Unleashing the power of meta-threading for evolution/structure-based function inference of proteins.
Protein threading is widely used in the prediction of protein structure and the subsequent functional annotation. Most threading approaches employ similar criteria for the template identification for use in both protein structure and function modeling. Using structure similarity alone might result in a high false positive rate in protein function inference, which suggests that selecting functional templates should be subject to a different set of constraints. In this study, we extend the functionality of eThread, a recently developed approach to meta-threading, focusing on the optimal selection of functional templates. We optimized the selection of template proteins to cover a broad spectrum of protein molecular function: ligand, metal, inorganic cluster, protein, and nucleic acid binding. In large-scale benchmarks, we demonstrate that the recognition rates in identifying templates that bind molecular partners in similar locations are very high, typically 70-80%, at the expense of a relatively low false positive rate. eThread also provides useful insights into the chemical properties of binding molecules and the structural features of binding. For instance, the sensitivity in recognizing similar protein-binding interfaces is 58% at only 18% false positive rate. Furthermore, in comparative analysis, we demonstrate that meta-threading supported by machine learning outperforms single-threading approaches in functional template selection. We show that meta-threading effectively detects many facets of protein molecular function, even in a low-sequence identity regime. The enhanced version of eThread is freely available as a webserver and stand-alone software at http://www.brylinski.org/ethread.


Interaction of Aspergillus fumigatus conidia with Acanthamoeba castellanii parallels macrophage-fungus interactions.
Aspergillus fumigatus and free-living amoebae are common inhabitants of soil. Mechanisms of A. fumigatus to circumvent the amoeba's digestion may facilitate overcoming the vertebrate macrophage defence mechanisms. We performed co-culture experiments using A. fumigatus conidia and the amoeba Acanthamoeba castellanii. Approximately 25% of the amoebae ingested A. fumigatus conidia after 1 h of contact. During intra-amoebal passage, part of the ingested conidia was able to escape the food vacuole and to germinate inside the cytoplasm of A. castellanii. Fungal release into the extra-protozoan environment by exocytosis of conidia or by germination was observed with light and transmission electron microscopy. These processes resulted in structural changes in A. castellanii, leading to amoebal permeabilization without cell lysis. In conclusion, A. castellanii internalizes A. fumigatus conidia, resulting in fungal intracellular germination and subsequent amoebal death. As such, this interaction highly resembles that of A. fumigatus with mammalian and avian macrophages. This suggests that A. fumigatus virulence mechanisms to evade macrophage killing may be acquired by co-evolutionary interactions among A. fumigatus and environmental amoebae.


Patient ratings of dialysis care with peritoneal dialysis vs hemodialysis.
In light of conflicting evidence of differential effects of dialysis modality on survival, patient experience becomes a more important consideration in choosing between hemodialysis and peritoneal dialysis. To compare patient satisfaction with hemodialysis and peritoneal dialysis in a cohort of patients who have recently begun dialysis. Cross-sectional survey at enrollment in a prospective inception cohort study of patients who recently started dialysis at 37 dialysis centers participating in the Choices for Healthy Outcomes in Caring for End-stage Renal Disease (CHOICE) study, a national multicenter study of dialysis outcomes, from October 1995 to June 1998. Of 736 enrolled incident dialysis patients, 656 (89%) returned a satisfaction questionnaire after an average of 7 weeks of dialysis. Data collected from a patient-administered questionnaire including 3 overall ratings and 20 items rating specific aspects of dialysis care. Patients receiving peritoneal dialysis were much more likely than those receiving hemodialysis to give excellent ratings of dialysis care overall (85% vs 56%, respectively; relative probability, 1.46 [95% confidence interval, 1.31-1.57]) and significantly more likely to give excellent ratings for each specific aspect of care rated. The 3 items with the greatest differences were in the domain of information provided (average of information items: peritoneal dialysis [69% excellent] vs hemodialysis [30% excellent]). The smallest differences were in ratings of accuracy of information from the nephrologist, response to pain, amount of fluid removed, and staff availability in an emergency. Adjustment for patient age, race, education, health status, marital status, employment status, distance from the center, and time since starting dialysis did not reduce the differences between peritoneal dialysis and hemodialysis patients. After several weeks of initiating dialysis, patients receiving peritoneal dialysis rated their care higher than those receiving hemodialysis. These findings indicate that clinicians should give patients more information about the option of peritoneal dialysis.


The phenomenology of lucid dreaming: an online survey.
In lucid dreams the dreamer is aware that he or she is dreaming. Although such dreams are not that uncommon, many aspects of lucid dream phenomenology are still unclear. An online survey was conducted to gather data about lucid dream origination, duration, active or passive participation in the dream, planned actions for lucid dreams, and other phenomenological aspects. Among the 684 respondents who filled out the questionnaire, there were 571 lucid dreamers (83.5%). According to their reports, lucid dreams most often originate spontaneously in adolescence. The average lucid dream duration is about 14 minutes. Lucid dreamers are likely to be active in their lucid dreams and plan to accomplish different actions (e.g., flying, talking with dream characters, or having sex), yet they are not always able to remember or successfully execute their intentions (most often because of awakening or hindrances in the dream environment). The frequency of lucid dream experience was the strongest predictor of lucid dream phenomenology, but some differences were also observed in relation to age, gender, or whether the person is a natural or self-trained lucid dreamer. The findings are discussed in light of lucid dream research, and suggestions for future studies are provided.


A diffusion wake model for tracer ultrastructure-permeability studies in microvessels.
We developed a time-dependent diffusion model for analyzing the concentration profiles of low-molecular-weight tracers in the interendothelial clefts of the capillary wall that takes into account the three-dimensional time-dependent filling of the surrounding tissue space. The model provides a connecting link between two methods to investigate transvascular exchange: electron-microscopic experiments to study the time-dependent wake formed by low-molecular-weight tracers (such as lanthanum nitrate) on the tissue side of the junction strand discontinuities in the interendothelial cleft of frog mesentery capillaries (R. H. Adamson and C. C. Michel. J. Physiol. Lond. 466: 303-327, 1993) and confocal-microscopic experiments to measure the spread of low-molecular-weight fluorescent tracers in the tissue space surrounding these microvessels (R. H. Adamson, J. F. Lenz, and F. E. Curry, Microcirculation 1: 251-265, 1994). We show that the interpretation of the presence of tracer as an all-or-none indication of a pathway across the junctional strand is likely to be incorrect for small solutes. Large-pore pathways, in which the local tracer flux densities are high, reach a threshold concentration for detection and are likely to be detected after relatively short perfusion times, whereas distributed small-pore pathways may not be detected until the tissue concentrations surrounding the entire vessel approach threshold concentrations. The analysis using this approach supports the hypothesis advanced by Fu et al. (J. Biomech. Eng. 116: 502-513, 1994) that the principal pathways for water and solutes of < 1.0 nm diameter across the interendothelial cleft may be different and suggests new experiments to test this hypothesis.


Unifying the relationships of species richness to productivity and disturbance.
Although species richness has been hypothesized to be highest at 'intermediate' levels of disturbance, empirical studies have demonstrated that the disturbance-diversity relationship can be either negative or positive depending on productivity On the other hand, hypothesized productivity diversity relationships can be positive, negative or unimodal, as confirmed by empirical studies. However, it has remained unclear under what conditions each pattern is realized, and there is little agreement about the mechanisms that generate these diverse patterns. In this study, I present a model that synthesizes these separately developed hypotheses and shows that the interactive effects of disturbance and productivity on the competitive outcome of multispecies dynamics can result in these diverse relationships of species richness to disturbance and productivity The predicted productivity diversity relationship is unimodal but the productivity level that maximizes species richness increases with increasing disturbance. Similarly, the predicted disturbance diversity relationship is unimodal but the peak moves to higher disturbance levels with increasing productivity Further, these patterns are well explained by the opposite effects of productivity and disturbance on competitive outcome that are suggested by the change in community composition along these two environmental gradients: higher productivity favours superior competitors while higher disturbance levels favour inferior competitors.


[The two leading hypothesis regarding the molecular mechanisms and etiology of preeclampsia, and the Mexican experience in the world context].
Preeclampsia (PE) is one of the most severe complications of pregnancy. PE is responsible for the highest rates of morbidity and mortality for both pregnant women and the neonate. In this review, we first address general aspects of PE and its diagnosis, along with some epidemiological aspects of this disease in the mexican population, in particular the experience from the Instituto Mexicano del Seguro Social. Even though over the last 20 years a great deal of evidence has accumulated regarding PE's pathophysiology, an exact mechanism to explain its etiology has not been established. This review aims to cover the status of two of the most important hypotheses in the etiology of PE: the immunological and the placental ischemia hypotheses. Recent data suggest that Natural Killer cells (NK) play a major role in the decidual spiral arteriole remodeling and in normal placental development. In genetic studies, KIR receptors present in NK cells have been involved in the susceptibility for the disease. In this review, we discuss data of our group regarding the presence of NK cells in the decidua, at the end of pregnancy and the genotypes of KIR receptors in normal and preeclamptic Mexican population. PE is characterized by abnormal placentation and hypoxia with an increase of anti-angiogenic factors; the Hypoxia-inducible factor 1-alfa (HIF1-alfa) is over expressed in PE. In this review, we also included some of our results concerning the polymorphisms and regulation of HIF in preeclamptic women.


The Development of a Thin-Filmed Noninvasive Tissue Perfusion Sensor to Quantify Capillary Pressure Occlusion of Explanted Organs.
A new thin-filmed perfusion sensor was developed using a heat flux gauge, thin-film thermocouple, and a heating element. This sensor, termed "CHFT+," is an enhancement of the previously established combined heat flux-temperature (CHFT) sensor technology predominately used to quantify the severity of burns [1]. The CHFT+ sensor was uniquely designed to measure tissue perfusion on explanted organs destined for transplantation, but could be functionalized and used in a wide variety of other biomedical applications. Exploiting the thin and semiflexible nature of the new CHFT+ sensor assembly, perfusion measurements can be made from the underside of the organ-providing a quantitative indirect measure of capillary pressure occlusion. Results from a live tissue test demonstrated, for the first time, the effects of pressure occlusion on an explanted porcine kidney. CHFT+ sensors were placed on top of and underneath 18 kidneys to measure and compare perfusion at perfusate temperatures of 5 and 20 °C. The data collected show a greater perfusion on the topside than the underside of the specimen for the length of the experiment. This indicates that the pressure occlusion is truly affecting the perfusion, and, thus, the overall preservation of explanted organs. Moreover, the results demonstrate the effect of preservation temperature on the tissue vasculature. Focusing on the topside perfusion only, the 20 °C perfusion was greater than the 5 °C perfusion, likely due to the vasoconstrictive response at the lower perfusion temperatures.


