The responses of oligodendrocyte precursor cells, astrocytes and microglia to a cortical stab injury, in the brain.
The cortical stab injury has been widely used for biochemical analysis of molecular changes following CNS injury. However, the cellular responses to this injury have not been accurately quantified. In order to provide a baseline for biochemical studies and future experiments on the manipulation of the CNS injury response we have undertaken a quantitative analysis of this injury. The proliferative and reactive responses of oligodendrocyte precursor cells, astrocytes and microglia were measured, using antibodies to NG2, glial fibrillary acidic protein (GFAP) and the cd11-b clone OX-42 to characterise these cell types at 2, 4, 7 and 14 days post-injury. Oligodendrocyte precursors and microglia proliferated rapidly during the first week, mostly within 0.3 mm of the lesion. Of the dividing cells over 60% were oligodendrocyte precursor cells with microglia making up the balance of the dividing cells. Minimal numbers of astrocytes divided in response to the lesion. Large cells with one or two short processes that were both NG2 and OX-42 positive were identified very close to the lesion at 2 and 4 days post-lesion but not thereafter. They are likely to be blood-derived cells that express NG2 or have ingested it. NG2 immunohistochemistry and platelet-derived growth factor alpha receptor (PDGFalpha-R) in situ hybridisation on neighbouring sections was performed. In the lesioned area only 12% of NG2 positive (+ive) cells were PDGFalpha-R +ive (a ratio of 1:8 for PDGFalpha-R +ive cells: NG2 +ive cells) compared with 33% in the unlesioned cortex and an almost 100% overlap in the spinal cord.


CD72 is a pan-tumor antigen associated to pediatric acute leukemia.
In the development of novel immunotherapeutic approaches, the step of target identification is a challenging process, because it aims at identifying robust tumor-associated antigens (TAAs) specific for the pathological population and causing no off-target effects. Here we propose CD72 as a novel and robust TAA for pediatric acute leukemias. We provided an outline of CD72 expression assessed by flow cytometry on a variety of cancer cell lines and primary samples, including normal bone marrow (BM) samples and hematopoietic stem and progenitor cells. We analyzed CD 72 expression on a cohort of 495 pathological pediatric BM aspirates, including: 215 B-cell precursor acute lymphoblastic leukemias (BCP-ALL), 156 acute myeloid leukemias (AMLs), 88 T-lineage ALLs or lymphoblastic lymphomas with BM infiltration, 13 B-lineage lymphoblastic lymphomas with BM infiltration, 9 myelodysplastic syndromes with increased blasts (5%-9% blasts on BM: MDS-IB1) and 14 non-hematopoietic solid tumors infiltrating BM. Results showed that CD72 is highly expressed in almost all BCP-ALL and the majority of AML at diagnosis, including BCP-ALL cases characterized by CD19 loss. These findings support a potential role for advanced diagnostics and novel immunotherapy approaches, providing a pan-ALL and AML target.


Comparative Effects of Different Light Sources on the Production of Key Secondary Metabolites in Plants In Vitro Cultures.
Plant secondary metabolites are known to have a variety of biological activities beneficial to human health. They are becoming more popular as a result of their unique features and account for a major portion of the pharmacological industry. However, obtaining secondary metabolites directly from wild plants has substantial drawbacks, such as taking a long time, posing a risk of species extinction owing to over-exploitation, and producing a limited quantity. Thus, there is a paradigm shift towards the employment of plant tissue culture techniques for the production of key secondary metabolites in vitro. Elicitation appears to be a viable method for increasing phytochemical content and improving the quality of medicinal plants and fruits and vegetables. In vitro culture elicitation activates the plant's defense response and increases the synthesis of secondary metabolites in larger proportions, which are helpful for therapeutic purposes. In this respect, light has emerged as a unique and efficient elicitor for enhancing the in vitro production of pharmacologically important secondary metabolites. Various types of light (UV, fluorescent, and LEDs) have been found as elicitors of secondary metabolites, which are described in this review.


Ammonia and pH inhibition in anaerobic treatment of wastewaters, Part II: Model development.
A new model to account for the influences of pH and ammonia on methane production in the anaerobic treatment of wastewaters is presented. The model is developed and evaluated by using two different sets of experimental data obtained using seeds from two different full-scale industrial anaerobic reactors. One of the seeds was obtained from an expanded granular sludge-blanket (EGSB) reactor treating a corn processing waste. The other seed was obtained from an upflow anaerobic sludge-blanket reactor (UASB) treating waste from a potato chips production plant. Model development is based on the data collected at four different pH values (6.8, 7.4, 7.8, 8.4) and with six different TAN (Total Ammonia Nitrogen) values (262mg/L (control), 1000, 1500, 2000, 2500, 3000). The proposed model has a considerably more convenient form compared to other models that have been used in the literature for similar purposes. For example, the model facilitates the calculation of quantities such as the optimal pH as a function of TAN concentration, or the TAN concentration leading to 50% inhibition (TAN50) as a function of pH. High levels of correlations were achieved by the application of the proposed model to the experimental data obtained during our studies.


Simultaneous Denoising and Localization Network for Photoacoustic Target Localization.
A significant research problem of recent interest is the localization of targets like vessels, surgical needles, and tumors in photoacoustic (PA) images.To achieve accurate localization, a high photoacoustic signal-to-noise ratio (SNR) is required. However, this is not guaranteed for deep targets, as optical scattering causes an exponential decay in optical fluence with respect to tissue depth. To address this, we develop a novel deep learning method designed to explicitly exhibit robustness to noise present in photoacoustic radio-frequency (RF) data. More precisely, we describe and evaluate a deep neural network architecture consisting of a shared encoder and two parallel decoders. One decoder extracts the target coordinates from the input RF data while the other boosts the SNR and estimates clean RF data. The joint optimization of the shared encoder and dual decoders lends significant noise robustness to the features extracted by the encoder, which in turn enables the network to contain detailed information about deep targets that may be obscured by noise. Additional custom layers and newly proposed regularizers in the training loss function (designed based on observed RF data signal and noise behavior) serve to increase the SNR in the cleaned RF output and improve model performance. To account for depth-dependent strong optical scattering, our network was trained with simulated photoacoustic datasets of targets embedded at different depths inside tissue media of different scattering levels. The network trained on this novel dataset accurately locates targets in experimental PA data that is clinically relevant with respect to the localization of vessels, needles, or brachytherapy seeds. We verify the merits of the proposed architecture by outperforming the state of the art on both simulated and experimental datasets.


Scopolamine causes delirium-like brain network dysfunction and reversible cognitive impairment without neuronal loss.
Delirium is a severe acute neuropsychiatric syndrome that commonly occurs in the elderly and is considered an independent risk factor for later dementia. However, given its inherent complexity, few animal models of delirium have been established and the mechanism underlying the onset of delirium remains elusive. Here, we conducted a comparison of three mouse models of delirium induced by clinically relevant risk factors, including anesthesia with surgery (AS), systemic inflammation, and neurotransmission modulation. We found that both bacterial lipopolysaccharide (LPS) and cholinergic receptor antagonist scopolamine (Scop) induction reduced neuronal activities in the delirium-related brain network, with the latter presenting a similar pattern of reduction as found in delirium patients. Consistently, Scop injection resulted in reversible cognitive impairment with hyperactive behavior. No loss of cholinergic neurons was found with treatment, but hippocampal synaptic functions were affected. These findings provide further clues regarding the mechanism underlying delirium onset and demonstrate the successful application of the Scop injection model in mimicking delirium-like phenotypes in mice.


Quick diagnosis units--an effective alternative to hospitalization for diagnostic workup: a systematic review.
This era of healthcare reform emphasizes improving value of care. Inpatient admissions for diagnostic evaluation put economic pressure on an already strained healthcare system. We conducted a systematic review of effectiveness of quick diagnosis units (QDUs), an established outpatient model for early diagnostic workups in Europe. We searched MEDLINE and Embase for studies that focused on implementation of quick/rapid diagnosis units, with relevant Medical Subject Headings terms and keywords. Of 2047 studies, we selected 13 for full-text screening and bibliography review. Of these, 5 studies included at least 2 primary outcomes of interest and were included in our review. These units functioned as outpatient clinics, staffed by internists, nurses, and clerical staff, with expedited scheduling of outpatient diagnostic tests. Our primary outcome measures were final diagnosis, the mean time to final diagnosis, inpatient bed-days saved per patient, and costs saved per patient. We also studied discharge disposition, care preferences, and safety data. About 18% to 30% of patients were diagnosed with malignancy, with an average time to diagnosis of 6 to 11 days. Inpatient bed-days saved per patient ranged from 4.5 to 7. Savings from fixed costs of hospitalization ranged from $2336(€1764) to $3304(€2514) for each patient enrolled in the protocol. The QDU model was preferred by 88% of patients, and patient satisfaction rates were 95% to 97%. QDUs seem an effective and cost-saving alternative to inpatient hospitalization, and appear to be a safe approach for diagnostic workup of potentially severe diseases in select patient populations, although there are limited safety data available.


Gastric emptying of solids after Roux-en-Y gastrectomy: is extragastric vagal innervation important?
Truncal vagotomy, antrectomy with Roux-en-Y gastrojejunostomy is frequently complicated by poor gastric emptying. The aim of this study was to determine whether the vagal denervation beyond the stomach (extragastric vagal denervation) contributes to this delay in gastric emptying. Three groups of six female mongrel dogs underwent antrectomy, Roux-en-Y gastrojejunostomy, and either truncal vagotomy, gastric vagotomy, or no vagotomy. After operation each dog underwent two separate radioisotope gastric-emptying studies with a small volume solid meal. The dogs were scanned by a gamma-camera continuously for 4 hours, and images of the gastric remnant were summed by computer every 6 minutes. Radioactivity in the gastric remnant region of interest was compared to overall activity and plotted as a function of time. The half-emptying times (X +/- SEM) for each group were truncal vagotomy 164 +/- 24 minutes, gastric vagotomy 79 +/- 23 minutes, and no vagotomy 117 +/- 10 minutes. Animals with a gastric vagotomy had a significantly faster rate of gastric emptying than did those with truncal vagotomy (p = 0.02, Scheffe's test). Therefore the extragastric vagal innervation appears to play a role in determining the rate of emptying of solids after antrectomy and Roux-en-Y gastrojejunostomy.


