A randomized, open-label study of the tolerability and efficacy of one or three daily doses of ivermectin plus diethylcarbamazine and albendazole (IDA) versus one dose of ivermectin plus albendazole (IA) for treatment of onchocerciasis.
Onchocerciasis ("river blindness") has been targeted for elimination. New treatments that kill or permanently sterilize female worms could accelerate this process. Prior studies have shown that triple drug treatment with ivermectin plus diethylcarbamazine and albendazole (IDA) leads to prolonged clearance of microfilaremia in persons with lymphatic filariasis. We now report results from a randomized clinical trial that compared the tolerability and efficacy of IDA vs. a comparator treatment (ivermectin plus albendazole, IA) in persons with onchocerciasis. The study was performed in the Volta region of Ghana. Persons with microfiladermia and palpable subcutaneous nodules were pre-treated with two oral doses of ivermectin (150 μg/kg) separated by at least 6 months prior to treatment with either a single oral dose of ivermectin 150 μg/kg plus albendazole 400 mg (IA), a single oral dose of IDA (IDA1, IA plus diethylcarbamazine (DEC. 6 mg/kg) or three consecutive daily doses of IDA (IDA3). These treatments were tolerated equally well. While adverse events were common (approximately 30% overall), no severe or serious treatment-emergent adverse events were observed. Skin microfilariae were absent or present with very low densities after all three treatments through 18 months, at which time nodules were excised for histological assessment. Nodule histology was evaluated by two independent assessors who were masked regarding participant infection status or treatment assignment. Significantly lower percentages of female worms were alive and fertile in nodules recovered from study participants after IDA1 (40/261, 15.3%) and IDA3 (34/281, 12.1%) than after IA (41/180, 22.8%). This corresponds to a 40% reduction in the percentage of female worms that were alive and fertile after IDA treatments relative to results observed after the IA comparator treatment (P = 0.004). Percentages of female worms that were alive (a secondary outcome of the study) were also lower after IDA treatments (301/574, 52.4%) than after IA (127/198, 64.1%) (P = 0.004). Importantly, some comparisons (including the reduced % of fertile female worms after IDA1 vs IA treatment, which was the primary endpoint for the study) were not statistically significant when results were adjusted for intraclass correlation of worm fertility and viability for worms recovered from individual study participants. Results from this pilot study suggest that IDA was well tolerated after ivermectin pretreatment. They also suggest that IDA was more effective than the comparator treatment IA for killing or sterilizing female O. volvulus worms. No other short-course oral treatment for onchocerciasis has been demonstrated to have macrofilaricidal activity. However, this first study was too small to provide conclusive results. Therefore, additional studies will be needed to confirm these promising findings. The study is registered at Cinicaltrials.gov under the number NCT04188301.


The effect of inhaling thinner and/or cigarette smoke on rat kidneys.
Although the effects of cigarette smoking and/or thinner inhalation on various organs have been investigated, there isn't enough study available in literature about their effects on kidneys. Therefore, in this study we investigated the effect of smoking and/or inhalation on the rat kidney. In this study, stand-alone inhalation of thinner and cigarette smoke and their application together were used to determine histopathologic changes, primarily the influences on rat kidneys. The study included 60 Wistar Albino species male rats. The 60 rats were divided into 4 groups of 15 rats each. Of the groups, three were working groups and the fourth was the control group. The rats in the first study group inhaled thinner only (T), those in the second group cigarette smoke only (CS), and the rats in the third group were made to inhale both thinner and cigarette smoke (TC). Each study group was divided into 3 subgroups each comprising 5 rats and inhalation was continued for periods of 2 wk, 4 wk, and 6 wk. Thinner was vaporized into the cage with a millipore pump at a constant pressure twice per day for 1 h for 5 days (toluene 2800-3000 ppm, acetone 500-600 ppm, isobutyl acetate 7000-8000 ppm, and isobutanol 6000-7000 ppm). Cigarette smoke was given 4 times per day for 15 min each, using a mechanism prepared with an aquarium motor (containing 1.2 mg nicotine,13 mg tar, and 13 mg carbonmonoxide; 60 puffs/min). After that, rat kidneys were removed. The kidneys were weighed and were given macroscopic and microscopic examination. There were significant differences for the thinner and thinner + cigarette smoke groups in comparison to the control group, observed in both proximal and distal tubules. However, changes in the cigarette smoke group were only in proximal tubules and were smaller in extent. Thinner has been widely used as a industrial substance. Thinner usage is an important health problem. Those sniffing thinner generally also use cigarettes. The findings of the present study reemphasize the importance of taking immediate measures in order to prevent thinner inhaling among homeless children, who pose an important social problem, and to protect people who work in industrial branches that widely use thinner.


Splicing error due to a splice acceptor site mutation in the ALD gene identified in a Japanese childhood cerebral adrenoleukodystrophy case.
X-linked adrenoleukodystrophy (ALD) is characterised by progressive multifocal demyelination of central nervous system and adrenocortical insufficiency. This disorder has been also associated with mutations in the ALD gene, encoding an ATP-binding transporter which is located in the peroxisomal membrane. Defect of the gene may lead to impaired peroxisomal beta-oxidation and increase of serum and tissue very long chain fatty acids (VLCFAs). Here we report the results of analysis of the ALD gene in a Japanese patient with childhood cerebral ALD. In our patient, by sequencing of the ALD cDNA, an 8 bp insertion (ACCCCCAG) was detected at the start of exon 9, which corresponded to nucleotides from position -1 to -8 of the 3' splice acceptor site of intron 8. Sequencing of genomic DNA showed a single nucleotide substitution at position-10 of the 3' splice acceptor site of intron 8 replacing a G with an A which activated a cryptic splice acceptor site. It is concluded that a splicing error was induced by a point mutation that created a novel splice acceptor site. This insertion created a nonsense codon downstream, producing a truncated ALD protein. His mother and younger sister with increased VLCFA ratios were heterozygotes of normal and mutant ALD genes.


A behavioral method for efficient screening of visual acuity in young infants. II. Clinical application.
Visual performance in 130 infants was assessed in a clinical setting with the forced-choice preferential looking (FPL) method described by Dobson et al.5 Over 90% of infants completed testing. Testing usually required less than 10 min. One group of infants tested also underwent complete ophthalmic examination. The second, larger group was screened with handlight examinations and FPL testing; any abnormalities detected were evaluated by full ophthalmic examination. Results so far indicate that the FPL test accurately identifies babies with binocular visual problems and that, when coupled with a handlight examination, it provides efficient screening for ocular problems in infants 0 through 16 weeks of age (postterm).


Low use of neuroleptic drugs in the treatment of psychotic major depression.
The adequacy of pharmacologic treatment received by patients with psychotic major depression was evaluated. The authors systematically assessed the pharmacotherapy received by 187 depressed patients before initiation of ECT and compared the medication trials of those with psychotic (N = 53) and nonpsychotic (N = 134) depression. Despite a median of four medication trials and median index episode duration of 20 weeks, only two (4%) of the patients with psychotic depression received at least one adequate pharmacotherapy trial. In contrast, 70 (52%) of the patients with nonpsychotic depression received at least one adequate trial. Twenty-five (47%) of the patients with psychotic depression received either no neuroleptic treatment (N = 11) or treatment for less than 3 weeks (N = 14). Only eight (15%) received a daily neuroleptic dose higher than 200 mg of chlorpromazine equivalents. These findings suggest that many patients with psychotic major depression referred for ECT receive inadequate pharmacotherapy because of either the absence or the inadequate use of neuroleptic medication.


Dual-emission fluorescent sensor based on AIE organic nanoparticles and Au nanoclusters for the detection of mercury and melamine.
A novel dual-emission ratiometric fluorescence probe is designed and developed by linking two parts, positively charged aggregation-induced emission (AIE) organic fluorescence nanoparticles (OFNs) as the reference and negatively charged Au nanoclusters (Au NCs) as the response, by electrostatic attraction for the first time. This probe can be used for not only visual but quantitative determination of Hg(2+) as well as melamine, because red fluorescence of Au NCs can be quenched by mercury ions and recovered by melamine, due to the strong affinity metallophilic Hg(2+)-Au interaction and stronger affinity Hg(2+)-N. During this process, the green fluorescence of AIE-OFNs remains constant owing to the protection of ε-polylysine (ε-Ply). In addition, the prepared dual-emission ratiometric fluorescence probe has good biocompatibility, indicating the potential of the probe in applications of biological imaging and detection. The results revealed that this dual-emission ratiometric fluorescence probe broadens the application of AIE-based organic fluorescent nanoparticles, and presents a new method to prepare more sensitive, biocompatible, and visual ratiometric fluorescent probes.


Barriers and Facilitators to the Uptake of Online and Telephone Services Targeting Health Risk Behaviours among Vocational Education Students: A Qualitative Study.
Uptake of online and telephone services targeting health behaviours is low among vocational education students and barriers and facilitators are unknown. This study aimed to explore barriers and facilitators to uptake of online and telephone services for smoking, nutrition, alcohol, and physical activity (SNAP) risk behaviours via semi-structured individual telephone interviews with fifteen vocational education students. Two authors independently completed thematic analysis, classified themes according to the COM-B (Capability, Opportunity, Motivation, Behaviour) framework, and discussed disagreements until consensus was reached. Facilitators to uptake of online (e.g., desire to learn something new, cost-free, accessible) and telephone services (e.g., prefer to talk to provider, complements online support) primarily related to capability and opportunity. For telephone services, difficulty understanding accent/language was a capability-related barrier. Opportunity-related barriers for online and telephone services were preference for face-to-face interaction and lack of time, while preference for apps/online programs was a barrier for telephone services. For online and telephone services, not wanting to change SNAP behaviours was a motivation-related barrier and being able to change SNAP risk behaviours themselves was a motivation-related barrier for online services. Barriers and facilitators to online and telephone services are relevant for designing interventions vocational education students are more likely to use.


