The cellular localization of adenosine receptors in rat neostriatum.
Using quantitative autoradiography of ligand binding sites combined with lesions of specific neuronal pathways, the cellular locations of A1 and A2 adenosine receptors, as well as a third binding site for the adenosine receptor ligand, [3H]N-ethylcarboxamidoadenosine, and a nucleoside transporter were investigated in rat neostriatum. Intrastriatal kainic acid administration resulted in the loss of 50% of A1 adenosine receptors and virtually abolished ligand binding to A2 receptors. A small reduction in [3H]cyclohexyladenosine binding to striatal A1 receptors was found after lesioning the corticostriatal input. A2 receptor sites were unaffected by this treatment. Destruction of dopaminergic neurons using 6-hydroxydopamine or the raphestriatal serotoninergic input using 5,7-dihydroxytryptamine affected neither A1 nor A2 binding sites. These results indicate the localization of both A1 and A2 adenosine receptors on neurons intrinsic to the neostriatum and probably postsynaptic to the dopaminergic input. In addition, a binding site for [3H]N-ethylcarboxamidoadenosine which is not affected by the adenosine receptor agonist, R-phenylisopropyladenosine, was also partly abolished after kainic acid injection. In contrast, no significant change in the binding of the nucleoside transporter ligand, [3H]nitrobenzylthioinosine, was observed after any lesions, indicating the widespread association of this site with various cell types.


The Functional Anatomy of Time: What and When in the Brain.
This Opinion article considers the implications for functional anatomy of how we represent temporal structure in our exchanges with the world. It offers a theoretical treatment that tries to make sense of the architectural principles seen in mammalian brains. Specifically, it considers a factorisation between representations of temporal succession and representations of content or, heuristically, a segregation into when and what. This segregation may explain the central role of the hippocampus in neuronal hierarchies while providing a tentative explanation for recent observations of how ordinal sequences are encoded. The implications for neuroanatomy and physiology may have something important to say about how self-organised cell assembly sequences enable the brain to exhibit purposeful behaviour that transcends the here and now.


[Management of male urinary incontinence after radical prostatectomy (CTMH AFU 2006-1/5): incidence and role of urodynamic assessment and electromyography].
The incidence of postprostatectomy urinary incontinence varies according to the technique used, over time and according to the type of management, with an incidence at one year ranging from just a few percent to more than 60%. Assessment is required in the case of persistent disabling urinary incontinence despite well conducted perineal rehabilitation one year after surgery or earlier in the case of severe incontinence. Urodynamic assessment is the essential examination to quantify urethral closure pressure. A review of the literature of urodynamic assessment and electromyography is presented.


Marital Status and Risk of Physical Frailty: A Systematic Review and Meta-analysis.
Evidence on associations between marital status and frailty is limited. The objectives of this study were to perform a systematic review for associations between marital status and physical frailty and to perform a meta-analysis to combine findings. Systematic review and meta-analysis. Community-dwelling older people with mean age ≥60 years. Systematic literature search using 5 databases was conducted in February 2019 to identify longitudinal and cross-sectional studies examining associations between marital status and Fried's phenotype-based frailty status. Additional studies were searched for by reviewing the reference lists of relevant articles and conducting forward citation tracking of included articles. Odds ratio (OR) of marital status and frailty was pooled using a random-effects meta-analysis. Subgroup analysis and analyses stratified by gender and marital status (married, widowed, divorced or separated, and never married) were completed. A total of 1565 studies were found, from which 3 studies with longitudinal data and 35 studies with cross-sectional data were included. Although longitudinal studies suggested that married men had lower frailty risks than unmarried men while married women had higher frailty risks than widowed women, meta-analysis was not possible because of different methodologies. Meta-analyses of cross-sectional data from 35 studies including 80,754 individuals showed that unmarried individuals were almost twice more likely to be frail than married individuals (pooled odds ratio = 1.88, 95% confidence interval = 1.70-2.07). A high degree of heterogeneity was observed (I2 = 69%) and was partially explained by reasons for not being married and study location. Stratified analyses showed that pooled risks of frailty in the unmarried compared with the married were not statistically different between women and women (P for difference = .62). Three and 35 studies, respectively, were found providing longitudinal and cross-sectional data regarding associations between marital status and frailty among community-dwelling older people. A meta-analysis of cross-sectional data showed almost twice higher frailty risk in unmarried individuals compared with married individuals. Marital status should be recognized as an important factor, and more longitudinal studies controlling for potential confounding factors are needed.


Formation of false stems in Cymopterus longiopes: an uplifting example of growth form change.
The leaves of Cymopterus longipes form prostrate rosettes early in the spring. As the weather warms, these leaves are elevated on a pseudoscape (false stem) which develops below the rosette through the elongation of the caudex (in the region between root and shoot). The effect of this growth form change on the water relations and photosynthesis in C. longipes was investigated. Pseudoscape height was not linked to phenology or plant size. Leaf conductance, leaf temperature, and leaf water potential were notably similar between plants with different pseudoscape height growing in different microsites. Experimental manipulation of the microclimate around plants growing naturally allowed us to demonstrate that increased temperature led to an increase in the rate of pseudoscape elongation. By changing the distance above the ground surface of the rosettes of some plants we determined that leaf temperature, leaf to air vapour concentration deficits, leaf conductances, and leaf water potentials were all influenced by pseudoscape height. Leaf conductance in C. longipes had a strong negative relationship with ΔW. Since the temperature response of net photosynthesis was extremely flat it was concluded that pseudoscape elongation may be an important morphological means of increasing water use efficiency.