Association between human papillomavirus DNA and temporal arteritis.
To examine the relationship between human papillomavirus (HPV) and giant cell arteritis (GCA) of the temporal artery. The study group consisted of 22 cases of histologically positive/biopsy confirmed GCA. The control groups consisted of 21 histologically negative temporal artery biopsies and fifteen cases of vascular margins of nephrectomies. For detection of the presence of HPV, two methods were used: 1) polymerase chain reaction (PCR) with INNO-LiPA HPV Genotyping Extra, 2) Cervista™ HPV HR. All cases were from the files of the Barnes-Jewish Hospital and Washington University in St. Louis. HPV DNA was detected by PCR and genotyping in 16 of 22 (73%) histologically positive cases of GCA and in only five of 21 (24%) histologically negative temporal artery biopsies. Among the vascular margin controls, only three of 15 (20%) were positive for HPV DNA. The second, independent method (CervistaTM) confirmed the aforesaid results with 100% concordance with the exception of three cases which had low genomic DNA for which it was not possible to perform the test. The differences in HPV positivity between the histologically positive and negative temporal artery biopsies and between the histologically positive temporal artery biopsies and controls were both statistically significant (p = 0.001 and 0.002, respectively). The results of our study revealed a statistically significant association between HPV positivity and biopsy confirmed temporal giant cell arteritis GCA (p = 0.001). Further studies are necessary to elucidate the pathophysiology underlying this association.


Sex difference in the mouse BAT transcriptome reveals a role of progesterone.
Brown adipose tissue (BAT) is a metabolically active organ that exhibits sex-differential features, that is, being generally more abundant and active in females than in males. Although sex steroids, particularly estrogens, have been shown to regulate BAT thermogenic function, the underlying molecular mechanisms contributing to sexual dimorphism in basal BAT activity have not been elucidated. Therefore, we assessed the transcriptome of interscapular BAT of male and female C57BL/6J mice by RNA sequencing and identified 295 genes showing ≥2-fold differential expression (adjusted P < 0.05). In silico functional annotation clustering suggested an enrichment of genes encoding proteins involved in cell-cell contact, interaction, and adhesion. Ovariectomy reduced the expression of these genes in female BAT toward a male pattern whereas orchiectomy had marginal effects on the transcriptional pattern, indicating a prominent role of female gonadal hormones in this sex-differential expression pattern. Progesterone was identified as a possible upstream regulator of the sex-differentially expressed genes. Studying the direct effects of progesterone in vitro in primary adipocytes showed that progesterone significantly altered the transcription of several of the identified genes, possibly via the glucocorticoid receptor. In conclusion, this study reveals a sexually dimorphic transcription profile in murine BAT at general housing conditions and demonstrates a role for progesterone in the regulation of the interscapular BAT transcriptome.


Meta-analysis of biosolid effects on persistence of triclosan and triclocarban in soil.
Biosolids are extensively used in agriculture as fertilizers while offering a practical solution for waste disposal. Many pharmaceutical and personal care products (PPCPs), such as triclosan and triclocarban, are enriched in biosolids. Biosolid amendment changes soil physicochemical properties, which may in turn alter the persistence of PPCPs and hence the risk for secondary contamination such as plant uptake. To delineate the effect of biosolids on PPCPs persistence, triclosan and triclocarban were used as model compounds in this study and their sorption (Kd) and persistence (t1/2) were determined in different soils before and after biosolid amendment. Biosolids consistently increased sorption of triclosan and triclocarban in soil. The Kd of triclosan increased by 3.9-21 times following amendment of a sandy loam soil with biosolids at 2-10%. The persistence of both compounds was prolonged, with t1/2 of triclosan increasing from 10 d in the unamended soil to 63 d after biosolid amendment at 10%. The relationship between t1/2 and Kd was further examined through a meta-analysis using data from this study and all relevant published studies. A significant linear relationship between t1/2 and Kd was observed for triclosan (r(2) = 0.69, p < 0.01) and triclocarban (r(2) = 0.38, p < 0.05) in biosolid-amended soils. On the average, when biosolid amendment increased by 1%, t1/2 of triclosan was prolonged by 7.5 d, while t1/2 of triclocarban was extended by 4.7 d. Therefore, biosolid amendment greatly enhances persistence of triclosan and triclocarban, likely due to enhanced sorption or decreased chemical bioavailability. This finding highlights the importance to consider the effect of biosolids when evaluating the environmental risks of these and other biosolid-borne PPCPs.


The Novelty of Icosapent Ethyl in the Management of Hypertriglyceridemia and Alleviating Cardiovascular Risk.
Hypertriglyceridemia is believed to be independently associated with an elevated risk of cardiovascular disease (CVD) events. Lifestyle changes and dietary modifications are recommended for individuals with high serum triglyceride (TG) levels (150-499 mg/dl), and pharmacological therapy in addition to lifestyle modification is recommended when serum TG levels ≥ 500 mg/dl. A residual cardiovascular risk remains even in statin appropriate treated patients with CVD risk factors, and in this patient population, hypertriglyceridemia poses an independent and increased risk of ischemic events. In December 2019, the US FDA approved icosapent ethyl (IPE) as an adjunct to a maximally tolerated statin to reduce the risk of CVD events in adults with serum triglycerides > 150 mg/dl and have either established cardiovascular disease or diabetes and two or more additional CVD risk factors. Since IPE significantly decreases total ischemic events in the aforementioned patient population, it would be intriguing to know whether IPE alone added an advantage to lifestyle modification in the low-risk population, who has serum triglyceride between 150 mg/dl and 499 mg/dl.


Advances in Conductive Hydrogel for Spinal Cord Injury Repair and Regeneration.
Spinal cord injury (SCI) treatment represents a major challenge in clinical practice. In recent years, the rapid development of neural tissue engineering technology has provided a new therapeutic approach for spinal cord injury repair. Implanting functionalized electroconductive hydrogels (ECH) in the injury area has been shown to promote axonal regeneration and facilitate the generation of neuronal circuits by reshaping the microenvironment of SCI. ECH not only facilitate intercellular electrical signaling but, when combined with electrical stimulation, enable the transmission of electrical signals to electroactive tissue and activate bioelectric signaling pathways, thereby promoting neural tissue repair. Therefore, the implantation of ECH into damaged tissues can effectively restore physiological functions related to electrical conduction. This article focuses on the dynamic pathophysiological changes in the SCI microenvironment and discusses the mechanisms of electrical stimulation/signal in the process of SCI repair. By examining electrical activity during nerve repair, we provide insights into the mechanisms behind electrical stimulation and signaling during SCI repair. We classify conductive biomaterials, and offer an overview of the current applications and research progress of conductive hydrogels in spinal cord repair and regeneration, aiming to provide a reference for future explorations and developments in spinal cord regeneration strategies.


Development and application of bioluminescence imaging for the influenza A virus.
Influenza A viruses (IAVs) cause seasonal epidemics and intermittent pandemics which threaten human health. Conventional assays cannot meet the demands for rapid and sensitive detection of viral spread and pathogenesis in real time cannot be used for high-throughput screens of novel antivirals. Bioluminescence imaging (BLI) has emerged as a powerful tool in the study of infectious diseases in animal models. The advent of influenza reverse genetics has enabled the incorporation of bioluminescent reporter proteins into replication-competent IAVs. This review briefly describes the current development and applications of bioluminescence in the study of viral infections and antiviral therapeutics for IAVs. BLI is expected to substantially accelerate the basic and applied research of IAV both in vitro and in vivo.


Understanding the metabolism of the anticancer drug Triapine: electrochemical oxidation, microsomal incubation and in vivo analysis using LC-HRMS.
α-N-Heterocyclic thiosemicarbazones are among the most promising ribonucleotide reductase inhibitors identified so far. Triapine, the most prominent representative of this class of substances, has been investigated in multiple phase I and II clinical trials. With regard to clinical practice, Triapine showed activity against hematological diseases, but ineffectiveness against a variety of solid tumors. However, the reasons are still vague and the amount of ADME (absorption, distribution, metabolism and excretion) data for Triapine available in the literature is very limited. Therefore, different analytical tools were used to investigate the metabolism of Triapine including electrochemical oxidations, liver microsomes and in vivo samples from mice. The main metabolic reactions, observed by all three methods, were dehydrogenation and hydroxylations, confirming that electrochemistry, as a purely instrumental approach, can be applied for the simulation of metabolic pathways. The dehydrogenated metabolite M1 was identified as a thiadiazole ring-closed oxidation product of Triapine. From a biological point of view, M1, as a key metabolite, is of interest since the crucial chemical property of α-N-heterocyclic thiosemicarbazones to bind metal ions is lost and cytotoxicity studies showed no anticancer activity of M1. The in vivo data of the urine samples revealed very high levels of the metabolites and Triapine itself already 15 min after treatment. This clearly indicates that Triapine is rapidly metabolised and excreted, which represents an important step forward to understand the possible reason for the inefficiency of Triapine against solid tumors.


Computation of electromagnetic fields for high-frequency magnetic resonance imaging applications.
A numerical method is presented to compute electromagnetic fields inside a 2 mm high resolution, anatomically detailed model of a human head for high-frequency magnetic resonance imaging (MRI) applications. The method uses the biconjugate gradient algorithm in combination with the fast Fourier transform to solve a matrix equation resulting from the discretization of an integrodifferential equation representing the original physical problem. Given the current distribution in an MRI coil, the method can compute both the electric field (thus the specific energy absorption rate (SAR)) and the magnetic field, also known as the B1 field. Results for the SAR and B1 field distribution, excited by a linear and a quadrature birdcage coil, are calculated and presented at 64 MHz, 128 MHz and 256 MHz, corresponding to the operating frequencies of the 1.5 T, 3 T and 6 T MRI systems. It is shown that compared with that at 64 MHz, the SAR at 128 MHz is increased by a factor over 5 and the SAR at 256 MHz is increased by a factor over 10, assuming the same current strength in the coil. Furthermore, compared with the linear excitation, the average SAR for the quadrature excitation is reduced by a factor over 2 and the maximum SAR is reduced by a factor over 3. It is also shown that the B1 field at high frequencies exhibits a strong inhomogeneity, which is attributed to dielectric resonance.