100 years of mathematical cosmology: Models, theories, and problems, Part A.
An elementary survey of mathematical cosmology is presented. We cover certain key ideas and developments in a qualitative way, from the time of the Einstein static universe in 1917 until today. We divide our presentation into four main periods, the first one containing important cosmologies discovered until 1960. The second period (1960-80) contains discussions of geometric extensions of the standard cosmology, singularities, chaotic behaviour and the initial input of particle physics ideas into cosmology. Our survey for the third period (1980-2000) continues with brief descriptions of the main ideas of inflation, the multiverse, quantum, Kaluza-Klein and string cosmologies, wormholes and baby universes, cosmological stability and modified gravity. The last period that ends today includes various more advanced topics such as M-theoretic cosmology, braneworlds, the landscape, topological issues, the measure problem, genericity, dynamical singularities and dark energy. We emphasize certain threads that run throughout the whole period of development of theoretical cosmology and underline their importance in the overall structure of the field. This is Part A of our survey covering the first two periods of development of the subject. The second part will include the third and fourth periods. We end this outline with an inclusion of the abstracts of all papers contributed to the Philosophical Transactions of the Royal Society A theme issue, 'The Future of Mathematical Cosmology'. This article is part of the theme issue 'The future of mathematical cosmology, Volume 1'.


Relevance of the immunoprecipitation assay to human immunogenicity of influenza vaccines.
Influenza vaccines representing each of the four U.S. manufacturers' output for the 1975-76 respiratory season were characterized clinically and assayed by immunoprecipitation. All vaccines contained 350 CCA units/dose each of the A/Port Chalmers/1/73 (H3N2) and A/Scotland/840/74 (H3N2) viruses plus 550 CCA units/dose of B/HK/5/72 virus. Two of the vaccines were whole virus while the other two were subunit products; one made by extraction with ethyl ether, the second by detergent treatment. The vaccines were compared for serologic efficacy in children naturally primed to the (H3N2) family of viruses and by immunoprecipitation techniques against monospecific goat antiserum to the viral hemagglutinin prepared at the Bureau of Biologics of the U.S. Food & Drug Administration. The subunit vaccines had significantly greater specific activity (human immunogenicity/unit mass of type-specific precipitable antigen) than the whole virus products. It is concluded that clinical immunogenicity is as much a function of antigen form (subunit vs whole virus) as it is of mass and that setting a level for precipitable antigen content alone is an insufficient criterion for potency standardization. Since antigen form, as well as mass, must be considered, immunoprecipitation may be useful for standardization of human immunogenicity only if candidate lots are compared by this technique to an homologous, reference vaccine of identical manufacture and form which is tested for potency in humans.


Adherence to Mediterranean Diet Offers an Additive Protection Over the Use of Statin Therapy: Results from the ATTICA Study (2002-2012).
The protective role of Mediterranean diet on cardiovascular disease (CVD) risk has been extensively discussed in the literature, but its incremental effect over the use of CVD risk reducing agents (such as hypolipidemic treatment) has rarely been evaluated. The ATTICA study was carried out in the Athens area during 2001-2002 and included 3042 participants free of CVD at baseline (49.8% men, aged 18-89 years). Adherence to Mediterranean diet was assessed using the MedDietScore (range 0-55) and statin use was recorded for all subjects. During 2011-2012, 2583 out of the 3042 baseline participants attended the 10-year follow-up of the ATTICA study (15% lost-to-follow-up) and CVD development was recorded. Adherence to Mediterranean diet (highest tertile) decreased CVD risk by 29.3% (Hazard Ratio (HR): 0.707, 95% Confidence Intervals (CI): 0.537-0.831) as compared with the lowest tertile, independently of statin use. Patients with hyperlipidemia on a statin that adopted unhealthy dietary habits (lowest tertile) had 75% increased CVD risk than normolipidemic subjects with healthy dietary habits (HR=1.75, 95%CI: 1.33-2.29). The addition of Mediterranean diet tertiles in the multivariable model reclassified 46.7% of the participants to CVD risk categories. Adherence to Mediterranean diet confers a considerable reduction in CVD risk, independently of gender, age, family history of CVD, diabetes mellitus, smoking status, hypertension and physical activity status. Therefore, CVD prevention strategies should involve the implementation of a Mediterranean diet in both the general population and patients on a statin.


[Cytophotometric and electron microscopic studies of chronic human skin lymphomas. II. Research on lymph node involvement].
Results of electron microscopic and cytophotometric studies of biopsy material from lymph nodes of patients with cutaneous lymphomas with low degree of malignancy are discussed, with special reference to early diagnostic criteria of the disease. Specific characteristics of tumor tissue involve the presence of atypical lymphocytes with marginal condensed chromatin extrusions of nuclear material, deep invaginations of the nuclear membrane, nuclear pockets, excess of the mean DNA content per nucleus above the diploid standard level, more than 5% of nuclei being in the hyperdiploid area. Electron microscopic and cytophotometric methods allowed to diagnose the tumor injury of lymph nodes, when the traditional histological techniques revealed no signs of malignancy.


Should the risk of acquired immunodeficiency syndrome deter hepatitis B vaccination? A decision analysis.
The current epidemic of acquired immunodeficiency syndrome (AIDS) and fear that its causative agent contaminates the currently available hepatitis B vaccine may have deterred vaccine use. We formulated a decision-analytic model that compares the risk of death from hepatitis B and AIDS in those vaccinated with the risk of death from hepatitis B alone in those who wait two years for a synthetic vaccine. For individuals with 5% annual risk of hepatitis B, the best current estimate is that vaccination now would save 25 lives per 100,000. The best current estimate of the rate of vaccine-induced AIDS is zero, and one can be 95% confident that the rate is less than eight per 100,000. The rate would have to be considerably higher before postponement of vaccination would be rational for those for whom vaccination has been recommended.


[New German guidelines for the treatment of depression - the central role of psychotherapy].
The paper introduces the new German Guidelines for the Treatment of Unipolar Depression in Adults. An overview is given of the long timespan of the development and the process of consensus decisions. We report the essential parts of the statements and recommendations. The recommendations in the guidelines stress the importance of psychotherapeutic approaches to the treatment of depression as a baseline or adjunct treatment to pharmacotherapy. We also describe conflictual issues, such as methodological problems in the psychotherapy section, bias in pharmacotherapy research, and competition in different fields of the health care system. The German Guidelines are a progressive step in the field of health care. They integrate the contributions of many different providers and levels of care.


A transient protective effect of low-level laser irradiation against disuse-induced atrophy of rats.
Satellite cells, a population of skeletal muscular stem cells, are generally recognized as the main and, possibly, the sole source of postnatal muscle regeneration. Previous studies have revealed the potential of low-level laser (LLL) irradiation in promoting satellite cell proliferation, which, thereby, boosts the recovery of skeletal muscle from atrophy. The purpose of this study is to investigate the beneficial effect of LLL on disuse-induced atrophy. The optimal irradiation condition of LLL (808 nm) enhancing the proliferation of Pax7+ve cells, isolated from tibialis anterior (TA) muscle, was examined and applied on TA muscle of disuse-induced atrophy model of the rats accordingly. Healthy rats were used as the control. On one hand, transiently, LLL was able to postpone the progression of atrophy for 1 week through a reduction of apoptosis in Pax7-veMyoD+ve (myocyte) population. Simultaneously, a significant enhancement was observed in Pax7+veMyoD+ve population; however, most of the increased cells underwent apoptosis since the second week, which suggested an impaired maturation of the population. On the other hand, in normal control rats with LLL irradiation, a significant increase in Pax7+veMyoD+ve cells and a significant decrease of apoptosis were observed. As a result, a strengthened muscle contraction was observed. Our data showed the capability of LLL in postponing the progression of disuse-induced atrophy for the first time. Furthermore, the result of normal rats with LLL irradiation showed the effectiveness of LLL to strengthen muscle contraction in healthy control.


Effects of metaphit, a proposed phencyclidine receptor acylator, on catalepsy in pigeons.
Metaphit, a derivative of phencyclidine (PCP), irreversibly binds to PCP sites in rat brain homogenates. PCP-induced catalepsy in pigeons, which is a pharmacologically specific and stereoselective phenomenon, was used to study pharmacological consequences of the proposed covalent bonding of metaphit to PCP sites. Metaphit pretreatment increased the cataleptic effects induced by cumulative doses of PCP-type drugs (i.e., PCP, ketamine and m-amino PCP) and of drugs that have PCP-like actions (i.e., dexoxadrol, LY 154716 and cyclazocine). Metaphit did not affect pentobarbital-induced loss of righting, head-drop and eye closure. Metaphit itself induced a PCP-like catalepsy. Isobolographic analysis of the interactions between metaphit and PCP-like drugs suggested that metaphit potentiated the catalepsy-inducing effects of these drugs. The possibility that metaphit exerts its potentiating effects by inhibition of PCP biotransformation was evaluated by measuring plasma and brain concentrations of PCP after pretreatment with either metaphit or SKF-525A, an inhibitor of the enzyme systems involved in PCP biotransformation. SKF-525A, but not metaphit, increased brain levels of PCP. The results suggest that metaphit acts not as an antagonist of PCP but as a less-potent, long-acting, specific PCP-like agonist. Potentiation by metaphit of the cataleptic effects of chemically diverse drugs with PCP-like actions does not appear to be based on inhibition of the enzyme systems involved in metabolism of those drugs.


Long-term ureteroscopic management of low-grade transitional cell carcinoma of the upper urinary tract.
Nephrouterectomy, or partial uterectomy, is the treatment of choice for transitional cell carcinoma (TCC) of the upper urinary tract. However, patients with solitary kidneys, bilateral tumors, renal insufficiency, or medical comorbidities require more conservative management. When the TCC is low grade, it would be desirable to manage such tumors endoscopically. Ten patients with low-grade TCC of the upper urinary tract have been managed for 2-6 years with ureteroscopy and electrofulguration or laser coagulation. All tumors have been managed successfully without evidence of progression. Recurrence is frequent in some patients and requires repeat treatment and vigilant surveillance.