Nonresonant ionization of oxygen molecules by femtosecond pulses: plasma dynamics studied by time-resolved terahertz spectroscopy.
We show that optical pump-terahertz probe spectroscopy is a direct experimental tool for exploring laser-induced ionization and plasma formation in gases. Plasma was produced in gaseous oxygen by focused amplified femtosecond pulses. The ionization mechanisms at 400- and 800-nm excitation wavelengths differ significantly being primarily of a multiphoton character in the former case and a strong-field process in the latter case. The generation of the plasma in the focal volume of the laser and its expansion on subnanosecond time scale is directly monitored through its density-dependent susceptibility. A Drude model used to evaluate the plasma densities and electron-scattering rates successfully captures the observations for a wide range of pump intensities. In addition, rotational fingerprints of molecular and ionic species were also observed in the spectra.


Early detection of radiation-induced lung damage with X-ray dark-field radiography in mice.
Assessing the advantage of x-ray dark-field contrast over x-ray transmission contrast in radiography for the detection of developing radiation-induced lung damage in mice. Two groups of female C57BL/6 mice (irradiated and control) were imaged obtaining both contrasts monthly for 28 weeks post irradiation. Six mice received 20 Gy of irradiation to the entire right lung sparing the left lung. The control group of six mice was not irradiated. A total of 88 radiographs of both contrasts were evaluated for both groups based on average values for two regions of interest, covering (irradiated) right lung and healthy left lung. The ratio of these average values, R, was distinguished between healthy and damaged lungs for both contrasts. The time-point when deviations of R from healthy lung exceeded 3σ was determined and compared among contrasts. The Wilcoxon-Mann-Whitney test was used to test against the null hypothesis that there is no difference between both groups. A selection of 32 radiographs was assessed by radiologists. Sensitivity and specificity were determined in order to compare the diagnostic potential of both contrasts. Inter-reader and intra-reader accuracy were rated with Cohen's kappa. Radiation-induced morphological changes of lung tissue caused deviations from the control group that were measured on average 10 weeks earlier with x-ray dark-field contrast than with x-ray transmission contrast. Sensitivity, specificity, and accuracy doubled using dark-field radiography. X-ray dark-field radiography detects morphological changes of lung tissue associated with radiation-induced damage earlier than transmission radiography in a pre-clinical mouse model. • Significant deviations from healthy lung due to irradiation were measured after 16 weeks with x-ray dark-field radiography (p = 0.004). • Significant deviations occur on average 10 weeks earlier for x-ray dark-field radiography in comparison to x-ray transmission radiography. • Sensitivity and specificity doubled when using x-ray dark-field radiography instead of x-ray transmission radiography.


Establishing the pathways and indications for performing isotope bone scans in newly diagnosed intermediate-risk localised prostate cancer - results from a large contemporaneous cohort.
To establish the pattern of isotope bone scan (BS) positivity in a large contemporaneous cohort of patients with newly diagnosed localised prostate cancer and compare with the European Association of Urology (EAU) guidelines, as imaging guidelines and clinical practice for using BS to stage newly diagnosed patients with intermediate-risk localised prostate cancer are not uniform in the literature. All patients with newly diagnosed prostate cancer were discussed in a specialist multidisciplinary team meeting and were prospectively entered in a database. Patients were categorised based on D'Amico classification. All intermediate- and high-risk patients had pelvic magnetic resonance imaging and BS unless contraindicated. The BS positivity in each group was analysed and the negative predictive value (NPV) calculated. A cohort of 2720 patients between 2002 and 2015 was retrospectively analysed. Of 976 patients in the D'Amico intermediate-risk category, 99 had primary Gleason pattern 4. Only one of the 99 patients had a positive BS and there were no positive BS in patients with Gleason primary pattern 3 in the intermediate-risk category. On subgroup analysis, based on prostate-specific antigen (PSA) level and Gleason grade alone, the BS-positivity rate in patients with a PSA level of <20 ng/mL and Gleason primary pattern 4 vs 3 was 6% and 0%, respectively, resulting in 100% NPV for a positive BS with Gleason primary pattern 3 and a PSA level of <20 ng/mL. The importance of clinical T stage (cT) was also noted, as eight of 146 patients had positive BS, who were high risk on cT stage, with a PSA level of <20 ng/mL and Gleason score <8. All eight patients had Gleason primary pattern 4. By limiting BS to the population at risk (all high-risk + intermediate-risk with primary pattern 4), 68 BS per year could have been avoided in a single centre. A limitation was that there was no histological confirmation of bony metastases. Extending the BS recommendation considering the new Gleason Grade Grouping is discussed. This study confirms that a staging BS can be safely avoided in patients with intermediate-risk prostate cancer with Gleason primary pattern 3 and to limit performing BS in all high-risk prostate cancer and in the intermediate-risk group when the primary Gleason pattern is 4, thereby reinforcing the current recommendations of the EAU guidelines.