Sunitinib acts primarily on tumor endothelium rather than tumor cells to inhibit the growth of renal cell carcinoma.
Sunitinib is a broad-spectrum small-molecule inhibitor of receptor tyrosine kinases (RTK) that serves as the present standard of care for first-line therapy of advanced clear cell renal cell carcinoma (ccRCC). A full understanding of the targets and mechanism of action of sunitinib in ccRCC treatment remains incomplete. In this study, we evaluated several tumor cell and endothelial targets of sunitinib and investigated which RTK(s) may specifically contribute to its therapeutic effects. Microarray expression profiling and Western blot analysis revealed that among known sunitinib targets, only platelet-derived growth factor receptor-beta and vascular endothelial growth factor receptor-2 (VEGFR-2) were overexpressed in ccRCCs relative to normal tissues. Sunitinib was unable to inhibit survival or proliferation of ccRCC cells at pharmacologically relevant concentrations (approximately 0.1 micromol/L) that inhibit RTK targets. In contrast, sunitinib inhibited endothelial cell proliferation and motility at the same concentrations by suppressing VEGFR-2 signaling. Moreover, whereas sunitinib inhibited the growth of ccRCC xenograft tumors and decreased tumor microvessel density as soon as 12 hours after treatment, sunitinib showed no significant effects on tumor cell proliferation or apoptosis up to 72 hours after treatment. Our findings indicate that sunitinib inhibits ccRCC growth primarily through an antiangiogenic mechanism and not through direct targeting of ccRCC tumor cells.


Underutilized time for health education of hospitalized patients.
Our anecdotal observations suggested that hospitalized patients had considerable time during the day when they were not occupied with diagnostic testing or other activities. Accordingly, we sought to quantify the fraction of free time that hospitalized patients had available to participate in health educational activities and if and when during their hospitalization they were interested in participating in these activities and felt capable of doing so. From June 25 through August 15, 2005, randomly selected consenting patients admitted to the Internal Medicine service of an academic safety-net hospital became subjects of a time-motion study that was conducted from admission to discharge or to hospital Day 6. Another randomly selected group received daily surveys, and patients in a third group were interviewed on Day 2 or 3 of their hospitalization. Time-motion data, surveys, and interviews were obtained from 13, 138, and 15 patients, respectively. Of the 316 patient-hours observed, 71% were classified as downtime. More than 80% of patients either "strongly agreed" or "agreed" that they were interested in and capable of being educated on all days of their hospitalization. The themes generated from the interviews included the desire to know more about self-management, prevention of disease recurrence or progression, and their primary illness. Adult medical inpatients have considerable time and strong motivation to participate in health educational activities throughout their hospitalization. The current structure for educating hospitalized patients should be supplemented to take these findings into account.


Partner sensitivity to communication behavior of young children with developmental disabilities.
Aspects of partner sensitivity to communication behaviors of 24 presymbolic children with developmental disabilities were examined. The children were grouped according to their movement abilities (normal vs. abnormal patterns) and communication status (intentional vs. preintentional). Participating communication partners were those with whom the children interacted on a regular basis and included their mothers, early childhood special educators, and speech-language pathologists. Procedures were developed whereby the partners served as informants in order to provide information regarding (a) recognition of the children's communicative cues and (b) consistency of cue recognition and descriptions across partners. Results indicated wide individual variability in the partners' basic recognition abilities as well as their consistency with each other. Further, the observed variations could not be attributed to the children's movement and communication abilities. It was concluded that sensitivity, as measured in the present investigation, was highly partner-child specific, with some children likely to be exposed to more optimal interactions than others.


Cost-effective therapy remission assessment in lymphoma patients using 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography: is an end of treatment exam necessary in all patients?
The aim of this study was to evaluate the necessity of 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) after end of treatment in lymphoma patients who had an interim FDG-PET/CT. In 38 patients with Hodgkin's disease (HD) and 30 patients with non-Hodgkin's lymphoma (NHL) interim PET/CT (intPET) after two to four cycles of chemotherapy and PET/CT after completion of first-line treatment (endPET) were carried out. Cost reduction was retrospectively calculated for the potentially superfluous endPET examinations. In 31 (82%) HD patients, intPET demonstrated complete remission (CR) which was still present on endPET. The remaining seven HD patients (18%) had partial remission (PR) on intPET. For NHL, 22 (73%) patients had CR on intPET analysis which was still present on endPET. In the remaining eight NHL patients, intPET revealed PR in seven and stable disease in one patient. None of all intPET complete responders progressed until the end of therapy. Thus, of the 196 PET/CT's carried out in our study population, 53 endPET's (27.0%) were carried out in interim complete responders. End-treatment PET/CT is unnecessary if intPET shows CR and the clinical course is uncomplicated. An imaging cost reduction of 27% in our study population could have been achieved by omitting end of treatment FDG-PET/CT in interim complete responders.


Molecular weight of Escherichia coli beta-galactosidase in concentrated solutions of guanidine hydrochloride.
The molecular weight of Escherichia coli beta-galactosidase was determined in 6m- and 8m-guanidine hydrochloride by meniscus-depletion sedimentation equilibrium, sedimentation velocity and viscosity. Sedimentation equilibrium revealed heterogeneity with the smallest component having a molecular weight of about 50000. At lower speeds, the apparent weight-average molecular weight is about 80000. By use of a calculation based on an empirical correlation for proteins that are random coils in 6m-guanidine hydrochloride, sedimentation velocity gave a molecular weight of 91000, and the intrinsic viscosity indicated a viscosity-average molecular weight of 84000. Heating in 6m-guanidine hydrochloride lowered the viscosity of beta-galactosidase in a variable manner.


(GT)N dinucleotide repeat polymorphism of haem oxygenase-1 promotor region is not associated with inflammatory bowel disease risk or disease course.
Haem oxygenase-1 (HO-1) up-regulation was suggested to reduce mucosal tissue damage in inflammatory bowel disease (IBD) and an up-regulation of HO-1 expression in patients with Crohn's disease (CD) and ulcerative colitis (UC) was demonstrated. A HO-1 gene promoter microsatellite (GT)(n) dinucleotide repeat polymorphism was associated with regulation of HO-1 in response to inflammatory stimuli. We therefore hypothesized that IBD patients might segregate into phenotypes with high or low HO-1 inducibility. Ethylenediamine tetraacetic acid blood samples were obtained from 179 CD patients, 110 UC patients and 56 control patients without inflammation. Genomic DNA was purified and the 5'-flanking region of the HO-1 gene containing the (GT)(n) dinucleotide repeat was amplified. Polymerase chain reaction (PCR) products were purified and the length of the PCR fragments was analysed. The number of (GT)(n) repeats in the population studied ranged from 13 to 42. The distribution of the allele frequencies was comparable in patients and controls for both the short and the long alleles. The frequencies of short-, middle- and long-sized alleles were not changed among the groups studied. No correlation was found between IBD and microsatellite instability detected in five individals. Our data indicate that (GT)(n) dinucleotide repeats of the HO-1 promotor region have no significance for the pathophysiology and disease course of IBD.


Cell specific regulation of NaV1.7 activity and trafficking in rat nodose ganglia neurons.
The voltage-gated sodium NaV1.7 channel sets the threshold for electrogenesis. Mutations in the gene encoding human NaV1.7 (SCN9A) cause painful neuropathies or pain insensitivity. In dorsal root ganglion (DRG) neurons, activity and trafficking of NaV1.7 are regulated by the auxiliary collapsin response mediator protein 2 (CRMP2). Specifically, preventing addition of a small ubiquitin-like modifier (SUMO), by the E2 SUMO-conjugating enzyme Ubc9, at lysine-374 (K374) of CRMP2 reduces NaV1.7 channel trafficking and activity. We previously identified a small molecule, designated 194, that prevented CRMP2 SUMOylation by Ubc9 to reduce NaV1.7 surface expression and currents, leading to a reduction in spinal nociceptive transmission, and culminating in normalization of mechanical allodynia in models of neuropathic pain. In this study, we investigated whether NaV1.7 control via CRMP2-SUMOylation is conserved in nodose ganglion (NG) neurons. This study was motivated by our desire to develop 194 as a safe, non-opioid substitute for persistent pain, which led us to wonder how 194 would impact NaV1.7 in NG neurons, which are responsible for driving the cough reflex. We found functioning NaV1.7 channels in NG neurons; however, they were resistant to downregulation via either CRMP2 knockdown or pharmacological inhibition of CRMP2 SUMOylation by 194. CRMP2 SUMOylation and interaction with NaV1.7 was consered in NG neurons but the endocytic machinery was deficient in the endocytic adaptor protein Numb. Overexpression of Numb rescued CRMP2-dependent regulation on NaV1.7, rendering NG neurons sensitive to 194. Altogether, these data point at the existence of cell-specific mechanisms regulating NaV1.7 trafficking.


A case study of psychodynamic group psychotherapy for bipolar disorder.
This study examines the effectiveness of long-term outpatient psychodynamic group psychotherapy for individuals with bipolar disorder who may have psychiatric comorbidity. The Integrative Outpatient Model (IOM) includes psychoeducation regarding illness, illness management, and exploration of dynamic and interpersonal issues. At one-year follow up, group members had significantly less depressive symptomatology and were less likely to be in a mood episode, compared to controls. There were no between-group differences in manic symptoms or global assessments of functioning. For group-treated patients, the number of days well per week improved significantly; there were no significant improvements in the control group. This pilot study indicates that psychodynamic group psychotherapy is feasible as a component of treatment for bipolar disorder diagnoses. The results suggest benefits on depressive, but not manic symptoms. The 73% retention rate suggests that further study of this treatment is warranted, especially in the cases of patients for whom pharmacotherapy alone is not sufficient.


The Questionnaire of Smoking Urges is sensitive to abstinence and exposure to smoking-related cues.
The Questionnaire of Smoking Urges (QSU) was designed to measure cravings elicited by abstinence from cigarette smoking. In the present study, the sensitivity of the QSU both to brief periods of abstinence and to exposure to smoking-related cues was investigated. A progressive ratio (PR) operant procedure was also employed, in which behaviour was maintained either by primary reinforcement (puffs on a cigarette) or by secondary reinforcement (tokens exchanged later for puffs on a cigarette) in separate experiments. Dependent smokers, who were not abstinent or who were abstinent for either 2 or 4 h, were tested in both a cue-rich and a no-cue environment. The results indicated that the QSU was sensitive both to brief periods of abstinence and to exposure to smoking-related cues, but the effect of smoking-related cues on QSU scores was maximal in non-abstinent smokers. In contrast, neither abstinence nor exposure to smoking-related cues significantly influenced the number of reinforcers earned, or the number of responses made, in either PR task. However, there was a significant interaction between gender and degree of abstinence on PR performance under primary reinforcement, and correlations between PR and QSU measures that were dependent on a complex interaction between the presence/absence of smoking-related cues and the type of reinforcer used. These results suggest that the QSU is sensitive to subtle influences on subjective urges to smoke in dependent smokers and, although PR measures are relatively insensitive to these influences, there is some evidence that PR performance is related to subjective measures of the urge to smoke.