Metatranscriptome analysis reveals the putative venom toxin repertoire of the biofouling hydroid Ectopleura larynx.
Cnidarians thriving in biofouling communities on aquaculture net pens represent a significant health risk for farmed finfish due to their stinging cells. The toxins coming into contact with the fish, during net cleaning, can adversely affect their behavior, welfare, and survival, with a particularly serious health risk for the gills, causing direct tissue damage such as formation of thrombi and increasing risks of secondary infections. The hydroid Ectopleura larynx is one of the most common fouling organisms in Northern Europe. However, despite its significant economic, environmental, and operational impact on finfish aquaculture, biological information on this species is scarce and its venom composition has never been investigated. In this study, we generated a whole transcriptome of E. larynx, and identified its putative expressed venom toxin proteins (predicted toxin proteins, not functionally characterized) based on in silico transcriptome annotation mining and protein sequence analysis. The results uncovered a broad and diverse repertoire of putative toxin proteins for this hydroid species. Its toxic arsenal appears to include a wide and complex selection of toxin proteins, covering a large panel of potential biological functions that play important roles in envenomation. The putative toxins identified in this species, such as neurotoxins, GTPase toxins, metalloprotease toxins, ion channel impairing toxins, hemorrhagic toxins, serine protease toxins, phospholipase toxins, pore-forming toxins, and multifunction toxins may cause various major deleterious effects in prey, predators, and competitors. These results provide valuable new insights into the venom composition of cnidarians, and venomous marine organisms in general, and offer new opportunities for further research into novel and valuable bioactive molecules for medicine, agronomics and biotechnology.


Rapid decline in lung function is temporally associated with greater metabolically active adiposity in a longitudinal study of healthy adults.
Adiposity is associated with low lung function, but the longitudinal relationship between lung function and adiposity is inadequately studied. To examine the bidirectional longitudinal associations between rapid decline in lung function and adiposity phenotypes in healthy adults. This secondary analysis used a 25-year longitudinal dataset from the Coronary Artery Risk Development in Young Adults (CARDIA) study that enrolled 5115 participants. In the first analysis, metabolic syndrome at or before CARDIA year (Y) 10 (Y10) was the predictor, and subsequent rapid decline in forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1) between Y10 and Y20 was the outcome. In the second analysis, rapid decline was the predictor, and incident metabolic syndrome at Y20 and/or Y25 was the outcome. In the third analysis, rapid decline was the predictor, and subsequent CT-assessed regional fat depots at Y25 were the outcome. Metabolic syndrome at or before Y10 is temporally associated with rapid decline in FVC between Y10 and Y20 (adjusted p=0.04), but this association was explained by body mass index (BMI) at Y10. Rapid decline in FVC or FEV1 is temporally associated with greater incident metabolic syndrome at Y20 and/or Y25 (adjusted OR 2.10 (1.69, 2.61); p<0.001, and 1.56 (1.26, 1.94); p<0.001, respectively) and greater CT-assessed intrathoracic visceral adiposity at Y25 (adjusted standardised β 0.09; p<0.001 for both analyses). These associations were not explained by BMI levels prior to the outcome measurement. Healthy adults with rapid decline in lung function are at risk for developing metabolic syndrome and for disproportionate accumulation of intrathoracic visceral fat. Metabolic abnormalities may be an early extrapulmonary manifestation of lung impairment that may be preventable by improving lung health.


Increase in Purkinje cell gain associated with naturally activated climbing fiber input.
These experiments were designed to test the hypothesis that climbing fiber inputs evoked by a peripheral stimulus increase the responsiveness of Purkinje cells to mossy fiber inputs. This hypothesis was based on a previous series of observations demonstrating that spontaneous climbing fiber inputs are associated with an accentuation of the Purkinje cell responses to subsequent mossy fiber inputs (10, 12). Furthermore, short-term nonpersistent interactions between climbing and mossy fiber inputs have been an important aspect of many theories of cerebellar function (5, 7, 8, 12, 36). Extracellular unitary recordings were made from Purkinje cells in lobule V of decerebrate, unanesthetized cats. To activate mossy and climbing fiber inputs, the forepaw was passively flexed by a Ling vibrator system. A data analysis was developed to sort the simple spike trials into two groups, based on the presence or absence of complex spikes activated by the stimulus. In addition, during those trials in which complex spikes were activated, the simple spike train was aligned on the occurrence of the complex spike. For each simple spike response to the forepaw input, the average firing rate during the response was compared to background both in those trials in which complex spikes were activated and in those in which they were not. The ratio of the response amplitudes in the histograms constructed from these two groups of trials permitted a quantification of the change in responsiveness when climbing fiber inputs were activated. The results show that both excitatory and inhibitory simple spike responses are accentuated when associated with the activation of a complex spike. Using an arbitrary level of a gain change ratio of 120% as indicating a significant modification, 64% of the response components analyzed increased their amplitude when climbing fiber input was present. Simple spike response components occurring prior to complex spike activation were usually not accentuated, although in a few cells the amplitude of this component of the response increased. In addition, in a small number of cells the occurrence of complex spikes was associated with a new simple spike component. For excitatory responses, the magnitude of the gain change ratio was shown to be inversely related to the amplitude of the simple spike response evoked by the mossy fiber inputs. The data obtained is consistent with the hypothesis that the climbing fiber input is associated with an increase in the responsiveness of Purkinje cells to mossy fiber inputs. The increased responsiveness occurs whether the simple spike modulation evoked by the peripheral stimulus is excitatory or inhibitory. The change in responsiveness is short term and nonpersistent. It is argued that the activation of climbing fiber inputs to the cerebellar cortex is associated with an increase in the gain of Purkinje cells to mossy fiber inputs activated by natural peripheral stimuli.


Rifabutin Is Bactericidal against Intracellular and Extracellular Forms of Mycobacterium abscessus.
Mycobacterium abscessus is increasingly recognized as an emerging opportunistic pathogen causing severe lung diseases. As it is intrinsically resistant to most conventional antibiotics, there is an unmet medical need for effective treatments. Repurposing of clinically validated pharmaceuticals represents an attractive option for the development of chemotherapeutic alternatives against M. abscessus infections. In this context, rifabutin (RFB) has been shown to be active against M. abscessus and has raised renewed interest in using rifamycins for the treatment of M. abscessus pulmonary diseases. Here, we compared the in vitro and in vivo activity of RFB against the smooth and rough variants of M. abscessus, differing in their susceptibility profiles to several drugs and physiopathologial characteristics. While the activity of RFB is greater against rough strains than in smooth strains in vitro, suggesting a role of the glycopeptidolipid layer in susceptibility to RFB, both variants were equally susceptible to RFB inside human macrophages. RFB treatment also led to a reduction in the number and size of intracellular and extracellular mycobacterial cords. Furthermore, RFB was highly effective in a zebrafish model of infection and protected the infected larvae from M. abscessus-induced killing. This was corroborated by a significant reduction in the overall bacterial burden, as well as decreased numbers of abscesses and cords, two major pathophysiological traits in infected zebrafish. This study indicates that RFB is active against M. abscessus both in vitro and in vivo, further supporting its potential usefulness as part of combination regimens targeting this difficult-to-treat mycobacterium.


Physiological regulation of MMPs and tPA/PAI in the arterial wall of rats by noradrenergic tone and angiotensin II.
The interactions between the sympathetic nervous system (SNS) and angiotensin II (ANG II), and their direct effects in vitro on the enzymes involved in vascular extracellular matrix (ECM) degradation, were examined. Rats were treated with guanethidine, losartan or the combined treatments. mRNA, protein and activity of matrix metalloproteinase (MMP)-2 and MMP-9 and mRNA of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) were quantified in abdominal aorta (AA) and femoral artery (FA). Norepinephrine (NE) or ANG II with adrenergic (β, α1 and α2) or losartan antagonists was tested for MMP mRNA response in cultured vascular smooth muscle cells (VSMCs). Combined treatment enhances the inhibition of MMP-2 mRNA and protein level induced by simple treatment in AA. However MMP-9 in AA and MMP mRNA in FA were reduced in the same order by treatments. MMP activities were not affected by treatments. The t-PA/PAI-1 ratio, which reflects the fibrinolytic balance, remained higher after treatments. In cultured VSMCs, NE induced stimulation of MMP mRNA via α2 and β adrenergic receptors and MMP-2 activity via β adrenergic receptors, while ANG II-induced stimulation was abrogated by losartan. Overall, there is a synergic inhibition of both systems on the level of MMP-2 in AA.


Psychotropic drug induced weight gain: mechanisms and management.
Most of the drugs commonly used in the treatment and prophylaxis of depression, mania, and psychotic illness have, as one of their prominent side effects, the ability to increase appetite, stimulate carbohydrate craving, and promote weight gain. These side effects are troublesome to patients, and frequently constitute a major reason for premature discontinuation of therapy. This review examines the relative likelihood of the occurrence of appetite stimulation and weight gain with various psychotropic medications. Potential mechanisms of these effects and strategies to minimize or avoid weight gain during pharmacotherapy of psychiatric illness are examined. Evidence suggests that those compounds, which either antagonize or downregulate serotonin receptors, are more likely to stimulate carbohydrate hunger and weight gain. Amitriptyline, chlorpromazine, mesoridazine, thioridazine, and lithium are most likely to produce weight gain. Compounds that have more pronounced serotonergic action, such as fluoxetine and fenfluramine, are more likely to decrease carbohydrate craving and promote weight loss.