A rapid large-scale procedure for purification of lecithin-cholesterol acyltransferase from human and animal plasma.
A rapid and convenient procedure was developed for large-scale purification of lecithin-cholesterol acyltransferase from the plasma of humans, pigs, dogs, goats and rabbits. The procedure included dextran sulfate-Mg2+ precipitation, Phenyl-Sepharose column, Affi-gel blue column, DEAE-Sepharose column, DEAE-Affi-gel blue column and hydroxyapatite column. Lecithin-cholesterol acyltransferase was purified approx. 20 000-fold with about 14% yield from human plasma. A similar result of purification was obtained from pigs, dogs, goats and rabbits. The final enzyme preparation from all five mammalian species was homogeneous as judged by SDS-polyacrylamide gel electrophoresis and high-performance gel filtration in the presence of SDS. The apparent molecular weight of the purified enzymes from humans, pigs, dogs, goats and rabbits were 65 000, 66 000, 65 000, 65 000 and 66 000, respectively, as determined by SDS-polyacrylamide gel electrophoresis and were 67 000, 67 000, 66 000, 66 000 and 67 000, respectively, by high-performance gel filtration. Studies with DEAE-Sepharose columns demonstrated that lecithin-cholesterol acyltransferase from these mammalian species was similar in molecular charge. The pH optimum for activity of purified enzyme ranged from 7.4 to 8.0 among these species. All purified lecithin-cholesterol acyltransferase species were activated by human apolipoprotein A-I and were similarly inhibited by p-hydroxymercuribenzoate and phenylmethylsulfonyl fluoride. We concluded that this purification scheme is suitable for rapid isolation of lecithin-cholesterol acyltransferase from the plasma of humans, pigs, dogs, goats and rabbits and, by inference, from other mammalian species. The availability of purified active lecithin-cholesterol acyltransferase from various animal species should facilitate phylogenetic and comparative studies of the enzyme.


The epistemology of modality and the problem of modal epistemic friction.
There are three theories in the epistemology of modality that have received sustained attention over the past 20 years (1998-2018): conceivability-theory, counterfactual-theory, and deduction-theory. In this paper we argue that all three face what we call the problem of modal epistemic friction (PMEF). One consequence of the problem is that for any of the three accounts to yield modal knowledge, the account must provide an epistemology of essence. We discuss an attempt to fend off the problem within the context of the internalism versus externalism debate about epistemic justification. We then investigate the effects that the PMEF has on reductive and non-reductive theories of the relation between essence and modality.


A report on successful introduction of tele mental health training for primary care doctors during the COVID 19 pandemic.
Treatment gaps of 60-70%, reflecting, amongst many other factors, Human Resources shortfalls means that 150 million India never accessed mental healthcare. In Punjab, mental health training is required in primary health centers. A short-term synchronous training was conceptualized by the National Institute of Mental Health and Neurosciences. A total of 114 primary care doctors participated for the training. Substantial positive changes in knowledge, attitudes and practices were noted. Task sharing and capacity building initiatives can be undertaken during the pandemic to meet the demand for mental healthcare service delivery.


Pediatric organ donation: impact of medical examiner refusal.
To examine the national Pediatric Intensive Care Unit (PICU) experience regarding Medical Examiner (ME) refusal of organ procurement from potential donors. To review our experience regarding PICU mortalities, organ donation, and impact of the ME on the organ donation process. National survey of PICU directors requesting demographics, type of ME system, perceptions of ME responsiveness to organ donation, and data regarding potential donors and their outcomes. Also, a retrospective chart review of all PICU deaths from 1990 to 1992 at a tertiary care center, noting the number of potential organ donors, ME cases, those harvested, rejected, and reason for rejection. PICU directors selected from a list of Pediatric Section members of the Society of Critical Care Medicine. The response rate was 59%. The chart review was performed in a 1000-bed hospital with a 12-bed PICU. PICU directors' perceptions of ME responsiveness to organ donation were not determined by size of PICU, area served, type of hospital, ME system, or means of contacting the ME. ME refusal accounted for 15% and 16% of total refusals in the survey and chart review, respectively. Family refusal accounted for 49% and 28% in these same groups. Survey respondents' hints and suggestions to decrease denial and increase organ donation focused on improved communication (61% and 33%), and education (16% and 55%). ME refusal does impact on pediatric organ donation, but not as significantly as family refusal. Increased organ procurement in ME-related cases will require improved communication between MEs, physicians, and the Organ Procurement Organizations (OPOs).