Hip arthritis presenting as knee pain.
A 68-year-old man with a history of left total knee replacement presented to his general practitioner with left knee pain. He reported pain onset after a fall in the garden. An X-ray of the knee was arranged but showed no abnormality to explain the pain. He was treated with simple analgesia. However, he reattended with the same knee pain. A further X-ray of the knee was requested, but again showed no abnormality. On his fourth presentation in 6 months, a further musculoskeletal examination was undertaken. This time the hip was also examined and showed that maximal pain was in fact on rotation of the hip joint. A subsequent X-ray of the hip showed severe osteoarthritis of the left hip with complete joint space loss and flattening of the femoral head. The patient was referred to an orthopaedic surgeon for a left hip replacement.


Purification and Characterization of S-Adenosyl-L-Methionine: Desoxyhemigossypol-6-O-Methyltransferase from Cotton Plants. An Enzyme Capable of Methylating the Defense Terpenoids of Cotton.
Cotton contains a unique group of terpenoids including desoxyhemigossypol, hemigossypol, gossypol, hemigossypolone, and the heliocides that are part of the plant's defense system against pathogenic fungi and insects. Desoxyhemigossypol is a key intermediate in the biosynthesis of these compounds. We have isolated, purified, and characterized from cotton stele tissue infected with Verticillium dahliae a methyltransferase (S-adenosyl-L-Met: desoxyhemigossypol-6-O-methyltransferase) that specifically methylates the 6-position of desoxyhemigossypol to form desoxyhemigossypol-6-methyl ether with a K(m) value of 4.5 µM for desoxyhemigossypol and a K(cat)/K(m) of 5.08 x 10(4) s(-1) (mol/L)(-1). The molecular mass of the native enzyme is 81.4 kD and is dissociated into two subunits of 41.2 kD on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels. The enzymatic reaction does not require Mg(+2) and is inhibited 98% with 10 mM p-chloromercuribenzoate. Desoxyhemigossypol-6-methyl ether leads to the biosynthesis of methylated hemigossypol, gossypol, hemigossypolone, and the heliocides, which lowers their effectiveness as phytoalexins and insecticides.


Human liver N-acetylglucosamine-6-sulphate sulphatase. Purification and characterization.
Human N-acetylglucosamine-6-sulphate sulphatase was purified at least 50,000-fold to homogeneity in 78% yield from liver with a simple three-step four-column procedure, which consists of a concanavalin A-Sepharose/Blue A-agarose coupled step, chromatofocusing and Cu2+-chelating Sepharose chromatography. In all, four forms were isolated and partially characterized. Forms A and B, both with a pI greater than 9.5 and representing 30% and 60% respectively of the recovered enzyme activity, were separated by hydroxyapatite chromatography of the enzyme preparation obtained from the Cu2+-chelating Sepharose step. Both forms A and B had native molecular masses of 75 kDa. When analysed by SDS/polyacrylamide-gel electrophoresis, form A consists of a single polypeptide of molecular mass 78 kDa, whereas form B contained 48 kDa and 32 kDa polypeptide subunits. Neither form A nor form B was taken up from the culture medium into cultured human skin fibroblasts. The two other forms (C and D), with pI values of 5.8 and 5.4 respectively, represented approx. 7% and 3% of the total recovered enzyme activity. The native molecular masses of forms C and D were 94 kDa and approx. 75 kDa respectively. Form C contained three polypeptides with molecular masses of 48, 45 and 32 kDa. N-Acetylglucosamine-6-sulphate sulphatase activity was measured with a radiolabelled disaccharide substrate derived from heparin. The development of this substrate enabled the isolation and characterization of N-acetylglucosamine-6-sulphate sulphatase to proceed efficiently. Forms A, B and C had pH optima of 5.0, Km values of 11.7, 14.2 and 11.1 microM respectively and Vmax. values of 105, 60 and 53 nmol/min per mg of protein respectively. The molecular basis of the multiple forms of this sulphatase is not known. It is postulated that the differences in structure and properties of the four enzyme forms are due to differences in the state of processing of a large subunit.


Procedural and interpretive skills of medical students: experiences and attitudes of fourth-year students.
Recent data do not exist regarding fourth-year medical students' performance of and attitudes toward procedural and interpretive skills, and how these differ from third-year students'. Cross-sectional survey conducted in February 2006 of 122 fourth-year students from seven U.S. medical schools, compared with their responses in summer 2005. Students estimated their cumulative performance of 22 skills and reported self-confidence and perceived importance using a five-point Likert-type scale. The response rate was 79% (96/122). A majority reported never having performed cardioversion, thoracentesis, cardiopulmonary resuscitation, blood culture, purified protein derivative placement, or paracentesis. One fifth of students had never performed peripheral intravenous catheter insertion, phlebotomy, or arterial blood sampling. Students reported increased cumulative performance of 17 skills, increased self-confidence in five skills, and decreased perceived importance in three skills (two-sided P < .05). A majority of fourth-year medical students still have never performed important procedures, and a substantial minority have not performed basic procedures.


Pension funds warrant a financial manager's review.
A hospital's pension funds may be managed by its finance department, another internal department, or an outside investment adviser. Whatever the arrangement, healthcare financial managers should be involved in the decision between internal and external management of pension funds. A financial manager also can play a prominent role in developing a pension fund policy that balances a hospital's commitment to legal requirements, pension plan goals, and communication with investment advisers.


Nanomechanical mapping helps explain differences in outcomes of eye microsurgery: A comparative study of macular pathologies.
Many ocular diseases are associated with an alteration of the mechanical and the material properties of the eye. These mechanically-related diseases include macular hole and pucker, two ocular conditions due to the presence of abnormal physical tractions acting on the retina. A complete relief of these tractions can be obtained through a challenging microsurgical procedure, which requires the mechanical peeling of the internal limiting membrane of the retina (ILM). In this paper, we provide the first comparative study of the nanoscale morphological and mechanical properties of the ILM in macular hole and macular pucker. Our nanoscale elastic measurements unveil a different bio-mechanical response of the ILM in the two pathologies, which correlates well to significant differences occurring during microsurgery. The results here presented pave the way to the development of novel dedicated microsurgical protocols based on the material ILM properties in macular hole or pucker. Moreover, they contribute to clarify why, despite a common aetiology, a patient might develop one disease or the other, an issue which is still debated in literature.


Impact of Colonoscopy Bowel Preparation Quality on Follow-up Interval Recommendations for Average-risk Patients With Normal Screening Colonoscopies: Data From the New Hampshire Colonoscopy Registry.
National guidelines for colonoscopy screening and surveillance assume adequate bowel preparation. We used New Hampshire Colonoscopy Registry (NHCR) data to investigate the influence of bowel preparation quality on endoscopist recommendations for follow-up intervals in average-risk patients following normal screening colonoscopies. The analysis included 9170 normal screening colonoscopies performed on average risk individuals aged 50 and above between February 2005 and September 2013. The NHCR Procedure Form instructs endoscopists to score based on the worst prepped segment after clearing all colon segments, using the following categories: excellent (essentially 100% visualization), good (very unlikely to impair visualization), fair (possibly impairing visualization), and poor (definitely impairing visualization). We categorized examinations into 3 preparation groups: optimal (excellent/good) (n=8453), fair (n=598), and poor (n=119). Recommendations other than 10 years for examinations with optimal preparation, and >1 year for examinations with poor preparation, were considered nonadherent. Of all examinations, 6.2% overall received nonadherent recommendations, including 5% of examinations with optimal preparation and 89.9% of examinations with poor preparation. Of normal examinations with fair preparation, 20.7% of recommendations were for an interval <10 years. Among those examinations with fair preparation, shorter-interval recommendations were associated with female sex, former/nonsmokers, and endoscopists with adenoma detection rate ≥20%. In 8453 colonoscopies with optimal preparations, most recommendations (95%) were guideline-adherent. No guideline recommendation currently exists for fair preparation, but in this investigation into community practice, the majority of the fair preparation group received 10-year follow-up recommendations. A strikingly high proportion of examinations with poor preparation received a follow-up recommendation greater than the 1-year guideline recommendation. Provider education is needed to ensure that patients with poor bowel preparation are followed appropriately to reduce the risk of missing important lesions.


A complete genetic linkage map and QTL analyses for bast fibre quality traits, yield and yield components in jute (Corchorus olitorius L.).
We report the first complete microsatellite genetic map of jute (Corchorus olitorius L.; 2n = 2x = 14) using an F6 recombinant inbred population. Of the 403 microsatellite markers screened, 82 were mapped on the seven linkage groups (LGs) that covered a total genetic distance of 799.9 cM, with an average marker interval of 10.7 cM. LG5 had the longest and LG7 the shortest genetic lengths, whereas LG1 had the maximum and LG7 the minimum number of markers. Segregation distortion of microsatellite loci was high (61%), with the majority of them (76%) skewed towards the female parent. Genomewide non-parametric single-marker analysis in combination with multiple quantitative trait loci (QTL)-models (MQM) mapping detected 26 definitive QTLs for bast fibre quality, yield and yield-related traits. These were unevenly distributed on six LGs, as colocalized clusters, at genomic sectors marked by 15 microsatellite loci. LG1 was the QTL-richest map sector, with the densest colocalized clusters of QTLs governing fibre yield, yield-related traits and tensile strength. Expectedly, favorable QTLs were derived from the desirable parents, except for nearly all of those of fibre fineness, which might be due to the creation of new gene combinations. Our results will be a good starting point for further genome analyses in jute.


