[The role of genotype, social stress, and season of the year in regulation of hormonal function of murine testis in vitro].
Micropopulations consisting of six male mice of different genotypes were studied (each of lines A/He, CBA/Lac, C57BL/6J, DD, YT, and PT was represented by one male). Interlinear differences in the level of social dominance and the effects of genotype, social hierarchy, and season on in vitro testosterone production by testes were examined under different incubation conditions. The testosterone production was estimated under control conditions and under stimulation with human chorionic gonadotropin (CG). Significant genetic differences in the initial and CG-stimulated testosterone production by testes incubated in vitro were found. By the control production, the genotypes fell into two groups: lines C57BL/6J, A/He, and CBA/Lac had low production of the hormone; lines YT, PT, and DD, high production. By responsiveness of gonads to CG, the genotypes fell into three groups: line CBA/Lac had low testosterone production by testes; lines C57BL/6J, A/He, YT, and DD, line PT, intermediate production; and line PT, high production. The obtained data indicate stability of genetic polymorphism for the responsiveness of testes to gonadotropins, because neither season nor the formation of social hierarchy could significantly change the interlinear differences. In line PT characterized by high hormonal activity of gonads in the control and under stimulation with gonadotropins, males became dominant in a significantly greater number of cases studied during the formation of hierarchy in micropopulations. The dynamics of both control production of a male sex hormone and responsiveness of testes to CG was established in vitro during the formation of social hierarchy; the effects of season on this dynamics were revealed. Specific characteristics of secretory activity of testes were detected in the control and under stimulation with gonadotropins, depending on incubation conditions. Seasonal and genotypic characteristics of the responsiveness of testes to CG were revealed under different incubation conditions. Genotypic characteristics indicate interlinear differences in the degree of inertia of testosterone biosynthesis on exposure to gonadotropins.


Unusual Recognition and Separation of Hydrated Metal Sulfates [M2(μ-SO4)2(H2O)n, M = Zn(II), Cd(II), Co(II), Mn(II)] by a Ditopic Receptor.
A ditopic receptor L1, having metal binding bis(2-picolyl) donor and anion binding urea group, is synthesized and explored toward metal sulfate recognition via formation of dinuclear assembly, (L1)2M2(SO4)2. Mass spectrometric analysis, (1)H-DOSY NMR, and crystal structure analysis reveal the existence of a dinuclear assembly of MSO4 with two units of L1. (1)H NMR study reveals significant downfield chemical shift of -NH protons of urea moiety of L1 selectively with metal sulfates (e.g., ZnSO4, CdSO4) due to second-sphere interactions of sulfate with the urea moiety. Variable-temperature (1)H NMR studies suggest the presence of intramolecular hydrogen bonding interaction toward metal sulfate recognition in solution state, whereas intermolecular H-bonding interactions are observed in solid state. In contrast, anions in their tetrabutylammonium salts fail to interact with the urea -NH probably due to poor acidity of the tertiary butyl urea group of L1. Metal sulfate binding selectivity in solution is further supported by isothermal titration calorimetric studies of L1 with different Zn salts in dimethyl sulfoxide (DMSO), where a binding affinity is observed for ZnSO4 (Ka = 1.23 × 10(6)), which is 30- to 50-fold higher than other Zn salts having other counteranions in DMSO. Sulfate salts of Cd(II)/Co(II) also exhibit binding constants in the order of ∼1 × 10(6) as in the case of ZnSO4. Positive role of the urea unit in the selectivity is confirmed by studying a model ligand L2, which is devoid of anion recognition urea unit. Structural characterization of four MSO4 [M = Zn(II), Cd(II), Co(II), Mn(II)] complexes of L1, that is, complex 1, [(L1)2(Zn)2(μ-SO4)2]; complex 2, [(L1)2(H2O)2(Cd)2(μ-SO4)2]; complex 3, [(L1)2(H2O)2(Co)2(μ-SO4)2]; and complex 4, [(L1)2(H2O)2(Mn)2(μ-SO4)2], reveal the formation of sulfate-bridged eight-membered crownlike binuclear complexes, similar to one of the concentration-dependent dimeric forms of MSO4 as observed in solid state. Finally, L1 is found to be highly efficient in removing ZnSO4 from both aqueous and semiaqueous medium as complex 1 in the presence of other competing Zn(II) salts via precipitation through crystallization. Powder X-ray diffraction analysis has also confirmed bulk purity of complex 1 obtained from the above competitive crystallization experiment.


Two extended arrays of a satellite DNA sequence at the centromere and at the short-arm telomere of Chinese hamster chromosome 5.
We have cloned a Chinese hamster chromosome-specific repeated sequence (SatCH5). This satellite is composed of a 33-bp unit organized in two extended tandem arrays. It is localized at the centromere and at the short-arm subtelomere of chromosome 5. Altogether, SatCH5 covers about 1-2 Mb per diploid genome and is not present in other species, including the Syrian hamster and mouse. Since it is known in the Chinese hamster and numerous other vertebrate species that telomeric (TTAGGG)n repeats are localized at the centromeres of several chromosomes, we studied the localization of SatCH5 relative to (TTAGGG)n sequences. Using two-color fluorescence in situ hybridization on stretched chromosomes and on DNA fibers, we have shown that at the centromere of chromosome 5 SatCH5 and the (TTAGGG)n arrays are contiguous. SatCH5 is the first chromosome-specific repetitive sequence located at both the pericentromeric and subtelomeric regions of the same chromosome.


Chromatin signatures and retrotransposon profiling in mouse embryos reveal regulation of LINE-1 by RNA.
How a more plastic chromatin state is maintained and reversed during development is unknown. Heterochromatin-mediated silencing of repetitive elements occurs in differentiated cells. Here, we used repetitive elements, including retrotransposons, as model loci to address how and when heterochromatin forms during development. RNA sequencing throughout early mouse embryogenesis revealed that repetitive-element expression is dynamic and stage specific, with most repetitive elements becoming repressed before implantation. We show that LINE-1 and IAP retrotransposons become reactivated from both parental genomes after fertilization. Chromatin immunoprecipitation for H3K4me3 and H3K9me3 in 2- and 8-cell embryos indicates that their developmental silencing follows loss of activating marks rather than acquisition of conventional heterochromatic marks. Furthermore, short LINE-1 RNAs regulate LINE-1 transcription in vivo. Our data indicate that reprogramming after mammalian fertilization comprises a robust transcriptional activation of retrotransposons and that repetitive elements are initially regulated through RNA.


"Your Brain Matters": Issues of Risk and Responsibility in Online Dementia Prevention Information.
The Internet has been argued to provide diverse sites for health communication and promotion, including issues that constitute major public health priorities such as the prevention of dementia. In this study, discursive psychology is used to examine how information about dementia risk prevention was presented on the websites of the most prominent English-language, nonprofit dementia organizations. We demonstrate how information about dementia risk and its prevention positions audiences as at-risk of developing dementia and constructs preventive behavior as a matter of individual responsibility. Websites represented participation in certain lifestyle practices as normative and emphasized audience members' personal responsibility for managing dementia risk. It is argued that such representations promote a moral identity in regard to brain health in which an ethic of self-responsibility is central. The implications of such identity construction in a context of increasing prevalence of dementia diagnosis are discussed.


Subretinal Fibrosis Detection Using Polarization Sensitive Optical Coherence Tomography.
Subretinal fibrosis (SRFib) is an important cause of permanent loss-of-vision diseases with submacular neovascularization, but a reliable diagnostic method is currently missing. This study uses polarization-sensitive optical coherence tomography (PS-OCT) to detect SRFib within retinal lesions by measurement of its birefringent collagen fibers. Twenty-five patients were enrolled with retinal pathology in one or both eyes containing (1) suspected SRFib, (2) lesions suspected not to be fibrotic, or (3) lesions with doubtful presence of SRFib. All eyes were evaluated for SRFIb using conventional diagnostics by three retinal specialists. PS-OCT images were visually evaluated for SRFib based on cumulative phase retardation, local birefringence, and optic axis uniformity. Twenty-nine eyes from 22 patients were scanned successfully. In 13 eyes, SRFib was diagnosed by all retinal specialists; of these, 12 were confirmed by PS-OCT and one was inconclusive. In nine eyes, the retinal specialists expected no SRFib, which was confirmed by PS-OCT in all cases. In seven eyes, the retinal specialists' evaluations were inconsistent with regard to the presence of SRFib. PS-OCT confirmed the presence of SRFib in four of these eyes and the absence of SRFib in two eyes and was inconclusive in one eye. In 21 out of 22 eyes, PS-OCT confirmed the evaluation of retinal specialists regarding the presence of SRFib. PS-OCT provided additional information to distinguish SRFib from other tissues within subretinal neovascular lesions in 6 out of 7 eyes. PS-OCT can identify and quantify SRFib in doubtful cases for which a reliable diagnosis is currently lacking.


[Androgen receptor inhibitors in prostate cancer: new drugs, but for which patient?]
The results of a recent randomised phase 3 clinical trial show that the androgen receptor antagonist darolutamide improves metastasis-free survival in men with non-metastatic, castration-resistant prostate cancer, compared with placebo. The trial included 1509 men with a prostate-specific antigen doubling time of 10 months or less. Non-metastatic disease was defined as the absence of metastases, using conventional imaging rather than the substantially more sensitive PSMA scans. The effect of darolutamide is similar to that of other androgen inhibitors, such as apalutamide and enzalutamide. The value of the current trial to Dutch clinical practice is limited, as the number of patients with non-metastatic, castration-resistant prostate cancer is low due to the increased use of PSMA scans and the reluctance of urologists to start androgen-deprivation therapy in the absence of metastatic disease.


Executive functions and the ability to sustain vigilance during sleep loss.
There is considerable individual variability in the ability to sustain performance during sleep loss. Preliminary evidence suggests that individuals with higher trait-like activation/functioning of the prefrontal cortex may be less vulnerable to fatigue. We tested this hypothesis in a sample of 54 healthy volunteers who were assessed bi-hourly on a variant of the Psychomotor Vigilance Test during 41 h of sleep deprivation. A subset of these subjects, representing the top and bottom 25% of the sample based on their ability to sustain vigilance performance during sleep deprivation, were compared with respect to baseline neurocognitive abilities. The sleep deprivation Resistant group (N = 13) scored significantly higher than the sleep deprivation Vulnerable (N = 13) group on all three baseline tasks assessing prefrontal executive function abilities (letter fluency, Stroop Color-Word test, Color Trails Form 2), whereas no differences were found on non-executive function tasks. Similarly, groups showed no differences on demographic variables including age, education, hand preference, morningness-eveningness preference, global intellectual ability, or pre-study sleep history. Findings are consistent with the hypothesis that greater prefrontal/executive functioning may be protective against the adverse effects of sleep deprivation and suggest that baseline executive function testing may prove useful for prediction of resilience during sleep loss.