In vivo validation of mathematically derived fractional flow reserve for assessing haemodynamics of coronary tandem lesions.
Our aim was to propose a prediction model for the post-stenting fractional flow reserve (FFR'd,pred) at a position distal to the tandem lesion. Using the FFR at a position proximal to the tandem lesion (FFRp), and the FFR gradients across proximal (ΔFFRp) and distal (ΔFFRd) stenoses, FFR'd,pred after treating either the distal or proximal lesion was predicted as FFRp-ΔFFRp/(1-1.33kΔFFRd) or FFRp-ΔFFRd/(1-1.33ΔFFRp), respectively. The flow fraction of the distal main branch (k) was estimated using the diameter ratio of side to distal main branches. For in vivo validation, 50 patients with a tandem lesion (diameter stenosis >50%) were evaluated. Compared to the conventional model that did not consider side branch flow, our predicted FFR showed closer correlation with the measured FFR (R2=0.83 vs. 0.57) and significant reduction in mean absolute errors (0.034±0.028 vs. 0.053±0.049, p<0.001). In particular, with a large side branch and low baseline FFR, decision making using the current model had greater predictive ability than with the conventional model. By predicting which stenosis is more severe and/or whether the remaining lesion after the first treatment is functionally significant, a tandem prediction model can help to plan optimised stent implantation.


A comparison between adult and paediatric snakebites and their outcomes in North Eastern South Africa.
Snakebites are common among rural communities. The aim of this study was to ascertain the differences between paediatric and adult snakebite patients regarding severity, management and outcome. This study included a total of 878 patients admitted to Ngwelezana Hospital, with a snakebite or snakebite-related complication, from September 1, 2008 to December 31, 2014. This included 274 paediatric patients (13 years and younger) and 604 adults. There was a male predominance (56%) in the paediatric group and a female predominance (51%) amongst adults. The duration between the time of the bite and presentation to the hospital was significantly longer in children. The vast majority of children and adults presented with cytotoxic envenomation. Laboratory parameters were worse amongst children in the cytotoxic group. 53 children (19%) and 44 adults (7%) required antivenom administration. Of those who received antivenom, 25% suffered adverse reactions in the paediatric group and 20% in the adult group. 56 Children (20%) underwent one or more procedures on their affected limbs compared to 26 adults (4%). The paediatric population carries a higher risk for serious morbidity and should be treated at a facility with the necessary resources. Children require antivenom more often due to severe envenomation. Delayed presentation carries significant morbidity.


A mosaic adeno-associated virus vector as a versatile tool that exhibits high levels of transgene expression and neuron specificity in primate brain.
Recent emphasis has been placed on gene transduction mediated through recombinant adeno-associated virus (AAV) vector to manipulate activity of neurons and their circuitry in the primate brain. In the present study, we created a novel vector of which capsid was composed of capsid proteins derived from both of the AAV serotypes 1 and 2 (AAV1 and AAV2). Following the injection into the frontal cortex of macaque monkeys, this mosaic vector, termed AAV2.1 vector, was found to exhibit the excellence in transgene expression (for AAV1 vector) and neuron specificity (for AAV2 vector) simultaneously. To explore its applicability to chemogenetic manipulation and in vivo calcium imaging, the AAV2.1 vector expressing excitatory DREADDs or GCaMP was injected into the striatum or the visual cortex of macaque monkeys, respectively. Our results have defined that such vectors secure intense and stable expression of the target proteins and yield conspicuous modulation and imaging of neuronal activity.


[Chondrosarcoma of the thyroid cartilage. Presentation of a case and review of the literature].
We present a case of Thyroid cartilage Chondrosarcoma with growing out, without injury of intralaryngeal noble structures and whose symptom of presentation was a cervical tumour. We review the cases of thyroid cartilage Chondrosarcomas in the literature.


Vincristine, cisplatin, and bleomycin with surgery in the management of advanced metastatic nonseminomatous testis tumors.
Most effective treatment regimens for advanced nonseminomatous testis tumors (NSTT) employ vinblastine (V), cisplatin (CDDP), and bleomycin (B) and adjunctive surgery. The toxicity of many of these multidrug programs, primarily from vinblastine-induced myelosuppression has resulted in significant patient morbidity and even death. Since 1978, the authors of this report have used vincristine (VCR), CDDP, and B with adjunctive surgery in patients with advanced NSTT. In the first 29 patients treated with VCR, CDDP, and B and adjunctive surgery, a complete clinical remission (CR) was achieved in 27 (93%) with 3 (11%) recurrences; 24 (83%) remain in CR 18 to 46 months (mean and median of 31 months). Twenty-six (90%) patients had either maximal abdominal tumor (Stage B3) or maximal pulmonary and/or abdominal disease (Stage C). Twenty patients had adjunctive surgery. No patient developed serious chemotoxicity. This treatment regimen is less toxic and equally effective as V, CDDP, and B combinations.


Drinking water access in California schools: Room for improvement following implementation of school water policies.
This study aims to investigate how access to free drinking water in California public schools changed after implementation of 2010 federal and state school water policies. Repeated cross-sectional surveys were conducted with administrators in a random sample of California public schools, stratified by school type and urban-centric geography, from 2010 to 2011 (n = 240) and from 2016 to 2018 (n = 240). Surveys assessed excellence in drinking water access, defined as 1) providing water in 4 of 5 key school locations, 2) having a high density of free water available, 3) providing water via a non-fountain source, 4) providing water that is perceived as safe, and 5) offering water sources that are reported as clean and functioning. Multivariate logistic regression was used to examine changes in excellence in drinking water access after implementation of school drinking water policies. Analysis was completed in 2019. In 2010-2011, 5% of schools met all water excellence criteria; in 2016-2018, 18% of schools met all excellence criteria. In adjusted models, post-legislation schools had 4 times the odds of meeting all drinking water excellence criteria compared to pre-legislation schools (OR: 4.34; 95% confidence interval = 2.07, 9.10). There were significant increases in public schools meeting the criteria for excellence in free drinking water access after school water policies were implemented; however, a majority of schools still lacked excellent water access. Findings suggest that policies mandating free water access in schools may help to improve excellence in access, and more work is needed to help all schools excel in this area.