Steroid myopathy in a child with juvenile rheumatoid arthritis. Case report.
An 8-year-old boy who had been diagnosed as systemic-onset juvenile rheumatoid arthritis were on treatment for 8 months with methotrexate and additional steroids during activation. At the end of the 8th month when the corticosteroid dose was 12.5 mg/day, he began to suffer from numbness and weakness in his hands. Physical examination, laboratory findings and electromyography results demonstrated myopathy. Steroid myopathy was considered. Corticosteroids were tapered and stopped. At follow-up clinical findings remitted and electromyography became normal at the 4th month. We present here this case to direct attention to drug-induced myopathy besides myopathy due to primary disease in connective tissue disorders whenever myopathy exists.


Fiducial registration with spoiled gradient-echo magnetic resonance imaging enhances the accuracy of subthalamic nucleus targeting.
A variety of imaging strategies may be used to derive reliable stereotactic coordinates when performing deep brain stimulation lead implants. No single technique has yet proved optimal. To compare the relative accuracy of stereotactic coordinates for the subthalamic nucleus (STN) derived either from fast spin echo/inversion recovery (FSE/IR) magnetic resonance imaging MRI alone (group 1) or FSE/IR in conjunction with T1-weighted spoiled gradient-echo MRI (group 2). A retrospective analysis of 145 consecutive STN deep brain stimulation lead placements (group 1, n = 72; group 2, n = 73) was performed in 81 Parkinson disease patients by 1 surgical team. From the operative reports, we recorded the number of microelectrode recording trajectories required to localize the desired STN target and the span of STN traversed along the implantation trajectory. In addition, we calculated the 3-dimensional vector difference between the initial MRI-derived coordinates and the final physiologically refined coordinates. The proportion of implants completed with just 1 microelectrode recording trajectory was greater (81% vs 58%; P < .001) and the 3-dimensional vector difference between the anatomically selected target and the microelectrode recording-refined target was smaller (0.6 ± 1.2 vs 0.9 ± 1.3; P = .04) in group 2 than in group 1. At the same time, the mean expanse of STN recorded along the implantation trajectory was 8% greater in group 2 (4.8 ± 0.6 vs 5.2 ± 0.6 mm; P < .001). A combination of stereotactic FSE/IR and spoiled gradient-echo MRI yields more accurate coordinates for the STN than FSE/IR MRI alone.


Long-term outcomes following ileocolic resection for Crohn's disease: does earlier elective resection affect disease recurrence rates?
Surgical resection in Crohn's disease is sometimes the only alternative treating disease complications or refractory disease. The implications of early resection on disease course are still debatable. We aimed to assess the influence of preoperative disease duration on long-term postoperative disease course. A retrospective analysis of all Crohn's disease patients who underwent an elective primary ileocolic resection between 2010 and 2021 in a single tertiary medical center. The cohort was divided based on disease duration, Group A (47 patients) had a disease duration shorter than 3 years (median of 1 year) and Group B (139 patients) had a disease duration longer than 3 years (median of 11 years). Surgeries were less complex among Group A as noted by higher rates of laparoscopic assisted procedures (68.1% vs. 45.3%, P = 0.006), shorter surgery duration (134 vs. 167 min, P < 0.0001) less estimated blood loss (72.5 vs. 333 mL, P = 0.016) and faster return of bowel function (3 vs. 4 days, P = 0.011). However, propensity score matching nullified all the differences. Younger age (OR = 0.86, P = 0.004), pre-op steroids (OR = 3.69, P = 0.037) and longer disease duration (OR = 1.18, P = 0.012) were found to be independently significantly associated with severe complications. After a median follow-up time of 71.38 months no significant differences were found between the groups in terms of endoscopic (P = 0.59), or surgical recurrences rates (P = 0.82). The main effect of preoperative short disease duration was noted within the surgical complexity; however, matching suggests confounders as cause of the difference. No significant long-term implication was noted on disease recurrence.


The dominant role of proofreading exonuclease activity of replicative polymerase ε in cellular tolerance to cytarabine (Ara-C).
Chemotherapeutic nucleoside analogs, such as Ara-C, 5-Fluorouracil (5-FU) and Trifluridine (FTD), are frequently incorporated into DNA by the replicative DNA polymerases. However, it remains unclear how this incorporation kills cycling cells. There are two possibilities: Nucleoside analog triphosphates inhibit the replicative DNA polymerases, and/or nucleotide analogs mis-incorporated into genomic DNA interfere with the next round of DNA synthesis as replicative DNA polymerases recognize them as template DNA lesions, arresting synthesis. To address the first possibility, we selectively disrupted the proofreading exonuclease activity of DNA polymerase ε (Polε), the leading-strand replicative polymerase in avian DT40 and human TK6 cell lines. To address the second, we disrupted RAD18, a gene involved in translesion DNA synthesis, a mechanism that relieves stalled replication. Strikingly, POLE1exo-/- cells, but not RAD18-/- cells, were hypersensitive to Ara-C, while RAD18-/- cells were hypersensitive to FTD. gH2AX focus formation following a pulse of Ara-C was immediate and did not progress into the next round of replication, while gH2AX focus formation following a pulse of 5-FU and FTD was delayed to the next round of replication. Biochemical studies indicate that human proofreading-deficient Polε-exo- holoenzyme incorporates Ara-CTP, but subsequently extend from this base several times less efficiently than from intact nucleotides. Together our results suggest that Ara-C acts by blocking extension of the nascent DNA strand and is counteracted by the proofreading activity of Polε, while 5-FU and FTD are efficiently incorporated but act as replication fork blocks in the subsequent S phase, which is counteracted by translesion synthesis.


A subset of dopamine neurons signals reward for odour memory in Drosophila.
Animals approach stimuli that predict a pleasant outcome. After the paired presentation of an odour and a reward, Drosophila melanogaster can develop a conditioned approach towards that odour. Despite recent advances in understanding the neural circuits for associative memory and appetitive motivation, the cellular mechanisms for reward processing in the fly brain are unknown. Here we show that a group of dopamine neurons in the protocerebral anterior medial (PAM) cluster signals sugar reward by transient activation and inactivation of target neurons in intact behaving flies. These dopamine neurons are selectively required for the reinforcing property of, but not a reflexive response to, the sugar stimulus. In vivo calcium imaging revealed that these neurons are activated by sugar ingestion and the activation is increased on starvation. The output sites of the PAM neurons are mainly localized to the medial lobes of the mushroom bodies (MBs), where appetitive olfactory associative memory is formed. We therefore propose that the PAM cluster neurons endow a positive predictive value to the odour in the MBs. Dopamine in insects is known to mediate aversive reinforcement signals. Our results highlight the cellular specificity underlying the various roles of dopamine and the importance of spatially segregated local circuits within the MBs.


Overexpression of Notch ligand Delta-like-1 by dendritic cells enhances their immunoregulatory capacity and exerts antiallergic effects on Th2-mediated allergic asthma in mice.
Dendritic cells (DCs) are professional antigen-presenting cells, and Notch ligand Delta-like-1 (DLL1) on DCs was implicated in type 1T helper (Th1) differentiation. In this study, we produced genetically engineered bone marrow-derived DCs that expressed DLL1 (DLL1-DCs) by adenoviral transduction. DLL1-DCs exerted a fully mature phenotype, and had positive effects on expression levels of interleukin (IL)-12 and costimulatory molecules. Coculture of allogeneic T cells with ovalbumin (OVA)-pulsed DLL1-DCs enhanced T cell proliferative responses and promoted Th1 cell differentiation. Furthermore, adoptive transfer of OVA-stimulated DLL1-DCs into asthmatic mice alleviated the cardinal features of allergic asthma, including immunoglobulin E (IgE) production, airway hyperresponsiveness (AHR), airway inflammation, and production of Th2-type cytokines. Notably, enhanced levels of the Th1-biased IgG2a response and interferon (IFN)-γ production were observed in these mice. Taken together, these data indicate that DLL1-DCs promoted Th1 cell development to alter the Th1/Th2 ratio and ameliorate Th2-mediated allergic asthma in mice.


In silico analysis of evolutionary patterns in restriction endonucleases.
Restriction endonucleases represent one of the best studied examples of DNA binding proteins. Type II restriction endonucleases recognize short sequences of foreign DNA and cleave the target on both strands with remarkable sequence specificity. Type II restriction endonucleases are part of restriction modification systems. Restriction modification systems occur ubiquitously among bacteria and archaea. Restriction endonucleases are indispensable tools in molecular biology and biotechnology. They are important model system for specific protein-nucleic acid interactions and also serve as good example for investigating structural, functional and evolutionary relationships among various biomolecules. The interaction between restriction endonucleases and their recognition sequences plays a crucial role in biochemical activities like catalytic site/metal binding, DNA repair and recombination etc. We study various patterns in restriction endonucleases type II and analyzed their structural, functional and evolutionary role. Our studies support X-ray crystallographic studies, arguing for divergence and molecular evolution. Conservation patterns of the nuclease superfamily have also been analyzed by estimating site-specific evolutionary rates for the analyzed structures related to respective chains in this study.


Nutritional quality, safety and sensory properties of smoked tench (Tinca tinca) pâté from Trasimeno Lake, Italy.
The present study evaluated the safety, nutritional and sensory properties of fish pâtés made from smoked tench (Tinca tinca) pulp. Two formulations of tench pâté were produced, one of which included olive oil and the other contained mascarpone cheese. The prepared pâté jars were thermally treated according to the method applied in the canning industry. The inactivation of Clostridium botulinum during thermal treatment was determined through a challenge test study, demonstrating the complete depletion of targeted bacteria. Tench pâtés showed high nutritional properties, especially the formulation with olive oil, which was characterised by lower contents of cholesterol and saturated fatty acids and a high level of monounsaturated fatty acids. The two experimental formulations possessed a specific sensory profile, due to the ingredients incorporated into the products. Consumers' evaluation established differences in the acceptance of the two products: the formulation with added olive oil was more appreciated by consumers, who displayed a higher purchase intent for this product. The study suggests that minced smoked tench is not only a promising ingredient for pâté production but that it also represents a value-added product able to contribute to freshwater food consumption.