Oxygen Reserve Index: Utility as an Early Warning for Desaturation in High-Risk Surgical Patients.
Perioperative pulse oximetry hemoglobin saturation (Spo2) measurement is associated with fewer desaturation and hypoxia episodes. However, the sigmoidal nature of oxygen-hemoglobin dissociation limits the accuracy of estimation of the partial pressure of oxygen (Pao2) >80 mm Hg and correspondingly limits the ability to identify when Pao2 >80 mm Hg but falling. We hypothesized that a proxy measurement for oxygen saturation (Oxygen Reserve Index [ORI]) derived from multiwavelength pulse oximetry may allow additional warning time before critical desaturation or hypoxia. To test our hypothesis, we used a Masimo multiwavelength pulse oximeter to compare ORI and Spo2 warning times during apnea in high-risk surgical patients undergoing cardiac surgery. This institutional review board-approved prospective study (NCT03021473) enrolled American Society of Anesthesiologists physical status III or IV patients scheduled for elective surgery with planned preinduction arterial catheter placement. In addition to standard monitors, an ORI sensor was placed and patients were monitored with a pulse oximeter displaying the ORI, a nondimensional parameter that ranges from 0 to 1. Patients were then preoxygenated until ORI plateaued. Following induction of anesthesia, mask ventilation with 100% oxygen was performed until neuromuscular blockade was established. Endotracheal intubation was accomplished using videolaryngoscopy to confirm placement. The endotracheal tube was not connected to the breathing circuit, and patients were allowed to be apneic. Ventilation was resumed when Spo2 reached 94%. We defined ORI warning time as the time from when the ORI alarm registered (based on the absolute value and the rate of change) until the Spo2 decreased to 94%. We defined the Spo2 warning time as the time for Spo2 to decrease from 97% to 94%. The added warning time provided by ORI was defined as the difference between ORI warning time and Spo2 warning time. Forty subjects were enrolled. Complete data for analysis were available from 37 patients. The ORI alarm registered before Spo2 decreasing to 97% in all patients. Median (interquartile range [IQR]) ORI warning time was 80.4 seconds (59.7-105.9 seconds). Median (IQR) Spo2 warning time was 29.0 seconds (20.5-41.0 seconds). The added warning time provided by ORI was 48.4 seconds (95% confidence interval [CI], 40.4-62.0 seconds; P < .0001). In adult high-risk surgical patients, ORI provided clinically relevant added warning time of impending desaturation compared to Spo2. This additional time may allow modification of airway management, earlier calls for help, or assistance from other providers. The potential patient safety impact of such monitoring requires further study.


Synthesis, Characterization and Evaluation of Cytotoxic Activities of Novel Aziridinyl Phosphonic Acid Derivatives.
New aziridine 2-phosphonic acids were prepared by monohydrolysis of the aziridine 2-phosphonates that were obtained by the modified Gabriel-Cromwell reaction of vinyl phosphonate or α-tosylvinyl phosphonate with a primary amine or a chiral amine. The cellular cytotoxicity of these compounds was tested against the HCT-116 colorectal cancer cell lines and the CCD-18Co normal colon fibroblast lines using the MTT assay. Three of the synthesized phosphonic acid derivatives 2e (ethyl hydrogen {(2S)-1-[(1S)-1-(naphthalen-2-yl)ethyl]aziridin-2-yl}phosphonate), 2h (ethyl hydrogen (1-benzylaziridin-2-yl)phosphonate), and 2i (ethyl hydrogen (1-cyclohexylaziridin-2-yl)phosphonate) showed higher cytotoxicity than the reference cancer treatment agent etoposide. Cell death was through a robust induction of apoptosis even more effectively than etoposide, a well-known apoptosis inducing agent.


[Dynamics of blood hematological parameters of white rats in postnatal ontogenesis].
In experiments on Wistar rats, dynamics of blood hematological and rheological parameters has been studied from birth to the 3-month age. Results of the study indicate an intensive activity of the red bone marrow anlagen during the first 3 weeks of postnatal ontogenesis. This is manifested in an increase of the number of cells in the erythron system, a change of erythrocyte acidic resistance, and a shift in the leukocytic formula. The boundary between the 2nd and 3rd postnatal weeks is critical: there occur a sharp deceleration of erythropoiesis and a change of the age-related erythrocyte composition and the blood leukocyte ratio towards those characteristic of adult rats. The rise in the number of leukocytes and erythrocytes does not cease after having passed this period. Until the 4-week age, the deformability index increases, which is accompanied by an increase of hemoglobin hydration and by improvement of the erythrocyte toroid form. Subsequently, inversion of these processes occurs.


Characterization of the Acyl-CoA synthetase activity of purified murine fatty acid transport protein 1.
Fatty acid transport protein 1 (FATP1) is an approximately 63-kDa plasma membrane protein that facilitates the influx of fatty acids into adipocytes as well as skeletal and cardiac myocytes. Previous studies with FATP1 expressed in COS1 cell extracts suggested that FATP1 exhibits very long chain acyl-CoA synthetase (ACS) activity and that such activity may be linked to fatty acid transport. To address the enzymatic activity of the isolated protein, murine FATP1 and ACS1 were engineered to contain a C-terminal Myc-His tag expressed in COS1 cells via adenoviral-mediated infection and purified to homogeneity using nickel affinity chromatography. Kinetic analysis of the purified enzymes was carried out for long chain palmitic acid (C16:0) and very long chain lignoceric acid (C24:0) as well as for ATP and CoA. FATP1 exhibited similar substrate specificity for fatty acids 16-24 carbons in length, whereas ACS1 was 10-fold more active on long chain fatty acids relative to very long chain fatty acids. The very long chain acyl-CoA synthetase activity of the two enzymes was comparable as were the Km values for both ATP and coenzyme A. Interestingly, FATP1 was insensitive to inhibition by triacsin C, whereas ACS1 was inhibited by micromolar concentrations of the compound. These data represent the first characterization of purified FATP1 and indicate that the enzyme is a broad substrate specificity acyl-CoA synthetase. These findings are consistent with the hypothesis that that fatty acid uptake into cells is linked to their esterification with coenzyme A.


Supported housing for people with severe mental disorders.
There has been a significant reduction in the number of people with severe mental illness who spend extended periods in long-stay hospitals. Psychiatric and social services, both statutory and voluntary, aim to assist these people to stay in their local community. District health authorities, local authorities, housing associations and voluntary organisations are jointly expected to provide support for people with severe mental disorder/s. This 'support' may well involve some sort of special housing. To determine the effects of supported housing schemes compared with outreach support schemes or 'standard care' for people with severe mental disorder/s living in the community. Cochrane Schizophrenia Group's Register of trials (February 2001) and the Cochrane Library (Issue 1, 2001) were searched using relevant phrases. These databases are compiled by methodical searches of BIOSIS, CINAHL, Dissertation abstracts, EMBASE, LILACS, MEDLINE, PSYNDEX, PsycINFO, RUSSMED, Sociofile, supplemented with hand searching of relevant journals and numerous conference proceedings. Reference list screening of relevant papers was performed. Relevant randomised, or quasi-randomised, trials dealing with people with 'severe mental disorder/s' allocated to supported housing, outreach support schemes or standard care focusing on outcomes of service utilisation, mental state, satisfaction with care, social functioning, quality of life, and economic data, were sought. Studies were reliably selected, quality rated and data extracted. For dichotomous data, relative risks (RR) would have been estimated, with the 95% confidence intervals (CI). Where possible, the number needed to treat statistic (NNT) was to have been calculated. Analysis would have been by intention-to-treat. Normal continuous data were to have been summated using the weighted mean difference (WMD). Scale data were to have been presented for only those tools that had attained pre-specified levels of quality. Tests of heterogeneity and for publication bias were to have been undertaken. No studies met the inclusion criteria although 139 citations were acquired from the searches. Dedicated schemes whereby people with severe mental illness are located within one site or building with assistance from professional workers have potential for great benefit as they provide a 'safe haven' for people in need of stability and support. This, however, may be at the risk of increasing dependence on professionals and prolonging exclusion from the community. Whether or not the benefits outweigh the risks can only be a matter of opinion in the absence of reliable evidence. There is an urgent need to investigate the effects of supported housing on people with severe mental illness within a randomised trial.


Short-term effects of olanzapine in Huntington disease.
The aim was to describe the short-term (6 months) effects of olanzapine on behavioral and motor clinical manifestations in a group of 11 patients with Huntington disease. An open-pilot study of olanzapine (5 mg) in patients with clinical and genetic diagnosis of Huntington disease was used. The Unified Huntington Disease Rating Scale for clinical assessment and the Total Functional Capacity score for the disease-stage evaluation were used. A statistical analysis was performed to compare the effects of olanzapine on the Unified Huntington Disease Rating Scale scores at time 0 (baseline) and at time 1 (6 months). Comparisons of motor scores, of single behavioral items, and of TFC scores were performed within the group. The behavioral assessment score of items regarding depression, anxiety, irritability, and obsessions showed a significant improvement (range of p, 0.0134-0.048). Given the total behavioral scores (sum of all the items investigated), five patients significantly improved their behavioral score after a 6-month treatment (range of p, 0.013-0.047). Choreic movements improved, although not significantly (0.05 < or = p < or = 1). Olanzapine is a potentially useful antipsychotic drug, with significant short-term effects on behavioral changes, mainly in patients with severe psychiatric symptoms at the onset. It might be considered as a possible therapeutic choice for treatment of Huntington disease.