Indirect Measurement of CRAC Channel Activity Using NFAT Nuclear Translocation by Flow Cytometry in Jurkat Cells.
Flow cytometry is a powerful technology to assess the presence of NFAT in the nuclei after CRAC channel activation. Here we described a simplified procedure for the analysis of CRAC channel activity using NFAT nuclear translocation by flow cytometry, based on the isolation of Jurkat E6-1 cell nuclei.


[Tactics in using aerosols for disinfection of therapeutic and prophylactic institutions].
Two Soviet sprayers (ABD-2600H and EOC-5) are recommended for the disinfection of the surfaces and indoor air in the curative and prophylactic facilities. A special impetus has been given to the use of chloramine aerosols that ensure higher efficacy of disinfection, reduce the aerosol consumption and the period of the presence of active chlorine in the air of the treated place.


Live and let die: Nef functions beyond HIV replication.
The viral Nef protein is important for the progression of the human and simian immunodeficiency virus (HIV/SIV) infection. So far, experimental evidence has suggested that Nef enhances viral replication and infectivity through a combination of different effects. Recent insights, however, indicate that its functions are more complex than previously anticipated. By targeting the T cell receptor, Nef may not only prime viral replication but, more importantly, ensure viral survival through distinct mechanisms of immune evasion and antiapoptosis.


An improved equivalent-input-disturbance approach for PMSM drive with demagnetization fault.
Closed-loop torque control system of permanent magnet synchronous motor (PMSM) drive is highly applied in industrial applications. However, high temperature and other external factors lead to permanent magnet (PM) demagnetization fault of the motor, which inevitably brings barriers to precise torque control. This paper presents a rejection method for demagnetization based on an improved equivalent-input-disturbance (EID) approach. A system model, which contains demagnetization fault, is first constructed. Then, an equivalent-input-demagnetization on the control input channel is used to describe the model. An improved EID approach is designed to reject the effect of the demagnetization fault. In particular, an improved sliding-mode observer rather than the Luenberger observer in a conventional EID theory is designed to estimate the equivalent-input-demagnetization. This greatly enhances the response speed and accuracy of the estimation and rejection, and then effectively improves the accuracy of torque tracking. Finally, the step change and the ramp change of a demagnetization are introduced into a hardware-in-the-loop experiment, separately. Comparisons with other methods show the effectiveness of the method.


The prevalence of parastomal hernia after formation of an end colostomy. A new clinico-radiological classification.
Parastomal hernia (PH) is a common complication of end colostomy, found in over 50% of patients. Abdominal computerized tomography (CT) may help diagnosis. The prevalence of PH may be higher than previously reported. We present a new CT classification for use in clinical practice. A cross-sectional, descriptive observational study was carried out, assessing the clinical and radiological prevalence of PH in 75 patients with an end colostomy operated on since 1997. Clinical examinations were performed by a single surgeon. Abdominal CTs were assessed by a single radiologist. PH was observed clinically in 33 (44%) of 75 patients and 27 (82%) were symptomatic. Using the classification 0 (Normal), I (Hernial sac containing stoma loop), II (Sac containing omentum), III (Sac containing a loop other than stoma), radiological PH was observed in 35 (47%) patients. Clinical/radiological concordance (Kappa index = 0.4) increased proportionally with sac size. All type-III PHs (n = 9) were symptomatic. The combined prevalence of PH detected by one or other method was 60.8%. Clinical and radiological prevalence of PH is high. As there is no gold standard for PH detection, we recommend a combination of the two methods. A new classification for use in clinical practice is proposed.


Peracetic acid application as an antimicrobial and its residual (HEDP): a holistic approach on the technological characteristics of chicken meat.
The most significant occurrence of food-borne diseases is due to Campylobacter and Salmonella contamination from chicken meat, and for this reason, strict regulations about strategies to improve the control of food pathogens are imposed by food safety authorities. Despite the efforts of poultry industry since the beginning of risk analysis and critical control point to reduce the burden of food-borne illness, technological barriers along the way are increasingly necessary to ensure safe food. The aim of this review was to carry out a scientific approach to the influence of peracetic acid (PAA) as an antimicrobial and its toxicological safety, in particular the stabilizer used in the formulation of PAA, 1-hydroxyethylidene 1,1-diphosphonic acid (HEDP), suggesting the possibility of researching the residual HEDP in meat, which would allow the approval of the PAA by the health authorities of several countries that still restrict it. This review also aims to ascertain the effectiveness of PAA, in different cuts and carcasses, by different application methods, comparing the effectiveness of this antimicrobial with other antimicrobials, and its exclusive or combined use, for the decontamination of poultry carcasses and raw parts. The literature results support the popularity of PAA as an effective intervention against pathogenic bacteria during poultry processing.