Two dominant inhibitory mutants of p21ras interfere with insulin-induced gene expression.
Insulin induces a rapid activation of p21ras in NIH 3T3 and Chinese hamster ovary cells that overexpress the insulin receptor. Previously, we suggested that p21ras may mediate insulin-induced gene expression. To test such a function of p21ras more directly, we studied the effect of different dominant inhibitory mutants of p21ras on the induction of gene expression in response to insulin. We transfected a collagenase promoter-chloramphenicol acetyltransferase (CAT) gene or a fos promoter-luciferase gene into NIH 3T3 cells that overexpressed the insulin receptor. The activities of both promoters were strongly induced after treatment with insulin. This induction could be suppressed by cotransfection of two inhibitory mutant ras genes, H-ras(Asn-17) or H-ras(Leu-61,Ser-186). In particular, insulin-induced activation of the fos promoter was inhibited completely by H-ras(Asn-17). These results show that p21ras functions as an intermediate in the insulin signal transduction route leading to the induction of gene expression.


Sclera color enhances gaze perception in humans.
Gaze perception is an essential behavior that allows individuals to determine where others are directing their attention but we know relatively little about the ways in which eye morphology influences it. We therefore tested whether eyes with conspicuous morphology have evolved to facilitate gaze perception. During a visual search task, we recorded the eye movements of human participants (Homo sapiens) as they searched for faces with directed gaze within arrays of faces with averted gaze or the reverse; the faces were large and upright, small and upright, or large and inverted. The faces had sclera that were conspicuous (white or colored lighter than the iris color) or inconspicuous (colored the same or darker than the iris color). We found that participants were fastest and most accurate in finding the faces with conspicuous sclera versus inconspicuous sclera. Our results demonstrate that eyes with conspicuous morphology facilitate gaze perception in humans.


Short term outcome and predictors of survival among birth asphyxiated babies at a tertiary academic hospital in Enugu, South East, Nigeria.
Birth asphyxia (BA) is a preventable cause of cerebral insults in newborns. It is associated with high morbidity and mortality. Of the 120 million babies born in third world countries annually, it is estimated that about 3.6 million will develop BA. We aimed to determine the short term outcome and predictors of survival among birth asphyxiated babies using Apgar score. This study was carried out in the Newborn Unit of Enugu State University Teaching Hospital. In-hospital deliveries (Inborn) and those from other centers (Out-born) with one minute Apgar score ≤ 6 were included. Interviewer administered questionnaire was used to collect data from caregivers. Information sought included gestational age (GA), birth weight (BW), Apgar score, place of delivery and outcome. Data was analyzed using SPSS. Bivariate and multivariate logistic regressions were done. Of the 150 neonates, 61.3% survived. Majority of the dead were out-born. The difference was statistically significant (p < 0.001). The inborn were about 1.2 times (AOR = 1.22; 95% CI: 1.06-1.78) more likely to survive BA. Among low birth weights (LBWs), 73.9% died, 23.7% of normal weights and 14.3% of macrosomics died. The difference was statistically significant (p < 0.001). The normal weights were about 2 (AOR = 2.23, 95% CI: 1.76-6.25) and the macrosomics about 5 times more likely to survive BA than LBWs. Regarding GA, 78.8%, 17.2% and 18.2% of the pre-terms, term and post-dates died respectively. The difference was statistically significant (p < 0.001). The term babies were about 11 (AOR = 11.27; 95% CI: 4.02-31-56) and post-dates about 9 (AOR = 8.79; 95% CI: 1.43-54.04) times more likely to survive BA than preterms. Other significant factors were degree of asphyxia (p = 0.003), and parental education (p < 0.001). BW, GA, degree of asphyxia, place of delivery and parental education all predicts survival among birth asphyxiated newborns.


A general framework to quantify and compare ecological impacts under temporal dynamics.
Biodiversity is diminishing at alarming rates due to multiple anthropogenic drivers. To mitigate these drivers, their impacts must be quantified accurately and comparably across drivers. To enable that, we present a generally applicable framework introducing fundamental principles of ecological impact quantification, including the quantification of interactions between multiple drivers. The framework contrasts biodiversity variables in impacted against those in unimpacted or other reference situations while accounting for their temporal dynamics through modelling. Properly accounting for temporal dynamics reduces biases in impact quantification and comparison. The framework addresses key questions around ecological impacts in global change science, namely, how to compare impacts under temporal dynamics across stressors, how to account for stressor interactions in such comparisons, and how to compare the success of management actions over time.


Dietary regulation of intestinal brush-border sugar and amino acid transport in carnivores.
The ability of omnivores and herbivores to regulate reversibly their intestinal brush-border nutrient transporters is functionally related to the unpredictably variable composition of their natural diets. To determine whether carnivores are able similarly to regulate the activities of their intestinal nutrient transporters, we fed to three species of vertebrates that are carnivorous as adults (cats, mink, and leopard frogs) diets with either at least 50% digestible carbohydrate or with negligible carbohydrate levels. Rates of transport for the sugars glucose and fructose and the amino acids (AAs) aspartate, leucine, lysine, and proline were measured throughout the intestine (only proline and glucose in the frogs) by an in vitro everted-sleeve method. Although all three species consume much carbohydrate during early development, only the mink was able to regulate sugar transporter activity in response to changes in levels of dietary carbohydrate. In contrast, the sugar transporters of the cat were unresponsive to varying carbohydrate levels, and long-term feeding of a high-carbohydrate diet caused down-regulation of sugar transport in frogs. Of the three species, only the mink is a member of a family that includes omnivorous species, whereas all members of the families to which the cat and frog belong are carnivorous as adults. All three species were able to regulate rates of AA transport, though the patterns and magnitude of the responses differed between species as well as between AAs, suggesting independent regulation of some AA transporters.(ABSTRACT TRUNCATED AT 250 WORDS)


Recovery of photodegraded rhodamine 6g in ester-containing polymer matrices.
Self-healing, rhodamine 6g, dye-doped polymers are reported. The amplified spontaneous emission (ASE) photodegrades after repeated exposure to 532 nm laser light at 10 Hz. Recovery of the ASE signal is observed in dye-doped thermoplastic polyurethane and glycol-modified poly(ethylene terephthalate); both polymers contain repeating ester groups in their backbone. The polymer ester groups are hypothesized to mediate the full recovery of rhodamine 6g from a photodegraded state. A small amount of ASE recovery after photodegradation is observed in dye-doped poly(vinyl alcohol), >98% hydrolyzed, where conversion of rhodamine 6g from a long-lived dark state contributes to the majority of the increased ASE signal in poly(vinyl alcohol) while small amounts of recovery from interactions with residual acetate groups are also possible.


Defining treatment refractoriness in schizophrenia.
The criteria for treatment refractoriness for the use of clozapine are necessarily set at a high level because of the potential risk of agranulocytosis with this treatment. However, a more liberal definition should be considered to better appreciate the limitations of current therapies and prepare for switching to the next generation of clozapine-like drugs that do not cause agranulocytosis. It is suggested that failure of therapy to bring about the best premorbid level of functioning be considered as a starting point for treatment-resistance.


Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients.
To evaluate the prophylactic use of enteral fluconazole to prevent invasive candidal infections in critically ill surgical patients. Invasive fungal infections are increasingly common in the critically ill, especially in surgical patients. Although fungal prophylaxis has been proven effective in certain high-risk patients such as bone marrow transplant patients, few studies have focused on surgical patients and prevention of fungal infection. The authors conducted a prospective, randomized, placebo-controlled trial in a single-center, tertiary care surgical intensive care unit (ICU). A total of 260 critically ill surgical patients with a length of ICU stay of at least 3 days were randomly assigned to receive either enteral fluconazole 400 mg or placebo per day during their stay in the surgical ICU at Johns Hopkins Hospital. The primary end point was the time to occurrence of fungal infection during the surgical ICU stay, with planned secondary analysis of patients "on-therapy" and alternate definitions of fungal infections. In a time-to-event analysis, the risk of candidal infection in patients receiving fluconazole was significantly less than the risk in patients receiving placebo. After adjusting for potentially confounding effects of the Acute Physiology and Chronic Health Evaluation (APACHE) III score, days to first dose, and fungal colonization at enrollment, the risk of fungal infection was reduced by 55% in the fluconazole group. No difference in death rate was observed between patients receiving fluconazole and those receiving placebo. Enteral fluconazole safely and effectively decreased the incidence of fungal infections in high-risk, critically ill surgical patients.


Multidetector CT of the postoperative colon: review of normal appearances and common complications.
If not properly recognized, the normal postoperative appearance of the pelvis following colorectal surgery can be misinterpreted as disease, including infection or recurrent tumor. However, multidetector computed tomography (CT) with the supplemental use of multiplanar reformation clearly demonstrates the expected postoperative anatomic changes in this setting. The high-resolution images achievable with multidetector CT enable the radiologist to play an important role in the postoperative assessment of patients following colon surgery. Whenever possible, the radiologist should be aware of the specific indication for the study, the type of surgery that was performed (ranging from segmental bowel excision to more extensive radical resection), and what anastomoses were created. This knowledge, as well as familiarity with the normal multidetector CT appearances of various postoperative complications, is critical for prompt diagnosis and appropriate management of these complications and for better differentiation of complications from normal findings.


Dynamical plasma response during driven magnetic reconnection.
Direct measurements of a collisionless current channel during driven magnetic reconnection are obtained for the first time on the Versatile Toroidal Facility. The size of the diffusion region is found to scale with the electron drift orbit width, independent of the ion mass and plasma density. Based on experimental observations, analytic expressions governing the dynamical evolution of the current profile and the formation of the electrostatic potential that develops in response to the externally imposed reconnection drive are established. This time response is closely linked to the presence of ion polarization currents.


Effects of glenohumeral rotations and translations on supraspinatus tendon morphology.
The purpose of this study was to evaluate the effects of glenohumeral rotations and humeral head translations on supraspinatus tendon morphology. A convenience sample of cadaver shoulders was used to measure supraspinatus tendon shape and dimensions from MRI images. Epidemiological evidence has indicated that shoulder elevation and external rotation may be risk factors for rotator cuff tendon pathology, but little is known about how these postures affect tendon morphology. Measurements of supraspinatus tendon morphology were made from three-dimensional reconstructions based on T2-weighted fast spin-echo magnetic resonance images. Seven cadaver arms were imaged at neutral, 45 degrees external and 45 degrees internal rotations at 0 degrees, 30 degrees, and 60 degrees of glenohumeral abduction. Measurements of the anterior, middle, and posterior portions of the tendon were made using ANALYZE software. The supraspinatus tendon was twisted at the muscle-tendon junction of the middle and posterior portions in 45 degrees external and 45 degrees internal axial rotations of the humerus, especially over 30 degrees of abduction. Abduction over 30 degrees shortened the entire supraspinatus tendon. External and internal rotation motions elongated the anterior and posterior portions, respectively. Arm posture affects morphology of the supraspinatus tendon. The results support the epidemiologic evidence linking external rotation and abduction to supraspinatus tendon disorders.