Prostaglandin and thromboxane synthesis by Lewis lung carcinoma during growth.
The five stable metabolites [prostaglandin F2 alpha, prostaglandin D2, prostaglandin E2 (PGE2), thromboxane B2, and 6-keto-prostaglandin F1 alpha] of arachidonic acid (AA) via the cyclooxygenase pathway were measured by high-resolution gas chromatography-mass spectrometry in Lewis lung carcinoma homogenates at various times after tumor implantation (11 to 25 days). Vegetating and necrotic sections of the primary tumor and lung metastases were examined. Vegetating tumor showed a very active AA metabolism. Synthesis of PGE2, the most abundant product, markedly increased during tumor growth (up to 30 micrograms/g). A high and increasing synthetic capacity was also noted for prostaglandin D2 (up to 9 micrograms/g). Minor time differences and lower levels (up to 1.4 micrograms/g) were found for the other AA metabolites. PGE2 and prostaglandin D2 were the major products in necrotic tumor, too, but synthesis was markedly less than in vegetating tumor, and no increase was noted over time. Metastatic tissue showed a different AA metabolic profile, as compared to primary tumor and surrounding lung tissue, with PGE2 and 6-keto-prostaglandin F1 alpha being the main metabolites.


Glucose and insulin secretory response patterns following diet and tolazamide therapy in diabetes.
Glucose and insulin secretory response patterns during glucose tolerance tests were determined in 28 maturity-onset diabetics, and the sequential effects of diet and a sulphonylurea, tolazamide, were assessed. Untreated diabetics showed hyperglycaemia, increased serum immunoreactive insulin response patterns, delayed insulin release, and relative insulin deficiency. Diet alone partially corrected the hyperglycaemia and serum immunoreactive insulin response but had no effect on the delayed insulin release or relative insulin deficiency. Tolazamide plus diet restored all values towards normal. The net effect of maintenance tolazamide therapy was to (1) restore the insulin secretory response pattern to normal, (2) reduce total pancreatic insulin output, and (3) improve the efficiency of insulin secretion. The results suggest that there is a rational basis for the use of sulphonylurea in all maturity-onset diabetics, including patients with mild carbohydrate intolerance and those who are apparently controlled by diet alone.


Biomolecular events in cancer revealed by attractor metagenes.
Mining gene expression profiles has proven valuable for identifying signatures serving as surrogates of cancer phenotypes. However, the similarities of such signatures across different cancer types have not been strong enough to conclude that they represent a universal biological mechanism shared among multiple cancer types. Here we present a computational method for generating signatures using an iterative process that converges to one of several precise attractors defining signatures representing biomolecular events, such as cell transdifferentiation or the presence of an amplicon. By analyzing rich gene expression datasets from different cancer types, we identified several such biomolecular events, some of which are universally present in all tested cancer types in nearly identical form. Although the method is unsupervised, we show that it often leads to attractors with strong phenotypic associations. We present several such multi-cancer attractors, focusing on three that are prominent and sharply defined in all cases: a mesenchymal transition attractor strongly associated with tumor stage, a mitotic chromosomal instability attractor strongly associated with tumor grade, and a lymphocyte-specific attractor.


The miR-183/96/182 Cluster Regulates Macrophage Functions in Response to Pseudomonas aeruginosa.
Macrophages (Mϕ) are an important component of the innate immune system; they play critical roles in the first line of defense to pathogen invasion and modulate adaptive immunity. MicroRNAs (miRNAs) are a newly recognized, important level of gene expression regulation. However, their roles in the regulation of Mϕ and the immune system are still not fully understood. In this report, we provide evidence that the conserved miR-183/96/182 cluster (miR-183/96/182) modulates Mϕ function in their production of reactive nitrogen (RNS) and oxygen species (ROS) and their inflammatory response to Pseudomonas aeruginosa (PA) infection and/or lipopolysaccharide (LPS) treatment. We show that knockdown of miR-183/96/182 results in decreased production of multiple proinflammatory cytokines in response to PA or LPS treatment in Mϕ-like Raw264.7 cells. Consistently, peritoneal Mϕ from miR-183/96/182-knockout versus wild-type mice are less responsive to PA or LPS, although their basal levels of proinflammatory cytokines are increased. In addition, overexpression of miR-183/96/182 results in decreased production of nitrite and ROS in Raw264.7 cells. We also provide evidence that DAP12 and Nox2 are downstream target genes of miR-183/96/182. These data suggest that miR-183/96/182 imposes global regulation on various aspects of Mϕ function through different downstream target genes.


Benefits of intermittent/continuous androgen deprivation in patients with advanced prostate cancer.
In 1941 Huggins described the effect of castration on prostate cancer. gonadotropin-releasing hormone (GNRH) analogues were introduced in 1985. Complete androgen blockade (association of GNRH analogue with antiandrogen) was introduced by Fernand Labrie to achieve suppression of suprarenal testosterone. Long time androgen deprivation lead to androgen independence of the prostate cancer cell. Our principal aim was to demonstrate longer survival rates on prostate cancer patients with intermittent androgen deprivation. 82 patients in the Urology Department of Vasile Goldis West University Arad were included into two groups, with continuous and intermittent androgen deprivation.Treatment efficiency was assessed by the level of testosterone and PSA.Adverse events (AE) and serious adverse events were reported according to Common Terminology Criteria of Adverse Events (CTCAE) of the National Cancer Institute (NCI). Evolution towards castrate resistant prostate cancer: 12.5% from the intermittent androgen deprivation group and 23.8% from the continuous androgen deprivation groupMortality rate: 15% of patients from the intermittent androgen deprivation group; 19% of patients from the continuous androgen deprivation group. Better quality of life (Qol) in periods without treatment due to testosteron recovery;Less AE's and metabolic syndrome (MS) related complications;Better survival and longer time of disease control andCost reduction.


Content validation of a tool for assessing risks for drug-related problems to be used by practical nurses caring for home-dwelling clients aged ≥65 years: a Delphi survey.
Home care services are becoming a critically important part of health care delivery as populations are aging. Those using home care services are increasingly older, more frail than previously, and use multiple medications, making them vulnerable to drug-related problems (DRPs). Practical nurses (PN) visit home-dwelling aged clients frequently and, thus, are ideally situated to identify potential DRPs and, if needed, to communicate them to physicians for resolution. This study developed and validated the content of a tool to be used by PNs for assessing DRP risks for their home-dwelling clients aged ≥65 years. The first draft of the tool was based on two systematic literature reviews and clinical experience of our research group. Content validity of the tool was determined by a three-round Delphi survey with a panel of 18 experts in geriatric care and pharmacotherapy. An agreement by ≥80% of the panel on an item was required. The final tool consists of 18 items that assess risks for DRPs in home-dwelling aged clients. It is divided into four sections: (1) Basic Client Data, (2) Potential Risks for DRPs in Medication Use, (3) Characteristics of the Client's Care and Adherence, and (4) Recommendations for Actions to Resolve DRPs. The Delphi process resulted in a structured DRP Risk Assessment Tool that is focused on the highest priority DRPs that should be identified and resolved. The tool also assists the PNs to identify solutions to these problems, which is a unique feature compared to similarly purposed prior tools.


Concrete grinding residue characterization and influence on infiltration.
Concrete grinding residue (CGR) is a slurry byproduct created by concrete pavement maintenance operations. Disposal of CGR slurry is presently regulated on the basis of very minimal information. The least immediate expense is incurred by spreading CGR slurry directly on vegetated roadway ditches and embankments. The direct disposal impacts to environmental quality in terms of soil physical or chemical properties are not known. Five CGR materials from widely dispersed sites in the United States were analyzed for particle size distribution and evaluated with a suite of USEPA physical and chemical analyses. Values found for the parameters examined are not considered harmful. An infiltration column study was also conducted in which two CGRs were mixed at 8 and 25% by weight and also surface applied 2.5 mm deep with two contrasting (relatively fine and coarse textured) soils. With the finer soil, statistically (p < 0.05) significant decrease in infiltration time (increased infiltration rate) was associated with the 25% and surface-applied CGR treatments, compared with the untreated control soil. The results indicate that excessive application of CGR may increase water infiltration into soil in the short-term. This should be kept in mind, but does not appear to be generally detrimental.


Analysis of the gene expression profile of mouse male meiotic germ cells.
Wide genome analysis of difference in gene expression between spermatogonial populations from 7-day-old mice and pachytene spermatocytes from 18-day-old mice was performed using Affymetrix gene chips representing approximately 12,500 mouse known genes or EST sequences, spanning approximately 1/3rd of the mouse genome. To delineate differences in the profile of gene expression between mitotic and meiotic stages of male germ cell differentiation, expressed genes were grouped in functional clusters. The analysis confirmed the previously described pre-meiotic or meiotic expression for several genes, in particular for those involved in the regulation of the mitotic and meiotic cell cycle, and for those whose transcripts are accumulated during the meiotic stages to be translated later in post-meiotic stages. Differential expression of several additional genes was discovered. In few cases (pro-apoptotic factors Bak, Bad and Bax), data were in conflict with the previously published stage-dependent expression of genes already known to be expressed in male germ cells. Northern blot analysis of selected genes confirmed the results obtained with the microarray chips. Six of these were novel genes specifically expressed in pachytene spermatocytes: a chromatin remodeling factor (chrac1/YCL1), a homeobox gene (hmx1), a novel G-coupled receptor for an unknown ligand (Gpr19), a glycoprotein of the intestinal epithelium (mucin 3), a novel RAS activator (Ranbp9), and the A630056B21Rik gene (predicted to encode a novel zinc finger protein). These studies will help to delineate the global patterns of gene expression characterizing male germ cell differentiation for a better understanding of regulation of spermatogenesis in mammals.


Future dryness in the southwest US and the hydrology of the early 21st century drought.
Recently the Southwest has experienced a spate of dryness, which presents a challenge to the sustainability of current water use by human and natural systems in the region. In the Colorado River Basin, the early 21st century drought has been the most extreme in over a century of Colorado River flows, and might occur in any given century with probability of only 60%. However, hydrological model runs from downscaled Intergovernmental Panel on Climate Change Fourth Assessment climate change simulations suggest that the region is likely to become drier and experience more severe droughts than this. In the latter half of the 21st century the models produced considerably greater drought activity, particularly in the Colorado River Basin, as judged from soil moisture anomalies and other hydrological measures. As in the historical record, most of the simulated extreme droughts build up and persist over many years. Durations of depleted soil moisture over the historical record ranged from 4 to 10 years, but in the 21st century simulations, some of the dry events persisted for 12 years or more. Summers during the observed early 21st century drought were remarkably warm, a feature also evident in many simulated droughts of the 21st century. These severe future droughts are aggravated by enhanced, globally warmed temperatures that reduce spring snowpack and late spring and summer soil moisture. As the climate continues to warm and soil moisture deficits accumulate beyond historical levels, the model simulations suggest that sustaining water supplies in parts of the Southwest will be a challenge.