LncRNA MT1DP promotes cadmium-induced DNA replication stress by inhibiting chromatin recruitment of SMARCAL1.
Cadmium (Cd) is a well-known carcinogenic metal and widespread environmental pollutant. The effect of Cd-induced carcinogenesis is partly due to accumulated DNA damage and chromosomal aberrations, but the exact mechanisms underlying the genotoxicity of Cd have not been clearly understood. Here, we found that one long non-coding RNA MT1DP is participated in Cd-induced DNA damage and replication stress. Through analyzing the residents from Cd-contaminated area in Southern China, we found that blood DNA repair genes are down-regulated in individuals with high urine Cd values compared to those with low urine Cd values, which contrast to the blood MT1DP levels. Through in vitro experiments, we found that MT1DP promotes Cd-induced DNA damage response, genome instability and replication fork stalling. Mechanically, upon Cd treatment, ATR is activated to enhance HIF-1α expression, which in turn promotes the transcription level of MT1DP. Subsequently MT1DP is recruited on the chromatin and binds to SMARCAL1 to competitive inhibit latter's interaction with RPA complexes, finally leading to increased replication stress and DNA damage. In summary, this study provides clear evidence for the role of epigenetic regulation on the genotoxic effect of Cd, and MT1DP-mediated replication stress may represent a novel mechanism for Cd-induced carcinogenesis.


Muscimol injections in the nucleus raphé dorsalis block the antinociceptive effect of morphine in rats: apparent lack of 5-hydroxytryptamine involvement in muscimol's effect.
The effect of morphine (3 mg kg-1 subcutaneously) on tail flick in the tail immersion test was studied in rats which had received a muscimol (100 ng) injection either in the nucleus raphé dorsalis (DR) or medianus (MR). The levels of 5-hydroxyindoleacetic acid (5-HIAA) were measured in the hippocampus and striatum of muscimol-injected animals. Muscimol injections in the DR reduced 5-HIAA concentrations in the striatum but not in hippocampus, whereas in animals which had received muscimol in the MR a selective decrease in hippocampal 5-HIAA levels was found. Muscimol injections in the DR blocked the effect of morphine while no effect was seen in animals which had received muscimol in the MR. An injection of 5,7-dihydroxytryptamine (6 micrograms in 3 microliter) in the DR did not change the effect of morphine or muscimol. These findings indicate that muscimol-sensitive neurones in the DR, which are probably not 5-hydroxytryptaminergic, are involved in the effect of morphine on tail flick in tail immersion. The muscimol-sensitive neurones involved in this effect of morphine do not seem to exist in the MR.


Evaluating the toxic effects of three priority hazardous and noxious substances (HNS) to rotifer Brachionus plicatilis.
Hazardous and noxious substances (HNS) spill in the marine environment is an issue of growing concern, and it will mostly continue to do so in the future owing to the increase of high chemical traffic. Nevertheless, the effects of HNS spill on marine environment, especially on aquatic organisms are unclear. Consequently, it is emergent to provide valuable information for the toxicities to marine biota caused by HNS spill. Accordingly, the acute toxicity of three preferential HNS and sub-lethal effects of acrylonitrile on Brachionus plicatilis were evaluated. The median lethal concentration (LC50) at 24 h were 47.2 mg acrylonitrile L-1, 276.9 mg styrene L-1, and 488.3 mg p-xylene L-1, respectively. Sub-lethal toxicity effects of acrylonitrile on feeding behavior, development, and reproduction parameters of B. plicatilis were also evaluated. Results demonstrated that rates of filtration and ingestion were significantly reduced at 2.0, 4.0, and 8.0 mg L-1 of acrylonitrile. Additionally, reproductive period, fecundity, and life span were significantly decreased at high acrylonitrile concentrations. Conversely, juvenile period was significantly increased at the highest two doses and no effects were observed on embryonic development and post-reproductive period. Meanwhile, we found that ingestion rate decline could be a good predictor of reproduction toxicity in B. plicatilis and ecologically relevant endpoint for toxicity assessment. These data will be useful to assess and deal with marine HNS spillages.


Acute changes in cardiac function by direct acting antiviral therapy for hepatitis C-infected patients with thalassemia.
Patients with thalassemia may also have cardiac abnormalities due to congenital problems, anemia, and increased burden of iron in their myocardium. This study was designed to evaluate the effects of direct acting antiviral (DAA) therapy on the cardiac function of hepatitis C virus (HCV)-infected patients with thalassemia. HCV-infected thalassemia patients were enrolled to this prospective evaluation. Daily tablets of 90 mg Ledipasvir (or 60 mg Daclatasvir) plus 400 mg Sofosbuvir (±ribavirin) were prescribed for the patients according to the Iran Hepatitis Network's guidelines. An echocardiography fellow collected the echocardiography findings before and after the treatment of all the patients. The patients were followed up for any cardiac events within 12 weeks after finishing the treatment. Thirty-two patients with the mean age of 24.2 ± 6.4 years were evaluated. All patients showed a sustained virological response at the 12th week after finishing the treatment. The patients' left ventricular end systolic diameter (3.0 vs 3.24; P = 0.003) and volume (33.8 vs 43.6; P = 0.001), global longitudinal strain of the left ventricle (-22.0 vs -20.6, P = 0.046), and average (-21.4 vs -20.3; P = 0.048), and the right ventricle size (3.12 vs 3.31; P = 0.012) were significantly increased after finishing the treatment. Changes in the abovementioned parameters were not correlated with the patients' myocardium iron load. There were no significant differences in other echocardiographic parameters ( P > 0.05) before and after the treatment. Sofosbuvir-based regimens for HCV treatment were safe for our HCV-infected patients with thalassemia. Our patients' ejection fraction remained unchanged. Hence, more specialized echocardiographic evaluations were recommended for those with a history of cardiac abnormalities, cardiac iron overload, and in case of any cardiac adverse event during DAA therapy in patients with thalassemia.


