Characterization of the hypothalamic proopiomelanocortin gene and beta-endorphin expression in the hypothalamic arcuate nucleus of mice elicited by inflammatory pain.
We examined proopiomelanocortin (POMC) mRNA and beta-endorphin expression in the hypothalamus of mice after various nociceptive stimuli. The time-course study (10 min, 30 min, 1 h, 2 h, and 10 h) showed that the POMC mRNA level significantly increases from 1 h after s.c. formalin injection and returns to the control level at 10 h. Intrathecal (i.t.) substance P (SP) injection also increases the hypothalamic POMC mRNA level from 1 h to 10 h. However, i.t. glutamate injection did not affect the hypothalamic POMC gene expression at all time points. We found that the POMC mRNA after s.c. formalin injection was located in the arcuate nucleus of the hypothalamus. In the same manner, beta-endorphin immunoreactivity was also increased in the hypothalamic arcuate nucleus. The expression of phosphorylated extracellular signal-regulated protein kinase 1/2 (pERK1/2), phosphorylated calcium/calmodulin-dependent protein kinase-IIalpha (pCaMK-IIalpha) protein and phosphorylated IkappaB (pIkappaB) protein was increased by s.c. formalin injection at various time points. We also found that increased pERK1/2, pCaMKIIalpha and pIkappaB protein after s.c. formalin injection was mainly located in the arcuate nucleus of hypothalamus in which cells containing beta-endorphin after s.c. formalin injection also express pERK1/2, pCaMK-IIalpha and pIkappaB immunoreactivity. In addition, formalin-induced POMC mRNA expression was significantly reduced by 10 min, pretreatment with i.c.v. PD98059 (mitogen-activated protein kinase (MAPK) pathways inhibitor; 6.6 mug) and KN93 (pCaMK-II inhibitor; 20 mug). In conclusion, POMC mRNA expression in the arcuate nucleus of the hypothalamus was increased by inflammatory pain stimuli, in which pERK1/2, pCaMK-IIalpha and NFkappaB may play an important role in the expression of the hypothalamic POMC gene and beta-endorphin expression.


[Complementary acoustic EEG control while recording early acoustically evoked potentials].
An easily performed method for the additional acoustical assessment of the EEG quality by the investigator during recording of human brainstem potentials is presented. By means of feedback of the audibly transposed "noiselike" EEG voltage to the opposite ear of the examined subject (instead of the usual masking noise) the subject can perceive self-produced disturbances (muscle activities) and minimize them for the period of examination. An example shows how this additional rejection of artifacts via "biofeedback" can effectively support methods that are already in use.


Corrigendum to "Detection of BRAF mutations from solid tumors using Tumorplex™ technology" [MethodsX 2 (2015), 316-322].
[This corrects the article DOI: 10.1016/j.mex.2015.06.002.].


Treatment of advanced esthesioneuroblastoma with high-dose chemotherapy and autologous bone marrow transplantation. A case report.
A 46-year-old woman presented with an advanced unresectable esthesioneuroblastoma which failed to respond to radiation therapy and one course of chemotherapy. She underwent treatment with high-dose chemotherapy (cyclophosphamide, doxorubicin, and vinblastine) followed by autologous bone marrow transplantation. The major toxicity from the regimen was severe oropharyngeal mucositis. A complete remission was achieved and the patient is free of disease and asymptomatic 3.5 years after treatment.


Application of parallel liquid chromatography/mass spectrometry for high throughput microsomal stability screening of compound libraries.
Solution-phase and solid-phase parallel synthesis and high throughput screening have enabled biologically active and selective compounds to be identified at an unprecedented rate. The challenge has been to convert these hits into viable development candidates. To accelerate the conversion of these hits into lead development candidates, early assessment of the physicochemical and pharmacological properties of these compounds is being made. In particular, in vitro absorption, distribution, metabolism, and elimination (ADME) assays are being conducted at earlier and earlier stages of discovery with the goal of reducing the attrition rate of these potential drug candidates as they progress through development. In this report, we present an eight-channel parallel liquid chromatography/mass spectrometry (LC/MS) system in combination with custom Visual Basic and Applescript automated data processing applications for high throughput early ADME. The parallel LC/MS system was configured with one set of gradient LC pumps and an eight-channel multiple probe autosampler. The flow was split equivalently into eight streams before the multiple probe autosampler and recombined after the eight columns and just prior to the mass spectrometer ion source. The system was tested for column-to-column variation and for reproducibility over a 17 h period (approximately 500 injections per column). The variations in retention time and peak area were determined to be less than 2 and 10%, respectively, in both tests. The parallel LC/MS system described permits time-course microsomal incubations (t(o), t5, t15, t30) to be measured in triplicate and enables estimations of t 1/2 microsomal stability. The parallel LC/MS system is capable of analyzing up to 240 samples per hour and permits the complete profiling up to two microtiter plates of compounds per day (i.e., 176 test substrate compounds + sixteen controls).


Long-term observation of the detrusor smooth muscle in rats. Its relationship to ovariectomy and estrogen treatment.
We studied the bladders of 24-month-old intact rats, rats that had been ovariectomized at the age of 6 months, and intact and ovariectomized rats treated by estrogen from the age of 16 months. The study thus comprized four groups: group I: bilaterally ovariectomized rats; group II: intact rats; group III: ovariectomized rats treated with estrogen; group IV: intact rats treated with estrogen. The weight and collagen concentration of the bladders were determined. The ovariectomized bladders weighed significantly less and had a higher collagen concentration than the intact bladders. Estrogen substitution for ovariectomized rats reversed these parameters. Detrusor strips were also used for organ bath studies. All bladders were similar in regard to the nerve-mediated frequency-response relationship. The atropine-resistant response was studied by adding scopolamine to the organ bath. Strips from ovariectomized rats had a significantly diminished atropine-resistant response, which was abolished by estrogen substitution. The present study suggests that micturition problems in menopause might have a structural as well as a pharmacological explanation.


A practical approach to developing cases for standardized patients.
This article outlines a process for developing standardized patient cases. The initial step in the process is to define the educational goals of the exercise. Following this step the patient characteristics, setting for the interaction and clinical information are developed. Clinical information, in addition to history, may include elements of nonverbal communication, actual or simulated abnormal physical findings, and laboratory results. Guidelines for the standardized patient regarding disclosure of information to the student and providing feedback to the student enhance the value of the case. If the case is to be used as part of an examination, a grading system must be developed. Issues of cost, validity, and reliability are briefly addressed.


Comparison of the interferon-tau expression from primary trophectoderm outgrowths derived from IVP, NT, and parthenogenote bovine blastocysts.
The expression of interferon-tau (IFN-tau) is essential for bovine embryo survival in the uterus. An evaluation of IFN-tau production from somatic cell nuclear transfer (NT)-embryo-derived primary trophectoderm cultures in comparison to trophectoderm cultured from parthenogenote (P) and in vitro matured, fertilized, and cultured (IVP) bovine embryos was performed. In Experiment 1, the success/failure ratio for primary trophectoderm colony formation was similar for IVP and NT blastocysts [IVP = 155/29 (84%); NT 104/25 (81%)], but was decreased (P = .05) for P blastocysts [54/43 (56%)]. Most trophectoderm colonies reached diameters of at least 1 cm within 3-4 weeks, and at this time, 72 hr conditioned cell culture medium was measured for IFN-tau concentration by antiviral activity assay. The amount of IFN-tau produced by IVP-outgrowths [4311 IU/mL (n = 155)] was greater (P < .05) than that from NT- [626 IU/mL (n = 104)] and P - [1595 IU/mL (n = 54)] derived trophectoderm. Differential expression of IFN-tau was confirmed by immunoblotting. In Experiment 2, colony formation was again similar for IVP and NT blastocysts [IVP = 70/5 (93%); NT 67/1 (99%)] and less (P < .05) for P blastocysts [65/27 (70%)]. Analysis of trophectoderm colony size after 23 days in culture showed a similar relationship with P-derived colonies being significantly smaller in comparison to IVP and NT colonies. A differential expression of IFN-tau was also observed again, but this time as measured over time in culture. Maximal IFN-tau production was found at day-14 of primary culture and diminished to a minimum by the 23rd day.


The social value of health: A frontier analysis of life expectancy gaps across 33 European countries.
We estimate the life expectancy gaps that can be bridged by improving the quality of public health and health care policies at the country level. Our model calculates the net effect of amenable deaths on life expectancy after controlling for time effects and factors affecting amenable deaths related to education, health policies (health expenditure to GDP and waiting lists), and per capita income in a two equation system. We further estimate the life expectancy gap that countries with lower quality health systems can bridge by catching up and reaching the existing health quality frontier and compute the social value of that upside potential.


Operative management of cervical cancer.
Radical abdominal hysterectomy with pelvic lymph node dissection remains the treatment of choice for most patients with early-stage cervical cancer. The radicality and extent of lymph node dissection and parametrial resection should be tailored to tumour- and patient-related risk factors. Adjuvant therapy after radical surgery improves local control in high-risk patients and some intermediate-risk patients. The absolute indications for adjuvant therapy include multiple or macroscopically involved nodes, parametrial invasion and positive surgical margins. Adjuvant therapy may be given as chemoradiation or as radiotherapy alone, depending on risk assessment and expected morbidity. Primary chemoradiation is an equally effective alternative, but adjuvant surgery or finishing hysterectomy after pelvic radiation is not beneficial. Promising new developments include neo-adjuvant chemotherapy followed by surgery for bulky early-stage disease, tailoring radicality to reduce therapeutic morbidity and integrating minimal access surgical techniques into current treatment protocols.


Quantification and modulation of thrombomodulin activity in isolated rat and human glomeruli.
Thrombomodulin (TM), the endothelial cell surface receptor for thrombin-mediated activation of protein C and of its anticoagulant system, is involved in maintaining vascular nonthrombogenicity, and depressed TM activity may induce intravascular fibrin formation. TM antigen was previously found by immunohistochemical methods in rabbit glomeruli. We therefore attempted to identify the corresponding TM activity in isolated detergent-solubilized rat and human glomeruli. Like purified lung TM, rat glomeruli extracts accelerated the hydrolysis by activated protein C of the chromogenic substrate S-2238 in the presence of 10 nM thrombin, as determined by spectrophotometry. One mg glomerular protein promoted the formation of 681 +/- 115 nmol activated protein C, the equivalent of the amount generated by 845 ng of purified rabbit TM. TM activity correlated with the protein content of the glomerular extracts (r = 0.94). These extracts prolonged rat plasma activated partial thromboplastin time. Incubation of glomeruli with tumor necrosis factor-alpha (TNF) or E. coli lipopolysaccharide depressed their TM-like activity in a dose and time dependent manner. Incubation with TNF suppressed their anticoagulant activity. In human glomeruli, TM activity was also found at a level which corresponded to their TM antigen content, and was determined by ELISA with mouse monoclonal antibody. These results indicate that measurement of glomerular TM activity might help to clarify the mechanisms of intraglomerular fibrin deposition in renal diseases.