Comparison of albicans vs. non-albicans candidemia in French intensive care units.
Candidemia raises numerous therapeutic issues for intensive care physicians. Epidemiological data that could guide the choice of initial therapy are still required. This analysis sought to compare the characteristics of intensive care unit (ICU) patients with candidemia due to non-albicans Candida species with those of ICU patients with candidemia due to Candida albicans. A prospective, observational, multicenter, French study was conducted from October 2005 to May 2006. Patients exhibiting candidemia developed during ICU stay and exclusively due either to one or more non-albicans Candida species or to C. albicans were selected. The data collected included patient characteristics on ICU admission and at the onset of candidemia. Among the 136 patients analyzed, 78 (57.4%) had candidemia caused by C. albicans. These patients had earlier onset of infection (11.1 +/- 14.2 days after ICU admission vs. 17.4 +/- 17.7, p = 0.02), higher severity scores on ICU admission (SOFA: 10.4 +/- 4.7 vs. 8.6 +/- 4.6, p = 0.03; SAPS II: 57.4 +/- 22.8 vs. 48.7 +/- 15.5, P = 0.015), and were less often neutropenic (2.6% vs. 12%, p = 0.04) than patients with candidemia due to non-albicans Candida species. Although patients infected with Candida albicans differed from patients infected with non-albicans Candida species for a few characteristics, no clinical factor appeared pertinent enough to guide the choice of empirical antifungal therapy in ICU.


Community resiliency: the potential for community health nursing theory development.
There is insufficient theory development within community health nursing that addresses the community as a collective and not simply as groupings of aggregates. Conceptual clarification of nursing's domains is needed, however, before theory development can take place. In an attempt to rectify this situation, this article discusses the environment domain. Community resiliency, or the ability of a community to deal with adversity and in so doing reach a higher level of functioning, is presented as a useful framework to gain greater understanding of this particular domain. Findings from research that have resulted in a community resiliency model for describing the environment domain, within which rural-based community health nurses (CHNs) work, are presented. The relevance for community health nursing theory is included with recommendations for future research and subsequent theory development.


Icing or cake? Grant competitions as a model for funding chronic disease prevention in Tasmania, Australia.
Competitive grant funding is a well-established mechanism for generating activity and interventions in the field of chronic disease prevention. Yet grant competitions may be burdensome for organizations, and money may not be enough to bring about lasting change in communities. In this study, we explore the dynamics of awarding and receiving money in the context of a state-level government grant competition to support community organizations and promote community-driven action for health and well-being in Tasmania, Australia. Drawing on reflections of successful grant recipients and real-time observation of grant decision-making, we consider the role and value of grant competitions both for individual organizations and for generating broader change processes. We found that grant competitions operated according to an 'icing-on-the-cake' approach to funding, whereby money was provided for extra activities and new initiatives. In this way, the grant competition was valuable not only for stimulating new programme activities but also to effect broader organizational change, such as developing planning capacity, igniting new directions and pushing organizations towards 'health'-focused activities. But for smaller organizations, grant funding was often stretched to support core work (i.e. cake rather than icing). Grants targeting specific focus areas could be a drain on resources if they diverted staff time away from core activities. We suggest an alternative approach to funding in which grants are able to be more responsive to the needs of community organizations and the support they require, as well as to desired outcomes. We describe the policy response to the results to date.


Context and sex differences exist in the acoustic structure of phee calls by newly-paired common marmosets (Callithrix jacchus).
Captive common marmosets of all ages robustly produce a "separation" phee call during brief separations from their group. In contrast, a second structural variant, which may function as an intergroup call, is produced in the home cage primarily by the reproductive adults. A previous study found that postpubertal but nonreproductive offspring rarely produce phee calls when in the home cage with the natal group, yet these marmosets call frequently after pairing with an opposite-sex partner. The sudden increase in home cage phee calls may indicate the rapid onset of intergroup calling. Alternatively, marmosets may be producing the separation phee variant as a result of separation from the natal group. The present study investigated whether phee calls produced by recently paired individuals in the home cage were structurally distinguishable from their calls recorded in a separation paradigm. We also tested whether sex differences, known to exist in the calls of mature adults, could be found in calls recorded from younger, nonreproductive animals separated from their natal groups. We analyzed 18 acoustic parameters of phee calls produced in the home cage after pairing and of calls produced during separation both from the natal group and from a new mate. Discriminant function analyses found that home cage calls were clearly discriminable from separation calls (average 91.7% correctly classified), indicating that the rapid increase in home cage phee call production shortly after pairing is not a consequence of separation from the family group. Postpubertal marmosets appear to show a rapid behavioral adjustment to separation from their natal groups. Additionally, sex was clearly discriminable in calls recorded both before and after pairing (average 86.8% correctly classified). Like calls recorded from well-established paired marmosets, phee calls produced by recently paired, postpubertal marmosets are discriminable by context and sex.


Viral gastroenteritis and laboratory detection of rotavirus.
Two major viruses have been clearly associated with gastroenteritis: the Norwalk agent and the rotavirus. The former is associated with epidemic outbreaks in adults or schoolchildren, while the latter causes endemic illness in young children during winter. Neither can be grown in routine cell cultures. Both of these viruses, and others, can be detected in patients' stools by electron microscopy. Enzyme linked immunosorbent assay (ELISA) kits are commercially available for detection of rotavirus antigen in stools. This test, which can be readily performed in the routine laboratory without specialized equipment, offers useful diagnostic and prognostic information.


Anti-aging effects of vitamin C on human pluripotent stem cell-derived cardiomyocytes.
Human pluripotent stem cells (hPSCs) have arisen as a source of cells for biomedical research due to their developmental potential. Stem cells possess the promise of providing clinicians with novel treatments for disease as well as allowing researchers to generate human-specific cellular metabolism models. Aging is a natural process of living organisms, yet aging in human heart cells is difficult to study due to the ethical considerations regarding human experimentation as well as a current lack of alternative experimental models. hPSC-derived cardiomyocytes (CMs) bear a resemblance to human cardiac cells and thus hPSC-derived CMs are considered to be a viable alternative model to study human heart cell aging. In this study, we used hPSC-derived CMs as an in vitro aging model. We generated cardiomyocytes from hPSCs and demonstrated the process of aging in both human embryonic stem cell (hESC)- and induced pluripotent stem cell (hiPSC)-derived CMs. Aging in hESC-derived CMs correlated with reduced membrane potential in mitochondria, the accumulation of lipofuscin, a slower beating pattern, and the downregulation of human telomerase RNA (hTR) and cell cycle regulating genes. Interestingly, the expression of hTR in hiPSC-derived CMs was not significantly downregulated, unlike in hESC-derived CMs. In order to delay aging, vitamin C was added to the cultured CMs. When cells were treated with 100 μM of vitamin C for 48 h, anti-aging effects, specifically on the expression of telomere-related genes and their functionality in aging cells, were observed. Taken together, these results suggest that hPSC-derived CMs can be used as a unique human cardiomyocyte aging model in vitro and that vitamin C shows anti-aging effects in this model.


Kallmann Syndrome: Eugenics and the Man behind the Eponym.
Kallmann syndrome is named after Franz Joseph Kallmann, a German-born psychiatrist who described in 1944 twelve subjects from three families who presented with a syndrome of missed puberty, anosmia, and color blindness. Yet, several other eponyms for the same syndrome can be found in the literature. Despite the fact that Kallmann syndrome is the most recognized eponym, very little is known about the man for whom the syndrome is named. A biographical note on Franz Joseph Kallmann and his historical context is presented.


Endogenous ion channel complexes: the NMDA receptor.
Ionotropic receptors, including the NMDAR (N-methyl-D-aspartate receptor) mediate fast neurotransmission, neurodevelopment, neuronal excitability and learning. In the present article, the structure and function of the NMDAR is reviewed with the aim to condense our current understanding and highlight frontiers where important questions regarding the biology of this receptor remain unanswered. In the second part of the present review, new biochemical and genetic approaches for the investigation of ion channel receptor complexes will be discussed.


Involvement of arachidonate metabolism in neurotensin-induced prolactin release in vitro.
Neurotensin increased in a concentration-dependent manner the level of hypophyseal [3H]arachidonic acid in vitro as well as prolactin release from hemipituitary glands. The effect of 1 microM neurotensin on arachidonate release was already present at 2.5 min, maximal at 5, and disappeared after a 10-min incubation. Neurotensin analogues produced an enhancement of hypophyseal arachidonate similar to their relative potencies in other cellular systems, whereas other peptides (somatostatin and vasoactive intestinal peptide) were devoid of any effect on the concentration of the fatty acid in the pituitary. Seventy micromoles RHC 80267, a rather selective inhibitor of diacylglycerol lipase, completely prevented the neurotensin-stimulated prolactin release and decreased arachidonate release both in basal or in neurotensin-induced conditions. Similar results were obtained with 50 microM quinacrine, a phospholipase A2 inhibitor. To clarify whether arachidonate released by neurotensin requires a further metabolism through specific pathways to stimulate prolactin release, we used indomethacin and BW 755c, two blockers of cyclooxygenase and lipoxygenase pathways. Thirty micromoles indomethacin, a dose active to inhibit cyclooxygenase, did not affect unesterified arachidonate levels either in basal or in neurotensin-induced conditions; moreover, the drug did not modify basal prolactin release but slightly potentiated the stimulatory effect of neurotensin on the release of the hormone. On the other hand, 250 microM BW 755c, an inhibitor of both cyclooxygenase and lipoxygenase pathways, significantly inhibited both basal and neurotensin-stimulated prolactin release and further potentiated the increase of the fatty acid concentrations produced by 1 microM neurotensin.(ABSTRACT TRUNCATED AT 250 WORDS)


Adverse Event Reporting: Harnessing Residents to Improve Patient Safety.
Reporting of adverse and near miss events are essential to identify system level targets to improve patient safety. Resident physicians historically report few events despite their role as front-line patient care providers. We sought to evaluate barriers to adverse event reporting in an effort to improve reporting. Our main outcomes were as follows: resident attitudes about event reporting and the frequency of event reporting before and after interventions to address reporting barriers. We surveyed first year residents regarding barriers to adverse event reporting and used this input to construct a fishbone diagram listing barriers to reporting. Barriers were addressed, and resident event reporting was compared before and after efforts were made to reduce obstacles to reporting. First year residents (97%) recognized the importance of submitting event reports; however, the majority (85%) had not submitted an event report in the first 6 months of residency. Only 7% of residents specified that they had not witnessed an adverse event in 6 months, whereas one third had witnessed 10 or more events. The main barriers were as follows: lack of knowledge about how to submit events (38%) and lack of time to submit reports (35%). After improving resident education around event reporting and simplifying the reporting process, resident event reporting increased 230% (68 to 154 annual reports, P = 0.025). We were able to significantly increase resident event reporting by educating residents about adverse events and near misses and addressing the primary barriers to event reporting. Moving forward, we will continue annual resident education about patient safety, focus on improving feedback to residents who submit reports, and empower senior residents to act as role models to junior residents in patient safety initiatives.