GS-9219--a novel acyclic nucleotide analogue with potent antineoplastic activity in dogs with spontaneous non-Hodgkin's lymphoma.
GS-9219, a novel prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl)guanine (PMEG), was designed as a cytotoxic agent that preferentially targets lymphoid cells. Our objective was to characterize the antiproliferative activity, pharmacokinetics, pharmacodynamics, and safety of GS-9219. GS-9219 was selected through screening in proliferation assays and through pharmacokinetic screening. The activation pathway of GS-9219 was characterized in lymphocytes, and its cytotoxic activity was evaluated against a panel of hematopoietic and nonhematopoietic cell types. To test whether the prodrug moieties present in GS-9219 confer an advantage over PMEG in vivo, the pharmacokinetics, pharmacodynamics (lymph node germinal center depletion), and toxicity of equimolar doses of GS-9219 and PMEG were evaluated after i.v. administration to normal beagle dogs. Finally, proof of concept of the antitumor efficacy of GS-9219 was evaluated in five pet dogs with spontaneous, advanced-stage non-Hodgkin's lymphoma (NHL) following a single i.v. administration of GS-9219 as monotherapy. In lymphocytes, GS-9219 is converted to its active metabolite, PMEG diphosphate, via enzymatic hydrolysis, deamination, and phosphorylation. GS-9219 has substantial antiproliferative activity against activated lymphocytes and hematopoietic tumor cell lines. In contrast, resting lymphocytes and solid tumor lines were less sensitive to GS-9219. GS-9219, but not PMEG, depleted the germinal centers in lymphoid tissues of normal beagle dogs at doses that were tolerated. In addition, GS-9219 displayed significant in vivo efficacy in five dogs with spontaneous NHL after a single administration, with either no or low-grade adverse events. GS-9219 may have utility for the treatment of NHL.


Comparative toxicity and renal distribution of the platinum analogs tetraplatin, CHIP, and cisplatin at equimolar doses in the Fischer 344 rat.
Tetraplatin [tetrachloro(dl-trans)1,2-diaminocyclohexane platinum(IV), NSC-363812] is a new anticancer platinum drug analog targeted for clinical development because of its effectiveness against cisplatin-resistant tumor cell lines and its improved formulation. The toxicity of tetraplatin was compared at equimolar doses to that of cisplatin [cis-diamminedichlorophatinum(II)] and CHIP [cis-dichloro,trans-dihydroxybis-isopropylamine platinum(IV), NSC-256927]. Adult male Fischer 344 rats received an iv bolus injection of 6.7, 13.3, 26.7, or 53.3 mumol/kg of one of these drugs in saline and were killed on Day 1, 3, 5, 8, or 15 postinjection for assessment of toxicity with emphasis on evaluation of nephrotoxicity. Rats to be killed on Day 15 were housed in metabolism cages for daily urine collection. Tetraplatin was less nephrotoxic than cisplatin at equimolar doses; CHIP was not nephrotoxic at these doses. Renal platinum contents were similar after all three drugs and did not appear to be related directly to the nephrotoxicity. Nephrotoxicity was detected 4-5 days after 6.7 mumol/kg cisplatin, was localized to the corticomedullary junction, and progressed with time and dose. Tetraplatin-induced alterations of renal function were first observed after 13.4 mumol/kg on Day 4 as an elevation of urine volume (up to 10-fold) and a smaller elevation of urinary glucose excretion. Tetraplatin lesions were localized in the mid- and outer cortex and, even at the highest dose, were less severe than those observed with cisplatin. There were other prominent toxic effects of tetraplatin, such as gastrointestinal toxicity and myelosuppression, which indicate that factors other than comparative nephrotoxicity may impact the clinical potential of this new agent.


Clinical and perinatal outcomes in eclamptic women with posterior reversible encephalopathy syndrome.
To compare the clinical and perinatal outcomes in eclamptic women with and without posterior reversible encephalopathy syndrome (PRES). This single-center, retrospective, cohort study was conducted between 2008 and 2013. The clinical and perinatal outcomes of eclamptic patients were obtained from hospital records. Magnetic resonance imaging was used for the diagnosis of PRES. Eighty-one eclamptic women were divided into two groups: 45 and 36 patients were included in the PRES and non-PRES groups, respectively. In the PRES group, headache and visual impairment together (60.0 %) were the most common presenting symptoms. In the non-PRES group, only headache was the most common (50 %) presenting symptom. Occipital and parietal lobes were the most frequently affected areas in the PRES group. Women in the PRES group had a higher body mass index value (p = 0.005), longer hospitalization time (p = 0.001), and higher level of proteinuria (p = 0.012) than those in the non-PRES group. Women in the non-PRES group had higher Apgar scores (p = 0.002) than those in the PRES group. This study indicates that PRES manifests predominantly with headache and visual impairment together. Adverse neonatal outcomes are also common in these patients.