Genome-scale metabolic modelling of SARS-CoV-2 in cancer cells reveals an increased shift to glycolytic energy production.
Cancer is considered a high-risk condition for severe illness resulting from COVID-19. The interaction between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and human metabolism is key to elucidating the risk posed by COVID-19 for cancer patients and identifying effective treatments, yet it is largely uncharacterised on a mechanistic level. We present a genome-scale map of short-term metabolic alterations triggered by SARS-CoV-2 infection of cancer cells. Through transcriptomic- and proteomic-informed genome-scale metabolic modelling, we characterise the role of RNA and fatty acid biosynthesis in conjunction with a rewiring in energy production pathways and enhanced cytokine secretion. These findings link together complementary aspects of viral invasion of cancer cells, while providing mechanistic insights that can inform the development of treatment strategies.


Incidence of heart failure in 2,737 older persons with and without diabetes mellitus.
To investigate in older persons whether diabetes mellitus is an independent risk factor for congestive heart failure (CHF). A prospective study was performed in 2,737 older persons investigating the incidence of new CHF in persons with and without diabetes mellitus. A long-term health-care facility. Eight hundred sixty-five men and 1,872 women, with a mean age of 81+/-9 years. At 43-month follow-up, new CHF developed in 272 of 690 persons (39%) with diabetes mellitus and in 467 of 2,047 persons (23%) without diabetes mellitus (p < 0.0001). Cox regression analysis showed that age (p = 0.0001, risk ratio = 1.048), hypertension (p = 0.0001, risk ratio = 2.524), coronary artery disease (p = 0.0001, risk ratio = 4.008), male gender (p = 0.0001, risk ratio = 1.399), and diabetes mellitus (p = 0.0003, risk ratio = 1.337) were significantly positively associated with the time to the development of CHF. Older persons with diabetes mellitus had a 1.3 times higher chance of developing CHF than those without diabetes mellitus after controlling the confounding effects of other prognostic variables.


Depression often undertreated in HIV/AIDS patients, psychiatrist warns.
The clinic for HIV-related concerns at Toronto's Mount Sinai Hospital marked its 10th anniversary with the 2nd Dr. Stephen Woo Memorials Lecture, and Cornell University psychiatrist John Markowitz used the opportunity to report that depression tends to be undertreated in patients with HIV/AIDS. However, symptoms often melt away with proper treatment. He said depression used to be considered a logical and inevitable consequence of the virus, but these views have been changing.


Cigarette smoke-induced Egr-1 represses T beta R-II expression in human skin dermal fibroblasts.
Tobacco smoking is one of the many factors that contribute to premature skin aging, but the exact mechanism by which smoking induces facial wrinkling is still poorly understood. To investigate the regulatory potential of early growth response-1 (Egr-1) on the premature skin aging by smoking, this study examined the hypothesis that cigarette smoke-induced Egr-1 represses T beta R-II expression in human skin dermal fibroblasts (HSDFs). The protein and mRNA expressions of Egr-1 and T beta R-II were detected using Western blot and real-time RTPCR in HSDFs after exposure to cigarette smoke extract (CSE). Egr-1 and T beta R-II promoter activities were analyzed in CSE-exposed fibroblasts using luciferase assay. T beta R-II promoter activity was also evaluated in HSDFs to be transfected with Egr-1 overexpression vector. To investigative Egr-1-specific effects, we utilized Egr-1 small interfering RNA (siRNA) to inhibit Egr-1 expression. The expressions of Egr-1 protein and mRNA were increased in a time and dose-dependent manner. CSE also induced Egr-1 at the transcription level. Egr-1 was induced though phosphorylation of Erk1/2 after CSE exposure in HSDFs. We also observed the immunostained Egr-1 proteins were mainly localized from the cytoplasm to the nucleus after CSE treatment by immunocytochemical analyzes. Furthermore, T beta R-II protein and mRNA levels were decreased in a dose-dependent manner by CSE and T beta R-II promoter activity was significantly repressed by CSE. HSDFs transfected with Egr-1 overexpression vector showed significantly reduced T beta R-II promoter activity. In addition, T beta R-II mRNA levels were upregulated in HSDFs transfected with Egr-1 siRNA, suggesting that T beta R-II expressional downregulation by CSE is induced via an Egr-1-dependent mechanism. This study suggests that the downregulation of T beta R-II expression by cigarette smoke-induced Egr-1 may contribute to smoking-induced premature skin aging.


Associations between TNFSF4 and TRAF1-C5 gene polymorphisms and systemic lupus erythematosus: a meta-analysis.
The aim of this study was to determine whether tumor necrosis factor superfamily 4 (TNFSF4) and TNF receptor-associated factor 1-complement 5 (TRAF1-C5) polymorphisms confer susceptibility to systemic lupus erythematosus (SLE). The authors conducted meta-analyses on associations between polymorphisms of the TNFSF4 (rs2205960, rs1234315, rs10489265) and TRAF1-C5 (rs10818488, rs3761847) genes and SLE susceptibility, using fixed and random effects models. A total of 21 comparative studies were included in this meta-analysis; meta-analysis showed an association between the minor allele of rs2205960 of TNFSF4 and SLE in all study subjects (odds ratio [OR]=1.356, 95% confidence interval [CI]=1.275-1.442, p<1.0×10(-9)). Meta-analysis revealed an association between the minor alleles of rs1234315 and rs10489265 of TNFSF4 and SLE in Asians (OR=1.366, 95% CI=1.295-1.440, p<1.0×10(-9); OR=1.463, 95% CI=1.208-1.771, p=9.7×10(-5)). The minor allele of rs10818488 of TRAF1-C5 was found to be significantly associated with SLE in Europeans (OR=1.210, 95% CI=1.115-1.313, p=5.0×10(-6)). The association p-values remained significant after multiple corrections. This meta-analysis confirms that TNFSF4 polymorphisms are associated with susceptibility to SLE in Asians and Europeans. An association was found between the rs10818488 polymorphism of TRAF1-C5 and susceptibility to SLE in Europeans.


[Complex assessment of the proliferation of epidermal and tumor cells in malignant skin lymphoma].
Keratinocyte and tumor cell proliferative activities in skin biopsy specimens of 49 patients with various forms of malignant lymphomas of the skin are analyzed. The mitotic index and 3H thymidine labeled nuclei index in the epidermal and tumor proliferate cells were under study; cytophotometry of the tumor cell DNA was carried out, as well as analysis of correlations of the examined parameters and the patients' life spans. The findings evidence an increase of the keratinocyte proliferative activity in epidermotropic malignant lymphomas of the skin, this pointing to the significance of epidermal abnormalities in the development of this condition.


Methods for detection of GMOs in food and feed.
This paper reviews aspects relevant to detection and quantification of genetically modified (GM) material within the feed/food chain. The GM crop regulatory framework at the international level is evaluated with reference to traceability and labelling. Current analytical methods for the detection, identification, and quantification of transgenic DNA in food and feed are reviewed. These methods include quantitative real-time PCR, multiplex PCR, and multiplex real-time PCR. Particular attention is paid to methods able to identify multiple GM events in a single reaction and to the development of microdevices and microsensors, though they have not been fully validated for application.


Effects of Acute and Chronic Gabapentin Treatment on Cardiovascular Function of Rats.
Gabapentin (GBP), a GABA analogue, is primarily used as an anticonvulsant for the treatment of partial seizures and neuropathic pain. Whereas a majority of the side effects are associated with the nervous system, emerging evidence suggests there is a high risk of heart diseases in patients taking GBP. In the present study, we first used a preclinical model of rats to investigate, firstly, the acute cardiovascular responses to GBP (bolus i.v. injection, 50 mg/kg) and secondly the effects of chronic GBP treatment (i.p. 100 mg/kg/day × 7 days) on cardiovascular function and the myocardial proteome. Under isoflurane anesthesia, rat blood pressure (BP), heart rate (HR), and left ventricular (LV) hemodynamics were measured using Millar pressure transducers. The LV myocardium and brain cortex were analyzed by proteomics, bioinformatics, and western blot to explore the molecular mechanisms underlying GBP-induced cardiac dysfunction. In the first experiment, we found that i.v. GBP significantly decreased BP, HR, maximal LV pressure, and maximal and minimal dP/dt, whereas it increased IRP-AdP/dt, Tau, systolic, diastolic, and cycle durations (* p < 0.05 and ** p < 0.01 vs. baseline; n = 4). In the second experiment, we found that chronic GBP treatment resulted in hypotension, bradycardia, and LV systolic dysfunction, with no change in plasma norepinephrine. In the myocardium, we identified 109 differentially expressed proteins involved in calcium pathways, cholesterol metabolism, and galactose metabolism. Notably, we found that calmodulin, a key protein of intracellular calcium signaling, was significantly upregulated by GBP in the heart but not in the brain. In summary, we found that acute and chronic GBP treatments suppressed cardiovascular function in rats, which is attributed to abnormal calcium signaling in cardiomyocytes. These data reveal a novel side effect of GBP independent of the nervous system, providing important translational evidence to suggest that GBP can evoke adverse cardiovascular events by depression of myocardial function.


Students experience self-esteem improvement during mountaineering.
Despite ample evidence in the literature of the correlation between sports participation in general and self-esteem, there is a dearth of information regarding the probable impact of specific sporting activities on self-concept. We, therefore, sought to assess the effect of mountaineering on self-esteem and its correlates in university students. This longitudinal study recruited 54 students (male 26%, female 74%) from different universities in the capital city of Iran, Tehran. The students participated in a mountaineering program in Mt. Damavand in July 2006. The Rosenberg Self-Esteem Scale (RSES), SF-36, and Hospital Anxiety and Depression Scale (HADS) were completed by all the participants before and after this activity. Their demographic data and mountaineering experience were also collected. Mean RSES after climbing was significantly higher than before the experience (24.78 +/- 2.4 vs. 23.67 +/- 3.3; P = .002). Self-esteem was correlated with bodily pain, and its improvement was correlated with mental health and depression (P < .05). Self-esteem and its improvement were not significantly correlated with age, sex, marital status, prior personal and family history of mountaineering, past history of mountain sickness, and reaching the summit (P > .05). This study showed that participation in a single mountaineering program improved students' sense of self-esteem. We suggest that taking up this activity might have benefits for students with depression.