Carbon turnover and ammonia emissions during composting of biowaste at different temperatures.
The effects of different process temperatures (40, 55, and 67 degrees C) during composting of source-separated household waste were studied in a 200 L compost reactor at an oxygen concentration of 16%. The overall decomposition measured as carbon mineralization, decomposition of different carbon constituents, and the dynamics of nitrogen mineralization and the microbial community, are reported. Ammonia emissions at 67 degrees C were more than double those at lower temperatures, and they were lowest at 40 degrees C. The decomposition rate, measured as CO2 emission, was highest at 55 degrees C. Decomposition of crude fat was slower at 40 degrees C than at 55 and 67 degrees C. The peak in microbial biomass was largest in the run at 40 degrees C, where substantial differences were seen in the microbial community structure and succession compared to thermophilic temperatures. Biowaste composting can be optimized to obtain both a high decomposition rate and low ammonia emissions by controlling the process at about 55 degrees C in the initial, high-rate stage. To reduce ammonia emissions it seems worthwhile to reduce the temperature after an initial high-temperature stage.


Improving Transition to Adulthood for Students with Autism: A Randomized Controlled Trial of STEPS.
Emerging adulthood is a period of heightened risk for young people with autism spectrum disorder (ASD). Due in part to a lack of evidence-based services and supports during the transition to adulthood, many emerging adults fail to matriculate into postsecondary education or thrive in productive employment. The Stepped Transition in Education Program for Students with ASD (STEPS) was developed to address the psychosocial, transition-related needs of emerging adults with ASD. Adolescents and emerging adults (n = 59) with ASD were randomly assigned to either STEPS or transition as usual (TAU). Results indicate that STEPS is acceptable to young people with ASD and their parents and that it can be implemented with high fidelity. Among secondary school students, those who completed STEPS exhibited significantly greater gains in transition readiness from high school, and these gains were largely sustained after program completion. Among students enrolled in postsecondary education, STEPS resulted in increased levels of student adaptation to college relative to those in TAU. Programming to address ASD-related challenges can promote successful educational transitions.


Pre-anesthetic oral clonidine is effective to prevent post-spinal shivering.
Shivering is a common event during spinal anesthesia. Customarily we just treat it rather than prevent it. This study was designed to evaluate the efficacy of oral clonidine as a premedication to prevent post-spinal shivering. One hundred males of ASA physical status I-III, aged above 40, scheduled for elective urological surgery under spinal anesthesia, were included in this study. All participants were randomly divided into the clonidine and control groups. They received either oral clonidine 150 micrograms (n = 48) or placebo (n = 52) 90 min before spinal anesthesia in a double-blind fashion. Spinal blockade was induced with heavy bupivacaine to a dermatomal level near T10. The shivering was graded as: none, no perceptible tension of muscles observed; mild, slight muscle tonus (masseter muscle); moderate, real shivering (proximal muscles); and severe, generalized shivering (whole body). The tympanic membrane temperature was recorded 30 min after spinal anesthesia. Data were expressed as mean +/- standard deviation. Chi-square and Student's t-test were used. A p value less than 0.05 was considered statistically significant. The incidence of post-spinal shivering, which was graded as none, mild, moderate, and severe, showed statistically significant differences (p < 0.05) between clonidine 150 micrograms and placebo (83% vs. 42%, 10% vs. 6%, 10% vs. 19%, 0% vs. 33%, respectively) during the 30 min immediately after spinal anesthesia. The respective mean tympanic temperature in oral clonidine and placebo groups showed no difference (clonidine vs. control = 35.9 +/- 0.8 degrees C vs. 35.9 +/- 0.7 degrees C). Pre-anesthetic medication with oral clonidine 150 micrograms is effective to prevent post-spinal shivering in patients undergoing elective urological surgery.


The repertoire of G-protein-coupled receptors in Xenopus tropicalis.
The G-protein-coupled receptor (GPCR) superfamily represents the largest protein family in the human genome. These proteins have a variety of physiological functions that give them well recognized roles in clinical medicine. In Xenopus tropicalis, a widely used animal model for physiology research, the repertoire of GPCRs may help link the GPCR evolutionary history in vertebrates from teleost fish to mammals. We have identified 1452 GPCRs in the X. tropicalis genome. Phylogenetic analyses classified these receptors into the following seven families: Glutamate, Rhodopsin, Adhesion, Frizzled, Secretin, Taste 2 and Vomeronasal 1. Nearly 70% of X. tropicalis GPCRs are represented by the following three types of receptors thought to receive chemosensory information from the outside world: olfactory, vomeronasal 1 and vomeronasal 2 receptors. X. tropicalis shares a more similar repertoire of GPCRs with mammals than it does with fish. An examination of the three major groups of receptors related to olfactory/pheromone detection shows that in X. tropicalis, these groups have undergone lineage specific expansion. A comparison of GPCRs in X. tropicalis, teleost fish and mammals reveals the GPCR evolutionary history in vertebrates.


[Outcomes of surgical revascularization in patients after stenting of lower-limb arteries].
The authors analysed immediate and remote results of primary "open" reconstructive operations and arterial reconstructions performed after previous stenting of lower-limb arteries. The study comprised a total of 93 patients presenting with lower-limb critical ischaemia. Group One consisted of 46 patients with localization of the lesion of lower-limb arteries above the inguinal ligament. Group Two was composed of 47 patients with localization of lower-limb arteries lesions below the inguinal ligament. Each group was subdivided into two subgroups: subgroups Ia and IIa included patients with previously endured stenting of arteries of the respective segment (23 and 22 patients, respectively), subgroups Ib and IIb included patients previously not subjected to either endovascular or surgical treatment (23 and 25 patients, respectively). All patients underwent "open" reconstructive vascular operations. The outcomes of intervention were assessed at the hospital stage, as well as at 6, 12 and 36 months of consecutive follow up. After 8 months of follow up patency of the shunts in all patients amounted to 100%, with the lower-limb salvage rate of 100%. After 1 year, despite differences between subgroups in each group, they were not statistically significant (p>0.05). After 3 years differences in shunts' patency and lower limb salvage rate in subgroups IIa and IIb were statistically significant (p<0.05). By the increment of the ankle-brachial index, the best result after 3 years was achieved in patients with primary arterial reconstruction (subgroups Ib and IIb) as compared to patients with previously endured endovascular interventions. The conclusion was drawn that shunts patency, limb salvage rate and increment of the ankle-brachial index in the remote period after performing primary arterial reconstructions below the Poupart's ligament were better than in patients with previously endured endovascular interventions.


Bovine brain ribonuclease is the functional homolog of human ribonuclease 1.
Mounting evidence suggests that human pancreatic ribonuclease (RNase 1) plays important roles in vivo, ranging from regulating blood clotting and inflammation to directly counteracting tumorigenic cells. Understanding these putative roles has been pursued with continual comparisons of human RNase 1 to bovine RNase A, an enzyme that appears to function primarily in the ruminant gut. Our results imply a different physiology for human RNase 1. We demonstrate distinct functional differences between human RNase 1 and bovine RNase A. Moreover, we characterize another RNase 1 homolog, bovine brain ribonuclease, and find pronounced similarities between that enzyme and human RNase 1. We report that human RNase 1 and bovine brain ribonuclease share high catalytic activity against double-stranded RNA substrates, a rare quality among ribonucleases. Both human RNase 1 and bovine brain RNase are readily endocytosed by mammalian cells, aided by tight interactions with cell surface glycans. Finally, we show that both human RNase 1 and bovine brain RNase are secreted from endothelial cells in a regulated manner, implying a potential role in vascular homeostasis. Our results suggest that brain ribonuclease, not RNase A, is the true bovine homolog of human RNase 1, and provide fundamental insight into the ancestral roles and functional adaptations of RNase 1 in mammals.


The clinical and molecular characterization of patients with dyshormonogenic congenital hypothyroidism reveals specific diagnostic clues for DUOX2 defects.
Mutations in the DUOX2 gene have been associated with transient or permanent congenital hypothyroidism due to a dyshormonogenic defect. This study aimed to verify the prevalence of DUOX2 mutations and the associated clinical features in children selected by criteria supporting a partial iodide organification defect (PIOD). Thirty children with PIOD-like criteria were enrolled and genotyped. A detailed clinical characterization was undertaken together with the functional analysis of the DUOX2 variations and the revision of the clinical and molecular data of the literature. In this large selected series, the prevalence of the DUOX2 mutations was high (37%). We identified 12 missense variants, one splice site, and three frameshift DUOX2 mutations. Functional analyses showed significant impairment of H2O2 generation with five missense variants. Stop-codon mutants were shown to totally abolish DUOX2 activity by nonsense-mediated RNA decay, exon skipping, or protein truncation. DUOX2 mutations, either mono- or biallelic, were most frequently associated with permanent congenital hypothyroidism. Moreover, the present data suggested that, together with goiter and PIOD, the most significant features to select patients for the DUOX2 analysis are the low free T4 and the high TSH concentrations at the first postnatal serum sampling, despite borderline blood spot TSH. Interestingly, the analysis of previously described DUOX2 mutated cases confirmed the validity of these findings. The defects in the peroxide generation system are common among congenital hypothyroidism patients with PIOD. The most robust clinical parameters for selecting patients for DUOX2 analysis have been identified, and several DUOX2 variants have been functionally characterized.


Eldercare and employed caregivers: a public/private responsibility?
The National Alliance for Caregiving (NAC) and the American Association of Retired Persons (AARP, 2004) have reported that 21% of the U.S. population provides family caregiving services to someone over 18 years old. Seventy-nine percent (79%) of these caregivers provide care for someone aged 50 or older. The majority of caregivers work full or part-time, and nearly two-thirds of employed caregivers make work-related adjustments in order to provide care (NAC & AARP, 2004). This article examines eldercare issues of employed caregivers, identifies current public and private policies addressing caregiver needs, presents a process model to assist organizations in creating family-friendly workplaces, and suggests social work roles that support family caregiving.