Effective dose estimation for pediatric upper gastrointestinal examinations using an anthropomorphic phantom set and metal oxide semiconductor field-effect transistor (MOSFET) technology.
There is a need for updated radiation dose estimates in pediatric fluoroscopy given the routine use of new dose-saving technologies and increased radiation safety awareness in pediatric imaging. To estimate effective doses for standardized pediatric upper gastrointestinal (UGI) examinations at our institute using direct dose measurement, as well as provide dose-area product (DAP) to effective dose conversion factors to be used for the estimation of UGI effective doses for boys and girls up to 10 years of age at other centers. Metal oxide semiconductor field-effect transistor (MOSFET) dosimeters were placed within four anthropomorphic phantoms representing children ≤10 years of age and exposed to mock UGI examinations using exposures much greater than used clinically to minimize measurement error. Measured effective dose was calculated using ICRP 103 weights and scaled to our institution's standardized clinical UGI (3.6-min fluoroscopy, four spot exposures and four examination beam projections) as determined from patient logs. Results were compared to Monte Carlo simulations and related to fluoroscope-displayed DAP. Measured effective doses for standardized pediatric UGI examinations in our institute ranged from 0.35 to 0.79 mSv in girls and were 3-8% lower for boys. Simulation-derived and measured effective doses were in agreement (percentage differences <19%, T > 0.18). DAP-to-effective dose conversion factors ranged from 6.5 ×10(-4) mSv per Gy-cm(2) to 4.3 × 10(-3) mSv per Gy-cm(2) for girls and were similarly lower for boys. Using modern fluoroscopy equipment, the effective dose associated with the UGI examination in children ≤10 years at our institute is < 1 mSv. Estimations of effective dose associated with pediatric UGI examinations can be made for children up to the age of 10 using the DAP-normalized conversion factors provided in this study. These estimates can be further refined to reflect individual hospital examination protocols through the use of direct organ dose measurement using MOSFETs, which were shown to agree with Monte Carlo simulated doses.


Polo-like kinase 1 inhibitors, mitotic stress and the tumor suppressor p53.
Polo-like kinase 1 has been established as one of the most attractive targets for molecular cancer therapy. In fact, multiple small-molecule inhibitors targeting this kinase have been developed and intensively investigated. Recently, it has been reported that the cytotoxicity induced by Plk1 inhibition is elevated in cancer cells with inactive p53, leading to the hypothesis that inactive p53 is a predictive marker for the response of Plk1 inhibition. In our previous study based on different cancer cell lines, we showed that cancer cells with wild type p53 were more sensitive to Plk1 inhibition by inducing more apoptosis, compared with cancer cells depleted of p53. In the present work, we further demonstrate that in the presence of mitotic stress induced by different agents, Plk1 inhibitors strongly induced apoptosis in HCT116 p53(+/+) cells, whereas HCT116 p53(-/-) cells arrested in mitosis with less apoptosis. Depletion of p53 in HCT116 p53(+/+) or U2OS cells reduced the induction of apoptosis. Moreover, the surviving HCT116 p53(-/-) cells showed DNA damage and a strong capability of colony formation. Plk1 inhibition in combination with other anti-mitotic agents inhibited proliferation of tumor cells more strongly than Plk1 inhibition alone. Taken together, the data underscore that functional p53 strengthens the efficacy of Plk1 inhibition alone or in combination by strongly activating cell death signaling pathways. Further studies are required to investigate if the long-term outcomes of losing p53, such as low differential grade of tumor cells or defective DNA damage checkpoint, are responsible for the cytotoxicity of Plk1 inhibition.


Do baseline characteristics predict response to treatment for low back pain? Secondary analysis of the UK BEAM dataset [ISRCTN32683578].
To identify characteristics of randomized controlled trial participants which predict greater benefits from physical treatments for low back pain. If successful, this would allow more appropriate selection of patients for different treatments. We did a secondary analysis of the UK Back pain Exercise And Manipulation trial (UK BEAM n = 1334) dataset to identify baseline characteristics predicting response to manipulation, exercise and manipulation followed by exercise (combined treatment). Rather than simply identifying factors associated with overall outcome, we tested for the statistical significance of the interaction between treatment allocation, baseline characteristics and outcome to identify factors that predicted response to treatment. We also did a post-hoc subgroup analysis to present separate results for trial participants with subacute and chronic low back pain to inform future evidence synthesis. Age, work status, age of leaving school, 'pain and disability', 'quality of life' and 'beliefs' at baseline all predicted overall outcome. None of these predicted response to treatment. In those allocated to combined treatment, there was a suggestion that expecting treatment to be helpful might improve outcome at 1 yr. Episode length at study entry did not predict response to treatment. Baseline participant characteristics did not predict response to the UK BEAM treatment packages. Using recognized prognostic variables to select patients for different treatment packages, without first demonstrating that these factors affect response to treatment, may be inappropriate. In particular, this analysis suggests that the distinction between subacute and chronic low back pain may not be useful when considering treatment choices.


Host Immune Response and Associated Clinical Features in a Primary Cytomegalovirus Eye Infection Model Using Anterior Chamber Inoculation.
To investigate the pathogenesis of cytomegalovirus (CMV)-associated anterior segment infection in immunocompetent hosts and evaluate the effects of ganciclovir and glucocorticoid treatment in management of the disease. We used an inoculation model to reproduce CMV anterior segment infection in immunocompetent rats. Flow cytometry, cytokine analysis, histopathological sections, and quantitative polymerase chain reaction were performed to investigate the immune response after CMV infection. The effects of ganciclovir and glucocorticoid treatment were also assessed. Anterior chamber inoculation of CMV in rats provoked characteristic pathological features of human CMV anterior segment infection. The innate and adaptive immunity sequentially developed in an anterior segment after inoculation, and the elevation of intraocular pressure (IOP) was highly associated with ocular infiltration and inflammation. Early ocular immune response reduced virus DNA in the anterior segment and alleviated viral lymphadenopathy. Early intervention with ganciclovir enhanced the release of cytokines associated with T response and facilitated recruitment of NKT and T cells in drainage lymph nodes. Glucocorticoid treatment, alone or combined with ganciclovir, decreased elevation of IOP but also impeded DNA clearance. The inoculation model reproduced characteristic pathological features of human CMV anterior segment infection. The use of glucocorticoid in current practice may hinder viral clearance, and ganciclovir therapy can assist cytokine expression to combat the virus.


[Pancreas divisum or embryonic pancreas. Anatomical study (apropos of 16 cases)].
The authors study the Pancreas divisum's rate in 242 cadavers. With two successive studies, they establish a rate of about 6.6%. They conform the sexual disparity and the presence of muscular fibre cells on a level with papilla duodeni minor.


Catalysis resolved using scanning tunnelling microscopy.
The technique of scanning tunnelling microscopy has revolutionised our understanding of surface chemistry, due to its ability to image at the atomic and molecular scale, the very realm at which chemistry operates. This critical review focuses on its contribution to the resolution of various problems in heterogeneous catalysis, including surface structure, surface intermediates, active sites and spillover. In the article a number of images of surfaces are shown, many at atomic resolution, and the insights which these give into surface reactivity are invaluable. The article should be of interest to catalytic chemists, surface and materials scientists and those involved with nanotechnology/nanoscience. (129 references.)The graphical abstract shows the reaction between gas phase methanol and oxygen islands on Cu(110), courtesy of Philip Davies of Cardiff University. The added-row island is shown as silver-coloured spheres (copper) and red (oxygen) on the copper surface. Methanol preferentially reacts with the terminal oxygen atoms in the island forming adsorbed methoxy and OH groups. Only the terminal oxygen atoms in the island are active sites for the reaction.


The effect of negative wound pressure therapy on haemodynamics in a laparostomy wound model.
We have recently shown that negative pressure wound therapy (NPWT) induces a decrease in microvascular blood flow in the small intestinal loop close to the dressing. The effect of NPWT is thus thought to be local. In this study, we investigate whether the application of NPWT in laparostomy affects the haemodynamics. Midline incisions were made in six pigs followed by NPWT at -120 mmHg for 20 minutes. The cardiac output, mean systemic arterial pressure, mean pulmonary artery pressu re, central venous pressure, left atrial pressure and superior mesenteric artery blood flow were recorded. The blood flow in a small branch of the superior mesenteric artery was then recorded under NPWT between -50 and -175 mmHg. Cardiac output was not affected by NPWT [P = not significant (n.s.)]. Neither the mean arterial pressure nor the mean pulmonary artery pressure was affected by NPWT (P = n.s.). Negative pressures of -50, -75, -100 and -125 mmHg did not alter the blood flow in the small branch of the superior mesenteric artery (P = n.s.). After application of -150 mmHg, a significant decrease in blood flow was seen (P < 0·01), while the application of -175 mmHg resulted in only a slight decrease in blood flow (P = n.s.). The effect of NPWT in laparotomy seems to be local and to have no influence on central haemodynamics or the blood flow to the superior mesenteric artery.


Ramus marginalis mandibulae nervus facialis palsy in hemifacial microsomia.
The paralysis of the ramus marginalis mandibulae nervus facialis may occur in Hemifacial Microsomia (HM); the combination of both HM and palsy contributes to an elongation of the mandibular body. This study explores a possible correlation between neurological deficit, muscular atony, and structural deficiency. Of 58 patients with HM who had come to the University of Rome (Sapienza) Pre-surgical Orthodontics Unit, 4 patients were afflicted with Hemifacial Microsomia and ramus marginalis mandibulae nervus palsy; these patients underwent physical, neurological, opthamologic and systemic examinations. The results were then analysed in order to determine a possible correlation between neuro-muscular and structural deficit. Electroneurographic and electromyographic examinations were performed to estimate facial nerve and muscles involvement. Neuroelectrographic exam showed a damage of the nervous motor fibres of the facial nerve ipsilateral to HM, with an associated damage of the muscular function, while neuro-muscular functions on the healthy side were normal. The peripheral nervous and muscular deficits affect the function of facial soft tissues and the growth of mandibular body with an asymmetry characterised by a hypodevelopment of the ramus (due to the HM) and by an elongation of the mandibular body (due to ramus marginalis mandibulae nerve palsy), so that the chin deviation is contralateral to HM. In these forms, a neurological examination is necessary to assess the neurological damage on the HM side. Neuromuscular deficiency can also contribute to a relapse tendency after a surgical-orthodontic treatment.


The role of stimulus cross-splicing in an event-related potentials study. Misleading formant transitions hinder automatic phonological processing.
The mental organization of linguistic knowledge and its involvement in speech processing can be investigated using the mismatch negativity (MMN) component of the auditory event-related potential. A contradiction arises, however, between the technical need for strict control of acoustic stimulus properties and the quest for naturalness and acoustic variability of the stimuli. Here, two methods of preparing speech stimulus material were compared. Focussing on the automatic processing of a phonotactic restriction in German, two corresponding sets of various vowel-fricative syllables were used as stimuli. The former syllables were naturally spoken while the latter ones were created by means of cross-splicing. Phonetically, natural and spliced syllables differed with respect to the appropriateness of coarticulatory information about the forthcoming fricative within the vowels. Spliced syllables containing clearly misleading phonetic information were found to elicit larger N2 responses compared to their natural counterparts. Furthermore, MMN results found for the natural syllables could not be replicated with these spliced stimuli. These findings indicate that the automatic processing of the stimuli was considerably affected by the stimulus preparation method. Thus, in spite of its unquestioned benefits for MMN experiments, the splicing technique may lead to interference effects on the linguistic factors under investigation.


