. TFQ was mostly synergistic with the ACT-partner drugs in asexual parasites regardless of genetic backgrounds. However, at fixed ratios of 1:3, 1:1 and 3:1, TFQ only interacted synergistically with naphthoquine, pyronaridine and piperaquine in gametocytes. This study indicated that TFQ and ACT-partner drugs will likely have increased potency against asexual stages of the malaria parasites, whereas some drugs may interfere with each other against the P. falciparum gametocytes.


Proteomic investigation on bio-corona of Au, Ag and Fe nanoparticles for the discovery of triple negative breast cancer serum protein biomarkers.
Nowadays, there are no targeted therapeutic modalities for triple negative breast cancer (TNBC). This disease is associated with poor prognosis and worst clinical outcome because of the aggressive nature of the tumor, delayed diagnosis, and non-specific symptoms in the early stages. Therefore, identification of novel specific TNBC serum biomarkers for screening and therapeutic purposes remains an urgent clinical requirement. New user-friendly and cheap methods for biomarker identification are needed, and nanotechnology offers new opportunities. When dispersed in blood, nanoparticles (NPs) are covered by a protein shell termed "protein corona" (PC). While alterations in protein patterns are challeging to detect by conventional blood analyses, PC acts as a "nano-concentrator" of serum proteins with affinity for NPs' surface. So, the characterization of PC could allow the detection of otherwise undetectable changes in protein concentration at an early stage of the disease or after chemotherapy or surgery. To explore this research idea, serum samples from 8 triple negative breast cancer (TNBC) patients and 8 patients without malignancy were allowed to interact with gold nanoparticles (AuNPs: 10.02 ± 0.91 nm), silver nanoparticles (AgNPs: 9.73 ± 1.70 nm) and magnetic nanoparticles (MNPs: (9.30 ± 0.67 nm). Here, in order to identify biomarker candidates in serum of TNBC patients, these nanomaterials were combined with electrophoretic separation (SDS-PAGE) to performed qualitative and quantitative comparisons of the serum proteomes of TNBC patients (n = 8) and healthy controls (n = 8) by liquid chromatography tandem-mass spectrometry (LC-MS/MS) analysis. The results were validated through a sequential window acquisition of all theoretical mass spectra (SWATH) analysis, performed in total serum samples (patients and controls) using this approach as a multiple reaction monitoring (MRM) analysis. SIGNIFICANCE: It is well known that several proteins presented in human serum are important biomarkers for the diagnosis or prognosis of different diseases, as triple negative breast cancer (TNBC). Determining how nanomaterials as gold nanoparticles (AuNPs: 10.02 ± 0.91 nm), silver nanoparticles (AgNPs: 9.73 ± 1.70 nm) and magnetic nanoparticles (MNPs: (9.30 ± 0.67 nm) interact with human serum will assist not only in understanding their effects on the biological system (biocompability and toxicity), but also to obtain information for developing novel nanomaterials with high specificity and selectivity towards proteins with an important biological function (prognostic and diagnostic protein biomarkers).


Improved T2 mapping accuracy with dual-echo turbo spin echo: effect of phase encoding profile orders.
Turbo spin echo (TSE) pulse sequences have been applied to estimate T(2) relaxation times in clinically feasible scan times. However, T(2) estimations using TSE pulse sequences has been shown to differ considerable from reference standard sequences due to several sources of error. The purpose of this work was to apply voxel-sensitivity formalism to correct for one such source of error introduced by differing phase encoding profile orders with dual-echo TSE pulse sequences. The American College of Radiology phantom and the brains of two healthy volunteers were imaged using dual-echo TSE as well as 32-echo spin-echo acquisitions and T(2) estimations from uncorrected and voxel-sensitivity formalism-corrected dual-echo TSE and 32-echo acquisitions were compared. In all regions of the brain and the majority of the analyses of the American College of Radiology phantom, voxel-sensitivity formalism correction resulted in considerable improvements in dual-echo TSE T(2) estimation compared with the 32-echo acquisition, with improvements in T(2) value accuracy ranging from 5.2% to 18.6%.