Hearing loss as a risk factor for agricultural injuries.
Previous studies suggested that hearing impairment based on self-report might increase the risk of agricultural injuries. However, self-reported hearing measures may be subject to inaccuracy and subjective perception. We assessed the association of agricultural injuries with hearing loss and other hearing characteristics using measured hearing. Study subjects were 150 farmers who participated in the Iowa Certified Safe Farm study. Injury information was collected by telephone interviews at 2-5 month intervals from September 1999 to October 2002. Hearing levels were measured annually using the pure tone audiometry from 1998 to 2002. Adjusted rate ratios of injuries were calculated using the multivariate Poisson regression model. Hearing loss in the better ear (RR = 1.62), hearing asymmetry (RR = 1.67), and fair/poor self-reported hearing (RR = 1.96) were significantly associated with the risk of agricultural injuries. It is notable that self-reported hearing might be a stronger predictor of injuries than pure tone audiometry (PTA). Exposure to noise elevated the risk of injuries in those farmers with hearing loss or hearing asymmetry. The occasional use of hearing protection was significantly associated with agricultural injuries. This study adds substantial evidence that hearing loss acts as a risk for agricultural injuries. Prevention of hearing loss and noise exposure may be important in reducing the burden of agricultural injuries.


Unusual distribution of floating seaweeds in the East China Sea in the early spring of 2012.
Floating seaweeds play important ecological roles in offshore waters. Recently, large amounts of rafting seaweed have been observed in the East China Sea. In early spring, juveniles of commercially important fish such as yellowtail accompany these seaweed rafts. Because the spatial distributions of seaweed rafts in the spring are poorly understood, research cruises were undertaken to investigate them in 2010, 2011, and 2012. Floating seaweed samples collected from the East China Sea during the three surveys contained only Sargassum horneri. In 2010 and 2011, seaweed rafts were distributed only in the continental shelf and the Kuroshio Front because they had become trapped in the convergence zone of the Kuroshio Front. However, in 2012, seaweed was also distributed in the Kuroshio Current and its outer waters, and massive strandings of seaweed rafts were observed on the northern coast of Taiwan and on Tarama Island in the Ryukyu Archipelago. Environmental data (wind, currents, and sea surface height) were compared among the surveys of 2010, 2011, and 2012. Two factors are speculated to have caused the unusual distribution in 2012. First, a continuous strong north wind produced an Ekman drift current that transported seaweed southwestward to the continental shelf and eventually stranded seaweed rafts on the coast of Taiwan. Second, an anticyclonic eddy covering northeast Taiwan and the Kuroshio Current west of Taiwan generated a geostrophic current that crossed the Kuroshio Current and transported the rafts to the Kuroshio Current and its outer waters. Such unusual seaweed distributions may influence the distribution of fauna accompanying the rafts.


Partial sleep deprivation as therapy for depression.
We investigated the influence of partial sleep deprivation on depressive symptoms in 30 patients with endogenous depression. The patients were awakened during the second half of the night and remained awake until the following evening. Antidepressant pharmacotherapy was not interrupted. Partial sleep deprivation significantly reduced the depression symptoms (mean value, 30.1%). The interindividual variations were considerable; deterioration was rare, and in 75% of the cases improvement occurred. Execution is simple, less stressful for the patient than total sleep deprivation, and can be carried out at home. Partial sleep deprivation has no contraindications except in the case of severe physical illness. The duration of the therapeutic effect is varied; repetition is possible. We discuss chronobiological hypothesis to explain the effect of sleep deprivation.


Calcium supplementation is associated with endothelium dependent attenuation of vascular smooth muscle reactivity in normotensive pregnant and nonpregnant rats.
The study tests the hypothesis that the blood pressure lowering effect of a high calcium diet is mediated through attenuation of vascular reactivity and examined the mechanisms involved in both normotensive pregnant and nonpregnant rats. The contractile responses of aortic rings of Wistar rats fed on high (1.7%, 2.1%) and normal (0.9%) calcium diets to phenylephrine, angiotensin II, KCl, and CaCl2 were studied. The relaxations to acetylcholine and potassium chloride, as well as the effects of endothelial denudation, pretreatment with indomethacin (10[-6] mol/L), methylene blue (10[-6] mol/L), and calcium free solution on the responses to phenylephrine were also examined. In both pregnant and nonpregnant rats, the contractile responses of aortic rings of animals fed a high calcium diet to all the agents were significantly attenuated, compared with those of controls. After endothelial denudation, or treatment with methylene blue, but not with indomethacin, the responses of the rings to phenylephrine were enhanced and not different from similarly treated rings from rats on a normal calcium diet. There was no difference in the contractile responses to phenylpehrine in calcium free solution. The relaxation to acetylcholine, but not to potassium chloride, was enhanced in rings from rats on a high calcium diet. The diminution in reactivity was not associated with corresponding changes in sensitivity of the tissues. It is concluded that in normotensive rats a high calcium diet is associated with diminished vascular smooth muscle reactivity that is endothelium dependent, and involves increased stimulation of the nitric oxide-guanylate cyclase pathway but not of the sodium-potassium ATPase or prostacyclin.


Association between alcohol consumption and chronic pain: a systematic review and meta-analysis.
Chronic pain represents a global health problem with a considerable economic burden. The relation of alcohol intake and chronic pain conditions was assessed in several studies with conflicting results. We used dose-response meta-analysis techniques to answer the question of whether alcohol intake is related to chronic pain occurrence. We searched MEDLINE, Embase, and other databases to identify cohort and case-control studies on alcohol consumption and chronic pain. Sixteen studies were eligible with a total population of 642 587 individuals. Fixed-effects and random-effects pooled estimates were obtained by weighting log odds ratios (ORs) in case-control studies and log incidence rate ratios in cohort studies by the inverse of their variance. A heterogeneity assessment and a dose-response analysis were carried out. Quality scoring was also performed. Our results show that any alcohol consumption was related to lower odds of chronic pain (pooled OR=0.76; 95% confidence interval [CI], 0.61-0.95). The association was non-linear. The ORs by quartile of alcohol doses were as follows: OR2nd quartile=0.74; 95% CI, 0.64-0.87; OR3rd quartile=0.67; 95% CI, 0.53-0.86; and OR4th quartile=0.75; 95% CI, 0.50-1.14. This association was observed for cohort studies (OR=0.77; 95% CI, 0.61-0.98) and European studies (OR=0.65; 95% CI, 0.48-0.87) only. Studies with complete adjustment for confounding factors showed a stronger relation than those with incomplete adjustment (OR=0.69; 95% CI, 0.48-0.99 and OR=0.85; 95% CI, 0.65-1.11, respectively). Alcohol consumption presents a non-linear inverse association with the occurrence of chronic pain. Although plausible mechanisms could explain this protective effect, other explanations, including reverse causation, are probable.


The effects of massage on pain, stiffness, and fatigue levels associated with ankylosing spondylitis: a case study.
To study the effects of massage on pain, stiffness, and fatigue in a patient recently diagnosed with ankylosing spondylitis (AS). A 47-year-old woman with AS diagnosed 11 months earlier received 7 massages across a 28-day period. Her pain, stiffness, and fatigue were recorded using visual analogue scales daily during the study period. Spinal mobility was measured at each massage session with finger-to-floor measurements for both forward and lateral flexion. The client also used a daily journal to supply pertinent information on quality of life. Improvement was recorded in all dependent variables, with stiffness intensity showing the greatest improvement, to a final value of 0.75 from an initial value of 5. Duration of stiffness also showed improvement, to a final value of 1.2 from an initial value of 3.5. Improvement was also found in general pain (final value: 1; initial value: 4), fatigue (final value: 1.5; initial value 5), and forward and lateral flexion (forward flexion distance-final: 4 inches; initial: 6 inches; lateral flexion, left distance: final, 16.5 inches; initial, 21 inches; right distance: final, 16.5 inches; initial, 20.5 inches). Massage shows promise as a treatment for symptoms associated with AS. Further study is needed to validate these effects and to determine the feasibility of massage as an adjunct to standard care for AS patients with mild-to-moderate symptoms of AS.


Monolayer stress microscopy: limitations, artifacts, and accuracy of recovered intercellular stresses.
In wound healing, tissue growth, and certain cancers, the epithelial or the endothelial monolayer sheet expands. Within the expanding monolayer sheet, migration of the individual cell is strongly guided by physical forces imposed by adjacent cells. This process is called plithotaxis and was discovered using Monolayer Stress Microscopy (MSM). MSM rests upon certain simplifying assumptions, however, concerning boundary conditions, cell material properties and system dimensionality. To assess the validity of these assumptions and to quantify associated errors, here we report new analytical, numerical, and experimental investigations. For several commonly used experimental monolayer systems, the simplifying assumptions used previously lead to errors that are shown to be quite small. Out-of-plane components of displacement and traction fields can be safely neglected, and characteristic features of intercellular stresses that underlie plithotaxis remain largely unaffected. Taken together, these findings validate Monolayer Stress Microscopy within broad but well-defined limits of applicability.