Demographic profile and pregnancy outcomes of adolescents and older mothers in Saudi Arabia: analysis from Riyadh Mother (RAHMA) and Baby cohort study.
To investigate the impact of maternal age on pregnancy outcomes with special emphasis on adolescents and older mothers and to investigate the differences in demographic profile between adolescents and older mothers. This study is a secondary analysis of pregnancy outcomes of women in Riyadh Mother and Baby cohort study according to maternal age. The study population was grouped according to maternal age into five subgroups; <20, 20-29, 30-34, 35-39 and 40+years. The age group 20-29 years was considered as a reference group. Investigation of maternal age impact on maternal and neonatal outcomes was conducted with adjustment of confounders using regression models. All mothers were married when conceived with the index pregnancy. Young mothers were less likely to be illiterate, more likely to achieve higher education and be employed compared with mothers ≥ 40 years. Compared with the reference group, adolescents were more likely to have vaginal delivery (and least likely to deliver by caesarean section (CS); OR=0.6, 95% CI 0.4 to 0.9, while women ≥40 years, were more likely to deliver by CS; OR 2.9, 95% CI 2.3 to 3.7. Maternal age was a risk factor for gestational diabetes in women ≥40 years; OR 1.7, 95% CI 1.3 to 2.1. Adolescents had increased risk of preterm delivery; OR 1.5, 95% CI 1.1 to 2.1 and women ≥40 years had similar risk; OR, 1.3, 95% CI 1.1 to 1.6. Adverse pregnancy outcomes show a continuum with the advancement of maternal age. Adolescents mother are more likely to have vaginal delivery; however, they are at increased risk of preterm delivery. Advanced maternal age is associated with increased risk of preterm delivery, gestational diabetes and CS.


Transsacral screw safe zone size by sacral segmentation variations.
Variations in sacral segmentation may preclude safe placement of transsacral screws for posterior pelvis fixation. We developed a novel automated 3D technique to determine the safe zone size for transsacral screws in the upper two sacral segments in 526 adult pelvis computed tomography scans. Safe zone sizes were then compared by gender and sacral segmentation variations (number of neuroforamen and the presence/absence of lumbosacral transitional vertebrae, ± LSTV). Ten millimeters was used as the safety threshold for a large screw. 3 (0.6%), 366 (70%), and 157 (30%) sacra had 3, 4, or 5 neuroforamen, respectively. Eighty-eight (17%) were +LSTV. Safe zone size depended on gender, number of neuroforamen in -LSTV sacra and presence of LSTV (p < 0.001) but not on the uni- or bilateral nature of the LSTV. 17% of -LSTV sacra were below the safety threshold in S1, 27% in S2, whereas 3% of +LSTV sacra were below in S1, 74% in S2. Of -LSTV sacra that cannot take an S1 screw safely, 77% can do so in S2, leaving only 4% of sacra that cannot accommodate a screw safely in either upper segment. The results demonstrate a predictable pattern of safe zone size based on gender and sacral segmentation variations.


High blood pressure and obesity: disparities among four French Overseas Territories.
The epidemiological characteristics of hypertension and obesity in French Overseas Territories (FOTs) have never been compared. This cross-sectional survey included representative population-based samples of 602, 601, 620 and 605 men and women aged more than 15 years, respectively, from four FOTs of Guadeloupe, Martinique, French Guiana, and French Polynesia. Hypertension was defined as blood pressure (BP) at least 140/90 mmHg or the current use of antihypertensive treatment. The prevalence of hypertension was 29.2% in Guadeloupe, 17.9% in French Guiana, 27.6% in Martinique and 24.5% in French Polynesia. Considering the Guadeloupe population as the reference group, prevalence of hypertension was significantly lower in French Guiana (P < 0.001), even after controlling for age and sex (P = 0.006). Awareness and treatment of hypertension were similar in French Guiana, Martinique and Guadeloupe (68.8-75.1% and 69.0-73.4%, respectively). Awareness was lower in French Polynesia (50.0%, adjusted P value = 0.04), as was treatment of hypertension (32.4%, adjusted P value = 0.001). Control of hypertension was also lower in French Polynesia (8.8%, adjusted P value = 0.001) compared with the other territories (29.7-31.8%). French Polynesia had the highest prevalence of obesity (33.1%, adjusted P value < 0.001) as compared with the other territories (17.9-22.8%). It had also the largest population attributable fraction of hypertension due to obesity (35.5%) compared with Guadeloupe (13.3%), Martinique (12.3%) and French Guiana (23.6%). Wide variations were observed in the prevalence and the management of hypertension between these FOTs, and an especially challenging low control of hypertension was found in French Polynesia. Obesity appears a key target to prevent hypertension, particularly in French Polynesia.


Traumatic rib fracture patterns associated with bone mineral density statuses derived from CT images.
The impact of decreased bone mineral density (BMD) on traumatic rib fractures remains unknown. We combined computed tomography (CT) and artificial intelligence (AI) to measure BMD and explore its impact on traumatic rib fractures and their patterns. The retrospective cohort comprised patients who visited our hospital from 2017-2018; the prospective cohort (control group) was consecutively recruited from the same hospital from February-June 2023. All patients had blunt chest trauma and underwent CT. Volumetric BMD of L1 vertebra was measured by using an AI software. Analyses were done by using BMD categorized as osteoporosis (<80 mg/cm3), osteopenia (80-120 mg/cm3), or normal (>120 mg/cm3). Pearson's χ2, Fisher's exact, or Kruskal-Wallis tests and Bonferroni correction were used for comparisons. Negative binomial, and logistic regression analyses were used to assess the associations and impacts of BMD status. Sensitivity analyses were also performed. The retrospective cohort included 2,076 eligible patients, of whom 954 (46%) had normal BMD, 806 (38.8%) had osteopenia, and 316 (15.2%) had osteoporosis. After sex- and age-adjustment, osteoporosis was significantly associated with higher rib fracture rates, and a higher likelihood of fractures in ribs 4-7. Furthermore, both the osteopenia and osteoporosis groups demonstrated a significantly higher number of fractured ribs and fracture sites on ribs, with a higher likelihood of fractures in ribs 1-3, as well as flail chest. The prospective cohort included 205 eligible patients, of whom 92 (44.9%) had normal BMD, 74 (36.1%) had osteopenia, and 39 (19.0%) had osteoporosis. The findings observed within this cohort were in concurrence with those in the retrospective cohort. Traumatic rib fractures are associated with decreased BMD. CT-AI can help to identify individuals who have decreased BMD and a greater rib fracture rate, along with their fracture patterns.


Chemoreceptor Responsiveness at Sea Level Does Not Predict the Pulmonary Pressure Response to High Altitude.
The hypoxic ventilatory response (HVR) at sea level (SL) is moderately predictive of the change in pulmonary artery systolic pressure (PASP) to acute normobaric hypoxia. However, because of progressive changes in the chemoreflex control of breathing and acid-base balance at high altitude (HA), HVR at SL may not predict PASP at HA. We hypothesized that resting oxygen saturation as measured by pulse oximetry (Spo₂) at HA would correlate better than HVR at SL with PASP at HA. In 20 participants at SL, we measured normobaric, isocapnic HVR (L/min · -%Spo₂⁻¹) and resting PASP using echocardiography. Both resting Spo₂ and PASP measures were repeated on day 2 (n = 10), days 4 to 8 (n = 12), and 2 to 3 weeks (n = 8) after arrival at 5,050 m. These data were also collected at 5,050 m in life-long HA residents (ie, Sherpa [n = 21]). Compared with SL, Spo₂ decreased from 98.6% to 80.5% (P < .001), whereas PASP increased from 21.7 to 34.0 mm Hg (P < .001) after 2 to 3 weeks at 5,050 m. Isocapnic HVR at SL was not related to Spo₂ or PASP at any time point at 5,050 m (all P > .05). Sherpa had lower PASP (P < .01) than lowlanders on days 4 to 8 despite similar Spo₂. Upon correction for hematocrit, Sherpa PASP was not different from lowlanders at SL but was lower than lowlanders at all HA time points. At 5,050 m, although Spo₂ was not related to PASP in lowlanders at any point (all R² ≤ 0.05, P > .50), there was a weak relationship in the Sherpa (R² = 0.16, P = .07). We conclude that neither HVR at SL nor resting Spo₂ at HA correlates with elevations in PASP at HA.


Reciprocal projections in hierarchically organized evolvable neural circuits affect EEG-like signals.
Modular architecture is a hallmark of many brain circuits. In the cerebral cortex, in particular, it has been observed that reciprocal connections are often present between functionally interconnected areas that are hierarchically organized. We investigate the effect of reciprocal connections in a network of modules of simulated spiking neurons. The neural activity is recorded by means of virtual electrodes and EEG-like signals, called electrochipograms (EChG), analyzed by time- and frequency-domain methods. A major feature of our approach is the implementation of important bio-inspired processes that affect the connectivity within a neural module: synaptogenesis, cell death, spike-timing-dependent plasticity and synaptic pruning. These bio-inspired processes drive the build-up of auto-associative links within each module, which generate an areal activity, recorded by EChG, that reflect the changes in the corresponding functional connectivity within and between neuronal modules. We found that circuits with intra-layer reciprocal projections exhibited enhanced stimulus-locked response. We show evidence that all networks of modules are able to process and maintain patterns of activity associated with the stimulus after its offset. The presence of feedback and horizontal projections was necessary to evoke cross-layer coherence in bursts of -frequency at regular intervals. These findings bring new insights to the understanding of the relation between the functional organization of neural circuits and the electrophysiological signals generated by large cell assemblies. This article is part of a Special Issue entitled "Neural Coding".