On the competition between six-membered and five-membered NHC towards alane centered ring expansion.
The combination of 6-SIDipp·AlH3 (1) and 5-IDipp resulted in the ring expansion of 6-NHC, while the five-membered NHC remained unchanged, which was subsequently explained by DFT studies. Besides, the substitution chemistry of 1 was also studied with TMSOTf and I2, which gave rise to the substitution of a hydride by triflate or iodide ligands.


Protocols for nuclei isolation and nuclear protein extraction from the resurrection plant Xerophyta viscosa for proteomic studies.
The plant nucleus is an important subcellular organelle but the isolation of pure and enriched nuclei from plants and subsequent extraction of nuclear proteins for proteomic studies is challenging. Here, we present protocols for nuclei isolation and nuclear protein extraction from the resurrection plant, Xerophyta viscosa, and show optimization and modification of the most critical steps.


Changes in vascular and metabolic reactivity as indices of ischaemia in the penumbra.
The reactivities of cerebral cortical blood flow (hydrogen clearance) and of compensated NADH fluorescence to local cortical electrical stimulation were examined on the marginal gyrus before and after transorbital occlusion of the middle cerebral artery in cats. Prestimulus cerebral blood flow (CBF) was 38.2 +/- 12.9 (SD) ml 100 g-1 min-1 and fell to 19.8 +/- 11.1 following occlusion (p less than 0.02). Peak hydrogen clearance rate (percent increase above prestimulus clearance) was 81.6 +/- 53.6 and fell to 19.9 +/- 29.8 after middle cerebral artery occlusion (p less than 0.01). Steady-state NADH fluorescence rose from 33.5 +/- 10.7 to 40.5 +/- 17.6% full-scale deflection following MCAO (p less than 0.01). Latency from stimulus to maximal fluorescence depression in response to cortical stimulation increased from 12.2 +/- 8.2 to 22.1 +/- 11.9 s (p less than 0.01). Hyperaemic responses at anteromedial sites on the marginal gyrus significantly exceeded those at posterolateral sites. The results are interpreted as indicating early ischaemic metabolic change; however, the presence of residual vasodilator responses to stimulation suggests that flow reduction and early ischaemic change in the territory studied are not simply due to inadequate collateral input, but may also reflect deafferentation or functional suppression. The possible significance of diminished vascular reactivity in the penumbra as a cause of increased vulnerability to extracellular release of excitatory amino acids is discussed.


Protein phosphorylation driven by intracellular calcium oscillations: a kinetic analysis.
Given the ubiquitous nature of signal-induced Ca2+ oscillations, the question arises as to how cellular responses are affected by repetitive Ca2+ spikes. Among these responses, we focus on those involving protein phosphorylation. We examine, by numerical simulations of a theoretical model, the situation where a protein is phosphorylated by a Ca(2+)-activated kinase and dephosphorylated by a phosphatase. This reversible phosphorylation system is coupled to a mechanism generating cytosolic Ca2+ oscillations; for definiteness, this oscillatory mechanism is based on the process of Ca(2+)-induced Ca2+ release. The analysis shows that the average fraction of phosphorylated protein increases with the frequency of repetitive Ca2+ spikes; the latter frequency generally rises with the extent of external stimulation. Protein phosphorylation therefore provides a mechanism for the encoding of the external stimulation in terms of the frequency of signal-induced Ca2+ oscillations. Such a frequency encoding requires precise kinetic conditions on the Michaelis-Menten constants of the kinase and phosphatase, their maximal rates, and the degree of cooperativity in kinase activation by Ca2+. In particular, the most efficient encoding of Ca2+ oscillations based on protein phosphorylation occurs in conditions of zero-order ultrasensitivity, when the kinase and phosphatase are saturated by their protein substrate. The kinetic analysis uncovers a wide variety of temporal patterns of phosphorylation that could be driven by signal-induced Ca2+ oscillations.


Potentiation by high potassium of lipopolysaccharide-induced nitric oxide production from cultured astrocytes.
Uptake of K+ is an important role of astrocytes to maintain physiological lower extracellular K+ concentration in the CNS. In this study, the effect of high K+ concentration was examined on the cellular function of astrocytes from embryonic rat brain in primary culture. Nitric oxide (NO) production induced by lipopolysaccharide (LPS) was measured as an index of cellular function of astrocytes. Increasing KCl concentration to about 40 mM did not directly evoke NO production, but doubled the level of LPS (1 ng/ml)-induced NO production. K-gluconate showed a similar enhancing effect although the degree of enhancement was about half of that of KCl. Neither NaCl nor Na-gluconate showed any effect. The K(+)-channel blocker, 4-aminopyridine, but not tetraethylammonium or apamin, inhibited the enhancing effect of KCl. The LPS-induced iNOS protein expression determined by immunoblotting analysis was enhanced by high K+ treatment. The level of iNOS mRNA determined by real-time RT-PCR technique was also augmented by the presence of 40 mM KCl. These results indicate that the elevation of extracellular K+ concentration regulates astrocytic cell functions through a mechanism involving K(A)-type K(+)-channels and that potentiation of NO production by high K+ is due to the augmentation of iNOS mRNA and iNOS protein levels.


A new mutation in the PAX2 gene in a Papillorenal Syndrome patient.
To present a new mutation in a patient with Papillorenal Syndrome (PAPRS). PAPRS is an autosomal dominant disease that involves ocular and renal abnormalities. We present a patient with PAPRS with a genetically diagnosed PAX2 and new pathogenic mutation. A complete ophthalmological, neurological, nephrological and Ears-Nose-Throat (ENT) examination were undertaken. The patient suffered from Focal Segmental Glomerulosclerosis (FSGS) and some typical ophthalmological signs of PAPRS, including optic nerve coloboma and optic disc pit (ODP) maculopathy associated with an abnormal retinal vessel distribution and numerous cilioretinal arteries in the right eye. The left eye showed similar vessel abnormalities although the optic disc had a normal morphology. A new mutation in the PAX2 gene was identified in a patient with ocular and renal abnormalities.


Occurrence of Trichothecenes in feed and cereals in Finland.
In 1985 82 samples of feed and food grain were analyzed for trichothecenes deoxynivalenol (DON), nivalenol (NV), diacetoxyscirpenol (DAS), T-2 toxin, HT-2 toxin and fusarenon-X (F-X). Trichothecenes were found in 77 of these samples. The highest amounts were DON 6300 ug/kg and DAS 1680 ug/kg.In 1986, in a corresponding study of 113 samples, trichothecenes were found in 110 samples. A new trichothecene in Finland, 3-acetyldeoxynivalenol (3-AcDON), was identified in 35 of these samples in concentration of 2-211 ug/kg.Analyzing methods were gas chromatography and GC-mass spectrometry. It is characteristic of the feed samples suspected of causing outbreaks in animals in Finland that several trichothecenes are often found in the same sample. As an example of this is a poultry feed with following results: DON 33 ug/kg, 3-AcDON 21 ug/kg, DAS 45 ug/kg, T-2 toxin 40 ug/kg, HT-2 toxin 12 ug/kg.


Evaluation of renal function in low-dose cyclosporine-treated patients using technetium-99m diaminocyclohexane: a cationic tubular excretion agent.
Technetium-99m diaminocyclohexane (DACH) is a new tubular agent excreted via a cationic transport mechanism, like cyclosporine-A (CsA). It is expected that 99mTc-DACH will permit effective assessment of tubular function in CsA-treated patients. To establish the pharmacokinetic characteristics of 99mTc-DACH and to ascertain whether this new agent is useful in CsA-treated patients, 11 healthy volunteers and 15 CsA-treated patients underwent renal imaging and clearance studies using 99mTc-DACH and chromium-51 ethylene diamine tetra-acetic acid (EDTA). 99mTc-DACH yielded satisfactory dynamic renal images in all participants. The mean plasma clearance of 99mTc-DACH was significantly greater than that of 51Cr-EDTA in volunteers (109.4¿19.7 ml/min versus 86.6 +/- 13.7 ml/min, P<0.05). However, the urinary excretion of 99mTc-DACH at 90 min was significantly lower than that of 51Cr-EDTA (46.1% +/- 9.3% versus 53.1% +/- 8.6%, P<0.05), most probably due to its partial parenchymal retention. The elimination half-life of 99mTc-DACH was significantly increased in CsA-treated patients in comparison to volunteers, and consequently the plasma clearance values were significantly suppressed in these patients, in contrast to 51Cr-EDTA and endogenous creatinine clearance values. In conclusion, our findings indicate that 99mTc-DACH, as a sensitive marker of cationic tubular function, could be used to monitor renal haemodynamics in patients receiving CsA treatment.


Salvage Percutaneous Cryoablation for Bleeding Upper Tract Urothelial Carcinoma.
Endoscopic access and treatment of bleeding upper urinary tract urothelial carcinomas (UTUCS) is sometimes difficult and inefficient as resection and/or laser coagulation are often incomplete. We report two cases of successful cryoablation of bleeding UTUCs. This study evaluated an adjunctive method in using cryoablation as a hemostatic technique. Cryoprobes were inserted inside the affected calices and a standard renal cryoablation protocol was used. Track ablation was performed during the pullback of the cryoprobes to prevent tumor seeding and bleeding. Cryoablation of the bleeding upper urinary tract tumors allowed to efficiently resolve macrohematuria in both patients and to provide prolonged remission in one patient. Taking advantage of the microcirculatory stasis and the hemostatic properties of cryoablation, we achieved palliative cessation of refractory macrohematuria while sparing nephrons, without the need for renal embolization in patients with bleeding UTUCs.


Dermoscopy of Pigmentary Disorders in Brown Skin.
Dermoscopy is a noninvasive technique for the diagnosis, prognosis, and monitoring of pigmentary disorders in brown skin. It can be used for the diagnosis of various facial melanoses, which can avoid the need for biopsy in many cases. It can also help in early identification of the adverse effect of topical steroids and hydroquinone when they are used for the treatment of these disorders. Dermoscopy can also reliably differentiate vitiligo from other disorders of hypopigmentation. It can also help in assessing the stability of vitiligo before surgery.