Reflex pathways from group II muscle afferents. 1. Distribution and linkage of reflex actions to alpha-motoneurones.
The interneuronally mediated reflex actions evoked by electrical stimulation of group II muscle afferents in low spinal cats have been reinvestigated with intracellular recording with motoneurones to knee flexors and ankle extensors. The results of Eccles and Lundberg (1959) have been confirmed and extended. There was wide convergence from flexors and extensors of group II excitation to flexor and group II inhibition to extensor motoneurones. Some quantitative differences in the effect from the different nerves are described. Latency measurements suggest that the minimal linkage is disynaptic in the excitatory interneuronal pathways and trisynaptic in the inhibitory pathways. Disynaptic group II EPSPs were found in 14% of the ankle extensor motoneurones but were much more common in unanaesthetized high spinal cats (Wilson and Kato 1965). From these results and corresponding ones on flexors (Holmqvist and Lundberg 1961) it is postulated that secondary afferents in addition to the weak monosynaptic connexions (Kirkwood and Sears 1975) have disynaptic excitatory pathways and trisynaptic inhibitory pathways to both flexor and extensor motoneurones. It is proposed that the group II actions of the flexor reflex pattern characterizing the anaesthetized low spinal cat are due to suppression of the inhibitory pathway to flexor motoneurones and the excitatory pathway to extensor motoneurones. In some ankle extensor motoneurones the disynaptic group II EPSPs occurred in combination with IPSPs from the FRA (including group II and III muscle afferents). The possibility is considered that these group II EPSPs are mediated by an interneuronal group II pathway with little or no input from group III muscle afferents but probably from extramuscular receptors. In other ankle extensor motoneurones group II EPSPs were combined with EPSPs from group III muscle afferents, cutaneous afferents and joint afferents. It is postulated that these group II EPSPs are mediated by an interneuronal pathway from the FRA which also supply interneuronal pathways giving inhibition to extensor or/and flexor motoneurones and excitation to flexors as postulated by Eccles and Lundberg (1959) and Holmqvist and Lundberg (1961).


Insight into the Bonding and Aggregation of Alkyllithiums by Experimental Charge Density Studies and Energy Decomposition Analyses.
In this Article, the organolithiums [((-)-sparteine)LitBu] (1), [(ABCO)LitBu]2 (2), and [(ABCO)2(LiiPr)4] (3) are investigated by means of experimental and theoretical charge density determination to elucidate the nature of the Li-C and Li-N bonds. Furthermore, the valence shell charge concentrations (VSCCs) in the nonbonding region of the deprotonated Cα-atom will provide some insight on the localization of the carbanionic lone pair. Analysis of the electron density (ρ(rBCP)), Laplacian (∇2ρ(rBCP)), and the energy decomposition (EDA) confirmed that the Li-C/N bond exhibits astonishingly similar characteristics, to reveal an increasingly polar contact with decreasing aggregate size. This explains former observations on the incorporation of halide salts in organolithium reagents. Furthermore, it could be shown that the bonding properties of the iPr group are similar to those of the tBu substituent. The accuracy of fit to all previously determined properties in organolithiums is remarkable.


Gallstone ileus. A case treated with minilaparotomy and a review of the literature.
Gallstone ileus is a rare complication of cholelithiasis which occurs in less than 1% of patients and is the cause of 1- 4% of cases of small bowel obstruction. The pathogenesis involves the formation of a bilioenteric fistula. We report the case of gallstone ileus in an 81-year old woman with typical abdominal pain, arterial hypertension and coronary artery disease. An abdominal computed tomography (CT) scan showed pneumobilia, dilated loops of small bowel and an ectopic gallstone obstructing the intestinal lumen. The patient underwent enterolithotomy and a 5-cm stone 20 cm from the ileocecal valve was removed. In the literature enterolithotomy alone is the procedure most frequently used for gallstone ileus. Enterolithotomy plus cholecystectomy and/or fistulectomy is only indicated in selected patients. The clinical signs and symptoms depend on the site of the obstruction and usually include abdominal pain, nausea and vomiting. The diagnostic test of choice is an abdominal CT scan. Cholecystoenteric fistula, Gallstone ileus, Minilaparotomy.


Reduced duration of dual antiplatelet therapy using an improved drug-eluting stent for percutaneous coronary intervention of the left main artery in a real-world, all-comer population: Rationale and study design of the prospective randomized multicenter IDEAL-LM trial.
Continuous improvements in stent technology make percutaneous coronary intervention (PCI) a potential alternative to surgery in selected patients with unprotected left main coronary artery (uLMCA) disease. The optimal duration of dual antiplatelet therapy (DAPT) in these patients remains undetermined, and in addition, new stent designs using a bioabsorbable polymer might allow shorter duration of DAPT. IDEAL-LM is a prospective, randomized, multicenter study that will enroll 818 patients undergoing uLMCA PCI. Patients will be randomized in a 1:1 fashion to intravascular ultrasound-guided PCI with the novel everolimus-eluting platinum-chromium Synergy stent with a biodegradable polymer (Boston Scientific, Natick, MA) followed by 4 months of DAPT or the everolimus-eluting cobalt-chromium Xience stent (Abbott Vascular, Santa Clara, CA) followed by 12 months of DAPT. The total follow-up period will be 5 years. A subset of 100 patients will undergo optical coherence tomography at 3 months. The primary end point will be major adverse cardiovascular events (composite of all-cause mortality, myocardial infarction, and ischemia-driven target vessel revascularization) at 2 years. Secondary end points will consist of the individual components of the primary end point, procedural success, a device-oriented composite end point, stent thrombosis as per Academic Research Consortium criteria, and bleeding as per Bleeding Academic Research Consortium criteria. IDEAL-LM is designed to assess the safety and efficacy of the novel Synergy stent followed by 4 months of DAPT vs the Xience stent followed by 12 months of DAPT in patients undergoing uLMCA PCI. The study will provide novel insights regarding optimal treatment strategy for patients undergoing PCI of uLMCA disease (www.clinicaltrials.gov, NCT 02303717).


Bioinformatic Prediction of Depression-Related Signaling Pathways Regulated by miR-146a in Peripheral Blood of Patients with Post-Stroke Depression.
It was aimed to explore the differential expression of miR-146a-5p in peripheral blood of patients with post-stroke depression (PSD), and to analyze its mechanism using bioinformatics. Stroke patients were selected as the research objects, and were divided into PSD ones and non-post-stroke depression (N-PSD) ones with the National Institutes of Health stroke scale (NHISS) and Hamilton Depression Scale-17 terms (HAMD-17) scores. Peripheral blood of patients was collected for serum miR-146a-5p detection. Targetscan7.1, miRDB, DIANA TOOLS, and more databases were used to predict the target genes of miR-146a-5p. String11.0 was applied to construct a protein interaction network, and GO and KEGG pathway enrichment analysis of target genes was performed. Compared with that of N-PSD patients, serum miR-146a-5p levels in PSD patients were significantly increased (P<0.05). The receiver operator characteristic (ROC) curve suggested that the sensitivity and specificity of miR-146a-5p in predicting PSD were 0.703 and 0.811, respectively. The human miR-146a-5p sequence was highly conserved, with a total of 43 target genes. It involved analysis of activity, signaling pathways, and transcriptional regulation, as well as related signaling pathways such as Toll-like receptors (TLR), neurotrophic factors, and nuclear factor kappa-B (NF-κB). In conclusion, the expression level of miR-146a-5p was abnormally increased in PSD patients, and it could be taken as a candidate marker for the diagnosis of PSD. miR-146a-5p could affect PSD through signaling pathways of TLRs, neurotrophic factors, and NF-κB.


Adipose tissue cellularity and lipolysis. Response to exercise and cortisol treatment.
Male rats a 5 wk of age were subjected to 13 wk of intensive treadmill running to study the effect of exercise on adipose tissue cellularity and lipolysis. Untrained controls of the same age remained sedentary in their cages for the duration of the experiment. Adipocyte numbers were similar in eqidiymal fat pads from trained and untrained rats (12.7 plus or minus 1.3 X 10(6) vs. 15.3 plus or minus 1.3 X 10(6) cells/pad), however trained rats had smaller fat pads containing smaller cells (0.09 plus of minus 0.01 vs. 0.20 plus or minus 0.04 mug triglyceride/cell). Adipocytes from trained rats possessed greater epinephrine-sensitive lipase activity than sedentary rats on a per cell, per milligram protein, per gram adipose tissue, or per fat pad basis. Although the smaller cells of the trained rats had greater epinephrine-sensitive lipase activity than the larger cells of the untrained rats, lipolysis was positively correlated with cell size within both treatment groups. Cortisol treatment of intact animals did not significantly affect in vitro adipose tissue lipolysis. The results of this study indicate that exercise training increased the potential of adipose tissue cells to release free fatty acids in response to epinephrine stimulation. Exercise training initiated at 5 wk of age had only a small effect on adipose tissue cell numbers but significantly decreased cell size.


Advances in the management of hepatitis C.
Significant advances have recently been made in the management of hepatitis C virus (HCV) with many of the changes now part of routine clinical practice. These include the use of non-invasive methods to assess liver fibrosis, interleukin 28B genotype testing to predict interferon responsiveness and the use of new anti-viral regimens for HCV genotype 1. Two new antiviral agents (boceprevir and telaprevir) have recently become available in Australia. These protease inhibitors are used in combination with pegylated interferon and ribavirin as triple therapy for genotype 1 HCV. This combination increases sustained virological response from approximately 45-50% to 66-75% in treatment naïve patients. However, these new regimens present novel challenges including complicated treatment algorithms based on virological response, numerous drug interactions and additional side effects especially in patients with advanced fibrosis. The protease inhibitors are the first of many antiviral drugs to become available to treat HCV, heralding the arrival of new agents that will offer greater chances of cure with improved safety and tolerability compared with current therapies.


[Mobile ultrasonography in a medical department].
We examined the usefulness and image quality of a mobile miniaturised ultrasound scanner in a medical ward. The instrument (SonoSite 180), weighing 2.4 kg, is a hand-carried system powered by batteries. In 25 days we recruited consecutively 36 patients aged 23-92. Four different operators evaluated the use of the scanner. We examined one group of patients with relatively simple diagnostic challenges (e.g. gallbladder stone) and one group of patients demanding more advanced visualisation (e.g. peptic ulcer, colitis). The scanner was easy to carry around and scanning was initiated in 10 seconds. We found satisfactory image quality on 81% of the examinations, despite the fact that in 28% of cases, bowel air and abdominal fat impaired acoustic penetration. Average scanning time was 7 +/- 3 minutes. In 83% of cases, mobile scanning adequately solved the clinical problem. Diagnostic work-up or treatment was changed because of scanning in 39% of the patients. In 64% of cases, standard-procedure referral to the department of radiology was avoided. In 81% of the examinations the operator was very satisfied with the scanner, also in cases that required advanced visualisation. This mobile scanner was simple to use and gave quick results in a medical ward. The operators were very satisfied: mobile scanning changed diagnostic work-up or treatment in 4 out of 10 cases. Mobile ultrasound scanning enables early diagnosis and seems to promote an efficient flow of patients in a hospital unit.