Acute and long-term effects of acebutolol on systemic and renal hemodynamics, body fluid volumes, catecholamines, active renin, aldosterone, and lymphocyte beta-adrenoceptor density.
Acebutolol is a relatively new beta-adrenoceptor blocking antagonist, possessing both beta 1-adrenoceptor selectivity and partial agonist activity (PAA). Its acute (24 h, 400 mg, twice daily) and long-term effects (3 weeks) on systemic and renal hemodynamics, body fluid volumes, hormones, and beta-adrenoceptor density on lymphocytes were studied in a single-blind placebo-controlled trial, in 10 hypertensive patients. The initial response to acebutolol (1-2 h) was a fall in heart rate (HR) (-9.6 +/- 2.7%), cardiac output (-16.0 +/- 3%), and stroke volume (SV) (-10.7 +/- 0.2%), and an increase in systemic vascular resistance (SVR) (18.0 +/- 3.9%). Mean arterial pressure (MAP) began to fall 2-3 h after dosing in parallel with a decrease in SVR. At the end of the acute study, MAP and SVR were decreased by 18.1 +/- 2.7% and 15.6 +/- 5.6%, respectively. By that time, HR and SV had returned to control values despite blockade of beta-adrenoceptors. After 3 weeks of treatment (mean dose of acebutolol 480 mg twice daily), the fall in MAP was 10.1 +/- 2.7% and HR was decreased by 13.0 +/- 2.3%. Renal blood flow and glomerular filtration rate did not change. Acute and long-term treatment had no effect on the density of lymphocyte-membrane beta-adrenoceptors. This could be explained by acebutolol's beta 1 selectivity or, alternatively, this could be due to the drug's PAA.


Assessment of RT-PCR detection of human mammaglobin for the diagnosis of breast cancer derived pleural effusions.
The present study investigates the diagnostic significance of human mammaglobin (hMAM) mRNA expression in pleural effusions (PE) from breast cancer (BC) patients. Two hundred and fifty PE samples, including 32 from patients who had diagnosis of BC, 116 from patients with other cancers, and 102 from patients with benign diseases, were subjected to nested reverse-transcription polymerase chain reaction (RT-PCR) for hMAM, and the results were compared with conventional cytology. hMAM was found expressed in 76/250 (30.4%) total PE and in 23/28 (sensitivity of 82.1%) of the PE subgroup owing to metastasis from BC. The specificity for hMAM detection method was 75.7%, whereas accuracy, positive predictive value, and negative predictive value were 76.4%, 30.3%, and 97.1%, respectively. hMAM was also detected in 46/116 (39.6%) PE specimens from other types of cancer and in 7/102 (6.8%) from benign diseases. Comparative analysis of RT-PCR and cytology showed that 14 PE samples from metastatic BC (50%) were positive by both PCR and cytology, 9 (32.1%) were positive only by PCR and 5 (17.9%) were negative by both tests, whereas no cases were found of positive cytology with negative PCR. RT-PCR increased sensitivity of BC effusion detection to 32.1% (McNemar test, P=0.004). We demonstrated that RT-PCR for hMAM test was more sensitive than cytomorphology suggesting that, although hMAM is not BC specific, it may be useful in adjunct to cytology for the routine screening of malignant BC effusions.


[The enhanced lethality of cells in suspension during simultaneous exposure to pulsed electrical and shock-wave acoustic fields].
We present the results of comparative experimental studies of the damaging effect of intense electrical field with a microsecond duration range, shock acoustic wave, and their combination on the ovary carcinoma cells. We found that upon a combined effect of pulse electrical and acoustic shock-wave fields of a moderate amplitude, practically all cells died. A qualitative physical model is proposed, which accounts for enhanced damage upon combined effect, on the one hand, by a decreased threshold of electric intensity of the cytoplasmic membrane breakdown at a temporal phase of pressure compression of the shock-wave pulse and, on the other hand, by a growth of cavitational embryos at a temporal phase of the action of stretching tensions of the shock-wave pulse, whose role is played by hydrophobic type pores appeared as a result of the membrane electrical breakdown. Possibilities of practical application of the proposed combined effect are discussed: in oncology for suppression of tumor growth and in biotechnology for cell disintegration and ecologically pure sterilization of liquid media.


The role of thoracic epidural analgesia in receptor-dependent and receptor-independent pulmonary vasoconstriction in experimental pancreatitis.
Acute pancreatitis commonly results in lung injury and deterioration of pulmonary endothelial function and vasoregulation. Despite a variety of potential risks with the use of thoracic epidural analgesia (TEA) in the critically ill, this technique is an important component of pain management in pancreatitis in selected cases. Although there is evidence that epidural analgesia improves lung function through effective pain relief, the influence of continuously applied epidural local anesthetics on pulmonary endothelial dysfunction is still unknown. In an in vivo model of TEA in awake rats with acute pancreatitis, we evaluated blood gas analysis, arterial blood pressure, and exhaled nitric oxide. This was followed by in vitro studies of receptor-dependent and receptor-independent pulmonary vasoconstriction using an isolated perfused lung model. Pulmonary myeloperoxidase activity, indicating leukocyte sequestration into the lungs and wet/dry ratio evaluating pulmonary edema, were also measured. Deteriorated oxygenation, metabolic and lactate acidosis, as well as exhaled nitric oxide levels occurring during acute pancreatitis, were reduced by TEA to levels observed in sham-operated animals. TEA also partially ameliorated the hypotension occurring in pancreatitis. In isolated perfused lungs, receptor-dependent vasoconstriction due to angiotensin II was reduced during acute pancreatitis, indicating pulmonary vascular smooth muscle cell dysfunction. Hypoxic pulmonary vasoconstriction was likewise abolished. Treatment with TEA partly restored the vasoreactivity to angiotensin II and hypoxia. Bradykinin-induced vasoconstriction, indicating pulmonary endothelial dysfunction, myeloperoxidase activity and the degree of pulmonary edema, was not influenced by TEA. Our study demonstrated that TEA improves pancreatitis-associated impairment of pulmonary vasoreactivity and gas exchange.


In-beam PET imaging for on-line adaptive proton therapy: an initial phantom study.
We developed and investigated a positron emission tomography (PET) system for use with on-line (both in-beam and intra-fraction) image-guided adaptive proton therapy applications. The PET has dual rotating depth-of-interaction measurable detector panels by using solid-state photomultiplier (SSPM) arrays and LYSO scintillators. It has a 44 mm diameter trans-axial and 30 mm axial field-of-view (FOV). A 38 mm diameter polymethyl methacrylate phantom was placed inside the FOV. Both PET and phantom axes were aligned with a collimated 179.2 MeV beam. Each beam delivered ∼50 spills (0.5 s spill and 1.5 s inter-spill time, 3.8 Gy at Bragg peak). Data from each beam were acquired with detectors at a given angle. Nine datasets for nine beams with detectors at nine different angles over 180° were acquired for full-tomographic imaging. Each dataset included data both during and 5 min after irradiations. The positron activity-range was measured from the PET image reconstructed from all nine datasets and compared to the results from simulated images. A (22)Na disc-source was also imaged after each beam to monitor the PET system's performance. PET performed well except for slight shifts of energy photo-peak positions (<1%) after each beam, due mainly to the neutron exposure of SSPM that increased the dark-count noise. This minor effect was corrected offline with a shifting 350-650 keV energy window for each dataset. The results show a fast converging of activity-ranges measured by the prototype PET with high sensitivity and uniform resolution. Sub-mm activity-ranges were achieved with minimal 6 s acquisition time and three spill irradiations. These results indicate the feasibility of PET for intra-fraction beam-range verification. Further studies are needed to develop and apply a novel clinical PET system for on-line image-guided adaptive proton therapy.


Kidney function and long-term medication adherence after myocardial infarction in the elderly.
The association of kidney function with long-term outpatient medication adherence in the elderly remains understudied. A cohort of 2103 patients over the age of 65 years enrolled in a pharmacy benefits program after hospital discharge for myocardial infarction was studied. Using linear mixed effects models, the association of baseline kidney function with long-term adherence to recommended medications after myocardial infarction was examined, including angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), β-blockers, and statins. The primary outcome measure was the percentage of days covered as calculated by pharmacy refill data for 12 serial 3-month intervals (totaling 36 months of follow-up). Overall long-term adherence to ACEIs/ARBs, β-blockers, and statins was poor. The mean percentage of days covered by 36 months was only 50% to 60% for all three medication classes. Patients with baseline kidney dysfunction had significantly lower long-term ACEI/ARB and β-blocker adherence compared with patients with higher baseline kidney function. Long-term statin adherence did not vary by baseline level of kidney function. Long-term medication adherence after myocardial infarction in the elderly is low, especially in patients with kidney dysfunction. Future strategies to improve medication adherence should pay special attention to the elderly with kidney dysfunction because they may be especially vulnerable to its adverse clinical consequences.


Differences in ocular blood flow in glaucoma between patients of African and European descent.
To investigate differences in ocular blood flow in individuals of African descent (AD) and European descent (ED) with open angle glaucoma (OAG). A retrospective data analysis was performed on OAG patients of AD and ED who were previously examined for ocular blood flow within the Department of Ophthalmology at Indiana University School of Medicine. Data analysis included blood pressure, heart rate, visual fields, intraocular pressure, ocular perfusion pressure, and color Doppler imaging of retrobulbar vessels. Color Doppler imaging measurements were performed on ophthalmic, central retinal, and nasal and temporal short posterior ciliary arteries, with peak systolic (PSV) and end diastolic velocities (EDV) as well as the Pourcelot vascular resistive index calculated for each vessel. Two-sample t tests of unequal variance were performed with P values <0.05 considered statistically significant. OAG patients of AD had statistically significant lower retrobulbar blood flow values than patients of ED including lower ophthalmic artery PSV (P=0.0001), ophthalmic artery EDV (P=0.0008), central retinal artery PSV (P=0.01), temporal short posterior ciliary artery PSV (P=0.0037), and nasal short posterior ciliary artery PSV (P<0.0001). No significant differences were found in terms of intraocular pressure or visual field parameters. Significantly lower blood flow values were identified in all retrobulbar blood vessels in AD compared with ED OAG patients. These findings suggest that the contribution of ocular blood flow to the disease process may be different in AD compared with ED OAG patients.