The flexibilization of employment relationships in the health sector: the reality in a Federal University Hospital in Brazil.
This was a socio-historical study that aimed to analyze the repercussions of the flexibilization of labor relationships within a University hospital (UH) using the thematic oral history method and triangulation of sources made up of workers' statements, institutional documents and relevant literature. It was observed that flexibilization, driven by state reform in the 1990s, had a structural impact on the trajectory of this institution, that, due to government downsizing policy, adopted outsourcing to maintain staff, leading to high staff turnover, various types of conflicts, and discontinuity and lack of organization of work processes. We conclude that the flexibilization of employment relationships became a handicap for this UH, disrupting services, negatively affecting students and service users, contributing to the deterioration of working conditions and lack of protection of workers.


Current and future prospects for nanotechnology in animal production.
Nanoparticles have been used as diagnostic and therapeutic agents in the human medical field for quite some time, though their application in veterinary medicine and animal production is still relatively new. Recently, production demands on the livestock industry have been centered around the use of antibiotics as growth promoters due to growing concern over microbial antibiotic resistance. With many countries reporting increased incidences of antibiotic-resistant bacteria, laws and regulations are being updated to end in-feed antibiotic use in the animal production industry. This sets the need for suitable alternatives to be established for inclusion in feed. Many reports have shown evidence that nanoparticles may be good candidates for animal growth promotion and antimicrobials. The current status and advancements of nanotechnological applications in animal production will be the focus of this review and the emerging roles of nanoparticles for nutrient delivery, biocidal agents, and tools in veterinary medicine and reproduction will be discussed. Additionally, influences on meat, egg, and milk quality will be reviewed.


Upregulation of aldose reductase during foam cell formation as possible link among diabetes, hyperlipidemia, and atherosclerosis.
Aldose reductase (AR) is the rate-limiting enzyme of the polyol pathway. In diabetes, it is related to microvascular complications. We discovered AR expression in foam cells by gene chip screening and hypothesized that it may be relevant in atherosclerosis. AR gene expression and activity were found to be increased in human blood monocyte-derived macrophages during foam cell formation induced by oxidized LDL (oxLDL, 100 microg/mL). AR activity as photometrically determined by NADPH consumption was effectively inhibited by the AR inhibitor epalrestat. oxLDL-dependent AR upregulation was further increased under hyperglycemic conditions (30 mmol/L D-glucose) as compared to osmotic control, suggesting a synergistic effect of hyperlipidemia and hyperglycemia. AR was also upregulated by 4-hydroxynonenal, a constituent of oxLDL. Upregulation was blocked by an antibody to CD36. AR inhibition resulted in reduction of oxLDL-induced intracellular oxidative stress as determined by 2'7'-dichlorofluoresceine diacetate (H2DCFDA) fluorescence, indicating that proinflammatory effects of oxLDL are partly mediated by AR. Immunohistochemistry showed AR expression in CD68+ human atherosclerotic plaque macrophages. These data show that oxLDL-induced upregulation of AR in human macrophages is proinflammatory in foam cells and may represent a potential link among hyperlipidemia, atherosclerosis, and diabetes mellitus.


NMR spin-lattice relaxation times of intracellular Na-23 on rat livers and related lipid peroxidation following CCl4 intoxication.
Liver tissues were isolated from rats acutely intoxicated with carbon tetrachloride, and Na-23 NMR signals were analyzed to investigate the T1 relaxation times of intracellular sodium ions under pathological conditions in presence of the paramagnetic shift reagent (dysprosium tripolyphosphate). We studied the significant increase of T1 found in CCl4 treated rats with respect to controls, which was elsewhere demonstrated as being independent of cell necrosis. Evidence is given that neither fat accumulation nor proliferative processes affect the observed T1 lengthening. When T1 relaxation times were measured in the liver of vitamin E treated rats subsequently intoxicated with carbon tetrachloride, a significative shortening of T1 with respect to CCl4-intoxicated rats was observed. These results were discussed in terms of the antioxidant action exerted by vitamin E, taking into account that peroxidation of microsomal lipids is the key factor in the process of carbon tetrachloride induced liver injury. Furthermore, the observed T1 changes were discussed in terms of the interactions of Na+ with cell membranes and/or the occurrence of viscosity changes.


Have you tried turning it off and on again? Oscillating selection to enhance fitness-landscape traversal in adaptive laboratory evolution experiments.
Adaptive Laboratory Evolution (ALE) is a powerful tool for engineering and understanding microbial physiology. ALE relies on the selection and enrichment of mutations that enable survival or faster growth under a selective condition imposed by the experimental setup. Phenotypic fitness landscapes are often underpinned by complex genotypes involving multiple genes, with combinatorial positive and negative effects on fitness. Such genotype relationships result in mutational fitness landscapes with multiple local fitness maxima and valleys. Traversing local maxima to find a global maximum often requires an individual or sub-population of cells to traverse fitness valleys. Traversing involves gaining mutations that are not adaptive for a given local maximum but are necessary to 'peak shift' to another local maximum, or eventually a global maximum. Despite these relatively well understood evolutionary principles, and the combinatorial genotypes that underlie most metabolic phenotypes, the majority of applied ALE experiments are conducted using constant selection pressures. The use of constant pressure can result in populations becoming trapped within local maxima, and often precludes the attainment of optimum phenotypes associated with global maxima. Here, we argue that oscillating selection pressures is an easily accessible mechanism for traversing fitness landscapes in ALE experiments, and provide theoretical and practical frameworks for implementation.


Theoretical evaluation of energy loss methods in the analysis of prosthetic heart valves.
The purpose of this paper is to clarify certain aspects of the 'energy loss' approach to the analysis of artificial heart valves. This involves the discussion of what is meant by 'energy loss'; the derivation of an appropriate energy equation; the scrutiny of the conditions under which it may be applied and of the assumptions involved in deriving a useful formulation in terms of readily measurable parameters; consideration of the extent to which these assumptions are valid in reported experiments using this formulation and the demonstration of the suitability and versatility of this approach when applied specifically to heart valve conduits.


Repeated Plasmodium vivax malaria relapses in a Peruvian sailor.
Two Plasmodium vivax recurrences in a Peruvian sailor with weight above the 60 kg (cap for primaquine dosage) highlight the importance of adequate radical cure weight dosage for patient treatment and control efforts, particularly within the military.


COVID-19 and pneumothorax: a multicentre retrospective case series.
Pneumothorax and pneumomediastinum have both been noted to complicate cases of coronavirus disease 2019 (COVID-19) requiring hospital admission. We report the largest case series yet described of patients with both these pathologies (including nonventilated patients). Cases were collected retrospectively from UK hospitals with inclusion criteria limited to a diagnosis of COVID-19 and the presence of either pneumothorax or pneumomediastinum. Patients included in the study presented between March and June 2020. Details obtained from the medical record included demographics, radiology, laboratory investigations, clinical management and survival. 71 patients from 16 centres were included in the study, of whom 60 had pneumothoraces (six with pneumomediastinum in addition) and 11 had pneumomediastinum alone. Two of these patients had two distinct episodes of pneumothorax, occurring bilaterally in sequential fashion, bringing the total number of pneumothoraces included to 62. Clinical scenarios included patients who had presented to hospital with pneumothorax, patients who had developed pneumothorax or pneumomediastinum during their inpatient admission with COVID-19 and patients who developed their complication while intubated and ventilated, either with or without concurrent extracorporeal membrane oxygenation. Survival at 28 days was not significantly different following pneumothorax (63.1±6.5%) or isolated pneumomediastinum (53.0±18.7%; p=0.854). The incidence of pneumothorax was higher in males. 28-day survival was not different between the sexes (males 62.5±7.7% versus females 68.4±10.7%; p=0.619). Patients aged ≥70 years had a significantly lower 28-day survival than younger individuals (≥70 years 41.7±13.5% survival versus <70 years 70.9±6.8% survival; p=0.018 log-rank). These cases suggest that pneumothorax is a complication of COVID-19. Pneumothorax does not seem to be an independent marker of poor prognosis and we encourage continuation of active treatment where clinically possible.


Nitric oxide production in the exhaled air of patients with pulmonary tuberculosis in relation to HIV co-infection.
Nitric oxide (NO) is essential for host defense in rodents, but the role of NO during tuberculosis (TB) in man remains controversial. However, earlier observations that arginine supplementation facilitates anti-TB treatment, supports the hypothesis that NO is important in the host defense against TB. Local production of NO measured in fractional exhaled air (FeNO) in TB patients with and without HIV co-infection has not been reported previously. Thus, our aim was to investigate levels of FeNO in relation to clinical symptoms and urinary NO metabolites (uNO). In a cross sectional study, FeNO and uNO were measured and clinical symptoms, chest x-ray, together with serum levels of arginine, tumor necrosis factor alpha (TNF-alpha) and interleukin 12 (IL-12) were evaluated in sputum smear positive TB patients (HIV+/TB, n = 36, HIV-/TB, n = 59), their household contacts (n = 17) and blood donors (n = 46) from Gondar University Hospital, Ethiopia. The proportion of HIV-/TB patients with an increased FeNO level (> 25 ppb) was significantly higher as compared to HIV+/TB patients, but HIV+/TB patients had significantly higher uNO than HIV-/TB patients. HIV+ and HIV-/TB patients both had lower levels of FeNO compared to blood donors and household contacts. The highest levels of both uNO and FeNO were found in household contacts. Less advanced findings on chest x-ray, as well as higher sedimentation rate were observed in HIV+/TB patients as compared to HIV-/TB patients. However, no significant correlation was found between FeNO and uNO, chest x-ray grading, clinical symptoms, TNF-alpha, IL-12, arginine levels or sedimentation rate. In both HIV negative and HIV co infected TB patients, low levels of exhaled NO compared to blood donors and household were observed. Future studies are needed to confirm whether low levels of exhaled NO could be a risk factor in acquiring TB and the relative importance of NO in human TB.


Evidence for growth of Sporothrix schenckii on dead but not on living sphagnum moss.
When clinical isolates of Sporothrix schenckii were inoculated onto the apices of living or dead sphagnum moss plants maintained under growth chamber conditions, populations of the fungus, assessed by standard dilution plate methods, increased swiftly up to about 70-fold on moist, dead plants but did not increase on the live moss. Light and scanning electron microscopy revealed fungal growth and sporulation on and within dead plants, but no evidence of either on live plants. These data provide indirect support for the contention that S. schenckii does not grow on living sphagnum in bogs, but rather that sporotrichosis epidemics associated with sphagnum moss are likely to result from contamination of the dead plants at some point(s) in the chain of events during or after harvest. One practical implication of our results is that precautions should be taken to insure that sphagnum moss is stored dry and that it is not wetted any sooner than necessary before use. We also report here improvement of the Mycoses isolation medium by an increase in cycloheximide from 400 to 800 mg/l, chloramphenicol from 50 to 250 mg/l, and the addition of rifampicin at 20 mg/l.