How old is your fold?
At present there exists no age estimate for the different protein structures found in nature. It has become clear from occurrence studies that different folds arose at different points in evolutionary time. An estimation of the age of different folds would be a starting point for many investigations into protein structure evolution: how we arrived at the set of folds we see today. It would also be a powerful tool in protein structure classification allowing us to reassess the available hierarchical methods and perhaps suggest improvements. We have created the first relative age estimation technique for protein folds. Our method is based on constructing parsimonious scenarios, which can describe occurrence patterns in a phylogeny of species. The ages presented are shown to be robust to the different trees or data types used for their generation. They show correlations with other previously used protein age estimators, but appear to be far more discriminating than any previously suggested technique. The age estimates given are not absolutes but they already offer intriguing insights, like the very different age patterns of alpha/beta folds compared with small folds. The alpha/beta folds appear on average to be far older than their small fold counterparts. Example trees and additional material are available at http://www.stats.ox.ac.uk/~abeln/foldage http://www.stats.ox.ac.uk/~abeln/foldage.


Therapeutic Drug Monitoring of Protein Kinase Inhibitors in the Treatment of Non-small Cell Lung Cancer.
Targeted therapy with protein kinase inhibitors (PKIs) represents one of the important treatment options for non-small cell lung cancer (NSCLC). It has contributed to improve patients' survival and quality of life significantly. These anticancer drugs are administrated orally in flat-fixed doses despite the well-known large interpatient pharmacokinetic variability and the possible need for dose individualization. To optimize and individualize dosing of PKIs, and thereby increasing the effectiveness and safety of the treatment, therapeutic drug monitoring (TDM) is the most frequently mentioned method. Unlike other areas of medicine, TDM has been rather exceptional in oncological practise since there is a little evidence or no data for concentration-effect relationships of PKIs. Therefore, the aim of this review is to summarize the pharmacokinetic characteristics of PKIs and provide the evidence supporting the use of TDM for personalised treatment of patients with NSCLC.


Diffraction tomographic reconstruction from intensity data.
The problem of reconstructing the complex index of refraction of a weakly inhomogeneous scattering object from measurements of the magnitude (intensity) of the transmitted wavefields in a set of scattering experiments within the context of diffraction tomography (DT) is addressed. It is shown that high quality approximate reconstructions can be obtained from such intensity data using standard reconstruction procedures of DT. The physical basis for the success of these procedures when applied to intensity data is discussed and computer simulations are presented comparing the approximate reconstructions generated from intensity data with the optimum reconstructions generated from both the magnitude and phase of the transmitted wavefields.


[Dependence of the radiosensitivity of yeast cells on the LET of radiations. Experiments on haploid cells].
The previously developed model was used to study the dependence of radiosensitivity (D0(-1) of Saccharomyces cerevisiae (the wild type and radiosensitive mutant) on linear energy transfer (LET) of ionizing radiation. D0(-1) (L) of haploid yeasts was shown to be associated, to a certain extent, with the capacity of radiation damages repair. As to the wild-type cells, the above function was represented by a curve showing a maximum, while a descending curve was characteristic of the radiosensitive mutant cells deficient in radiation damages repair. The influence of the repair processes on cell radiosensitivity decreased with increasing LET.


A monoclonal antibody to the calmodulin-binding (Ca2+ + Mg2+)-dependent ATPase from pig stomach smooth muscle inhibits plasmalemmal (Ca2+ + Mg2+)-dependent ATPase activity.
A monoclonal antibody (2B3) directed against the calmodulin-binding (Ca2+ + Mg2+)-dependent ATPase from pig stomach smooth muscle was prepared. This antibody reacts with a 130,000-Mr protein that co-migrates on SDS/polyacrylamide-gel electrophoresis with the calmodulin-binding (Ca2+ + Mg2+)-ATPase purified from smooth muscle by calmodulin affinity chromatography. The antibody causes partial inhibition of the (Ca2+ + Mg2+)-ATPase activity in plasma membranes from pig stomach smooth muscle, in pig erythrocytes and human erythrocytes. It appears to be directed against a specific functionally important site of the plasmalemmal Ca2+-transport ATPase and acts as a competitive inhibitor of ATP binding. Binding of the antibody does not change the Km of the ATPase for Ca2+ and its inhibitory effect is not altered by the presence of calmodulin. No inhibition of (Ca2+ + Mg2+)-ATPase activity or of the oxalate-stimulated Ca2+ uptake was observed in a pig smooth-muscle vesicle preparation enriched in endoplasmic reticulum. These results confirm the existence in smooth muscle of two different types of Ca2+-transport ATPase: a calmodulin-binding (Ca2+ + Mg2+)-ATPase located in the plasma membrane and a second one confined to the endoplasmic reticulum.


Potentiation of the behavioural effects of the antidepressant phenelzine by deuterium substitution.
Phenelzine in the rat induced biphasic behavioural stimulation, which was profoundly potentiated by deuterium substitution. Doses of 12.5 or 25.0 mg/kg phenelzine had little or no effect on spontaneous activity, whereas the same doses of deuterated phenelzine produced hyperactivity, wet-dog shakes, forepaw padding, splayed hind limbs, backward walking, sniffing and stereotyped grooming 2-12 h after injection. Similarly, the behavioural response induced by 50.0 mg/kg phenelzine was strongly potentiated by deuterium substitution. It appears likely that the increased behavioural response induced by deuterated phenelzine may be due to its greater potency as a monoamine oxidase inhibitor compared to undeuterated phenelzine. Since phenelzine is an antidepressant that is particularly efficacious in the treatment of severe anxiety, a deuterated analogue of the drug seems likely to be clinically useful.


Ontogeny of tracheal system structure: a light and electron-microscopy study of the metathoracic femur of the American locust, Schistocerca americana.
Does oxygen delivery become more challenging for insects as they increase in size? To partially test this hypothesis, we used quantitative light and electron microscopy to estimate the oxygen delivery capacity for two steps of tracheal oxygen delivery within the metathoracic femur (jumping leg) for 2nd instar (about 47 mg) and adult (about 1.7 g) locusts, Schistocerca americana. The fractional cross-sectional areas of the major tracheae running longitudinally along the leg were similar in adults and 2nd instars; however, since the legs of adults are longer, the mass-specific diffusive conductances of these tracheae were 4-fold greater in 2nd instars. Diffusive gas exchange longitudinally along the leg is easily possible for 2nd instars but not adults, who have many air sacs within the femur. Mitochondrial content fell proximally to distally within the femur in 2nd instars but not adults, supporting the hypothesis that diffusion was more important for the former. Lateral diffusing capacities of the tracheal walls were 12-fold greater in adults than 2nd instars. This was primarily due to differences in the smallest tracheal class (tracheoles), which had thinner epidermal and cuticular layers, greater surface to volume ratios, and greater mass-specific surface areas in adults. Adults also had greater mitochondrial contents, larger cell sizes and more intracellular tracheae. Thus, larger insects do not necessarily face greater problems with oxygen delivery; adult grasshoppers have superior oxygen delivery systems and greater mass-specific aerobic capacities in their legs than smaller/younger insects.


Life after proteolysis: Exploring the signaling capabilities of classical cadherin cleavage fragments.
Classical cadherins are a group of Ca(++) dependent transmembrane cell adhesion molecules, mostly known for their ability to perform homophylic interactions with like-cadherin molecules on the surface of neighboring cells. Over the past decade, many studies have also established cadherins as key players of intracellular signaling events by modifying the activity of Rho GTPases, members of the Wnt signaling pathway, and receptor tyrosine kinases. Given the utility of these molecules, it is not surprising that they play multiple roles during different embryological and adult processes. Yet, these activities have been primarily tied to their full-length molecules. And, while the activity of full-length molecules is undoubtedly an essential part of how cadherins perform in vivo, it is becoming increasingly evident that the proteolytic fragments of these molecules may also play a role. This is an exciting development because proteolysis of cadherins was previously thought to be a simple clearing-mechanism meant to regulate the levels of cadherin molecules on the cell-surface.Here, we will further discuss our recent findings by McCusker and colleagues, showing that both N-terminal and C-terminal fragments of cadherin-11 retain biological activity in Xenopus embryos. We will also review the current literature demonstrating that both the extracellular and intracellular fragments of other classical cadherins are capable of activating certain signaling events tied to Epithelial to Mesenchymal Transitions (EMTs), cell survival, cell proliferation and cell migration.


Research involving adolescents as subjects : ethical considerations.
Research involving adolescents as subjects is much more difficult to carry out than it ought to be. The excessive burdens in the field are borne by those who design and carry out the research, and also by those who review and monitor such research to ensure compliance with regulations and other policies designed to protect the rights and welfare of research subjects. This chapter is an overview of issues that are specific to research that involves adolescents. Problems and challenges are reviewed, and potential solutions suggested. The chapter also provides suggestions for improving current regulatory policies and practices so as to reduce bureaucratic impediments.


Classification in sport: A question of fairness.
Competitor classification schemes have been a part of sport since its origins. Eligibility criteria have developed towards inclusion and increasing diversity. The pool of competitors has expanded from the ancient Olympic Games, eligible only to free Greek men, via nineteenth-century English sport favouring primarily the upper class of so-called gentlemen amateurs, to the current global and diverse pool of men, women, children, and able-bodied as well as disabled persons. Hence, the challenge of sound classification schemes has increased. This article examines the principles of fair classification of athletes. With the help of normative theory as well as practical examples, a fair equality of opportunity principle for sport (FEOPs) is formulated. It is demonstrated how sound classification schemes combine the normative backing from FEOPs with relevant scientific insights. Current classification challenges and possibilities for change are discussed. It is suggested that in several sports, biological sex classes can be abandoned, and that in some sports, sex classes can be replaced by body size classes. It is argued, too, that sports in which body height exerts a significant and systematic impact on performance should classify accordingly. In the final part, classification is discussed in light of new techno-scientific possibilities, among them the possibility of innovative performance-enhancing prosthetics.