Telomerase: a key player in the pathogenesis of non-alcoholic fatty liver disease?
Introduction: Telomerase is a basic nuclear protein reverse transcriptase, which plays a key role in maintaining telomere stability, genome integrity, long-term cell activity, and potential continued proliferation.Area covered: This narrative review discusses key research advances involving telomerase in the development and progression of nonalcoholic fatty liver disease (NAFLD). The review evaluates 9a) whether the assessment of telomerase can be used as a noninvasive diagnostic tool; and (b) whether modification of telomerase function might be a useful potential therapeutic target for treatment of NAFLD. Furthermore, the relationship between telomerase and other chronic metabolic diseases is evaluated.Expert opinion: Several experimental and preclinical studies have suggested that telomerase plays an important role in the development of NAFLD. However, further mechanistic studies are needed to prove a causal relationship and to better elucidate whether the measurement of telomerase has utility as a diagnostic tool or whether pharmacological manipulation of telomerase has therapeutic potential in NAFLD treatment.


The mec-4 gene is a member of a family of Caenorhabditis elegans genes that can mutate to induce neuronal degeneration.
Three dominant mutations of mec-4, a gene needed for mechanosensation, cause the touch-receptor neurons of Caenorhabditis elegans to degenerate. With deg-1, another C. elegans gene that can mutate to induce neuronal degeneration and that is similar in sequence, mec-4 defines a new gene family. Cross-hybridizing sequences are detectable in other species, raising the possibility that degenerative conditions in other organisms may be caused by mutations in similar genes. All three dominant mec-4 mutations affect the same amino acid. Effects of amino-acid substitutions at this position suggest that steric hindrance may induce the degenerative state.


Fluoxetine augmentation in bipolar disorder patients on maintenance lithium treatment.
Lithium augmentation during long-term treatment with antidepressants has long been considered an effective therapeutic strategy in the treatment of depressive syndromes. This paper deals with an 'opposite' strategy, i.e. the use of serotonin reuptake inhibitors (SRIs) during maintenance lithium treatment in bipolar disorder (BP) patients who may present a breakthrough depressive syndrome. The study involved 26 patients on maintenance lithium treatment for a mean of 38 months (mean serum lithium level=0.57 mEq/l). Mean fluoxetine dose was 29.3 mg/day for a mean period of 7.36 weeks. Median HDRS scores before and after fluoxetine augmentation were 14 and 6, respectively. The results provide evidence for the efficacy of fluoxetine augmentation in the treatment of breakthrough depressions occurring in bipolar disorder patients during maintenance lithium treatment. The neuropharmacological explanation of the augmentation is not yet well understood, but it is conceivable that the improvement of the depressive symptoms may be related to the increase in serotonergic function provided by combination of the two treatments.


Deterioration of rat liver mitochondria under conditions of metabolite deprivation.
In a previous study [Parce, Cunningham & Waite (1978) Biochemistry 17, 1634-1639] changes in mitochondrial phospholipid metabolism and energy-linked functions were monitored as coupled mitochondria were aged in iso-osmotic sucrose solution at 18 degrees C. The sequence of events that occur in mitochondrial deterioration under the above conditions have been established more completely. Total adenine nucleotides are depleted early in the aging process, and their loss parallels the decline in respiratory control. Related to the loss of total adenine nucleotides is a dramatic decrease in ADP and ATP translocation (uptake). The decline of respiratory control is due primarily to a decrease in State-3 respiration; loss of this respiratory activity can be related to the decline in ADP translocation. Mitochondrial ATPase activity does not increase significantly until State-4 respiration has increased appreciably. At the time of loss of respiratory control the ATPase activity increases to equal the uncoupler-stimulated activity. The H+/O ratio and P/O ratios do not decrease appreciably until respiratory control is lost. Similarly, permeability of the membrane to the passive diffusion of protons increases only after respiratory control is lost. There observations reinforce our earlier conclusion that there are two main phases in mitochondrial aging. The first phase is characterized by loss of the ability to translocate adenine nucleotides. The second phase is characterized by a decline in the ability of the mitochondrion to conserve energy (i.e. maintain a respiration-driven proton gradient) and to synthesize ATP.


Relationship between polymorphism of methylenetetrahydrofolate dehydrogenase and congenital heart defect.
To investigate the relationship between G1958A gene polymorphism of methylenetetrahydrofolate dehydrogenase (MTHFD) and occurrence of congenital heart disease (CHD) in North China. One hundred and ninety-two CHD patients and their parents were included in this study as case group in Liaoning Province by birth defect registration cards, and 124 healthy subjects (age and gender matched) and their parents were simultaneously selected from the same geographic area as control. Their gene polymorphism of MTHFD G1958A locus was examined with PCR-RFLP, and serum folic acid and homocysteine (Hcy) levels were tested with radio-immunoassay and fluorescence polarization immunoassay (FPIA). There existed gene polymorphism at MTHFD G1958A locus in healthy subjects living in North China. The percentages of GG, GA, and AA genotype were 57.98%, 35.57%, and 6.45% respectively, and the A allele frequency was 24.23%, which was significantly different from Western population. No difference was observed when comparing genotype distribution and allele frequency between the case and control groups, so was the result from the comparison between genders. The A allele frequency of arterial septal defect patients' mothers (10.87%) was significantly lower than that of controls (28.15%) (P=0.014), with OR=0.31 (95% CI: 0.09-0.84), and no difference in the other subgroups. The percentage of at least one parent carrying A allele in arterial septal defect subgroup (43.48%) was significantly lower than that in controls (69.64%) (P=0.017), with OR=0.34 (95% CI: 0.12-0.92). The analysis of genetic transmission indicated that there was no transmission disequillibrium in CHD nuclear families. Their serum folic acid level was significantly higher than that of controls (P=0.000), and Hcy level of the former was higher than that of the latter with no statistical significance (P>0.05). Serum Hcy and folic acid levels of mothers with gene mutation were lower than those of mothers with no mutation. No significant difference of genotype distribution and allele frequency existed between CHD patients and healthy population. MTHFD G1958A mutation in parents (particularly in mother) can decrease the risk of arterial septal defect in offspring. The possible mechanism of protection might be mutation, which can increase MTHFD enzyme activity, folic acid metabolism and homocysteine remethylation, and decrease Hcy level.


Potential clinical efficacy and cost benefit of a transesophageal echocardiography-guided low-molecular-weight heparin (enoxaparin) approach to antithrombotic therapy in patients undergoing immediate cardioversion from atrial fibrillation.
An alternative clinical management strategy and cost analysis model is presented for patients with atrial fibrillation of >2 days' duration who may benefit from immediate cardioversion with self-administered low-molecular-weight heparin (enoxaparin) as a bridge antithrombotic therapy to warfarin, after a negative transesophageal echo-cardiography (TEE) screening for thrombus. Assuming no difference in stroke or bleeding rates, our cost minimization model shows that the TEE-guided enoxaparin treatment costs are $1353 lower per patient than an intravenous unfractionated heparin approach. Sensitivity analyses for stroke and bleeding reveal that the treatment-cost economic dominance of the TEE-guided enoxaparin approach may be enhanced by an expected improvement in clinical outcome.


Silica-based monolithic sensing plates for waveguide-mode sensors.
We developed a monolithic sensing plate for a waveguide-mode sensor. The plate consists of a SiO(2) glass substrate and a thin silicon layer the surface of which is thermally oxidized to form a SiO(2) glass waveguide. We confirmed that the sensing plate is suitable for high-sensitivity detection of molecular adsorption at the waveguide surface. In addition, a significant enhancement of the sensitivity of the sensor was achieved by perforating the waveguide with holes with diameters of a few tens of nanometers by selective etching of latent tracks created by swift heavy-ion irradiation. Possible strategies for optimizing the plate are discussed.


Incorporation of Pt Nanoparticles on the Surface of TeO₂-Branched Porous Si Nanowire Structures for Enhanced Room-Temperature Gas Sensing.
A new gas sensor working in room temperature, which is compatible with silicon fabrication technology is presented. Porous silicon nanowires (NWs) were synthesized by metal-assisted chemical etching method and then TeO₂ NWs branches were attached to their stem by thermal evaporation of Te powders in the presence of air. Afterwards TeO₂ branched porous Si NWs were functionalized by Pt via sputtering followed by low temperature thermal annealing. Scanning electron microscopy, transmission electron microscopy and energy-dispersive X-ray spectroscopy collectively confirmed successful formation of TeO₂ branched porous Si NWs functionalized by Pt nanoparticles. Their gas sensing properties in the presence of CO, C6H6 and C7H8 were tested at room temperature, for Si wafer, pristine porous Si NWs, pristine TeO₂ branched porous Si NWs, and Pt functionalized TeO₂ branched porous Si NWs sensors. Pt functionalized TeO₂ branched porous Si NWs have higher responses to all tested gases than the other sensors. The origin of high response is discussed in detail. This new room temperature gas sensor can open a new aperture for development of gas sensors with minimum energy consumption which are compatible with silicon fabrication technology.