Cross-reactivity of commercially available anti-human monoclonal antibodies with canine cytokines: establishment of a reliable panel to detect the functional profile of peripheral blood lymphocytes by intracytoplasmic staining.
The process for obtaining monoclonal antibodies against a specific antigen is very laborious, involves sophisticated technologies and it is not available in most research laboratories. Considering that most cytokines remain partially conserved among species during evolution, the search for antibody cross-reactivity is an important strategy for immunological studies in veterinary medicine. In this context, the amino acid sequence from human and canine cytokines have demonstrated 49-96 % homology, suggesting high probability of cross-reactivity amongst monoclonal antibodies. For this, 17 commercially available anti-human monoclonal antibodies [IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8 (#1, #2), IL-10, IL-12, IL-13, IL-17A, IFN-γ (#1, #2), TNF-α (#1, #2) and TGF-β], were evaluated in vitro for intracellular cytokine detection in a stimulated canine blood culture by flow cytometry and confocal microscopy. Lymphocytes from peripheral blood of healthy and two unhealthy dogs were analyzed. Eleven anti-human mAbs [IL-1α, IL-4, IL-5, IL-6, IL-8 (#1, #2), IL-12, IL-17A, TNF-α (#1, #2) and TGF-β] cross-reacted against canine intracellular cytokines. The specificity of the assays was not affected after Fc-blocking. Three anti-human cytokine mAbs [IL-4, IL-8 (#2) and TGF-β] when evaluated by confocal microscopy also cross-reacted with intracellular canine cytokines. The identification of human mAbs that cross-reacted with canine cytokines may support their use as immunological biomarkers in veterinary medicine studies. The identification of these 11 anti-human cytokine mAbs that cross-reacted with canine cytokines will be useful immunological biomarkers for pathological conditions by flow cytometry and fluorescence microscopy in dogs.


Reconstructive surgery of postinfarction left ventricular aneurysms: techniques and unsolved problems.
The progress in the surgical treatment of postinfarction left ventricular (LV) aneurysm surgery has reduced the operative mortality considerably, while the selection of the optimal LV repair technique remains unclear. Any of the surgical techniques presented in this review has its own advantages and disadvantages. The main goal of this study was to perform a selective literature review of LV aneurysm repair techniques, the most widespread being the linear repair and patch ventriculoplasty.


The evolutionary origin of the vasopressin/V2-type receptor/aquaporin axis and the urine-concentrating mechanism.
In this mini-review, current evidence for how the vasopressin/V2-type receptor/aquaporin axis developed co-evolutionary as a crucial part of the urine-concentrating mechanism will be presented. The present-day human kidney, allowing the concentration of urine up to a maximal osmolality around 1200 mosmol kg(-1)-or urine to plasma osmolality ratio around 4-with essentially no sodium secreted is the result of up to 3 billion years evolution. Moving from aquatic to terrestrial habitats required profound changes in kidney morphology, most notable the loops of Henle modifying the kidneys from basically a water excretory system to a water conserving system. Vasopressin-like molecules has during the evolution played a significant role in body fluid homeostasis, more specifically, the osmolality of body liquids by controlling the elimination/reabsorption of fluid trough stimulating V2-type receptors to mobilize aquaporin water channels in the renal collector tubules. Recent evidence supports that all components of the vasopressin/V2-type receptor/aquaporin axis can be traced back to early precursors in evolutionary history. The potential clinical and pharmacological implications of a better phylogenetic understanding of these biological systems so essential for body fluid homeostasis relates to any pathological aspects of the urine-concentrating mechanism, in particular deficiencies of any part of the vasopressin-V2R-AQP2 axis causing central or nephrogenic diabetes insipidus-and for broader patient populations also in preventing and treating disturbances in human circadian regulation of urine volume and osmolality that may lead to enuresis and nocturia.


Distribution of neutralizing antibodies to California and Bunyamwera serogroup viruses in horses and rodents in California.
Neutralization tests were done on sera from 141 horses from high elevation regions of California. Antibody prevalences to Jamestown Canyon, snowshoe hare, and California encephalitis viruses in the California serogroup and Northway virus in the Bunyamwera serogroup were 55%, 43%, 18%, and 46%, respectively. In 51 horses from rural low elevation regions, seroprevalences were 31%, 35%, 35%, and 37%, respectively. Twenty-four horses from a suburban lowland area were seronegative, except for a single horse with a low titer to snowshoe hare virus. Seroprevalence to Jamestown Canyon and snowshoe hare viruses was associated with increasing age. Only 2 of 177 rodents from the Sierra Nevada had antibodies to Northway virus; none had antibodies to Jamestown Canyon or snowshoe hare viruses.


The Antitumor Activity of a Novel Fluorobenzamidine against Dimethylhydrazine- Induced Colorectal Cancer in Rats.
Colorectal cancer is among the leading causes of death worldwide. The incidence of deaths is expected to be 11.4 million in 2030. We aimed to evaluate the in vitro and in vivo antioxidant and antitumor activities of a novel Bithiophene- Fluorobenzamidine (BFB) against DMH-induced colorectal cancer in rats. The antiproliferative activity of BFB against HCT-116 colon cancer cells and apoptotic genes was assessed. In vivo study was also conducted in which 80 adult male rats were divided into 5 groups; control, BFB, and the other 3 groups were injected with DMH (20mg/kg, s.c., for 9 weeks). Group 4 was injected with 5 doses of cisplatin (2.5mg/kg, i.p over 21 weeks) and group 5 was injected with 3 doses/week of BFB (2.5mg/kg, i.p, for 21 weeks). BFB exhibited weak to moderate in vitro antioxidant activity. It had a strong antiproliferative activity with IC50 ~0.3µg/ml. BFB induced extrinsic apoptosis through the upregulation of FasL, TRAL, p53 and caspase-8, and intrinsic apoptosis through the downregulation of Bcl-2 and survivin. BFB decreased the tumor incidence, multiplicity and size and improved the decreased body weight. BFB also ameliorated the functions of kidney and liver and antioxidants deteriorated by DMH. BFB significantly improved the pathological changes caused by DMH in colon tissues. BFB showed a very promising antitumor activity against colorectal cancer induced by DMH in rats without causing hepato- or nephrotoxicity.


Aneurysm of atrial septum associated with rheumatic mitral stenosis simulating tumour of right atrium.
We present a case of aneurysm of interatrial septum associated with rheumatic mitral stenosis, which supports the theory that claims that the pressure gradient between the atriums plays an important part in its aetiology. The angiographic image of a filling defect in the right atrium may cause an erroneous diagnosis of atrial tumour. The levophase of right angiography and cross-sectional echocardiography confirmed the diagnosis of aneurysm of interatrial septum.


Primary pancreatic lymphoma forming a giant mass in a short period: A case report.
A 69 year old man with chief complaints of vomiting and nausea was referred to our hospital. Ultrasonographic examination on 19 May 1998 showed a hypoechoic homogeneous mass 6 cm in diameter in the head of the pancreas. Degree of intravascular infiltration was angiographically mild despite its large size. Tumor-marker levels were normal. On 9 August 1998, however, ultrasonography showed the mass to have rapidly grown (10 cm in diameter) including a heterogeneous internal structure. The mass had a linear or branching signal pattern.


2-(4-Methyl-phen-yl)-6-nitro-1,3-benzoxazole.
The title compound, C14H10N2O3, is a π-conjugated mol-ecule containing a benzoxazole aromatic fused heterobicycle. The benzoxazole ring system is planar within 0.01 Å. The mol-ecule assumes an approximately flat conformation, the benzoxazole ring system forming dihedral angles of 6.52 (12) and 7.4 (3)° with the benzene ring and the nitro group, respectively. In the crystal, mol-ecules are connected by very weak C-H⋯O hydrogen inter-actions, forming chains running parallel to the a or c axes. The methyl H atoms are disordered over two sets of sites of equal occupancy rotated by 60°.


Effects of ozone exposure on inactivation of intra- and extracellular enterovirus 71.
In this study, the potential of ozone in inactivating enterovirus 71 (EV71) free particles was investigated using either various ozone flow rates of 100, 80 or 60 mg/h or a constant flow rate of 80 mg/h, given to culture medium or various pH culture media containing EV71, respectively. Results demonstrated that EV71 inactivation by ozone was related to the kinetics of ozone solubility, approximately 99% inactivation being obtained in the exponential phase of ozone solubility. However, the inactivation rate was dependent on the ozone input flow rate and positively enhanced at acidic pH. Inactivation of intracellular EV71 was also studied. At a constant ozone supply of 60 mg/h, a significant reduction of intracellular virus titer (> or =99%, p < 0.01) was obtained after 45 or 60 min exposure but with low cell viability. Upon 30 min exposure, however, 45% cell viability was retained. The results indicate that the inactivating effect of ozone on intracellular EV71 virus is dependent on exposure duration.


Two successive magneto-structural transformations and their relation to enhanced magnetocaloric effect for Ni55.8Mn18.1Ga26.1 Heusler alloy.
In the present work, two successive magneto-structural transformations (MSTs) consisting of martensitic and intermartensitic transitions have been observed in polycrystalline Ni55.8Mn18.1Ga26.1 Heusler alloy. Benefiting from the additional latent heat contributed from intermediate phase, this alloy exhibits a large transition entropy change ΔStr with the value of ~27 J/kg K. Moreover, the magnetocaloric effect (MCE) has been also evaluated in terms of Maxwell relation. For a magnetic field change of 30 kOe, it was found that the calculated value of refrigeration capacity in Ni55.8Mn18.1Ga26.1 attains to ~72 J/kg around room temperature, which significantly surpasses those obtained for many Ni-Mn based Heusler alloys in the same condition. Such an enhanced MCE can be ascribed to the fact that the isothermal entropy change ΔST is spread over a relatively wide temperature interval owing to existence of two successive MSTs for studied sample.