Cancer risk associated with long-term use of acetaminophen in the prospective VITamins and lifestyle (VITAL) study.
Acetaminophen (paracetamol) is a widely used over-the-counter drug, but concerns of genotoxic effects have been raised. After we recently found an almost two-fold increased risk of hematologic malignancies associated with high use of acetaminophen in the prospective VITamins And Lifestyle (VITAL) study, we herein further examined the association between acetaminophen use and cancer risk in the VITAL cohort. A total of 62,841 men and women aged 50 to 76 years were recruited from 2000 to 2002, and incident malignancies other than nonmelanoma skin cancer (n = 5,750) were identified through December 2008 via linkage to the Surveillance, Epidemiology, and End Results cancer registry. HRs associated with acetaminophen use for incidence of total cancers and nonhematologic cancer subcategories were estimated with Cox proportional hazards models that were adjusted for age, demographics, cancer risk factors, and medical conditions that may be indications for acetaminophen use. Use of acetaminophen was not associated with total cancer risk. We also observed no associations for most major nonhematologic cancer sites, including cancers of the gastrointestinal system, lung, urinary tract, skin, prostate, or female organs. This study failed to provide evidence of an association between acetaminophen use and total cancer risk or incidence of nonhematologic malignancies. Together with our previous findings, the analyses from the VITAL study suggest a particular sensitivity of the hematopoietic system to the mutagenic effects of acetaminophen.


Circ-HACE1 Aggravates Cigarette Smoke Extract-Induced Injury in Human Bronchial Epithelial Cells via Regulating Toll-Like Receptor 4 by Sponging miR-485-3p.
Smoking is the most common cause of chronic obstructive pulmonary disease (COPD), and the early diagnosis for COPD remains poor. Exploring the molecular mechanism and finding feasible biomarkers will be beneficial for clinical management of COPD. Circular RNAs (circRNAs) are noncoding RNAs that act as miRNA sponges to regulate the expression levels of genes, leading to the changes of cellular phenotypes and disease progression. CircRNA HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (circ-HACE1) was abnormally expressed after the induction of cigarette smoke extract (CSE) in cell model. This study was performed to explore its function and mechanism in COPD. Circ-HACE1, microRNA-485-3p (miR-485-3p) and toll-like receptor 4 (TLR4) detection was performed by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability and apoptosis/cell cycle were respectively examined using cell counting kit-8 (CCK-8) and flow cytometry. Inflammatory cytokines were determined by enzyme-linked immunosorbent assay (ELISA). Oxidative stress was evaluated through the measurement of malondialdehyde (MDA) and superoxide dismutase (SOD). The target binding analysis was conducted via dual-luciferase reporter assay. Western blot was employed for protein expression detection of TLR4. Circ-HACE1 was overexpressed in smokers or smokers with COPD and CSE upregulated circ-HACE1 expression in 16HBE cells. Knockdown of circ-HACE1 attenuated CSE-stimulated cell viability and cell cycle repression, as well as the enhancement of cell apoptosis, inflammatory response and oxidative stress. MiR-485-3p was a target of circ-HACE1. Circ-HACE1 regulated CSE-induced cell injury via targeting miR-485-3p. TLR4 was a downstream target of miR-485-3p, and miR-485-3p inhibited the CSE-induced cell damages by directly downregulating the level of TLR4. Circ-HACE1/miR-485-3p regulated TLR4 expression in CSE-treated 16HBE cells, and TLR4 overexpression also reversed all effects of si-circ-HACE1 on CSE-treated 16HBE cells. These findings elucidated that circ-HACE1 contributed to the CSE-induced cell damages in COPD cell models via regulating TLR4 by acting as the sponge of miR-485-3p.


Using the ACNP Proficiency Testing Program to develop critical thinking. American College of Nuclear Physicians.
Critical thinking is cited as one of the essential skills for clinical practice. Educators need to be aware of barriers that may hinder the development of this skill in students and cultivate strategies to encourage it. This article describes one strategy to develop critical thinking. Students participated in a critical thinking exercise by imaging the American College of Nuclear Physicians (ACNP) Renal Imaging Proficiency Test Phantom, critiquing their results, and comparing their results to results collected nationally in other nuclear medicine facilities and the true values reported by the ACNP. Students were instructed to review pertinent imaging principles before discussing the imaging results. They also were supplied with a list of questions pertinent to the review. Students experienced the complexity of designing a SPECT imaging protocol and how the final results are affected by the choices made by the technologist. They learned the importance of and method for proper matrix selection, determination of pixel size and the necessity for quality control. The imaging exercise was a successful means of helping students connect clinical practice with theory through the use of critical thinking.


Primary headaches in HIV-infected patients.
Headache in patients with human immunodeficiency virus (HIV) infection may indicate life-threatening illnesses such as opportunistic infections or neoplasms. Alternatively, such patients may develop benign self-limiting headaches. Hence, defining the various types of headache in these patients is essential for proper management. This study describes the clinical characteristics of primary headaches occurring in a group of HIV-infected patients. Of 115 patients seen from 1990 to 1996, 44 (38%) had headaches. Primary headaches were present in 29 (66%) patients and secondary causes were identified in 15 (34%). Among those with primary headaches, migraine occurred in 22 (76%), tension-type headache in 4 (14%), and cluster headache in 3 (10%) patients. Half of those with migraine (n=ll), 1 patient with tension-type headache, and 1 patient with cluster headache developed chronic daily headaches which were severe and refractory to conventional headache or antiretroviral therapy. We conclude that primary headaches in patients with HIV infection are: (1) the commonest type of headache; (2) may present for the first time in individuals with severe immunosuppression; (3) usually bear no relationship to antiretroviral drug therapy; (4) polypharmacy, depression, anxiety, and insomnia are commonly associated comorbidities; (5) frequently do not respond to conventional management and carry a poor prognosis; and (6) do not require neuroradiological and/or cerebrospinal fluid evaluations.


Botulism.
This simulation is targeted to emergency medicine residents and medical students. This case focuses on the diagnosis and management of botulism toxicity, while highlighting the logistical complications of botulism toxicity. Botulism is a potentially life-threatening emergency that often presents with subtle symptoms, which can progress to paralysis and respiratory failure. A descending flaccid paralysis is typical, initially affecting smaller muscles such as oculomotor, then larger facial muscles. 1,2 Early indications of respiratory compromise are important to recognize. It is important for emergency medicine physicians to be familiar with botulism and recognize the presentation quickly to safely treat the patient. Clinical findings may include: dilated pupils, diplopia, xerostomia, dysphagia, and nausea and vomiting. 3 Treatment priorities include assessment and management of the airway, close monitoring, and coordinating with local agencies to obtain botulinum antitoxin.1. By the end of this simulation learners will be able to: 1) develop a differential for descending paralysis and recognize the signs and symptoms of botulism; 2) understand the importance of consulting public health authorities to obtain botulinum antitoxin in a timely fashion; 3) recognize that botulism will progress during the time period antitoxin is obtained. Early indications of respiratory compromise are expected to worsen during this time window.Secondary learning objectives include: 4) employ advanced evaluation for neurogenic respiratory failure such as physical examination, negative inspiratory force (NIF), forced vital capacity (FVC), and partial pressure of carbon dioxide (pCO2), 5) discuss and review the pathophysiology of botulism, 6) discuss the epidemiology of botulism. This simulation was conducted using a high-fidelity mannequin with intubating capabilities and real-time vital sign monitoring. Following the simulation, the participants underwent a debriefing session and discussion on botulism. This case was designed as a high-fidelity simulation, but it can be adapted to a low-fidelity simulation or case discussion. Following the simulation and debriefing session, participants were provided with a survey to rate the simulation and provide feedback to instructors. Participants were asked open-ended questions about the strengths and areas of improvement of the case, and were asked to rate how they valued the learning content of the case on a 5-point scale. Emergency medicine residents expressed positive feedback on the scenario. The residents appreciated the change in clinical course of the patient over time as well as the presentation of botulism.Discussion: This simulation is an effective way of teaching about botulism to emergency medicine residents. We used a primary nurse asking questions to progress the case and stimulate the learners to think about certain specific aspects of the case, such as the patient's weakness or disposition.Topics: Toxicology, botulism, emergency medicine, medical simulation.


Sustained activation of detoxification pathways promotes liver carcinogenesis in response to chronic bile acid-mediated damage.
Chronic inflammation promotes oncogenic transformation and tumor progression. Many inflammatory agents also generate a toxic microenvironment, implying that adaptive mechanisms must be deployed for cells to survive and undergo transformation in such unfavorable contexts. A paradigmatic case is represented by cancers occurring in pediatric patients with genetic defects of hepatocyte phosphatidylcholine transporters and in the corresponding mouse model (Mdr2-/- mice), in which impaired bile salt emulsification leads to chronic hepatocyte damage and inflammation, eventually resulting in oncogenic transformation. By combining genomics and metabolomics, we found that the transition from inflammation to cancer in Mdr2-/- mice was linked to the sustained transcriptional activation of metabolic detoxification systems and transporters by the Constitutive Androstane Receptor (CAR), a hepatocyte-specific nuclear receptor. Activation of CAR-dependent gene expression programs coincided with reduced content of toxic bile acids in cancer nodules relative to inflamed livers. Treatment of Mdr2-/- mice with a CAR inhibitor blocked cancer progression and caused a partial regression of existing tumors. These results indicate that the acquisition of resistance to endo- or xeno-biotic toxicity is critical for cancers that develop in toxic microenvironments.


Low-calcium diets increase both production and clearance of 1,25-dihydroxyvitamin D3 in rats.
Administration of large doses of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] to animals induces 1,25(OH)2D3 side-chain oxidative pathways. This study determined if the elevated plasma 1,25(OH)2D3 seen in rats fed low-Ca diets is associated not only with an increased production rate (PR) but also with an increased metabolic clearance rate (MCR) of the hormone. In vitamin D-replete rats fed a Ca-deficient diet for 3-4 wk, the PR increased 21-fold, plasma levels 15-fold, and the MCR by 37%. The increased MCR in Ca-deficient rats was associated with a 48% increase in hepatic microsomal UDP glucuronyl transferase enzyme activity, whereas 1,25(OH)2D3 catabolism by homogenates of liver and small intestinal mucosa was unchanged. In contrast to the effects of low-Ca diets, acute (7 h) pharmacological elevation of plasma 1,25(OH)2D3 to 1.5 ng/ml in normal rats did not influence the MCR. Thus chronically elevated 1,25(OH)2D3 levels are necessary to stimulate clearance. In conclusion, 1,25(OH)2D3 clearance in rats can be stimulated not only by chronic pharmacological doses of 1,25(OH)2D3 but also by the physiological stimulus of a low-Ca diet. Hence, plasma 1,25(OH)2D3 levels can be regulated by changes in both PR and MCR.