Differences in Short-Term Outcomes and Hospital-Based Resource Utilization Between Septal Reduction Strategies for Hypertrophic Obstructive Cardiomyopathy.
Given clinical equipoise in a subset of obstructive hypertrophic cardiomyopathy (OHCM) patients who are candidates for both alcohol septal ablation (ASA) or septal myectomy (SM), other considerations such as cost, readmissions, and hospital length of stay (LOS) may be important to optimize healthcare resource utilization and inform shared decision making. In this retrospective observational analysis of the United States Nationwide Readmissions Database years 2012-2014, we identified adults who underwent isolated septal reduction (SR) for OHCM. We studied the differences in short-term outcomes (inpatient mortality and 90-day readmission rate) and in-hospital resource utilization (LOS and costs) between the SR strategies. Of the 2250 patients in this study, ASA was performed in 1113 (49.5%) and SM in 1137 (50.5%). Inpatient mortality occurred in 21 patients (0.9%), with similar rates between strategies (10 SM patients [0.9%] vs 11 ASA patients [1.0%]; P=.30). Of the 2229 patients who survived to discharge, 298 (13.4%) were readmitted 386 times within 90 days with a similar readmission rate between SM (14.9%) and ASA (11.8%; P=.16). During the index admission, average LOS and cost were significantly lower for ASA (3.9 days, United States [US] $20,322) compared with SM (7.6 days, US $39,470; P<.001). Average LOS and cost during 90-day readmissions were similar between ASA and SM. Combining index admissions and readmissions, patients undergoing ASA had significantly lower LOS and hospitalization costs. In this non-randomized observational study of OHCM patients undergoing isolated septal reduction, ASA was associated with similar short-term outcomes, including mortality, but substantially lower hospitalization costs and LOS compared with SM.


JUE Insight: Distributional Impacts of Retail Vaccine Availability.
We examine the potential for exploiting retailer location choice in targeting health interventions. Using geospatial data, we quantify proximity to vaccines created by a U.S. federal program distributing COVID-19 vaccines to commercial retail pharmacies. We assess the distributional impacts of a proposal to provide vaccines at Dollar General, a low-priced general merchandise retailer. Adding Dollar General to the federal program would substantially decrease the distance to vaccine sites for low-income, rural, and minority U.S. households, groups for which COVID-19 vaccine take-up has been disproportionately slow.


Ameliorative effect of propolis against cyclophosphamide-induced toxicity in mice.
Cyclophosphamide (CTX) is a common anticancer agent used for the treatment of several malignancies. However, upon treatment, it induces severe toxicity due to its oxidative stress capability. Propolis, a natural product collected by honey bees, has shown several biological activities, such as free radical scavenging and antioxidant agent. This study elucidates the protective effects of propolis against CTX-induced changes in mice. Forty-eight male Swiss albino mice were divided into four groups; group 1 was intraperitoneally (i.p.) injected with 200 µL of phosphate buffer saline (PBS), group 2 was injected with 100 mg/kg/d propolis, group 3 was injected with a single dose of CTX (200 mg/kg), and group 4 was injected with a single dose of CTX (200 mg/kg) followed by propolis (100 mg/kg) for 7 consecutive days. After 12 d, mice were bled and then sacrificed to analyze the hematological, biochemical, and histological parameters. The results indicated that CTX-injected mice showed an increase in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, and creatinine and a decrease in the total number of white blood cells (WBCs) and platelets. Moreover, dramatically changes in the histological architectures of the liver and kidney were observed. The mice that were injected with CTX/propolis showed an improvement in the levels of ALT, AST, urea, creatinine, WBCs, and platelets. Moreover, the histological picture of the liver and kidney was significantly improved. In conclusion, propolis might be considered an effective agent in ameliorating the toxicity resulted from CTX treatment.


Metabolic activation of CaMKII by coenzyme A.
Active metabolism regulates oocyte cell death via calcium/calmodulin-dependent protein kinase II (CaMKII)-mediated phosphorylation of caspase-2, but the link between metabolic activity and CaMKII is poorly understood. Here we identify coenzyme A (CoA) as the key metabolic signal that inhibits Xenopus laevis oocyte apoptosis by directly activating CaMKII. We found that CoA directly binds to the CaMKII regulatory domain in the absence of Ca(2+) to activate CaMKII in a calmodulin-dependent manner. Furthermore, we show that CoA inhibits apoptosis not only in X. laevis oocytes but also in Murine oocytes. These findings uncover a direct mechanism of CaMKII regulation by metabolism and further highlight the importance of metabolism in preserving oocyte viability.


Advantages of the experimental animal hollow organ mechanical testing system for the rat colon rupture pressure test.
Many studies have been conducted on colorectal anastomotic leakage to reduce the incidence of anastomotic leakage. However, how to precisely determine if the bowel can withstand the pressure of a colorectal anastomosis experiment, which is called anastomotic bursting pressure, has not been determined. A task force developed the experimental animal hollow organ mechanical testing system to provide precise measurement of the maximum pressure that an anastomotic colon can withstand, and to compare it with the commonly used method such as the mercury and air bag pressure manometer in a rat colon rupture pressure test. Forty-five male Sprague-Dawley rats were randomly divided into the manual ball manometry (H) group, the tracing machine manometry pressure gauge head (MP) group, and the experimental animal hollow organ mechanical testing system (ME) group. The rats in each group were subjected to a cut colon rupture pressure test after injecting anesthesia in the tail vein. Colonic end-to-end anastomosis was performed, and the rats were rested for 1 week before anastomotic bursting pressure was determined by one of the three methods. No differences were observed between the normal colon rupture pressure and colonic anastomotic bursting pressure, which were determined using the three manometry methods. However, several advantages, such as reduction in errors, were identified in the ME group. Different types of manometry methods can be applied to the normal rat colon, but the colonic anastomotic bursting pressure test using the experimental animal hollow organ mechanical testing system is superior to traditional methods.


N-terminal tail of a viral histone H4 encoded in Cotesia plutellae bracovirus is essential to suppress gene expression of host histone H4.
An endoparasitoid wasp, Cotesia plutellae, possesses a symbiotic bracovirus (CpBV), which facilitates parasitism of a specific host, such as larvae of the diamondback moth, Plutella xylostella. A viral histone H4 (CpBV-H4) has been found in the CpBV genome and its gene product plays a role in impairing the host insect cellular immune response. Based on its high similarity to histone H4 of P. xylostella apart from its extended N-terminal tail, it has been suspected to alter host gene expression. Histone subunits were purified from parasitized P. xylostella larvae and found to contain both host and viral H4s, confirming a previous report of a possible epigenetic mode of action. Moreover, this study showed that the host H4 levels in the parasitized larvae clearly decreased during the parasitization period, whereas CpBV-H4 levels maintained a significant level without significant changes. To understand the decrease of host H4 levels, transcription levels of host H4 were monitored by quantitative reverse-transcriptase PCR (RT-PCR) and showed a significant decrease in parasitized P. xylostella larvae, whereas no significant change of the mRNA level was detected in nonparasitized larvae. This transcriptional control of host H4 expression was also observed by inducing transient expression of CpBV-H4 in nonparasitized P. xylostella. Moreover, co-injection of CpBV-H4 and its specific double-stranded RNA recovered the host H4 expression level. To identify a functional domain of CpBV-H4 involved in the transcriptional control, the extended N-terminal tail of CpBV-H4 was removed by preparing a truncated viral H4 construct in an expression vector by deleting the N-terminal tail of 38 amino acid residues and inducing its expression in nonparasitized P. xylostella larvae. The truncated CpBV-H4 clearly lost its inhibitory effects on host H4 transcription. Moreover, the presence of CpBV-H4 affects the spreading of host haemocytes by an epigenetic effect, which is at least partly restored in larvae expressing the truncated version of CpBV-H4. This study suggests that the viral H4 encoded in CpBV can alter host gene expression with its extended N-terminal tail.


The practice of primary care sports medicine in the USA.
To investigate and to characterise the practice patterns, academic rank, and income variables that exist in order to better understand the career of a sports medicine physician in the USA. A cross-sectional survey of family physicians holding a Certificate of Added Qualifications in Sports Medicine through the American Board of Family Medicine as of January 2006. The survey was completed by 325 of 862 physicians (a return rate of 38%). Of all respondents, 212 (65%) reported completing a Primary Care Sports Medicine Fellowship, 276 (85%) were male and 49 (15%) were female, and 300 (92%) reported having a MD, while 25 (8%) had a DO. Clinical duties represented the largest proportion of the physicians' schedules (7.94 half days/week), and the majority of physicians performed routine athletic event coverage. The average salary for all physicians was $166,000 US. Higher-income groups included: men ($172,000 vs $132 000 for women); regions including Central, South East, and South West; full professors; and non-student health or urgent care clinical work. With control for all other variables, four groups demonstrated significantly higher odds of being high income earners (annual gross salary > $200,000 US). These groups included age over 40, male sex, practice owner, and seeing over 10 patients per half day. Salary can be related to age, gender, number of patients seen, and practice ownership. No statistical difference among salaries was found between MDs and DOs, osteopathic manipulative therapy (OMT) practice, region of the country, or how practices are marketed.


Inhibition of paclitaxel metabolism in vitro in human hepatocytes by Ginkgo biloba preparations.
Since the late 1980s, chemotherapy-induced cognitive impairment, also known as "chemobrain", has been a recognized side effect in patients undergoing cancer treatment ( Matsuda et al., 2005 ). Although products containing Ginkgo biloba may be used by patients undergoing chemotherapy with paclitaxel and other agents, the potential for an herb-drug interaction with this combination has not been adequately explored. This report describes the inhibition of paclitaxel metabolism by Ginkgo preparations in vitro in human hepatocytes. Hydrolyzate of Ginkgo extract (10-100 mM in terpene lactone concentration) caused a dose-dependent inhibition of the 6α -hydroxylation of paclitaxel, the enzymatic activity responsible for the majority of the clearance of that drug in clinical applications; parent extract had no effect. Contrary to the assumed therapeutic benefit of Ginkgo, its concomitant use with paclitaxel could result in elevated blood levels of the chemotherapeutic, with attendant exacerbation of cognitive impairment and other toxic effects associated with cancer therapy.


[Implantation of a program of terminal evaluation of graduating medicalstudent performance to estimate the efficacy of the curriculum in the ++Ribeirão Preto Medical School].
To describe the main steps in the implementation of such assessment, as well as to present the measures taken in order to overcome the difficulties that have been found. The proposed two-step assessment consists of a test of cognitive aspects based on Multiple Choice Questions (MCQ) and practical exams of clinical skills in each of 5 terminal areas. Students enrolled as volunteer for either step or both. The examinations were developed and carried out by faculty members nominated by the involved Departments under the supervision of an institutional work group. The rates of student enrollment for the summative assessment has been recorded and the responses of both students and faculty members were evaluated by means of specific questionnaires. In the first two years, adhesion of students to the MCQ test was consistently high, but volunteering to the practical exams was persistently low. Moreover, there was a sharp decrease in faculty involvement, from the first to the second year. To overcome these difficulties, a number of measures were implemented aiming at increasing student adhesion and faculty involvement, as well as to improve assessment methods. As a consequence, a remarkable increase in both student adhesion and faculty involvement was recorded. The measures taken resulted in sharp increases in both acceptance of the proposed assessment and the quality of the examination methods, which have allowed a more reliable characterization of the strenghts and weaknesses of the local curriculum.