Hepatoblast-like cells enriched from mouse embryonic stem cells in medium without glucose, pyruvate, arginine, and tyrosine.
In order to enrich hepatocytes differentiated from embryonic stem cells, we developed a novel medium. Since only hepatocytes have the activity of ornithine transcarbamylase, phenylalanine hydroxylase, galactokinase, and glycerol kinase, we expected that hepatocytes would be enriched in a medium without arginine, tyrosine, glucose, and pyruvate, but supplemented with ornithine, phenylanaline, galactose, and glycerol (hepatocyte-selection medium, HSM). Embryoid bodies were transferred onto dishes coated with gelatin in HSM after 4 days of culture. At 18 days after embryoid body formation, a single type of polygonal cell survived with an enlarged intercellular space and micorvilli. These cells were positive for indocyanine green uptake and for mRNAs of albumin, transthyretin, and alpha-feto protein, but negative for mRNAs of tyrosine aminotransferase, alpha1-antitrypsin, glucose-6-phosphatase, and phosphoenol pyruvate carboxykinase. Since cells in HSM were positive for cytokeratin (CK)8 and CK18 (hepatocyte markers) and for CK19 (a marker of bile duct epithelial cells), we concluded that they were hepatoblasts. They showed weaker expression of CCAAT/enhancer-binding protein (C/EBP)alpha than fetal liver (18.5 days of gestation) and expression of C/EBPbeta at a similar level to that of fetal liver. These data support our conclusion that HSM allows the selection of hepatoblast-like cells.


Association of SV40 with human tumors.
In 1994, PCR and protein studies suggested that SV40 DNA sequences and proteins were present in 29/48 (60%) USA human mesothelioma samples. Sequence analysis confirmed that the sequences were homologous to SV40. One year later, SV40 was also found in 5/9 human mesotheliomas, and in 1996 SV40 was also reported to be present in 1/3 of the tumor specimens examined. These reports, in combination with an earlier study in 1992 which had detected SV40 in human brain tumors, raised concerns that SV40 was associated with certain types of human tumors, specifically mesothelioma, bone, and brain tumors. These findings raised concerns, because these tumor types are the same malignancies that had been observed in animals injected with SV40. However, a study in 1996 and a presentation made at the International Mesothelioma Interest Group, IMIG in 1997 failed to detect SV40 in mesotheliomas, suggesting the possibility that laboratory artifacts, such as PCR contamination, had caused the previous positive findings. In 1997, the FDA, the NIH, and the CDC organized an international conference in Bethesda to review the literature and to address the possibility that SV40 was present in, and was possibly the cause of, some human tumors. The results of that conference were reported the same year in a meeting review in Oncogene by Carbone and colleagues. Briefly, the consensus was that before accepting the possibility that SV40 was present in human tumors, a multi-laboratory study needed to be conducted. It was recommended that a blinded multi-laboratory study be directed by an independent scientist not previously associated with the controversial reports of SV40 in human specimens. It was also recommended that this study include laboratories that had reported positive findings as well as laboratories that had failed to detect SV40 in human specimens. Since 1997, about 30 independent reports have been published on this topic, including the multi-laboratory study. Evidence in favor and against a possible association of SV40 with human cancer was reviewed at an international consensus meeting at the University of Chicago on 20, 21 April 2001, entitled "Malignant Mesothelioma: Therapeutic Options and the Role of SV40, 2001". The main focus was the association of SV40 with mesothelioma and other human tumors. At the end of the meeting, a panel discussion, which included independent experts who had not published on this topic, critically reviewed the evidence presented at the meeting. The results of the meeting and of the final panel discussion are outlined below.


The hemizona assay (HZA): development of a diagnostic test for the binding of human spermatozoa to the human hemizona pellucida to predict fertilization potential.
The authors present their initial results with the hemizona assay (HZA), which was developed to predict the fertilizing potential of spermatozoa. The HZA uses the matching halves of a human zona pellucida from a nonfertilizable and nonliving oocyte, providing an internal control on zona-to-zona variability. Maximal binding of human sperm to the hemizona usually occurred after 4 to 5 hours of coincubation. Sperm from fertile men exhibited significantly higher binding capacity to hemizonae compared with sperm from men who had fertilization failure during in vitro fertilization (IVF) treatment. The HZA index is calculated as follows: (bound sperm from subfertile male) divided by (bound sperm from fertile male) X 100. These findings demonstrate that the HZA may be a useful diagnostic tool in male infertility evaluations.


Pterostilbene attenuates intrauterine growth retardation-induced colon inflammation in piglets by modulating endoplasmic reticulum stress and autophagy.
Endoplasmic reticulum (ER) stress and autophagy are implicated in the pathophysiology of intestinal inflammation; however, their roles in intrauterine growth retardation (IUGR)-induced colon inflammation are unclear. This study explored the protective effects of natural stilbene pterostilbene on colon inflammation using the IUGR piglets and the tumor necrosis factor alpha (TNF-α)-treated human colonic epithelial cells (Caco-2) by targeting ER stress and autophagy. Both the IUGR colon and the TNF-α-treated Caco-2 cells exhibited inflammatory responses, ER stress, and impaired autophagic flux (P < 0.05). The ER stress inducer tunicamycin and the autophagy inhibitor 3-methyladenine further augmented inflammatory responses and apoptosis in the TNF-α-treated Caco-2 cells (P < 0.05). Conversely, pterostilbene inhibited ER stress and restored autophagic flux in the IUGR colon and the TNF-α-treated cells (P < 0.05). Pterostilbene also prevented the release of inflammatory cytokines and nuclear translocation of nuclear factor kappa B p65, reduced intestinal permeability and cell apoptosis, and facilitated the expression of intestinal tight junction proteins in the IUGR colon and the TNF-α-treated cells (P < 0.05). Importantly, treatment with tunicamycin or autophagosome-lysosome binding inhibitor chloroquine blocked the positive effects of pterostilbene on inflammatory response, cell apoptosis, and intestinal barrier function in the TNF-α-exposed Caco-2 cells (P < 0.05). Pterostilbene mitigates ER stress and promotes autophagic flux, thereby improving colon inflammation and barrier dysfunction in the IUGR piglets and the TNF-α-treated Caco-2 cells.


Stability of rat skin collagen during recovery from under-nutrition.
The growth of young rats was arrested for 6 weeks from 48 h after receiving an injection of L-[5-3H]proline. The 3H in the hydroxyproline of the newly synthesized skin collagen remained steady during under-nutrition and did not decrease during the subsequent recovery period. It was concluded that in this animal model the renewed growth did not induce degradation of the pre-existing collagen fibres.


Effect of neurokinin-1 receptor antagonists on serotoninergic, noradrenergic and hippocampal neurons: comparison with antidepressant drugs.
Neurokinin-1 (NK1) receptor antagonists have been reported to possess antidepressant and anxiolytic properties in controlled trials. Since antidepressant and anxiolytic drugs act mainly by enhancing serotonin (5-HT) and norepinephrine (NE) neurotransmission in forebrain areas, the main focus of the present review is to critically examine the electrophysiological effects of NK1 receptor antagonists on serotoninergic and noradrenergic neurons, and then hippocampal neurons. It is concluded that NK1 antagonists increase the firing and burst activity of 5-HT neurons, increase burst activity of NE neurons, and modulate postsynaptic transmission at the hippocampus level. Further research is needed in order to develop more selective ligands for the human NK1 receptor and to gain better knowledge of required brain penetration and optimal pharmacodynamic conditions for their use in patients.


[The efficacy of care as perceived by adolescents presenting anxiety-based school refusal].
School refusal is a complex disorder which is sometimes difficult to treat and which has potentially significant consequences on the child's schooling and mental health. A qualitative study was carried out in 2014-2015 on the feelings of adolescents and their parents with regard to the efficacy of care. The results show that, while adolescents and parents do not share the same representation of the care objectives, they agree on the therapeutic levers identified as been effective: time and relationships.


How carbohydrates sculpt cells: chemical control of morphogenesis in the yeast cell wall.
In budding yeast, the neck that connects the mother and daughter cell is the site of essential functions such as organelle trafficking, septum formation and cytokinesis. Therefore, the morphology of this region, which depends on the surrounding cell wall, must be maintained throughout the cell cycle. Growth at the neck is prevented, redundantly, by a septin ring inside the cell membrane and a chitin ring in the cell wall. Here, we describe recent work supporting the hypothesis that attachment of the chitin ring, which forms at the mother-bud neck during budding, to β-1,3-glucan in the cell wall is necessary to stop growth at the neck. Thus, in this scenario, chemistry controls morphogenesis.


The Hamburg Stroke Data Bank: goals, design and preliminary results.
A stroke data bank has been developed which consists of 1500 items, including clinical and laboratory findings, past medical history, treatment and outcome. In addition to previously published registries, the Hamburg Stroke Data Bank allows storage of time-dependent data: multiple findings can be entered at different times after stroke onset. The data bank runs on any MS-DOS microcomputer and can be operated without computer knowledge. The stroke registry is conceived to support a prospective, local, multicentre study of stroke. This paper describes objectives, data bank structure and preliminary results of the pilot phase, which includes data of 441 patients with completed stroke and reversible ischaemic deficits. Demographic characteristics, incidence of stroke types, associated risk factors and outcome are evaluated.


A prospective study of managers' turnover and health in a healthcare organization.
To assess turnover and health of Swedish healthcare managers, and identify important supporting factors relating to work and individual resources. Individual managers' own sustainability in terms of turnover and health may be influenced by managerial working conditions and individual resources. A 4-year prospective questionnaire study of 216 healthcare managers. Turnover and indicators of good health (healthy work attendance and no burnout) were related to work factors and individual resources using Cox regressions with constant time at risk. Forty per cent of the healthcare managers had left after 4 years. Fifty-two per cent had a healthy work attendance record and the proportion with no burnout had increased. Experiencing moderate/high job control was a predictor of remaining in the managerial position. Good health was predicted by having energy left for domestic work and being thoroughly rested after sleep. Managerial turnover seems high in Swedish healthcare and linked to working conditions, while sustained health are linked to individual resources. Healthcare organizations should focus not only on developing individuals in their managerial role but also on strengthening the conditions that allow managers to exercise their leadership and to ensuring that the managers most suitable for their posts do not leave.


Experimental bladder substitution using a biodegradable graft of natural tissue.
A controlled canine experimental study has been performed to test the application of a biodegradeable graft to vesical augmentation. The graft, after providing initial bladder enlargement, is progressively reabsorbed while serving as a foundation for the regeneration and healing of the layers of the bladder remnant. Follow-up studies at 1 year revealed no urinary infection, calculi, extravasation of urine, or rejection of the material. Normal bladder capacities were maintained throughout the study and the reconstructed bladders functioned normally. The biodegradable graft was equally successful when applied either to a histologically normal bladder remnant, or to a pathological bladder of intramural fibrosis. These results suggest that this material may be well suited to clinical bladder substitution in humans.