Accumulation of advanced glycation endproducts in patients with systemic lupus erythematosus.
To investigate whether advanced glycation endproducts (AGEs) are increased in patients with systemic lupus erythematosus (SLE), and are related to atherosclerosis, which is accelerated in SLE, and its traditional and non-traditional disease-related risk factors. Fifty-five SLE patients with inactive disease and 55 age- and sex-matched controls were included. The amount of skin autofluorescence (AF), as a measure for the accumulation of AGEs, was assessed by measuring UV-A light excitation-emission matrices (AF-EEMS). Traditional risk factors and disease-related factors were recorded. Plasma levels of C-reactive protein (CRP), as a marker for systemic inflammation, were assessed. Intima-media thickness (IMT) of the common carotid artery was determined by ultrasound. Skin AF-EEMS was increased in SLE patients as compared with controls (1.50 +/- 0.5 a.u. vs 1.28 +/- 0.4 a.u., P = 0.006). Regarding all included risk factors, univariate analyses in patients revealed that AF-EEMS was associated with age (r = 0.48, P < 0.001), IMT (r = 0.35, P = 0.01), creatinine (r = 0.29, P = 0.03), SLICC damage index (r = 0.29, P = 0.03) and disease duration (r = 0.32, P = 0.02). In multivariate analysis, age and disease duration were independent predictors of accumulation of AGEs in SLE (P < 0.001, P = 0.03, respectively). AGEs are increased in SLE compared with controls. Our findings indicate that AGE accumulation is associated with disease duration and might contribute to the development of accelerated atherosclerosis in SLE and, therefore, could be used for assessment of risk for long-term vascular complications.


[Depressive disorders associated with neurocysticercosis: prevalence and clinical correlations].
To determine the frequency and features of psychiatric morbidity in a cross-section of 38 outpatients with neurocysticercosis. Diagnosis of neurocysticercosis was established by CT scan, MRI and CSF analysis. Psychiatric diagnoses were made by using the Present State Examination and the Schedule for Affective Disorders and Schizophrenia. Lifetime version; cognitive state was assessed by Mini-Mental State Examination and Strub & Black's Mental Status Examination. Depression was the most frequent psychiatric diagnosis (52.6%) as shown by PSE. Active disease and intracranial hypertension were associated with higher psychiatric morbidity, and previous history of mood disorders was strongly related to current depression. Depression syndromes are frequent in patients with neurocysticercosis. The extent to which organic mechanisms related to brain lesions may underlie the observed mental changes is yet unclear, though the similar sex distribution of patients with and without depression, as well as the above mentioned correlations, provide further evidence of the role played by organic factors in the cause of these syndromes. The results of this study are discussed in the light of the data available for other organic psychiatric disorders.


Heart rate and plasma norepinephrine responsivity to orthostatic challenge in anxiety disorders. Comparison of patients with panic disorder and social phobia and normal control subjects.
Heart rate and plasma norepinephrine responsivity to a physiologic challenge, ie, orthostasis, were measured in 20 patients with panic disorder (PD) and 20 age- and sex-matched normal control subjects. While the two groups exhibited similar supine heart rates, patients with PD had a significantly greater heart rate response to orthostatic challenge. Plasma norepinephrine responses did not differ between patients with PD and normal control subjects. In a matched subgroup of 14 patients with PD, 14 normal control subjects, and 14 patients with social phobia, the patients with social phobia exhibited supine and upright plasma norepinephrine levels that were significantly higher than those of the other two diagnostic groups. Taken together, and in the context of findings from other studies, these preliminary observations suggest that the anxiety disorders may demonstrate differing patterns of autonomic dysfunction.


[The effect of plasma asymmetric dimethylarginine (ADMA) level and L-arginine/ADMA ratio on the development of coronary collaterals].
It has been shown that asymmetric dimethylarginine (ADMA), an endogenous competitive antagonist of nitric oxide (NO) synthase, inhibits angiogenesis by reducing the production and bioavailability of NO. We investigated the effect of plasma ADMA level and L-arginine/ADMA ratio on the development of coronary collateral arteries. The study consisted of 94 patients (66 males, 28 females; mean age 59+/-11 years) who underwent coronary angiography for suspected coronary artery disease and were found to have severe stenosis (>95%) in at least one major coronary artery. The patients were evaluated in two groups with poor (Rentrop score 0-1, n=44) and good (score 2-3, n=50) coronary collateral circulation according to the Rentrop collateral scoring system. Plasma levels of ADMA and L-arginine were measured by high-performance liquid chromatography. The two groups were similar with regard to basal characteristics and cardiovascular risk factors (p>0.05) except for stable angina, which was more common in patients with Rentrop score 2-3 collateral circulation (p<0.001). Despite similar L-arginine levels (p>0.05), patients with Rentrop score 0-1 had a significantly higher ADMA level (p=0.003) and lower L-arginine/ADMA ratio (p=0.019). Multivariate logistic regression analysis showed that plasma ADMA concentration was an independent predictor of coronary collateral development (odds ratio=0.674; 95% confidence interval=0.508-0.894; p=0.006). Elevated plasma ADMA concentrations are associated with a poorly developed coronary collateral circulation, suggesting that dysregulation of the NO synthase pathway may result in impaired collateral development.


2'-(R)-Fluorinated mC, hmC, fC and caC triphosphates are substrates for DNA polymerases and TET-enzymes.
A deeper investigation of the chemistry that occurs on the newly discovered epigenetic DNA bases 5-hydroxymethyl-(hmdC), 5-formyl-(fdC), and 5-carboxy-deoxycytidine (cadC) requires chemical tool compounds, which are able to dissect the different potential reaction pathways in cells. Here we report that the 2'-(R)-fluorinated derivatives F-hmdC, F-fdC, and F-cadC, which are resistant to removal by base excision repair, are good substrates for DNA polymerases and TET enzymes. This result shows that the fluorinated compounds are ideal tool substances to investigate potential C-C-bond cleaving reactions in the context of active demethylation.


Oxidative Stress Contributes to Fracture/Cast-Induced Inflammation and Pain in a Rat Model of Complex Regional Pain Syndrome.
Clinical evidence suggests that vitamin C (Vit C) may protect against the development of complex regional pain syndrome (CRPS) after fracture or surgery. Tibia fracture followed by 4 weeks of cast immobilization (fracture/cast) in rats results in nociceptive, vascular, and bone changes resembling clinical CRPS. In this study, fracture/cast rats were treated with the oxidative stress inhibitors Vit C, N-acetyl cysteine, or 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl to examine their effects on CRPS-related nociceptive and vascular changes. Administration of these agents significantly reduced fracture/cast-induced cutaneous allodynia by 64 to 78%, muscle hyperalgesia by 34 to 40%, and hind limb unweighting by 48 to 89%. Treatments with Vit C and N-acetyl cysteine reduced the oxidative stress markers malondialdehyde in the skin, muscle, and sciatic nerve, and lactate in the gastrocnemius muscle of the fracture/cast limb. Furthermore, Vit C treatment inhibited the post-fracture upregulation of substance P and calcitonin gene-related peptide in the sciatic nerve and the increased expression of the pain-related inflammatory mediators, including interleukin (IL)-6, and nerve growth factor in the skin and IL-1β, and IL-6 in the muscle of the post-fracture/cast limb. These data suggest that oxidative stress may contribute to the nociceptive features of the rat CRPS model. Vit C reduced the CRPS-like signs, oxidative stress, and the upregulation of neuropeptide production and inflammatory mediators observed after tibia fracture and casting in rats. Limiting oxidative stress by use of Vit C or alternative strategies could reduce the risk of developing CRPS after surgery or other forms of trauma.


[Study of the effect of microconcentrations of glucose on the biosynthesis of penicillin].
A method of "acute" experiments with significant dilution of the fermentation broth is proposed for studying the effect of easily assimilable substrates on growth of the culture and production of the antibiotic by it. The effect of microconcentrations of glucose on the parameters of the process kinetics was studied with respect to penicillin. The specific effect of microconcentrations of glucose on the specific rate of the culture growth and productivity was noted.


Virtual reality pain control during burn wound debridement of combat-related burn injuries using robot-like arm mounted VR goggles.
This is the first controlled study to explore whether adjunctive immersive virtual reality (VR) can reduce excessive pain of soldiers with combat-related burn injuries during wound debridement. Patients were US soldiers burned in combat attacks involving explosive devices in Iraq or Afghanistan. During the same wound care session using a within-subject experimental design, 12 patients received half of their severe burn wound cleaning procedure (~6 minutes) with standard of care pharmacologies and half while in VR (treatment order randomized). Three 0 to 10 Graphic Rating Scale pain scores for each of the treatment conditions served as the primary variables. Patients reported significantly less pain when distracted with VR. "Worst pain" (pain intensity) dropped from 6.25 of 10 to 4.50 of 10. "Pain unpleasantness" ratings dropped from "moderate" (6.25 of 10) to "mild" (2.83 of 10). "Time spent thinking about pain" dropped from 76% during no VR to 22% during VR. Patients rated "no VR" as "no fun at all" (<1 of 10) and rated VR as "pretty fun" (7.5 of 10). Follow-up analyses showed VR was especially effective for the six patients who scored 7 of 10 or higher (severe to excruciating) on the "worst pain" (pain intensity) ratings. These preliminary results provide the first evidence from a controlled study that adjunctive immersive VR reduced pain of patients with combat-related burn injuries during severe burn wound debridement. Pain reduction during VR was greatest in patients with the highest pain during no VR. These patients were the first to use a unique custom robot-like arm mounted VR goggle system.


Presynaptic mechanism underlying cAMP-induced synaptic potentiation in medial prefrontal cortex pyramidal neurons.
cAMP, a classic second messenger, has been proposed recently to participate in regulating prefrontal cortical cognitive functions, yet little is known about how it does so. In this study, we used forskolin, an adenylyl cyclase activator, to examine the effects of cAMP on excitatory synaptic transmission in the medial prefrontal cortex (mPFC) using whole-cell patch-clamp recordings from visually identified layer II-III or V pyramidal cells in vitro. We found that bath application of forskolin significantly increased the amplitude of excitatory postsynaptic currents (EPSCs) in a concentration- and age-dependent manner. This enhancement was completely abolished by coapplication of cAMP-dependent protein kinase (PKA) inhibitor and p42/p44 mitogen-activated protein kinase (MAPK) kinase inhibitor, but not application of either drug alone. The membrane-permeable cAMP analog adenosine 3',5'-cyclic monophosphorothioate, Sp-isomer, triethylammonium salt, or activation of beta-adrenergic receptor by isoproterenol mimicked the effect of forskolin to potentiate EPSCs. However, neither exchange protein activated by cAMP (Epac) inhibitor brefeldin A nor hyperpolarization and cyclic nucleotide-activated channel blocker 4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride (ZD7288) affected forskolin response. The augmentation of EPSCs by forskolin was accompanied by a reduction of the synaptic failure rate, coefficient of variation and paired-pulse ratio of EPSCs, and an increase in release probability and number of releasable synaptic vesicles. Forskolin also significantly increased the frequency of miniature EPSCs without altering their amplitude distribution. These results indicate that cAMP acts presynaptically to elicit a synaptic potentiation on the layer V pyramidal neurons of mPFC through converging activation of PKA and p42/p44 MAPK signaling pathways.