Have there been sustained impacts of the COVID-19 pandemic on trends in smoking prevalence, uptake, quitting, use of treatment, and relapse? A monthly population study in England, 2017-2022.
Studies conducted during the early stages of the pandemic documented mixed changes in smoking behaviour: more smokers quitting successfully but little change in prevalence. This study aimed to examine whether there have been sustained impacts of the COVID-19 pandemic on smoking patterns in England. Data were from 101,960 adults (≥ 18 years) participating in the Smoking Toolkit Study, a monthly representative household survey, between June 2017 and August 2022. Interviews were conducted face-to-face until March 2020 and via telephone thereafter. Generalised additive models estimated associations of the pandemic onset (March 2020) with current smoking, uptake, cessation, quit attempts, and use of support. Models adjusted for seasonality, sociodemographic characteristics, and (where relevant) dependence and tobacco control mass-media expenditure. Before the COVID-19 pandemic, smoking prevalence fell by 5.2% per year; this rate of decline slowed to 0.3% per year during the pandemic (RRΔtrend = 1.06, 95% CI = 1.02, 1.09). This slowing was evident in more but not less advantaged social grades (RRΔtrend = 1.15, 1.08, 1.21; RRΔtrend = 1.00, 0.96, 1.05). There were sustained step-level changes in different age groups: a 34.9% (95% CI = 17.7, 54.7%) increase in smoking prevalence among 18-24-year-olds, indicating a potential rise in uptake, in contrast to a 13.6% (95% CI = 4.4, 21.9%) decrease among 45-65-year-olds. In both age groups, these step-level changes were followed by the pre-pandemic declines stopping, and prevalence remaining flat. There were sustained increases in quitting among past-year smokers, with a 120.4% (95% CI = 79.4, 170.9%) step-level increase in cessation and a 41.7% (95% CI = 29.7, 54.7%) increase in quit attempts. The main limitation was the change in modality of data collection when the pandemic started; while this may have contributed to the step-level changes we observed, it is unlikely to explain changes in the slope of trends. In England, the rate of decline in adult smoking prevalence stagnated during the COVID-19 pandemic through to 2022. At the start of the pandemic, a potential reduction in smoking prevalence among middle-aged adults and increases in quitting among smokers may have been offset by an increase in smoking among young adults. The slowing in the rate of decline was pronounced in more advantaged social grades.


Evaluation of the adaptive speckle suppression filter for coronary optical coherence tomography imaging.
During the last few years, optical coherence tomography (OCT) has demonstrated considerable promise as a method of high-resolution intravascular imaging. The goal of this study was to apply and to test the applicability of the rotating kernel transformation (RKT) technique to the speckle reduction and enhancement of OCT images. The technique is locally adaptive. It is based on sequential application of directional masks and selection of the maximum of all outputs. This method enhances the image features by emphasizing thin edges while suppressing a noisy background. Qualitatively, the RKT algorithm provides noticeable improvement over the original image. All processed images are smoother and have better-defined borders of media, intima, and plaque. The quantitative evaluation of RKT performance showed that in terms of average contrast-to-noise ratio, there is a significant improvement in image quality between original and enhanced images. The RKT image enhancement technique shows great promise in improving OCT images for superior boundary identification.


Unique Eu(II) Coordination Environments with a Janus Cryptand.
Two new Eu(II)-containing cryptates were prepared with a new nitrogenous cryptand functionalized with three benzo groups. The introduction of three aromatic rings into the ligand backbone imparts lopsided geometrical features on the resulting Eu(II) coordination environments. In both complexes, the interactions between Eu and the amines on the aromatic side of the molecule are weaker than those on the nonaromatic side, resulting in one discrete unit with two distinct faces. One of the new complexes is, to the best of our knowledge, the first direct observation of a bis-aquo Eu(II)-containing cryptate with two nonadjacent inner-sphere water molecules. In addition to solid-phase structure, the electronic UV-visible and emission spectra of the new complexes were studied in acetonitrile. Experimental results show that the decreased Lewis basicity of the aromatic face hypsochromically shifts absorbances and emissions from a structurally related compound without the benzo groups.


A case of superficial siderosis ameliorated after closure of dural deficit detected by MRI-CISS (constructive interference in steady state) imaging.
A 64-year-old male developed headache, dizziness, and difficulty hearing, two years after an operation for chronic subdural hematoma due to head injury. These symptoms gradually worsened over the following 15 years. As he showed bloody cerebrospinal fluid (CSF) and marginal hypointensity on the surface of the brain and spinal cord on T2/T2*-weighted MRI, he was diagnosed with superficial siderosis (SS), although the source of the bleeding was unclear and anti-hemorrhagic drugs were ineffective. When he was admitted to our hospital, neurological examination disclosed horizontal gaze-evoked nystagmus, severe bilateral hearing loss, scanning speech, and limb and truncal ataxia. CISS (constructive interference in steady state) MRI detected a dural defect at the Th2-3 level on the anterior side of the spinal canal. On operation, a 2 mm × 6 mm size dural defect with blood clots was found at the Th2-3 level. After closure of the dural defect, bloody CSF became transparent, and his persistent headache, dizziness, and hearing impairment improved. Brain and whole spine MRI, especially CISS imaging, should be considered for detecting the source of bleeding in intractable cases of SS.


Changing the Smoking Trajectory: Evaluating the Impact of School-Based Tobacco Interventions on Changes to Susceptibility to Future Smoking.
School-based programs and policies can reduce student smoking rates. However, their impact on never-smoking students has not been investigated despite the clear transition between non-susceptible, susceptible, and ever tried smoking statuses. The objective of this paper was to examine the longitudinal student-level impact of six changes in school-based tobacco control programs and policies on student transitions in susceptibility to smoking over one year. Two multinomial logistic regression models identified the relative risk of a change in self-reported susceptibility to smoking or in trying a cigarette among never-smoking students in each of the six intervention schools compared to the relative risk among never-smoking students in control schools. Model 1 identified the relative risk of a change in smoking susceptibility status among baseline non-susceptible never smoking students, while Model 2 identified the relative risk of a change in smoking susceptibility status among baseline susceptible never smoking students. Students at some intervention schools were at increased risk of becoming susceptible to or trying a cigarette at one year follow-up. Intervention studies should examine changes to susceptibility to future smoking when evaluating impact to ensure that school-based tobacco control programs and policies do not negatively change the risk status of never-smoking students.


Cardioprotective Potential of Iron Chelators and Prochelators.
Heart is a particularly sensitive organ to iron overload and cardiomyopathy due to the excessive cardiac iron deposition causes most deaths in disorders such as beta-thalassemia major. Free or loosely bound iron ions readily cycle between ferrous and ferric states and catalyze Haber-Weiss reaction that yields highly reactive and toxic hydroxyl radicals. Treatment with iron chelators (desferrioxamine, deferiprone, and deferasirox) substantially improved cardiovascular morbidity and mortality in iron overloaded patients. Furthermore, iron chelators have been studied in various cardiovascular disorders with known or presumed oxidative stress roles (e.g., ischemia/reperfusion injury) also in patients with normal body iron contents. The pharmacodynamic and pharmacokinetic properties of these chelators are critical for effective therapy. For example, the widely clinically used but hydrophilic chelator desferrioxamine suffers from poor plasma membrane permeability, which means that high and clinically unachievable concentrations/doses must be employed to obtain cardioprotection. Therefore, small-molecular and lipophilic chelators with oral availability are more suitable for this purpose, particularly in states without systemic iron overload. Apart from agents that are already used in clinical practice, aroylhydrazone iron chelators, namely salicylaldehyde isonicotinoyl hydrazone (SIH), have provided promising results. However, the use of classical iron-chelating agents is associated with a risk of toxicity due to indiscriminate iron depletion. Recent studies have therefore focused on "masked" prochelators that have little or no affinity for iron until site-specific activation by reactive oxygen species.


Applying Bioinformatic Platforms, In Vitro, and In Vivo Functional Assays in the Characterization of Genetic Variants in the GH/IGF Pathway Affecting Growth and Development.
Heritability accounts for over 80% of adult human height, indicating that genetic variability is the main determinant of stature. The rapid technological development of Next-Generation Sequencing (NGS), particularly Whole Exome Sequencing (WES), has resulted in the characterization of several genetic conditions affecting growth and development. The greatest challenge of NGS remains the high number of candidate variants identified. In silico bioinformatic tools represent the first approach for classifying these variants. However, solving the complicated problem of variant interpretation requires the use of experimental approaches such as in vitro and, when needed, in vivo functional assays. In this review, we will discuss a rational approach to apply to the gene variants identified in children with growth and developmental defects including: (i) bioinformatic tools; (ii) in silico modeling tools; (iii) in vitro functional assays; and (iv) the development of in vivo models. While bioinformatic tools are useful for a preliminary selection of potentially pathogenic variants, in vitro-and sometimes also in vivo-functional assays are further required to unequivocally determine the pathogenicity of a novel genetic variant. This long, time-consuming, and expensive process is the only scientifically proven method to determine causality between a genetic variant and a human genetic disease.


[Enteral tube feeding of patients with duodenal ulcer before and after the operation].
The results of treatment of 947 patients, suffering duodenal ulcer stenosis, to whom the enteral nutrition (EN) probe was introduced before and after operation, were analyzed. There was noted a positive impact of EN on metabolic processes, water-electrolyte balance, lowering of operative-anesthesiologic risk, lethality and postoperative complications rate, securing possibility of operative intervention performance in a planned order.


Glomerulonephritis with mesangial deposits of IgA unassociated with systemic disease.
Typical features of IgA-associated nephritis were found in renal biopsies from 16 of 355 consecutive patients. Generalized segmental mesangial proliferation was noted in biopsies from most patients, and dense deposits were detected by electron microscopy in mesangial regions of approximately 50% of biopsies. Immunofluorescent studies showed IgA to be the predominant immunoglobulin in glomueruli; IgG was present in less than 50% of biopsies and IgM in only 12%. The serum IgA value was significantly increased (P les than 0.001) in 50% of patients and the mean IgA/IgG ratio was significantly increase (P less than 0.001) for the patient group as a whole, which suggests a selective increase in IgA. Mesangial deposits of C3 were present in 15 of 16 biopsies and properdin was noted in all biopsies tested; C4 was not demonstrated in any biopsy. This suggests activation of the alternative complement pathway. The results of this study support the concept that IgA-associated nephritis is a unique condition that in some patients gives rise to idiopathic recurrent hematuria. Although the prognosis is good in the majority of patients, the renal disease may progress.


Anti-inflammatory properties of ebselen in a model of sephadex-induced lung inflammation.
Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), is a seleno-organic compound which protects tissues against oxidative stress. Furthermore, recent data has suggested that this compound possesses a range of anti-inflammatory properties. In this study the authors have investigated the effects of ebselen on Sephadex-induced lung oedema and bronchoalveolar lavage (BAL) tumour necrosis factor (TNF)-alpha and endothelin(ET)-1 levels in rats. Sephadex administration induced lung oedema which was accompanied by an increase in BAL TNF-alpha and ET-1 levels. Ebselen administration (1-30 mg x kg(-1), i.p. at 0, 4 and 12 h post Sephadex) significantly inhibited lung oedema (dose that produced 50% of the maximum inhibition of lung oedema 4.6 mg x kg(-1)) and BAL TNF-alpha levels in a dose-related manner with no effect on ET-1 levels. These data suggest that ebselen may be a useful therapy in lung pathologies in which bronchiolar inflammation is a feature.