The En-Gedi Spring Site and the Judahite Expansion into the Judaean Desert in the Late Iron Age.
This article discusses the results of the excavations conducted in the Iron II site near the En-Gedi Spring in 1961-1962 and 2019. The site, consisting of a prominent stone platform documented as early as the 19th century and other recently discovered structural remains, is interpreted as a Judahite outpost built in a strategic location within the oasis of En-Gedi. On the basis of the ceramic assemblage, it is suggested that this site was founded during the early 7th century BCE and was abandoned before the end of that century-making it the earliest Iron Age occupation in the oasis. Combined with historical considerations and a regional analysis, the En-Gedi Spring site enhances our understanding of the Judahite expansion into the Judaean Desert during the late Iron Age.


Ethnicity recording in general practice computer systems.
Ethnicity data in general practice (GP) computerized medical records can be utilized to audit equity in health care. We evaluated a patient profiling project targeted to improve ethnicity recording. Data extracted from 16 practices showed an increase in ethnicity recording from <1% before the intervention to 48% after. Recorded codes could be mapped onto the basic national statistics six-category ethnicity classification headings, and their proportions were similar to the 2001 census values. Recording of data using multiple coding hierarchies has reduced the utility of data as clinically important ethnic subgroups cannot be identified. Practitioners should be encouraged to use the single recommended ethnicity coding hierarchy.


Analysis of 155 consecutive forensic exhumations with emphasis on undetected homicides.
A total of 155 consecutive forensic exhumations performed in Münster, Germany from 1967 to 2001 were evaluated retrospectively on the basis of the autopsy report, the police report and the death certificate. Histology and toxicology were performed in most cases. The postmortem intervals varied from 8 days to 8 years. Compared to other countries, the autopsy rate was low (1.2-1.4%) and the exhumation rate high (0.016%): principle of reciprocity. The cause of death could be clearly determined in 103 cases (66.5%) and histology or toxicology were decisive in 40%. Some findings were discernable using immunohistochemistry after considerable postmortem intervals, such as acute myocardial infarction after 1 year and pneumonia after 2 years and a diazepam intoxication was determined after 4.5 years. Major deviations between the cause of death as stated on the death certificate and as diagnosed after autopsy existed in 57 cases (37%). A more detailed analysis revealed five subgroups. 1. primary suspicion of intoxication (n=18) confirmed in 6 cases including 3 homicides (with parathion, clozapin, diazepam) which are described in more detail. 2. primary suspicion of homicide other than poisoning (n=51) confirmed in 19 cases. There was a serial killing of 15 patients by injection of air. In the remaining 4 cases, a shaken infant, craniocerebral injuries from blows with beer bottles, a craniocerebral gunshot and a multiplicity of blunt force injuries were diagnosed. The latter two cases are described in more detail. Superficial external examinations and the low autopsy rate were 2 common reasons for the occurrence of "buried homicides" (n=22)-not a single forensic autopsy had been performed directly after the death of the victims. 3. primary suspicion of medical malpractice (n=39). 4. accidents including traffic accidents (n=30). 5. clarification of the cause of death, circumstances or identity (n=17). Exhumations were frequently successful for recovering evidence which should better have been collected immediately after the death of an individual. Exhumations can also be regarded as an instrument to evaluate the quality of death certificates and death investigations.


miR-181a increases FoxO1 acetylation and promotes granulosa cell apoptosis via SIRT1 downregulation.
Oxidative stress impairs follicular development by inducing granulosa cell (GC) apoptosis, which involves enhancement of the transcriptional activity of the pro-apoptotic factor Forkhead box O1 (FoxO1). However, the mechanism by which oxidative stress promotes FoxO1 activity is still unclear. Here, we found that miR-181a was upregulated in hydrogen peroxide (H2O2)-treated GCs and a 3-nitropropionic acid (NP)-induced in vivo model of ovarian oxidative stress. miR-181a overexpression promoted GC apoptosis, whereas knockdown of endogenous miR-181a blocked H2O2-induced cell apoptosis. Moreover, we identified that Sirtuin 1 (SIRT1), a deacetylase that suppresses FoxO1 acetylation in GCs, was downregulated by miR-181a and reversed the promoting effects of H2O2 and miR-181a on FoxO1 acetylation and GC apoptosis. Importantly, decreased miR-181a expression in the in vivo ovarian oxidative stress model inhibited apoptosis by upregulating SIRT1 expression and FoxO1 deacetylation. Together, our results suggest that miR-181a mediates oxidative stress-induced FoxO1 acetylation and GC apoptosis by targeting SIRT1 both in vitro and in vivo.