Echocardiographic and clinical predictors of cardiac amyloidosis: limitations of apical sparing.
The accuracy of an apical-sparing strain pattern on transthoracic echocardiography (TTE) for predicting cardiac amyloidosis (CA) has varied in prior studies depending on the underlying cohort. We sought to evaluate the performance of apical sparing and other TTE strain findings to screen for CA in an unselected population and determine the frequency that patients with echocardiographic concern for CA undergo evaluation for amyloidosis in clinical practice. As strain is routinely performed at our institution on all clinical TTEs, we identified all TTEs performed from 2016 through 2019 with reported concern for CA or apical sparing. We determined the performance characteristics for echocardiographic strain findings in discriminating CA including apical sparing, the ejection fraction to global longitudinal strain ratio (EF/GLS), and the septal apical-septal basal ratio (SA/SB); other clinical predictors of confirmed CA; and predictors of patients who underwent complete evaluation for CA. CA was confirmed by endomyocardial biopsy or diagnostic cardiac imaging. A total of 547 TTEs, representing 451 patients, reported concern for CA and had adequate strain for analysis. A total of 111 patients underwent complete evaluation for amyloidosis with 100 patients undergoing complete cardiac evaluation for CA. In those 100 patients, multivariable predictors of confirmed CA were age [odds ratio (OR) 3.37 per 5 years], a visual apical-sparing pattern (OR 10.85), and left ventricular ejection fraction (LVEF)/GLS > 4.1 (OR 35.37). CA was less likely in those with coronary artery disease (OR 0.04), hypertension (OR 0.18), and increased systolic blood pressure (OR 0.60 per 5 mm Hg increase). SA/SB [area under the curve (AUC) 0.72, 95% confidence interval (CI) 0.60-0.84] and LVEF/GLS (AUC 0.72, 95% CI 0.60-0.84) both had improved discrimination for CA compared with the apical-sparing ratio (AUC 0.66, 95% CI 0.54-0.79). Many patients with suggestive TTE findings did not receive an evaluation for amyloidosis. Complete evaluation was more likely with Caucasian race (OR 2.1), increased septal thickness (OR 1.4), increased body mass index (OR 1.2), and if the report specifically stated 'amyloid' (OR 1.9). Evaluations were less likely in patients with comorbidities. While hypertension reduced the likelihood of evaluating for CA, 34% of patients with CA had hypertension (>130/80 mm Hg) at time of diagnosis. In a broad population of patients undergoing TTE, apical sparing on strain imaging increased the likelihood of CA diagnosis but with modest sensitivity and specificity. GLS/EF ratio may be a more reliable tool to screen for CA. The low rate of complete evaluation in patients with concerning TTE findings indicates a strong need for practice improvement and enhanced disease awareness.


Personalized Statin Therapy and Coronary Atherosclerotic Plaque Burden in Asymptomatic Low/Intermediate-Risk Individuals.
Current guidelines for the primary prevention of atherosclerotic cardiovascular disease are based on the estimation of a predicted 10-year cardiovascular disease risk and the average relative risk reduction estimates from statin trials. In the clinical setting, however, decision-making is better informed by the expected benefit for the individual patient, which is typically lacking. Consequently, a personalized statin benefit approach based on absolute risk reduction over 10 years (ARR10 benefit threshold ≥2.3%) has been proposed as a novel approach. However, how this benefit threshold relates with coronary plaque burden in asymptomatic individuals with low/intermediate cardiovascular disease risk is unknown. In this study, we compared the predicted ARR10 obtained in each individual with plaque burden detected by coronary computed tomography angiography. Plaque burden (segment volume score, segment stenosis score, and segment involvement score) was assessed in prospectively recruited asymptomatic subjects (n = 70; 52% male; median age 56 years [interquartile range 51-64 years]) with low/intermediate Framingham risk score (< 20%). The expected ARR10 with statin in the entire cohort was 2.7% (1.5-4.6%) with a corresponding number needed to treat over 10 years of 36 (22-63). In subjects with an ARR10 benefit threshold ≥2.3% (vs. < 2.3%), plaque burden was significantly higher (p = 0.02). These findings suggest that individuals with higher coronary plaque burden are more likely to get greater benefit from statin therapy even among asymptomatic individuals with low cardiovascular risk.


Exploring expressivity and emotion with artificial voice and speech technologies.
Emotion in audio-voice signals, as synthesized by text-to-speech (TTS) technologies, was investigated to formulate a theory of expression for user interface design. Emotional parameters were specified with markup tags, and the resulting audio was further modulated with post-processing techniques. Software was then developed to link a selected TTS synthesizer with an automatic speech recognition (ASR) engine, producing a chatbot that could speak and listen. Using these two artificial voice subsystems, investigators explored both artistic and psychological implications of artificial speech emotion. Goals of the investigation were interdisciplinary, with interest in musical composition, augmentative and alternative communication (AAC), commercial voice announcement applications, human-computer interaction (HCI), and artificial intelligence (AI). The work-in-progress points towards an emerging interdisciplinary ontology for artificial voices. As one study output, HCI tools are proposed for future collaboration.


The quality of the psychotherapeutic process in brain-injured patients.
This paper reviews the various mental processes which occur in patients with organic brain damage and the changes to which these patients are subjected. At the early stages directly following injury, it is necessary to restructure the personality and help it emerge from the chaotic state characterizing this phase. Later treatment concentrates on giving meaning to the different object relationships and the dialectic between self-representation and object representation. Special stress is put on the therapist's role as a receptacle for the aggressive contents which the patient transfers to him and on the necessity, on he therapist's part, to master his own counter-transference reactions and to present an identification model permitting the restoration of the patient's inner world. The psychotherapeutic model is based on the already existing models in other area of mental pathology, which have been developed in recent years, in particular in the theory of narcissism and object relations.


Modulation of platelet responses to collagen by Clq receptors.
We recently described specific binding sites for Clq on human blood platelets that cross-react with antibodies against Clq receptors (ClqR) on lymphoblastoid cells. Inasmuch as Clq inhibits collagen-induced platelet aggregation, we compared the effects of ClqR occupancy by purified Clq, monoclonal (IIl/B5) and polyclonal anti-ClqR antibodies on collagen-induced platelet adhesion, release, and aggregation. Washed platelets in buffered Tyrode's solution containing 2 mM magnesium were preincubated (30 min, 22 degrees C) with antibodies, Clq, or appropriate control buffers and antiserum. Platelet aggregation and release measurements were made using 14C-serotonin-labeled platelets stimulated with type I collagen. Adhesion assays were performed in the presence of magnesium under static conditions at 22 degrees C with 51Cr-labeled platelets and collagen-coated microtiter wells. Concentrations of IIl/B5, polyclonal anti-Clq R antiserum, or Clq causing 82 to 92% (n = 7) inhibition of collagen-induced release and 67 to 98% inhibition of aggregation, failed to inhibit magnesium-dependent platelet adhesion to collagen. Inasmuch as divalent cation-independent platelet-collagen interactions have also been described, further studies were performed to compare the divalent cation requirement of ClqR occupancy by Clq and inhibition of platelet-collagen interactions. Whereas, Clq binding to platelets was divalent cation independent, neither Clq nor anti-ClqR antibodies prevented platelet adhesion to collagen in the presence of EDTA. These data suggest that under defined in vitro conditions, ClqR modulate collagen-induced platelet aggregation and secretion, but not platelet adhesion.


The vascular adventitia: its role in the arterial injury response.
The belief that the adventitia serves only a structural purpose has changed over the last decade. Studies have begun to elucidate the role the adventitia plays in the arterial response to injury. The adventitial fibroblast plays an integral part in the development of neointimal hyperplasia. Adiponectin, an adipokine produced from periadventitial adipose tissue, exhibits numerous vasoprotective properties. Stem cells arise, in part, from the adventitia, and stem cell recruitment into the adventitia from the vasa vasorum has been shown to be important in the development of neointimal hyperplasia. The exact role the vasa vasorum plays in neointimal growth is poorly understood and different studies endorse conflicting viewpoints. Thus, understanding the nuances of adventitial pathophysiology will allow us to better appreciate the mechanisms behind the pathology of neointimal hyperplasia. This review will summarize recent findings on the active role the adventitia plays toward the development of neointimal hyperplasia.


Arrhythmogenic right ventricular cardiomyopathy/dysplasia mimicking rape homicide: a case report.
Arrhythmogenic right ventricular cardiomyopathy (ARVC), also known as arrhythmogenic right ventricular dysplasia, is a known cause of sudden unexplained death in young, otherwise healthy adults. In the forensic setting, several cases of fatal ARVC have been reported, mostly occurring during physical exercise. However, a very few cases present where the death scene is mistaken for a homicide. We report here the case of a 23-year-old woman, found dead, lying in the snow on an isolated property. The woman's genitals were exposed, with her trousers down over her thighs. Rape homicide was strongly suspected, but autopsy findings proved otherwise.


Thrombotic risk determined by rare and common SERPINA1 variants in a population-based cohort study.
Severe alpha-1-antitrypsin deficiency (AATD), phenotype PiZZ, was associated with venous thromboembolism (VTE) in a case-control study. This study aimed to determine the genetic variation in the SERPINA1 gene and a possible thrombotic risk of these variants in a population-based cohort study. The coding sequence of SERPINA1 was analyzed for the Z (rs28929474), S (rs17580), and other qualifying variants in 28,794 subjects without previous VTE (born 1923-1950, 60% women), who participated in the Malmö Diet and Cancer study (1991-1996). Individuals were followed from baseline until the first event of VTE, death, or 2018. Resequencing the coding sequence of SERPINA1 identified 84 variants in the total study population, 21 synonymous, 62 missense, and 1 loss-of-function variant. Kaplan-Meier analysis showed that homozygosity for the Z allele increased the risk of VTE whereas heterozygosity showed no effect. The S (rs17580) variant was not associated with VTE. Thirty-one rare variants were qualifying and included in collapsing analysis using the following selection criteria, loss of function, in frame deletion or non-benign (PolyPhen-2) missense variants with minor allele frequency (MAF) <0.1%. Combining the rare qualifying variants with the Z variant showed that carrying two alleles (ZZ or compound heterozygotes) showed increased risk. Cox regression analysis revealed an adjusted hazard ratio of 4.5 (95% confidence interval 2.0-10.0) for combinations of the Z variant and rare qualifying variants. One other variant (rs141620200; MAF = 0.002) showed an increased risk of VTE. The SERPINA1 ZZ genotype and compound heterozygotes for severe AATD are rare but associated with VTE in a population-based Swedish study.