Small but mighty: the causes and consequences of micronucleus rupture.
Micronuclei are small DNA-containing nuclear structures that are spatially isolated from the main nucleus. They are frequently found in pathologies, including cancer. It was recently shown that these nuclear structures are not only biomarkers of disease but also play an active role in tumor biology. Many consequences of micronucleus formation on tumor biology are dependent on the frequent and irreversible rupture of their nuclear envelopes, which results in the exposure of their DNA contents to the cytoplasm. In this review, we discuss models of defective nuclear envelope deposition on missegregated chromosomes that lead to nuclear envelope rupture. Furthermore, we expound upon the various downstream consequences of micronucleus nuclear envelope rupture on cells. These consequences include a massive DNA rearrangement phenomenon called chromothripsis and activation of the cGAS-STING innate immune signaling pathway, which can be a double-edged sword with tumorigenesis and tumor prevention functions. Although micronuclei are small structures, the impact they have on cells and their microenvironment is quite large.


Tristriazolotriazines: a core for luminescent discotic liquid crystals.
The synthesis and structural, thermal, optical and theoretical characterization of new tris[1,2,4]triazolo[1,3,5]triazines were performed to support their application as liquid crystals and advanced materials.


Combined pancreas and liver therapies: resection and ablation in hepato-pancreatico-biliary malignancies.
Combined pancreatic and liver resection for hepato-pancreatico-biliary disease is generally considered contraindicated since it is thought to provide little if any survival benefit with high risk of morbidity. Our goal was to review our experience with combined pancreatic and liver resections to better define characteristics that increase risk for perioperative complications after combined resections. A review of prospectively collected IRB approved hepato-pancreatico-biliary database was performed from October 2002 to April 2012. Twenty-one cases were identified including all histologies. Perioperative outcomes were examined and the overall mean length of stay was 12.1 days (range: 6-26 days) and no perioperative mortalities (<90 days) were observed. With respect to morbidity 43% of patients experienced any grade of complication, 29% were Grade 3 with no Grade 4 or 5 complications noted. We found a statistically indicated association between BMI > 25 and risk of Grade 3 complications (P = 0.149). The median survival following operation was 11 months (range: 3-148 months). Combined pancreas and liver resection for metastatic disease should only be considered in highly selected patients. Tumor histology as well as BMI > 25 (overweight and obese patients) should be considered in the decision making process in an effort to minimize surgical morbidity while potentially improving survival.


Effects of mechanical forces and stretch on intercellular gap junction coupling.
Mechanical forces provide fundamental physiological stimulus in living organisms. Recent investigations demonstrated how various types of mechanical load, like strain, pressure, shear stress, or cyclic stretch can affect cell biology and gap junction intercellular communication (GJIC). Depending on the cell type, the type of mechanical load and on strength and duration of application, these forces can induce hypertrophic processes and modulate the expression and function of certain connexins such as Cx43, while others such as Cx37 or Cx40 are reported to be less mechanosensitive. In particular, not only expression but also subcellular localization of Cx43 is altered in cardiomyocytes submitted to cyclic mechanical stretch resulting in the typical elongated cell shape with an accentuation of Cx43 at the cell poles. In the heart both cardiomyocytes and fibroblasts can alter their GJIC in response to mechanical load. In the vasculature both endothelial cells and smooth muscle cells are subject to strain and cyclic stretch resulting from the pulsatile flow. In addition, vascular endothelial cells are mainly affected by shear stress resulting from the blood flow parallel to their surface. These mechanical forces lead to a regulation of GJIC in vascular tissue. In bones, osteocytes and osteoblasts are coupled via gap junctions, which also react to mechanical forces. Since gap junctions are involved in regulation of cell growth and differentiation, the mechanosensitivity of the regulation of these channels might open new perspectives to explain how cells can respond to mechanical load, and how stretch induces self-organization of a cell layer which might have implications for embryology and the development of organs. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions.


Changes in pain and other symptoms in patients with painful multiple myeloma-related vertebral fracture treated with kyphoplasty or vertebroplasty.
Patients with painful vertebral compression fractures produced by multiple myeloma (MM) often experience reduction in pain after spinal augmentation with kyphoplasty or vertebroplasty. Previous studies have shown pain reduction and improvement in functional status after augmentation, but no studies have examined the effect of augmentation on other cancer-related symptoms. We hypothesized that reduction in pain severity would be significantly associated with improvement in other reported symptoms. We retrospectively studied 79 patients who rated pain and symptom severity both before and after kyphoplasty or vertebroplasty. Pain was significantly reduced after spinal augmentation (1.3 on a 0 to 10 scale; effect size [ES] = .59; P < .001), as were anxiety (1.3; ES = .47), drowsiness (1.3; ES = .39), fatigue (1.1; ES = .32), depression (.7; ES = .28), and difficulty thinking clearly (.7; ES = .26) (all P < .05). Greater reduction in pain was associated with a greater number of symptoms being reduced. Interestingly, insomnia worsened regardless of any amount of improvement in pain. Because appropriate symptom control contributes to the overall well-being of cancer patients, future studies of pain reduction procedures should include measures of other symptoms to fully characterize the potential benefit of treating pain. Appropriate symptom control contributes to overall well-being for cancer patients. This study demonstrated that pain reduction after spinal augmentation with vertebroplasty or kyphoplasty was positively associated with reduction in other patient-reported cancer-related symptoms. Future studies of these augmentation procedures should measure multiple symptoms, in addition to pain and functional status.


Midbrain disconnection: an aetiology of severe central neonatal hypotonia.
A full term girl exhibited massive hypotonia related to severe posterior fossa abnormalities consisting of pontocerebellar hypoplasia with midbrain disconnection. The latter was due to lack of one and marked hypoplasia of the other cerebral peduncles. In addition, there was mild vermian and cerebellar hypoplasia. Compared to usual pontocerebellar hypoplasia, the midbrain disconnection is a distinctive feature of our case. It is a rare malformation only three similar cases have previously been described.


The radioimmunoassay of placental protein 5 and circulating levels in maternal blood in the third trimester of normal pregnancy.
A radioimmunoassay has been developed for placental protein 5 (PP5), a product of the human placenta. Circulating concentrations of PP5 were measured in the third trimester of normal pregnancy in 400 women. Concentrations of PP5 showed a skewed distribution and rose progressively to reach a plateau in the last four weeks of pregnancy. The development of this assay will permit studies on the potential clinical application of maternal PP5 levels during normal and abnormal pregnancy.


Technical aspects and complications of end-ileostomies.
During a period of 10 years (1980-1990) we constructed or reconstructed 358 end-ileostomies: 224 were primary constructions, 96 were reconstructed by laparotomy, and 38 were local reconstruction. Only 2 ileostomies were primarily located on the left side. The mean length was 5 cm. We had 11.6% reoperations after primary stomy and 7.3% and 7.9% reoperations after reconstruction by laparotomy and local approach, respectively. There were 12.9% and 8.7% reoperations after emergency and elective primary operations, respectively. Closing the lateral gutter or fixation of ileum to the rectus fascia did not influence significantly the number of reoperations. Postoperative discolored stomy did not indicate more dysfunction of the ileostomy. Stenosis of the ileostomy, peristomal fistulas, and peristomal dermatitis were seen in 23 (10.3%), 21 (9.4%), and 18 (8%) of the patients after primary ileostomies, respectively. Patients with Crohn's disease had significantly more of these problems than patients with ulcerative colitis. Only a few patients had retraction of the ileostomy (2.7%), stomal prolapse (1.8%), or parastomal herniation (1.8%). Women had significantly more parastomal herniation than men; otherwise there were no differences between the sexes.


A novel substance P pathway linking the dorsal and ventral horn in the upper lumbar segments of the rat spinal cord.
We report here the presence of a novel substance P pathway existing at a segmental level in the upper lumbar region (L1/L2) of the rat spinal cord. Substance P-containing fibres were seen directly linking a number of discrete areas of the rat spinal cord, including dorsal and ventral regions. These fibers were found closely associated with a specific group of motoneurones, the mediolateral motor nucleus in the ventral horn. This motoneurone group appeared as a 'focusing' nucleus around which substance P-containing tracts appeared to congregate. An intrinsic spinal cord origin of substance P-containing neurones in these interconnecting pathways is suggested as deafferentation achieved either by section of appropriate dorsal roots, or pharmacologically by neonatal treatment with capsaicin, had no effect on the appearance of the nucleus in the ventral spinal cord or of the associated substance P-containing tracts. Likewise, mid-thoracic lesions of the spinal cord (to determine supraspinal contributions) including hemisection, dorsolateral funiculus lesions and lesions of the region around the central canal, induced no change. The significance of these interconnecting substance P-immunoreactive fibre tracts is not known. However, the intimate association of substance P-containing fibres with a specific group of motoneurons indicates that they may modulate motor function.


Focal hepatic glycogenosis associated with metastatic insulinoma presenting as mass lesions.
One of the important functions of the liver is glycogen storage. Most processes associated with increased hepatic glycogen, or glycogenoses, are metabolic and affect the entire liver leading to diffuse glycogenosis. We present a case in which the liver contained multiple small pale nodules that on initial assessment were recognized to be composed of glycogenated hepatocytes. Most of the known causes of hepatic glycogenosis were not pertinent to this case. After cutting many deeper levels and obtaining additional sections, small foci of insulinoma were revealed in the center of each of these lesions. The glycogenosis surrounding the foci of insulinoma can be best explained as a local effect of insulin on the hepatocytes, a phenomenon that has been previously described in primate models, but not in human subjects. Here, we report the first case of metastatic insulinoma causing local hepatic glycogenosis.


Depot-medroxyprogesterone acetate: an update.
Depo-Provera is a contraceptive approved by the US Food and Drug Administration (FDA) since 1992 and used worldwide by more than 90 million women. Despite the fact that progestins are endogenous hormones that are secreted by the body, its excess might lead to detrimental health effects. Whether progestins as contraceptives are friends or foes is a questionable matter. In this manuscript, we drive the attention to both usage and side effects Depo-Provera. Depot-medroxyprogesterone acetate (DMPA) is a highly effective, convenient non-daily hormonal contraceptive option that has been available worldwide for many years. The experience with DMPA provides a large body of long-term data regarding the efficacy and safety of this contraceptive method; this long-term experience has established that the use of DMPA does not increase the risk of cardiovascular events, breast cancer, other gynecologic malignancy, or postmenopausal fracture; however, patients are often more concerned about the relatively immediate effects of contraceptives such as potential changes in menstrual cycle, body weight, and mood disturbances. Concerns about such issues may lead to reluctance to initiate therapy or premature discontinuation. Counseling and understanding of women's concerns and experiences using Depo-Provera is important and could help health care providers redesign counseling strategies to improve contraceptive continuation and improve patient adherence.