[Combined treatment of bladder radiation injuries].
A scheme of therapy of radiation cystitis is suggested. It was developed on the basis of evaluation of literature data and clinical examination of 205 patients with radiation injury of the urinary bladder (104 cases has severe injuries). The method is based on general and local therapy of damaged tissues by antiinflammatory drugs, anesthetics and stimulators of reparative regeneration. Severe ulcerative and incrustation cystites, refractory to conservative therapy, were treated by surgery, using antiseptics and reparation stimulators before, during and after operation. As a result, there were hardly any complications after reconstruction of the bladder with intestinal and peritoneal tissues, 104 patients (96.1%) were cured completely and ability to work was restored in 70 patients. (76.9%).


Unravelling the impact of fat content on the microbial dynamics and spatial distribution of foodborne bacteria in tri-phasic viscoelastic 3D models.
The aim of the current study is to develop and characterise novel complex multi-phase in vitro 3D models, for advanced microbiological studies. More specifically, we enriched our previously developed bi-phasic polysaccharide (Xanthan Gum)/protein (Whey Protein) 3D model with a fat phase (Sunflower Oil) at various concentrations, i.e., 10%, 20%, 40% and 60% (v/v), for better mimicry of the structural and biochemical composition of real food products. Rheological, textural, and physicochemical analysis as well as advanced microscopy imaging (including spatial mapping of the fat droplet distribution) of the new tri-phasic 3D models revealed their similarity to industrial food products (especially cheese products). Furthermore, microbial growth experiments of foodborne bacteria, i.e., Listeria monocytogenes, Escherichia coli, Pseudomonas aeruginosa and Lactococcus lactis on the surface of the 3D models revealed very interesting results, regarding the growth dynamics and distribution of cells at colony level. More specifically, the size of the colonies formed on the surface of the 3D models, increased substantially for increasing fat concentrations, especially in mid- and late-exponential growth phases. Furthermore, colonies formed in proximity to fat were substantially larger as compared to the ones that were located far from the fat phase of the models. In terms of growth location, the majority of colonies were located on the protein/polysaccharide phase of the 3D models. All those differences at microscopic level, that can directly affect the bacterial response to decontamination treatments, were not captured by the macroscopic kinetics (growth dynamics), which were unaffected from changes in fat concentration. Our findings demonstrate the importance of developing structurally and biochemically complex 3D in vitro models (for closer proximity to industrial products), as well as the necessity of conducting multi-level microbial analyses, to better understand and predict the bacterial behaviour in relation to their biochemical and structural environment. Such studies in advanced 3D environments can assist a better/more accurate design of industrial antimicrobial processes, ultimately, improving food safety.


Distinguishing primary from secondary Δ(4) -3-oxosteroid 5β-reductase (SRD5B1, AKR1D1) deficiency by urinary steroid analysis.
Deficiency of Δ(4) -3-oxosteroid 5β-reductase (5β-reductase), a bile acid synthesis disorder, presents findings of neonatal cholestasis and hyper-3-oxo-Δ(4) bile aciduria. The 5β-reductase enzyme participates in not only bile acid synthesis but also hepatic steroid metabolism. Deficiency of 5β-reductase includes 2 types: primary deficiency, with an SRD5B1 gene mutation; and secondary deficiency, lacking a mutation. Secondary deficiency is caused by fulminant liver failure from various aetiologies including neonatal hemochromatosis (NH). Distinguishing primary from secondary deficiency based on γ-glutamyltransferase (GGT), serum total bile acids (TBA), and urinary bile acid analysis using gas chromatography-mass spectroscopy (GC-MS) is very difficult. SRD5B1 gene analysis is the only reliable method. We examined urinary steroid analysis as a way to distinguish primary from secondary 5β-reductase deficiency. We examined 12 patients with cholestatic jaundice, normal or slightly elevated GGT, and hyper-3-oxo-Δ(4) bile aciduria using urinary steroid analysis by GC-MS of both cortisol and cortisone compounds, such as 5β-tetrahydrocortisol (5β-THF) and 5β-tetrahydrocortisone (5β-THE). Patients previously were diagnosed with primary 5β-reductase deficiency (n = 3), deficiency secondary to NH (n = 3) and deficiency secondary to other liver disorders (n = 6). Urinary steroid analysis in 3 primary deficiency and 3 NH patients showed low 5β-THE and elevated 5α/5β-THE ratios, making distinction difficult without also considering the clinical course and abdominal magnetic resonance imaging (MRI) findings, such as a very low signal intensity in liver and/or pancreas, especially in T2 -weighted images. In the six patients with other secondary deficiencies, urinary 5β-THF and 5α/5β-THF differed from those in primary deficiency (P < 0·05). Urinary steroid analysis can distinguish primary and NH-related deficiencies from other secondary deficiencies.


Shape-Dependent Interactions of Manganese Oxide Nanomaterials with Lipid Bilayer Vesicles.
Interactions of transition-metal-oxide nanomaterials with biological membranes have important environmental implications and applications in ecotoxicity and life-cycle assessment analysis. In this study, we quantitatively assess the impact of MnO2 nanomaterial morphology-one-dimensional (1D) nanowires, 2D nanosheets, and 3D nanoflowers-on their interaction with phospholipid vesicles as a model for biological membranes. Confocal microscopy suggests visual evidence for the interaction of undisrupted vesicles with dispersed MnO2 nanomaterials of different morphologies, and it further supports the observation that minimal dye leakage of the vesicle inner solution was detected during the interaction with MnO2 nanomaterials during the dye leakage assay. Upon titration of vesicles to dispersions of MnO2 nanowires, nanosheets, and nanoflowers, each roughly 10 times larger than the vesicles, dynamic light scattering reveals two diffusive time scales associated with aggregates in the mixture. While the longer time scale corresponds to the dispersed MnO2 control population, the appearance of a shorter timescale with vesicle addition indicates interaction between the dispersed metal oxide nanomaterials and the vesicles. The interaction is shape-dependent, being more pronounced for MnO2 nanowires than for nanosheets and nanoflowers. Furthermore, the shorter diffusive time scale is intermediate between the vesicle and nanomaterial controls, which may suggest a degree of metal oxide aggregate breakup. Vesicle adsorption isotherms and zeta potential measurements during titration corroborate vesicle attachment on the nanomaterials. Our results suggest that the dispersed nanomaterial shape plays an important role in mediating nondestructive vesicle-nanomaterial interactions and that lipid vesicles act as efficient surfactants for MnO2 nanomaterials.


Spirometric and anthropometric improvements in response to elexacaftor/tezacaftor/ivacaftor depending on age and lung disease severity.
Introduction: Triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) was introduced in August 2020 in Germany for people with CF (pwCF) ≥12 years (yrs.) of age and in June 2021 for pwCF ≥6 yrs of age. In this single-center study, we analyzed longitudinal data on the percent-predicted forced expiratory volume (ppFEV1) and body-mass-index (BMI) for 12 months (mo.) after initiation of ETI by linear mixed models and regression analyses to identify age- and severity-dependent determinants of response to ETI. Methods: We obtained data on 42 children ≥6-11 yrs, 41 adolescents ≥12-17 yrs, and 143 adults by spirometry and anthropometry prior to ETI, and 3 and 12 mo. after ETI initiation. Data were stratified by the age group and further sub-divided into age-specific ppFEV1 impairment. To achieve this, the age strata were divided into three groups, each according to their baseline ppFEV1: lowest 25%, middle 50%, and top 25% of ppFEV1. Results: Adolescents and children with more severe lung disease prior to ETI (within the lowest 25% of age-specific ppFEV1) showed higher improvements in lung function than adults in this severity group (+18.5 vs. +7.5; p = 0.002 after 3 mo. and +13.8 vs. +7.2; p = 0.012 after 12 mo. of ETI therapy for ≥12-17 years and +19.8 vs. +7.5; p = 0.007 after 3 mo. for children ≥6-11 yrs). In all age groups, participants with more severe lung disease showed higher BMI gains than those with medium or good lung function (within the middle 50% or top 25% of age-specific ppFEV1). Regression analyses identified age as a predictive factor for FEV1 increase at 3 mo. after ETI initiation, and age and ppFEV1 at ETI initiation as predictive factors for FEV1 increase 12 mo. after ETI initiation. Discussion: We report initial data, which suggest that clinical response toward ETI depends on age and lung disease severity prior to ETI initiation, which argue for early initiation of ETI.


A new lectin-gold complex for ultrastructural localization of galacturonic acids.
We report the development of a cytochemical affinity technique for detection of galacturonic acids at the ultrastructural level. The highly purified gonad lectin from Aplysia depilans (AGL) was tagged with colloidal gold particles and used for labeling carbohydrates in resin-embedded sections of various plant and fungal tissues. Patterns of AGL binding sites were compared to those obtained with a D-galactose-specific lectin, Ricinus communis agglutinin I. Differences in labeling patterns were noted, indicating that the lectins exhibited differential carbohydrate binding. In addition, the considerable loss of labeling over isolated wheat coleoptile walls treated for removal of pectin, after incubation with the AGL-gold complex, strongly suggested an affinity of AGL for pectic substances. A series of cytochemical controls, including sugar inhibition tests, has proven the specificity of the technique and the high affinity of AGL towards galacturonic acids. The potential value of this new lectin for ultrastructural studies on cell wall pectic substances in plant biology and pathology is demonstrated.


Anaesthesia or psychotherapy: eradicating thoughts or working them through.
The author presents two sessions from the analysis of a depressive narcissistic doctor, which are characterised by a mixture of co-operation and pseudo-co-operation. The dialogue is in parts intellectualised, complicated, lifeless and schizoid. Points at which the patient shows surprising insights are then partly denigrated by him, on the basis that change is not to be expected. Semi-lifeless contact assists the defensive claustrophobia that he experiences in meaningful contact. It becomes very clear that he is then afraid of entering into an openly aggressive conflict that entails the existential threat of object loss. However, this has so far been avoided. The secret pleasure in an anal-narcissistic, sadomasochistic addiction to doubt persists in the partial denigration. The patient's artificially maintained self-doubt and doubt of the object reinforce a genuine confusion that consists in never knowing exactly what lies behind the helpful and needed object.