Homelessness and Children's Use of Mental Health Services: A Population-Based Study.
This study examined whether children who become homeless differ from other low-income children in their mental health service use before and after their first homeless episode, and to what extent homelessness is associated with an increased likelihood of mental health service use. Differences between children with and without new onset of sheltered homelessness in the use of mental health services emerged following homelessness and widened over time. Sheltered homelessness and foster care placement history were associated with increased odds of receiving inpatient and ambulatory mental health services. Findings underscore the importance of collaborations between homeless assistance, foster care, and mental healthcare in efforts to mitigate family homelessness and collateral needs among homeless children.


The PRK2 kinase is a potential effector target of both Rho and Rac GTPases and regulates actin cytoskeletal organization.
The Ras-related Rho family GTPases mediate signal transduction pathways that regulate a variety of cellular processes. Like Ras, the Rho proteins (which include Rho, Rac, and CDC42) interact directly with protein kinases, which are likely to serve as downstream effector targets of the activated GTPase. Activated RhoA has recently been reported to interact directly with several protein kinases, p120 PKN, p150 ROK alpha and -beta, p160 ROCK, and p164 Rho kinase. Here, we describe the purification of a novel Rho-associated kinase, p140, which appears to be the major Rho-associated kinase activity in most tissues. Peptide microsequencing revealed that p140 is probably identical to the previously reported PRK2 kinase, a close relative of PKN. However, unlike the previously described Rho-binding kinases, which are Rho specific, p140 associates with Rac as well as Rho. Moreover, the interaction of p140 with Rho in vitro is nucleotide independent, whereas the interaction with Rac is completely GTP dependent. The association of p140 with either GTPase promotes kinase activity substantially, and expression of a kinase-deficient form of p140 in microinjected fibroblasts disrupts actin stress fibers. These results indicate that p140 may be a shared kinase target of both Rho and Rac GTPases that mediates their effects on rearrangements of the actin cytoskeleton.


Current research on the immunomodulatory effect of allogeneic blood transfusion.
This review summarizes three aspects of current research on the immunomodulatory effect of allogeneic transfusion. Representatives of three laboratories-each of which is actively engaged in research on transfusion-induced immunomodulation-summarize their current investigative approach. First, current animal models of transfusion-induced immunomodulation are presented and research on the tumor growth-promoting effect of allogeneic transfusion is described. Second, mechanisms underlying an immunomodulatory effect of transfusion are summarized and experiments on the induction of transplant tolerance by selective introduction of donor-type MHC antigens is presented. Third, the potential clinical impact of increased infection and tumor recurrence resulting from transfusion-induced immunomodulation is assessed. The potential role of donor-derived hematopoietic stem cells is presented as an area of future investigation in the area of transfusion-induced immunomodulation.


A porphyrin pathway impairment is responsible for the phenotype of a dominant disease lesion mimic mutant of maize.
The maize lesion mimic gene Les22 is defined by dominant mutations and characterized by the production of minute necrotic spots on leaves in a developmentally specified and light-dependent manner. Phenotypically, Les22 lesions resemble those that are triggered during a hypersensitive disease resistance response of plants to pathogens. We have cloned Les22 by using a Mutator-tagging technique. It encodes uroporphyrinogen decarboxylase (UROD), a key enzyme in the biosynthetic pathway of chlorophyll and heme in plants. Urod mutations in humans are also dominant and cause the metabolic disorder porphyria, which manifests itself as light-induced skin morbidity resulting from an excessive accumulation of photoexcitable uroporphyrin. The phenotypic and genetic similarities between porphyria and Les22 along with our observation that Les22 is also associated with an accumulation of uroporphyrin revealed what appears to be a case of natural porphyria in plants.


Gene expression profiling of Arabidopsis meiocytes.
Meiosis is a special type of cell division present in all organisms that reproduce by sexual reproduction. It ensures the transition between the sporophytic and gametophytic state and allows gamete production through meiotic recombination and chromosome number reduction. In this paper, we describe a technique for the isolation of Arabidopsis thaliana male meiocytes. From this cellular material, it was then possible to develop large-scale transcriptome studies using CATMA microarrays and thus to obtain an overview of genes expressed during Arabidopsis meiosis. The expression profiles were studied with either stringent statistical criteria or by performing clustering. Both methods resulted in gene clusters enriched in meiosis-specific genes (from 14- to 55-fold). Analysis of these data provided a unique set of genes that will be pivotal to further analysis aimed at understanding the meiotic process.


Disentangling the pathways of land use impacts on the functional structure of fish assemblages in Amazon streams.
Agricultural land use is a primary driver of environmental impacts on streams. However, the causal processes that shape these impacts operate through multiple pathways and at several spatial scales. This complexity undermines the development of more effective management approaches, and illustrates the need for more in-depth studies to assess the mechanisms that determine changes in stream biodiversity. Here we present results of the most comprehensive multi-scale assessment of the biological condition of streams in the Amazon to date, examining functional responses of fish assemblages to land use. We sampled fish assemblages from two large human-modified regions, and characterized stream conditions by physical habitat attributes and key landscape-change variables, including density of road crossings (i.e. riverscape fragmentation), deforestation, and agricultural intensification. Fish species were functionally characterized using ecomorphological traits describing feeding, locomotion, and habitat preferences, and these traits were used to derive indices that quantitatively describe the functional structure of the assemblages. Using structural equation modeling, we disentangled multiple drivers operating at different spatial scales, identifying causal pathways that significantly affect stream condition and the structure of the fish assemblages. Deforestation at catchment and riparian network scales altered the channel morphology and the stream bottom structure, changing the functional identity of assemblages. Local deforestation reduced the functional evenness of assemblages (i.e. increased dominance of specific trait combinations) mediated by expansion of aquatic vegetation cover. Riverscape fragmentation reduced functional richness, evenness and divergence, suggesting a trend toward functional homogenization and a reduced range of ecological niches within assemblages following the loss of regional connectivity. These results underscore the often-unrecognized importance of different land use changes, each of which can have marked effects on stream biodiversity. We draw on the relationships observed herein to suggest priorities for the improved management of stream systems in the multiple-use landscapes that predominate in human-modified tropical forests.


Expression of cell cycle regulatory genes in chronic myelogenous leukemia.
Cell cycle regulatory genes are frequently altered in a variety of malignancies. The structure and pattern of expression of eight genes involved in cell division cycle control were studied in leukemic cell samples prepared from bone marrow of patients affected by chronic myelogenous leukemia. Ten cell preparations were obtained from patients in the chronic phase, five from those in myeloid blast crisis and five from those in the lymphoid acute phase. Moreover, bone marrow CD34+ cells, purified from healthy subjects and patients with chronic myelogenous leukemia (both during chronic and acute phases), were analyzed. The investigated genes were RB1, p53 and six cyclin-dependent kinase inhibitor genes (p15INK4B, p16INK4A, p18INK4C, p21WAF1/CIP1, p27Kip1, p57Kip2). We found that none of these genes is structurally altered in either the chronic or acute phases, with the single exception of the p16INK4A gene, which was homozygously deleted in 1 case of lymphoid evolution. p57Kip2 expression is down-regulated during the evolution towards the blast crisis both in malignant and CD34+ cells. In addition, a significant up-regulation of p15INK4B gene expression is observable during the development of the acute phase of malignancy. The transcriptional modulation of some cyclin-dependent kinase inhibitors might contribute to the fatal blast crisis of chronic myelogenous leukemia.


Implementation of Intravenous Drip Infusion Therapy with Peripheral Venous Catheters and the Incidence of Related Complications in Home-Based Medical Care Settings in Japan.
Home-based medical care is rapidly expanding in Japanese health care settings. We aimed to clarify the implementation status of drip injection with peripheral venous catheters (PVCs) and the incidence of related complications. We investigated the number of patients who required intravenous drip infusion therapy at home. We also examined the incidence rate of PVC-related complications and their statistical correlation with patients' characteristics. Of 139 patients, 30 (21.6%) received intravenous drip infusion therapy through PVCs at home. Patients' activities of daily living (bed-ridden) and the presence of underlying disease (terminal cancer) were significantly correlated with the requirement for drip infusion therapy (p < 0.0001 and p < 0.0001, respectively). A high incidence of PVC-related complications (75%: 15 out of 20 patients) was observed. More than 50% of patients experienced multiple needling due to difficulty in securing venous access. This is the first report to reveal the relatively high incidence of PVC-related complications in home-based medical care settings. Safer vascular devises should be incorporated for more stable intervention.


Automated behavioural analysis reveals the basic behavioural repertoire of the urochordate Ciona intestinalis.
Quantitative analysis of animal behaviour in model organisms is becoming an increasingly essential approach for tackling the great challenge of understanding how activity in the brain gives rise to behaviour. Here we used automated image-based tracking to extract behavioural features from an organism of great importance in understanding the evolution of chordates, the free-swimming larval form of the tunicate Ciona intestinalis, which has a compact and fully mapped nervous system composed of only 231 neurons. We analysed hundreds of videos of larvae and we extracted basic geometric and physical descriptors of larval behaviour. Importantly, we used machine learning methods to create an objective ontology of behaviours for C. intestinalis larvae. We identified eleven behavioural modes using agglomerative clustering. Using our pipeline for quantitative behavioural analysis, we demonstrate that C. intestinalis larvae exhibit sensory arousal and thigmotaxis. Notably, the anxiotropic drug modafinil modulates thigmotactic behaviour. Furthermore, we tested the robustness of the larval behavioural repertoire by comparing different rearing conditions, ages and group sizes. This study shows that C. intestinalis larval behaviour can be broken down to a set of stereotyped behaviours that are used to different extents in a context-dependent manner.