Analgesic effects of intrathecal tramadol in patients undergoing caesarean section: a randomised, double-blind study.
Intrathecal tramadol combined with local anaesthetics has been used for postoperative analgesia following lower abdominal and perineal surgery. The present study evaluated the effect of intrathecal tramadol on spinal block characteristics and neonatal outcome after elective caesarean section. Eighty full-term parturients scheduled for elective caesarean section were randomly divided into two groups. In the fentanyl group, patients received intrathecal 0.5% bupivacaine 10 mg with fentanyl 10 μg; in the tramadol group, patients were given the same dose of bupivacaine with tramadol 10 mg. Sensory and motor block characteristics, duration of postoperative analgesia, maternal side effects, and neonatal outcome were compared. One patient in the tramadol group and two patients in the fentanyl group were excluded from data analysis. Median [interquartile range] duration of postoperative analgesia in the tramadol and the fentanyl groups was 300 [240-360] min and 260 [233-300] min respectively (P = 0.02). The incidence of shivering was lower in patients who received tramadol (5%) than those who had fentanyl (32%) (P = 0.003). Apgar scores, umbilical cord acid-base measurement and neurologic and adaptive capacity scores were comparable between the two groups. Compared to intrathecal fentanyl 10 μg, tramadol 10 mg, as an adjunct to bupivacaine for subarachnoid block for caesarean section, showed a longer duration of analgesia with a reduced incidence of shivering.


Clinical implications of left atrial function assessed by speckle tracking echocardiography.
Left atrial (LA) function has a significant impact on cardiovascular diseases and has been assessed by several noninvasive methods. However, several limitations, including the dependence of image quality, single plane assessment, and time-consuming procedures, have prevented widespread clinical application of the assessment of LA function. Strain imaging using tissue Doppler echocardiography enables quantification of LA function. Recently, two-dimensional speckle tracking echocardiography (2D-STE) has been developed as a noninvasive, simple, and reproducible tool for assessment of LA function in patients with cardiovascular disease. 2D-STE enables detection of early LA dysfunction even before LA morphological changes. LA dysfunction determined by 2D-STE can provide additional prognostic information to conventional echocardiographic parameters in patients with cardiovascular diseases. Hence, 2D-STE appears to be a promising technique for diagnosis and therapeutic decision-making. However, standardization of analysis techniques and software applications of 2D-STE is still lacking. Here, we review recent studies on clinical implications of LA function assessed by 2D-STE and summarize the remaining problems to be solved to improve the clinical utility of this tool.


Detection of Hypoxia-Induced and Iron Depletion-Induced Mitophagy in Mammalian Cells.
Mitochondrial quality and quantity are not only regulated by mitochondrial fusion and fission but also by mitochondria degradation. Mitophagy, an autophagy specific for damaged or unnecessary mitochondria, is believed to be an important pathway for mitochondrial homeostasis. To date, several stimuli are known to induce mitophagy. Some of these stimuli, however, including hypoxia, iron depletion, and nitrogen starvation, induce mild mitophagy, which is difficult to detect through decreased mitochondrial mass. Recently, we have clearly detected mitophagy induced under these conditions using mito-Keima as a reporter. In this chapter, we describe the protocols for induction and detection of hypoxia-induced and iron depletion-induced mitophagy using mito-Keima-expressed cells.


Epidemiology, clinical profile and treatment patterns of venous thromboembolism in cancer patients in Taiwan: a population-based study.
Venous thromboembolism (VTE) is a clinically significant complication that is well documented among Caucasian cancer patients. However, evidence regarding VTE incidence and treatment among Asian cancer patients is very limited. The objective of this study is to investigate the incidence, risk factors and management of VTE among Taiwanese cancer patients. Using Taiwan's National Health Insurance Research Database, we identified 43,855 newly diagnosed cancer patients between 2001 and 2008. Two alternative algorithms for identifying VTE event were explored to better quantify a range of incidence rates of VTE in our cancer patients. Multivariable logistic regression models were used to explore VTE risk factors. The incidence rates of VTE were 9.9 (algorithm 1) and 3.4 (algorithm 2) per 1,000 person-years, respectively. The incidence rates were higher in certain cancers, particularly liver, pancreas, and lung. Significant risk factors for VTE were site of cancer, prior history of VTE, chemotherapy and major surgeries. Long-term anticoagulant therapy was initiated in 64.1% patients with VTE and 72.2% of them received warfarin alone. Approximately two-thirds of patients with VTE received ≤ 3 months of anticoagulant therapy. Incidence of cancer-related VTE is lower among Taiwanese compared to Caucasian populations. Nevertheless, risk factors for cancer-related VTE found in our study were consistent with current literature.


Glisson's capsule matrix structure and function is altered in patients with cirrhosis irrespective of aetiology.
Glisson's capsule is the interstitial connective tissue that surrounds the liver. As part of its normal physiology, it withstands significant daily changes in liver size. The pathophysiology of the capsule in disease is not well understood. The aim of this study was to characterise the changes in capsule matrix, cellular composition, and mechanical properties that occur in liver disease and to determine whether these correlate with disease severity or aetiology. Samples from ten control patients, and six with steatosis, seven with moderate fibrosis, and 37 with cirrhosis were collected from autopsies, intraoperative biopsies, and liver explants. Matrix proteins and cell markers were assessed by staining and second harmonic generation imaging. Mechanical tensile testing was performed on a test frame. Capsule thickness was significantly increased in cirrhotic samples compared with normal controls irrespective of disease aetiology (70.12 ± 14.16 μm and 231.58 ± 21.82 μm, respectively), whereas steatosis and moderate fibrosis had no effect on thickness (90.91 ± 11.40 μm). Changes in cirrhosis included an increase in cell number (fibroblasts, vascular cells, infiltrating immune cells, and biliary epithelial cells). Key matrix components (collagens 1 and 3, hyaluronan, versican, and elastin) were all deposited in the lower capsule, although only the relative amounts per area of hyaluronan and versican were increased. Organisational features, including crimping and alignment of collagen fibres, were also altered in cirrhosis. Unexpectedly, capsules from cirrhotic livers had decreased resistance to loading compared with controls. The liver capsule, similar to the parenchyma, is an active site of disease, demonstrating changes in matrix and cell composition as well as mechanical properties. We assessed the changes in composition and response to stretching of the liver outer sheath, the capsule, in human liver disease. We found an increase in key structural components and numbers of cells as well as a change in matrix organisation of the capsule during the later stages of disease. This allows the diseased capsule to stretch more under any given force, suggesting that it is less stiff than healthy tissue.


COVID-19 effects on diet, sleep, and physical activity among mid- to late-adolescents residing in the deep south in the United States.
This study investigated the differential impact of COVID-19 on United States (US) adolescents' physical health as a function of sociodemographic factors over 18 months. It was hypothesized that the impact of COVID-19 and its mitigation efforts on physical health factors would vary by sociodemographic factors. Data were drawn from a longitudinal study in which participants (ages 16 or 18) self-reported sleep, diet, and physical activity over 18months. Participants were enrolled between 2018 and 2022. Participants (n = 190, 73% Black/African American, 53% female) provided 1330 reports over 194 weeks (93 weeks before and 101 weeks after COVID-19 restrictions implementation). Physical health outcomes moderated by demographic factors were measured and assessed over 18 months. Multilevel models and general estimated equations estimated the impact of COVID-19 restrictions on participants' health outcomes. Sleep and physical activity worsened after COVID-19 regardless of moderating factors, but some specific outcomes varied across subgroups. This study diversifies the literature on the impact of COVID-19 and its mitigation measures on adolescents' social health. Further, it is based in the US's Deep South, largely populated by those identifying as Black/African American or of low socioeconomic status. Both subgroups are underrepresented in US-based health outcomes research. COVID-19 directly and indirectly impacted adolescents' physical health. Understanding if and how COVID-19 impacted adolescents' health will inform nursing practice to adapt to and overcome adverse sequelae to promote positive patient health outcomes.


[Blastomogenic action of combined total x-ray irradiation and the administration of 131I on young rats].
The combined irradiation of rats, aged 36--42 days (the thyroid uptake--6900 rad) would induce the development of neoplasms characteristic of each factor exposure. The incidence of thyroid tumors (75.0%) was close to that induced by a separate 131I exposure (72.5%) the thyroid uptake being 6200 rad.


Polypeptide profiles of chlorophyll . protein complexes and thylakoid membranes of spinach chloroplasts.
In addition to the major chlorophyll . protein complexes I and II, two minor chlorophyll proteins have been observed in sodium dodecyl sulfate (SDS))-polyacrylamide gels of spinach chloroplast membranes. These minor pigmented zones appeared to be derived from the light-harvesting chlorophyll a/b . protein and from the reaction centre complex of Photosystem II. Data are presented on the polypeptide profiles of purified digitonin-subschloroplast particles, with special regard to the effect of solubilization temperature and extraction of lipids. The results are compared with the SDS-polypeptide pattern of spinach thylakoids obtained under exactly the same conditions with respect to electrophoresis technique, solubilization method and presence of lipid. In addition, the effects of temperature and lipid extraction on the distinct chlorophyll . protein complexes appearing in SDS gel electrophoretograms of chloroplast membranes were studied by slicing the chlorophyll-containing regions and subjecting them to a second run with or without heating or extraction with acetone. By supplementing these data with an examination of the polypeptide composition of cytochrome f and coupling factor, it has been possible to identify most of the major chloroplast membrane polypeptides.


IgM response and resistance to ascites tumor growth.
Antibody response and protection against Ehrlich ascites tumor (EAT) was studied in eight EAT-immunized strains of mice (AL/N, BALB/C, C57BL/6J, F1 (C57BL/6 x BALB/C), C57BL/10J, B10.BR, CBA/Ca, SW). The results showed a close association between IgM response and resistance to subsequent tumor challenge. Thus, protection was only achieved in those animals giving a measurable IgM response against EAT cell surface antigens, i.e., all inbred strains of mice tested, except CBA/Ca, and some outbred SW mice. The lack of IgM response to these antigens in CBA/Ca was not linked to the strain H-2 haplotype. Resistance could be passively transferred to nonimmunized mice by means of serum, or purified IgM, from protected immune animals. Moreover, complement depletion by cobra venom factor treatment did not modify the protection afforded to those mice. IgM reactivity to EAT cells was completely abolished by previous cell trypsinization. Trypsin removed but did not destroy the antigen(s) recognized by the IgM, since all its activity could be absorbed with the supernatant of the EAT cell trypsinization. Absorption assays with this supernatant treated with different agents, showed that lipids, simple peptides and nucleic acids were not important components of the antigenic determinants. On the contrary, its susceptibility to beta-galactosidase and particularly to a mild periodate oxidation, suggested that determinants recognized by the IgM against the EAT cell surface are carbohydrate in nature.