Peripheral blood monocytes derived from HIV+ individuals mediate antibody-dependent cellular cytotoxicity (ADCC).
Monocytes/macrophages serve a number of immunologic functions and play a major role in the host defense against infection. Abnormal functions of monocytes have been reported in AIDS and HIV+ individuals. A recent report from our laboratory demonstrated that peripheral blood monocytes (PBM) derived from AIDS patients were de novo "activated" as assessed by direct cell-mediated cytotoxicity (CMC) and secretion of cytotoxic factors and tumor necrosis factor-alpha (TNF alpha). Thus, both the direct cytotoxicity as well as the antibody-dependent cellular cytotoxicity (ADCC) exerted by the monocytes may contribute to the destruction of HIV-infected/coated cells and the immunopathogenesis of AIDS. The present study investigated the ability of HIV+ PBM to mediate ADCC against antibody-coated target cells in an 18-hr 51Cr release assay. Initial studies examined ADCC using a macrophage resistant target Raji and rabbit anti-Raji serum. The results show that the majority of PBM from HIV+ individuals mediate ADCC activity while the majority of PBM from normal healthy controls was not cytotoxic. While activation of PBM with recombinant interferon-gamma (rIFN-gamma) enhances the ADCC activity of normal PBM, treatment of HIV+ PBM with IFN-gamma resulted in significant enhancement of ADCC. Both untreated and treated PBM from HIV+ individuals had significantly higher ADCC than PBM from normal individuals. Of interest, a significant ADCC activity was found by PBM derived from two HIV- high risk individuals whether untreated or treated with rIFN-gamma. The ADCC results with RAJI target cells prompted us to investigate whether ADCC can also be obtained using HIV-infected T4+ cells. We selected a macrophage and TNF resistant T4+ CEM cell line as target for ADCC. The target was coated with inactivated HIV and pooled human anti-HIV serum was used. Studies with a few HIV+ individuals demonstrate that significant ADCC is obtained with PBM from HIV+ individuals but little or no ADCC by normal PBM and the ADCC was specific for HIV. The ADCC was also significantly enhanced by treatment of PBM with rIFN-gamma. The results of this study clearly indicate that PBM from HIV+ individuals are endowed with the capacity to mediate ADCC against HIV-infected/coated cells and thus, we postulate that PBM may play a direct role in vivo in lysis or suppression of HIV-coated/infected cells and in the pathogenesis of AIDS.


Free radical intermediates produced by autoxidation of 1,8-dihydroxy-9-anthrone (dithranol) in pyridine.
The autoxidation of the antipsoriatic agent dithranol, monitored by an ESR-spectrometer, proceeds through several free radical intermediates. The initial radical, attacking a bulky spin trapping agent in a sterically comparatively hindered constellation, may be the active therapeutic form of dithranol.


Intra-arterial Modulation of the Trigeminal Nerve Ganglion in Patients with Refractory Trigeminal Neuralgia.
Nerves and nerve ganglions are supplied by segmental arteries and the vasa nervorum, but the intra-arterial route has not been used for diagnostic or therapeutic purposes. We present the results of intra-arterial delivery of medication for modulating trigeminal nerve ganglion function in patients with refractory trigeminal neuralgia. We administered intra-arterial lidocaine in doses up to 50 mg in the middle meningeal artery territory adjacent to the arterial branch that supplies the trigeminal nerve ganglion. We performed electrophysiologic monitoring to serially assess the latency and amplitude of R1 and R2 responses in the blink reflex before and concurrent with each incremental dose of lidocaine. Clinical outcome assessment included a 10-point numeric rating, 4-point severity grading, and the pain-free time interval pre- and post-treatment. Intra-arterial lidocaine was administered to three patients with trigeminal neuralgia (35-year-old woman, 57-year-old man, and 34-year-old woman). In all patients, there was a latency prolongation and amplitude reduction of R1 or R2 responses or both which was evident after 5-10 mg of lidocaine administration; a more pronounced effect was seen with increasing doses. The second and third patients reported improvement in pain severity on all scales with pain-free intervals of 5 and 3 days, respectively. There was improvement in facial hyperalgesia in all three patients in all dermatomes. All three patients' symptoms had returned to baseline severity 1 month later. We found that modulation of trigeminal nerve activity via the intra-arterial route is possible based on consistent intraprocedural electrophysiologic suppression and short-term clinical improvement in patients with refractory trigeminal neuralgia.