Vasomotor control of capillary transit time heterogeneity in the canine coronary circulation.
A set of indicator-dilution studies of the coronary circulation of the intact functioning heart was carried out in the dog to provide a data base for defining the effect of changes in vasomotor control on the exchange of materials across the myocardial capillaries. The reference substance used was 125I-labeled albumin; the diffusible substance used was 14C-labeled sucrose. Model analyses of the data were carried out. In previous models of the capillary exchange in the coronary circulation, it had been assumed that a single capillary transit time is representative of the whole. The data acquired here indicate that there is a very large heterogeneity of capillary transit times in the intact heart, and that the single transit time model is approximately true only when the resistance vessels are maximally dilated. The present pattern of findings is explained best by a model of the coronary microcirculation based on capillary-large vessel units with a variable heterogeneity of flow or capillary lengths, hence of transit times. We conclude that a major determinant of the extraction of each diffusible substance, on a microscopic level, is the distribution of capillary transit times.


Hemodialysis Access: US for Preprocedural Mapping and Evaluation of Maturity and Access Dysfunction.
Patients with kidney failure require kidney replacement therapy. While renal transplantation remains the treatment of choice for kidney failure, renal replacement therapy with hemodialysis may be required owing to the limited availability and length of time patients may wait for allografts or for patients ineligible for transplant owing to advanced age or comorbidities. The ideal hemodialysis access should provide complication-free dialysis by creating a direct connection between an artery and vein with adequate blood flow that can be reliably and easily accessed percutaneously several times a week. Surgical arteriovenous fistulas and grafts are commonly created for hemodialysis access, with newer techniques that involve the use of minimally invasive endovascular approaches. The emphasis on proactive planning for the placement, protection, and preservation of the next vascular access before the current one fails has increased the use of US for preoperative mapping and monitoring of complications for potential interventions. Preoperative US of the extremity vasculature helps assess anatomic suitability before vascular access creation, increasing the rates of successful maturation. A US mapping protocol ensures reliable measurements and clear communication of anatomic variants that may alter surgical planning. Postoperative imaging helps assess fistula maturation before cannulation for dialysis and evaluates for early and late complications associated with arteriovenous access. Clinical and US findings can suggest developing stenosis that may progress to thrombosis and loss of access function, which can be treated with percutaneous vascular interventions to preserve access patency. Vascular access steal, aneurysms and pseudoaneurysms, and fluid collections are other complications amenable to US evaluation. ©RSNA, 2023 Supplemental material is available for this article. Test Your Knowledge questions for this article are available through the Online Learning Center.


Anticancer activity of hispidin via reactive oxygen species-mediated apoptosis in colon cancer cells.
Few studies have been performed on the anticancer activity of hispidin, a phenolic compound produced from the medicinal mushroom Phellinus linteus. Herein, we studied hispidin-induced apoptosis, which is associated with the generation of reactive oxygen species (ROS) in colon cancer cells. Hispidin was found to reduce cell viability both in mouse and human colon cancer cells. Apoptotic cell morphological changes were observed by microscopy, and apoptosis was assessed in hispidin-treated cells using a biochemical method. The results showed accumulation of the sub-G1 cell population and increase in early apoptosis in a dose-dependent manner. In addition, hispidin induced apoptosis through up-regulation of both intrinsic and extrinsic apoptotic pathways. Although the molecular mechanism underlying hispidin-induced apoptosis is known to involve the generation of ROS, however hispidin did not show any apoptosis in the pre-treatment with a ROS scavenger, N-acetyl-L-cysteine. In conclusion, hispidin induces both intrinsic and extrinsic apoptotic pathways mediated by ROS in colon cancer cells, thereby suggesting that hispidin could be a promising new anticancer agent.


Three-dimensional structure of YaaE from Bacillus subtilis, a glutaminase implicated in pyridoxal-5'-phosphate biosynthesis.
The structure of YaaE from Bacillus subtilis was determined at 2.5-A resolution. YaaE is a member of the triad glutamine aminotransferase family and functions in a recently identified alternate pathway for the biosynthesis of vitamin B(6). Proposed active residues include conserved Cys-79, His-170, and Glu-172. YaaE shows similarity to HisH, a glutaminase involved in histidine biosynthesis. YaaD associates with YaaE. A homology model of this protein was constructed. YaaD is predicted to be a (beta/alpha)(8) barrel on the basis of sequence comparisons. The predicted active site includes highly conserved residues 211-216 and 233-235. Finally, a homology model of a putative YaaD-YaaE complex was prepared using the structure of HisH-F as a model. This model predicts that the ammonia molecule generated by YaaE is channeled through the center of the YaaD barrel to the putative YaaD active site.


Consequences of maternal complications in women's lives in the first postpartum year: a prospective cohort study.
Maternal complications are common during and following childbirth. However, little information is available on the psychological, social and economic consequences of maternal complications on women's lives, especially in a rural setting. A prospective cohort study was conducted in southern Rajasthan, India, among rural women who had a severe or less-severe, or no complication at the time of delivery or in the immediate postpartum period. In total, 1,542 women, representing 93% of all women who delivered in the field area over a 15-month period and were examined in the first week postpartum by nurse-midwives, were followed up to 12 months to record maternal and child survival. Of them, a subset of 430 women was followed up at 6-8 weeks and 12 months to capture data on the physical, psychological, social, or economic consequences. Women with severe maternal complications around the time of delivery and in the immediate postpartum period experienced an increased risk of mortality and morbidity in the first postpartum year: 2.8% of the women with severe complications died within one year compared to none with uncomplicated delivery. Women with severe complications also had higher rates of perinatal mortality [adjusted odds ratio (AOR)=3.98, confidence interval (CI) 1.96-8.1, p=0.000] and mortality of babies aged eight days to 12 months (AOR=3.14, CI 1.4-7.06, p=0.004). Compared to women in the uncomplicated group, women with severe complications were at a higher risk of depression at eight weeks and 12 months with perceived physical symptoms, had a greater difficulty in completing daily household work, and had important financial repercussions. The results suggest that women with severe complications at the time of delivery need to be provided regular follow-up services for their physical and psychological problems till about 12 months after childbirth. They also might benefit from financial support during several months in the postpartum period to prevent severe economic consequences. Further research is needed to identify an effective package of services for women in the first year after delivery.


[Features of the formation and retention of a motor-defensive conditioned reflex in rats of various strains].
Comparison of the dynamics of elaboration and stabilization of a motor defensive conditioned reflex in rats of Wistar line and in grey rats showed that the latter significantly forestalled the white laboratory rats in the speed of conditioning. Their behaviour was characterized by a higher level of excitability and activity and a weaker passive defensive behaviour; this probably contributed to a more effective formation of temporary connection with biologically negative reinforcement. Individual typological differences did not conceal the interlinear ones, while in stress situations they can sometimes be at the foreground.


[Molecular mechanism of biological clock: for chronobiological approach to stress].
Recent progress in molecular chronobiology revealed that the clock genes control intracellular feedback loops. CLOCK protein and BMAL1 protein, first discovered as components of the circadian clock in mammals, are known to function as transcriptional activators in the circadian feedback loop of drosophila. PERIOD and TIMELESS proteins work as inhibitors for these activators in drosophila and possibly in mammals. The clock genes described above are also expressed in peripheral tissues with circadian rhythmicity. Cultured rat-1 fibroblast shows circadian expression of clock genes after serum shock or forskolin stimulation. These results indicate that the clock genes function not only as components of the endogenous clock, but also as a coordinator of the circadian activity of peripheral tissues. It will be important to study stress from the aspect of circadian rhythm.


Myelopathy associated with decompression sickness: a report of six cases.
Four scuba divers and 2 professional deep sea divers developed spinal cord symptoms due to decompression sickness. Symptoms developed during or immediately after ascent in 4 cases and were delayed in 2. In 2 cases new symptoms appeared during a jet flight. In 4 cases paraparesis was associated with a sensory level in the mid or low dorsal region indicating the thoracic cord as the major site of involvement. In the other 2 cases the clinical findings were suggestive of combined lesions in the lower cervical and lumbar cord. Therapeutic recompression led to improvement in each case. Three cases who were re-examined after intervals of 3 to 7 years each showed residual corticospinal and minor sensory signs. One of these cases met with a violent death 3.5 years after the acute episode; examination of the cord showed multifocal white matter degeneration in the posterior and lateral columns between C7 and T4 with secondary ascending and descending tract degeneration. The mechanism of spinal cord damage in decompression sickness is discussed.


Difference in tree growth responses to climate at the upper treeline: Qilian Juniper in the Anyemaqen Mountains.
Three ring-width chronologies were developed from Qilian Juniper (Sabina przewalskii Kom.) at the upper treeline along a west-east gradient in the Anyemaqen Mountains. Most chronological statistics, except for mean sensitivity (MS), decreased from west to east. The first principal component (PC1) loadings indicated that stands in a similar climate condition were most important to the variability of radial growth. PC2 loadings decreased from west to east, suggesting the difference of tree-growth between eastern and western Anyemaqen Mountains. Correlations between standard chronologies and climatic factors revealed different climatic influences on radial growth along a west-east gradient in the study area. Temperature of warm season (July-August) was important to the radial growth at the upper treeline in the whole study area. Precipitation of current May was an important limiting factor of tree growth only in the western (drier) upper treeline, whereas precipitation of current September limited tree growth in the eastern (wetter) upper treeline. Response function analysis results showed that there were regional differences between tree growth and climatic factors in various sampling sites of the whole study area. Temperature and precipitation were the important factors influencing tree growth in western (drier) upper treeline. However, tree growth was greatly limited by temperature at the upper treeline in the middle area, and was more limited by precipitation than temperature in the eastern (wetter) upper treeline.