Modified sandwich vacuum pack technique for temporary closure of abdominal wounds: an african perspective.
South Africa has very high levels of accidental trauma as well as interpersonal violence. There are more admissions for trauma in South Africa than for any other disease; therefore it can be regarded as the Number 1 disease in the country. Complex abdominal injuries are common, requiring specific management techniques. The aim is to document our experience with the Modified Sandwich Vacuum Pack technique for temporary closure of abdominal wounds. After providing a short historical overview, we will demonstrate the technique which we carefully adapted over the last decade to the present Modified Sandwich Vacuum Pack technique. In the last 5 years we utilized our Modified Sandwich Vacuum Pack technique 153 times in 69 patients. Five (5) patients were under the age of 12 years. In the patient group over 12 years the most common indication for using our technique were penetrating injuries (40), abdominal sepsis (28), visceral edema (10), abdominal compartment syndrome (9), abdominal packs (6), Abdominal wall defects (2). In the group under 12-years the 2 children had liver ruptures (posttraumatic) and 3 liver transplantations. The average cost for the materials used with our technique was ZAR 96. (10 Euro and 41 cents). In our experience the Modified Sandwich Vacuum Pack technique is an effective, cheap methodology to deal with open abdomens in the African setting. A drawback may be the technical expertise required, particular in centers dealing with low numbers of complex abdominal trauma.


Gamma Knife Radiosurgery does not alter the copy number aberration profile in sporadic vestibular schwannoma.
Ionizing radiation is a known etiologic factor in tumorigenesis and its role in inducing malignancy in the treatment of vestibular schwannoma has been debated. The purpose of this study was to identify a copy number aberration (CNA) profile or specific CNAs associated with radiation exposure which could either implicate an increased risk of malignancy or elucidate a mechanism of treatment resistance. 55 sporadic VS, including 18 treated with Gamma Knife Radiosurgery (GKRS), were subjected to DNA whole-genome microarray and/or whole-exome sequencing. CNAs were called and statistical tests were performed to identify any association with radiation exposure. Hierarchical clustering was used to identify CNA profiles associated with radiation exposure. A median of 7 (0-58) CNAs were identified across the 55 VS. Chromosome 22 aberration was the only recurrent event. A median aberrant cell fraction of 0.59 (0.25-0.94) was observed, indicating several genetic clones in VS. No CNA or CNA profile was associated with GKRS. GKRS is not associated with an increase in CNAs or alteration of the CNA profile in VS, lending support to its low risk. This also implies that there is no major issue with GKRS treatment failure being due to CNAs. In agreement with previous studies, chromosome 22 aberration is the only recurrent CNA. VS consist of several genetic clones, addressing the need for further studies on the composition of cells in this tumor.


Rapid and robust evolution of collateral sensitivity in Pseudomonas aeruginosa antibiotic-resistant mutants.
The analysis of trade-offs, as collateral sensitivity, associated with the acquisition of antibiotic resistance, is mainly based on the use of model strains. However, the possibility of exploiting these trade-offs for fighting already resistant isolates has not been addressed in depth, despite the fact that bacterial pathogens are frequently antibiotic-resistant, forming either homogeneous or heterogeneous populations. Using a set of Pseudomonas aeruginosa-resistant mutants, we found that ceftazidime selects pyomelanogenic tobramycin-hypersusceptible mutants presenting chromosomal deletions in the analyzed genetic backgrounds. Since pyomelanogenic resistant mutants frequently coexist with other morphotypes in patients with cystic fibrosis, we analyzed the exploitation of this trade-off to drive extinction of heterogeneous resistant populations by using tobramycin/ceftazidime alternation. Our work shows that this approach is feasible because phenotypic trade-offs associated with the use of ceftazidime are robust. The identification of conserved collateral sensitivity networks may guide the rational design of evolution-based antibiotic therapies in P. aeruginosa infections.


[Infectious diarrhoea in children under five years].
to determine the prevalence of rotavirus in acute diarrhea among children under 5 years and to describe the epidemiology, clinical trials of rotavirus diarrhea and compare them with those of other gastroenteritis. A Prospective study during 1 year (1 January 2007-31 December 2007) was conducted in the department of Pediatrics B of the Children's Hospital of Tunis. 117 children aged under than 5 years and admitted for acute community gastroenteritis were included in the study. A search of rotavirus in the stool, collected within 48 hours of admission, was performed by a rapid detection of viral antigens: proteins specific RV group A (VP6 protein of the capsid) using enzyme immunoassay technique: sandwich ELISA (IDEIA Rotavirus Dako). Rotavirus diarrhea accounted for 25% of acute gastroenteritis. The average age of rotavirus gastroenteritis was 11 months +/- 1.78. We have noted a male predominance with a sex ratio of 1.2. The seasonal distribution of rotavirus gastroenteritis showed three peaks of incidence (January, May and July). The respiratory signs were more frequently found in rotavirus gastroenteritis group. Rotavirus gastroenteritis had a higher severity score compared with other gastroenteritis (8.44 vs 6.75 P = 0.01). The duration of hospitalization was longer in rotavirus group with a difference close to significance p = 0.07. The seasonal distribution of rotavirus gastroenteritis has three peaks of incidence. The gastroenteritis Rotavirus affects very young infants and has more severe symptoms than other gastroenteritis and is significantly associated with respiratory signs.


A history of atrial fibrillation and outcomes in chronic advanced systolic heart failure: a propensity-matched study.
Atrial fibrillation (AF)-associated poor outcomes in heart failure (HF) are often attributed to older age, advanced disease, and comorbidity burden of HF patients with AF. Therefore, we examined the effect of AF on outcomes in a propensity-matched study in which patients with and without AF were well balanced on all measured baseline characteristics. Of the 2708 advanced chronic systolic HF patients in the Beta-Blocker Evaluation of Survival Trial, 653 had a history of AF. Propensity scores for AF were calculated for each patient and were used to assemble a cohort of 487 pairs of patients with and without AF who were balanced on 74 baseline characteristics. Matched Cox regression analyses were used to estimate associations of AF with outcomes during 23 months of mean follow-up. All-cause mortality occurred in 187 (rate, 2046/10,000 person-years of follow-up) and 181 (rate, 1885/10,000 person-years) matched patients with and without AF, respectively [matched hazard ratio (HR) when AF was compared with no-AF 1.03, 95% confidence interval (CI) 0.79-1.33; P = 0.84]. Heart failure hospitalization occurred in 215 (rate, 3171/10,000 person-years) and 184 (rate, 2405/10,000 person-years) matched patients with and without AF, respectively (matched HR when AF was compared with no-AF 1.28, 95% CI 1.00-1.63; P = 0.049). Hazard ratios and 95% CIs for AF-associated HF hospitalization for bucindolol and placebo groups were, respectively, 1.08 (0.81-1.43) and 1.54 (1.17-2.03; P for interaction = 0.09). A history of AF had no intrinsic association with mortality but was associated with HF hospitalization in chronic systolic HF.


Targeted therapy in severe asthma today: focus on immunoglobulin E.
Asthma is a complex chronic inflammatory disease of multifactorial etiology. International guidelines increasingly recognize that a standard "one size fits all" approach is no longer an effective approach to achieve optimal treatment outcomes, and a number of disease phenotypes have been proposed for asthma, which has the potential to guide treatment decisions. Among the many asthma phenotypes, allergic asthma represents the widest and most easily recognized asthma phenotype, present in up to two-thirds of adults with asthma. Immunoglobulin E (IgE) production is the primary and key cause of allergic asthma leading to persistent symptoms, exacerbations and a poor quality of life. Therefore, limiting IgE activity upstream could stop the entire allergic inflammation cascade in IgE-mediated allergic asthma. The anti-IgE treatment omalizumab has an accepted place in the management of severe asthma (Global Initiative for Asthma [GINA] step 5) and represents the first (and, currently, only) targeted therapy with a specific target in severe allergic asthma. This review summarizes current knowledge of the mechanisms and pathogenesis of severe asthma, examines the actual role of IgE in asthma and the biological rationale for targeting IgE in allergic asthma and reviews the data for the efficacy and safety of omalizumab in the treatment of severe asthma. Current knowledge of the role of IgE in asthma, extensive clinical trial data and a decade of use in clinical practice has established omalizumab as a safe and effective targeted therapy for the treatment of patients with severe persistent IgE-mediated allergic asthma.


An in vitro system to study tumor dormancy and the switch to metastatic growth.
Recurrence of breast cancer often follows a long latent period in which there are no signs of cancer, and metastases may not become clinically apparent until many years after removal of the primary tumor and adjuvant therapy. A likely explanation of this phenomenon is that tumor cells have seeded metastatic sites, are resistant to conventional therapies, and remain dormant for long periods of time. The existence of dormant cancer cells at secondary sites has been described previously as quiescent solitary cells that neither proliferate nor undergo apoptosis. Moreover, these solitary cells has been shown to disseminate from the primary tumor at an early stage of disease progression and reside growth-arrested in the patients' bone marrow, blood and lymph nodes. Therefore, understanding mechanisms that regulate dormancy or the switch to a proliferative state is critical for discovering novel targets and interventions to prevent disease recurrence. However, unraveling the mechanisms regulating the switch from tumor dormancy to metastatic growth has been hampered by the lack of available model systems. In vivo and ex vivo model systems to study metastatic progression of tumor cells have been described previously. However these model systems have not provided in real time and in a high throughput manner mechanistic insights into what triggers the emergence of solitary dormant tumor cells to proliferate as metastatic disease. We have recently developed a 3D in vitro system to model the in vivo growth characteristics of cells that exhibit either dormant (D2.OR, MCF7, K7M2-AS.46) or proliferative (D2A1, MDA-MB-231, K7M2) metastatic behavior in vivo. We demonstrated that tumor cells that exhibit dormancy in vivo at a metastatic site remain quiescent when cultured in a 3-dimension (3D) basement membrane extract (BME), whereas cells highly metastatic in vivo readily proliferate in 3D culture after variable, but relatively short periods of quiescence. Importantly by utilizing the 3D in vitro model system we demonstrated for the first time that the ECM composition plays an important role in regulating whether dormant tumor cells will switch to a proliferative state and have confirmed this in in vivo studies. Hence, the model system described in this report provides an in vitro method to model tumor dormancy and study the transition to proliferative growth induced by the microenvironment.