With a Little Help from 31P NMR: The Complete Picture on Localized and Long-Range Li+ Diffusion in Li6PS5I.
Li6PS5I acts as a perfect model substance to study length scale-dependent diffusion parameters in an ordered matrix. It provides Li-rich cages which offer rapid but localized Li+ translational jump processes. As jumps between these cages are assumed to be much less frequent, long-range ion transport is sluggish, resulting in ionic conductivities in the order of 10-6 S cm-1 at room temperature. In contrast, the site disordered analogues Li6PS5X (X = Br, Cl) are known as fast ion conductors because structural disorder facilities intercage dynamics. As yet, the two extremely distinct jump processes in Li6PS5I have not been visualized separately. Here, we used a combination of 31P and 7Li NMR relaxation measurements to probe this bimodal dynamic behavior, that is, ultrafast intracage Li+ hopping and the much slower Li+ intercage exchange process. While the first is to be characterized by an activation energy of ca. 0.2 eV as directly measured by 7Li NMR, the latter is best observed by 31P NMR and follows the Arrhenius law determined by 0.44 eV. This activation energy perfectly agrees with that seen by direct current conductivity spectroscopy being sensitive to long-range ion transport for which the intercage jumps are the rate limiting step. Moreover, quantitative agreement in terms of diffusion coefficients is also observed. The solid-state diffusion coefficient D σ obtained from conductivity spectroscopy agrees very well with that from 31P NMR (D NMR ≈ 4.6 × 10-15 cm2 s-1). D NMR was directly extracted from the pronounced diffusion-controlled 31P NMR spin-lock spin-lattice relaxation peak appearing at 366 K.


JAK2(V617I) results in cytokine hypersensitivity without causing an overt myeloproliferative disorder in a mouse transduction-transplantation model.
A germline JAK2(V617I) point mutation results in hereditary thrombocytosis and shares some phenotypic features with myeloproliferative neoplasm, a hematologic malignancy associated with a somatically acquired JAK2(V617F) mutation. We established a mouse transduction-transplantation model of JAK2(V617I) that recapitulated the phenotype of humans with germline JAK2(V617I). We directly compared the phenotypes of JAK2(V617I) and JAK2(V617F) mice. The JAK2(V617I) mice had increased marrow cellularity with expanded myeloid progenitor and megakaryocyte populations, but this phenotype was less severe than that of JAK2(V617F) mice. JAK2(V617I) resulted in cytokine hyperresponsiveness without constitutive activation in the absence of ligand, whereas JAK2(V617F) resulted in constitutive activation. This may explain why JAK2(V617I) produces a mild myeloproliferative phenotype in the mouse model, as well as in humans with germline JAK2(V617I) mutations.


What are the policy and program implications of individual budget style service models for low-income older renters?
To explore the policy and program implications of the Australian aged care reforms for low-income older renters. Interviews and focus groups with low-income older renters and service providers of both housing and in-home aged care were undertaken. Analysis of the findings emphasised the complex world of aged care service provision, particularly for low-income renters and their service providers. Societal, systemic and systematic change is required to ensure easier access to services. Policy and programming must be driven from both the bottom up and the top down, and not take a "market-making by government" approach.


Assessment of Kidney Function in Patients With Extreme Obesity: A Narrative Review.
To discuss the evidence and caveats associated with estimated and measured creatinine clearance (eClCr and mClCr) and glomerular filtration rate (eGFR and mGFR) assessments of kidney function in patients with more extreme forms of obesity. PubMed (1976 to mid-May 2020) was used, with bibliographies of retrieved articles searched for additional articles. Articles using gold standard mGFR to evaluate eClCr, mClCr, and eGFR assessments of kidney function in patients with more extreme forms of obesity were included. The overestimation of GFR by mClCr is well established, but mClCr is an alternative to mGFR assessments for determining medication dosing in patients with extremes of body size or muscle mass, or in patients receiving narrow therapeutic index medications when eGFR is likely to be inaccurate. The vast majority of studies comparing eGFR assessments with gold standard indicators of kidney function were attempts to validate eGFR equations for diagnosing and staging chronic kidney disease (CKD). For dosing medications in patients with stable kidney function and extreme obesity, a deindexed 4-variable Modification of Diet in Renal Disease or CKD Epidemiology Collaboration equation is an alternative to Cockcroft-Gault. Consistent use of the same equation by provider and between providers within any given setting is of paramount importance. In patients with extreme obesity and stable kidney function, eClCr or eGFR using deindexed values provides estimates of function for dosing adjustments of medications with elimination by the kidneys, but more research is needed with respect to the best size descriptor to use with estimating equations.


Change in body weight after hormone replacement therapy in postmenopausal women is dependent on basal circulating leptin.
To address the effect of leptin in the modulation of change in body weight after hormone replacement therapy (HRT), we prospectively examined the responses of body weight and serum leptin after estrogen-progestin replacement in postmenopausal women. Subjects consisted of 63 postmenopausal women aged 54-82 years on HRT for osteoporosis. Thirty three of the subjects received 0.3 mg of conjugated equine estrogen (CEE) (group 1) while 30 were on 0.625 mg of CEE daily (group 2). All subjects also took 5 mg of medrogestone acetate and 750 mg elemental calcium supplement daily. Fasting serum leptin was measured by RIA at baseline, 1 and 3 months after treatment. Data were expressed as mean +/- S.E.M. Serum leptin was highly related to body weight both at baseline (r = 0.40, P < 0.001) and after 3 months of HRT (r = 0.42, P < 0.001). When divided the subjects into three equal groups according to baseline leptin levels, it was found that serum leptin significantly decreased in subjects with high baseline leptin at 3 months (-9.4 +/- 5.7%, P < 0.05) while it increased in subjects whose baseline leptin levels were in the lowest tertile at 1 month (33.2 +/- 8.3%, P < 0.001) and 3 month (27.8 +/- 8.3%, P < 0.01). In regards to body weight, those with leptin in the highest tertile demonstrated a reduction of body weight at 3 (-1.9 +/- 0.6%, P < 0.05) and 12 months (-3.2 +/- 0.5%, P < 0.05) after HRT while those whose serum leptin levels were in the lowest and middle tertiles did not demonstrate change in body weight. By repeated measured analysis of variance, it was found that the decrease in body weight in subjects with high serum leptin was independent of the doses of estrogen. Postmenopausal hormone replacement does not cause weight gain. However, it results in a small reduction in body weight particularly in subjects with higher basal leptin concentrations.


Group A streptococcal meningitis: case report and review of the literature.
Group A streptococcus is an uncommon cause of meningitis in children. We report a single case of Group A streptococcus meningitis, in an apparently healthy 6-week-old infant. Twenty-five cases in the English-language literature in the last 25 years and our case are reviewed. The commonest associated illness was otitis media. Of the 25 patients, 24 survived. Antibiotic therapy, which consisted of penicillin in the majority of patients, was effective. Ceftriaxone was an alternative agent. Neurological sequelae were not uncommon. This report emphasizes the fact that Group A streptococcus can cause meningitis in healthy children without apparent recognizable foci of infection.


The detection of heat-aggregated IgG (as a model for immune complexes) by reverse passive haemagglutination using a human monoclonal rheumatoid factor coupled to erythrocytes.
A human monoclonal IgM rheumatoid factor (RF) produced in vitro by an Epstein-Barr virus (EBV)-immortalized cell line was purified by protein A-Sepharose adsorption and coupled by the chromic chloride method to human erythrocytes. The RF-coupled cells were incorporated in reverse passive haemagglutination (RPH) assays to detect immune complexes (IC) using heat-aggregated human IgG as a model system. The sensitivity of the RPH was comparable to an enzyme-linked immunosorbent assay (ELISA) using sheep C1q for the detection of ICs.


New data of spiders (Arachnida, Araneae) of Cyprus. 1. Dysderidae found in caves.
This paper is the first in a series describing the previously unstudied cave spiders from Cyprus. Two new species, Dysderocrateskibrisensis sp. n. and Harpacteakalavachiana sp. n., are described. Detailed morphological descriptions and diagnostic characteristics are presented. This is the first report of the genus Dysderocrates Deeleman-Reinhold & Deeleman, 1988 from Cyprus.


Effect of L-glutamate and kainate on rat cerebellar cGMP levels in vivo.
L-glutamate and kainate administered intracerebroventricularly (i.c.v.) both produced dose-dependent increases in rat cerebellar cGMP. The increased cGMP produced by L-glutamate, but not that produced by kainate, could be completely abolished by the glutamate antagonist glutamate diethylester which had no effect alone. The data suggest that L-glutamate and kainate may be acting upon different sub-populations of glutamate receptors, both of which may be involved in the regulation of cerebellar cGMP levels.


Rational design of polymeric nanozymes with robust catalytic performance via copper-ligand coordination.
Incorporating copper (Cu) ions into polymeric particles can be a straightforward strategy for mimicking copper enzymes, but it is challenging to simultaneously control the structure of the nanozyme and of the active sites. In this report, we present a novel bis-ligand (L2) containing bipyridine groups connected by a tetra-ethylene oxide (4EO) spacer. In phosphate buffer the Cu-L2 mixture forms coordination complexes that (at proper composition) can bind polyacrylic acid (PAA) to produce catalytically active polymeric nanoparticles with well-defined structure and size, which we refer to as 'nanozymes'. Manipulating the L2/Cu mixing ratio and using phosphate as a co-binding motif, cooperative copper centres are realized that exhibit promoted oxidation activity. The structure and activity of the so-designed nanozymes remain stable upon increasing temperature and over multiple cycles of application. Increasing ionic strength causes enhanced activity, a response also seen for natural tyrosinase. By means of our rational design we obtain nanozymes with optimized structure and active sites that in several respects outperform natural enzymes. This approach therefore demonstrates a novel strategy for developing functional nanozymes, which may well stimulate the application of this class of catalysts.


The orientation bandwidth of cyclopean channels.
Orientation bandwidths of cyclopean channels were estimated using a notched noise technique. Observers were presented with random dot stereograms depicting a horizontal or vertical target sinusoidal depth modulation and a mask consisting of sinusoidal depth modulations whose orientations flanked that of the target. Masking reduced as the orientation difference between signal and mask increased. The orientation bandwidth of the masking effect was similar to that found for stimuli defined by luminance contrast, and showed no systematic difference for horizontal and vertical targets. These results suggest that the elongated summation found by Tyler, C. W., and Kontsevich, L. L. (2001). Stereoprocessing of cyclopean depth images: Horizontally elongated summation fields. Vision Research, 41, 2235-2243, for horizontal stimuli occurs after a processing non-linearity.