Ethnopharmacological uses of Erythrina senegalensis: a comparison of three areas in Mali, and a link between traditional knowledge and modern biological science.
This paper describes ethnopharmacological knowledge on the uses of Erythrina senegalensis DC (Fabaceae) in traditional medicine in three different areas (Dioila, Kolokani and Koutiala) in Mali. Data were collected using interviews of traditional healers selected randomly. The main reported diseases for which E. senegalensis was used by the traditional healers were amenorrhea, malaria, jaundice, infections, abortion, wound, and body pain (chest pain, back pain, abdominal pain etc). The fidelity level (which estimates the agreement of traditional healers on the same area about a reported use of the plant) was calculated to compare the results from the three areas. Certain differences were noticed, the most striking was the fact that amenorrhea was the most reported disease in Dioila and Kolokani with 21% of agreement for both areas, while this use was not reported in Koutiala at all. Similarities existed between the three areas on the use of the plant against malaria and infections, although with different degree of agreement among the healers. We also report the results of a literature survey on compounds isolated from the plant and their biological activities. A comparison of these results with the ethnopharmacological information from Mali and other countries showed that some of the traditional indications in Mali are scientifically supported by the literature. For instance, the use of E. senegalensis against infectious diseases (bilharzias, schistosomiasis, pneumonia etc.) is sustained by several antibacterial and antifungal compounds isolated from different parts of the plant. The comparison also showed that pharmacologists have not fully investigated all the possible bioactivities that healers ascribe to this plant.


New drugs on the horizon for cerebral edema: what's in the clinical development pipeline?
Research has advanced our understanding of the molecular and cellular mechanisms of cerebral edema and has propelled the development of novel antiedema therapeutics. Current evidence supports aberrant neuro-glial ion transport as a central mechanism that underlies pathological fluid accumulation after central nervous system injury. Novel agents in clinical development show potential in altering the natural history and treatment of cerebral edema. Using the PubMed and Google Scholar databases, we review recent advances in our understanding of cerebral edema and describe agents under active investigation, their mechanism, and their application in recent and ongoing clinical trials. Pharmacotherapies that target molecular mechanisms underlying the compensatory post-injury response of ion channels and transporters that lead to pathological alteration of osmotic gradients are the most promising therapeutic strategies. Repurposing of drugs such as glyburide that inhibit the aberrant upregulation of ion channels such as SUR1-TRPM4, and novel agents, such as ZT-1a, which reestablish physiological regulation of ion channels such as NKCC1/KCC, could be useful adjuvants to prevent and even reverse fluid accumulation in the brain parenchyma.


Impact of Serial B-Type Natriuretic Peptide Changes for Predicting Outcome in Asymptomatic Patients With Aortic Stenosis.
The aim of this study was to determine the impact on the outcome of serial B-type natriuretic peptide (BNP) changes during follow-up in asymptomatic patients with ≥ moderate aortic stenosis (AS) and preserved left ventricular ejection fraction. We prospectively screened 69 patients who underwent comprehensive transthoracic echocardiography, BNP level measurement at baseline and after every 6 or 12 months. Annualized BNP changes were calculated as the difference between the last and baseline BNP measurements divided by the duration of follow-up. The primary endpoint was the occurrence of symptoms, aortic valve replacement, or cardiovascular death. During a follow-up of 30 ± 19 months, 43 patients experienced a cardiac event. These patients were significantly older (73 ± 9 vs 65 ± 16 years; P = 0.010), had more often dyslipidemia (79% vs 42%; P = 0.038), more severe AS (peak velocity: 3.9 ± 0.6 vs 3.5 ± 0.6 m/s; P = 0.002), larger indexed left atrial area (10.2 ± 2.5 vs 8.7 ± 1.9 cm(2)/m(2); P = 0.006), and a higher increase in annualized BNP (+90 ± 155 vs +7 ± 49 pg/mL/y; P = 0.010). Patients with higher annualized BNP changes (> 20 pg/mL/y) had a significantly lower cardiac event-free survival (1 year: 63 ± 8% vs 97 ± 3%; 3 years: 31 ± 8% vs 68 ± 8%; P < 0.001). Using the multivariate Cox proportional hazards model, higher annualized BNP changes were significantly associated with increased risk of cardiac events (hazard ratio: 2.73, 95% confidence interval: 1.27-5.86; P = 0.010) after adjustment for age, dyslipidemia, and echocardiographic parameters. In asymptomatic patients with AS and preserved left ventricular ejection fraction, the use of serial BNP changes may help to anticipate development of class I indication for aortic valve replacement.


Extracellular creatine kinase may modulate purinergic signalling.
Extracellular purine nucleotides and nucleosides including ADP and ATP regulate a wide array of physiological processes including platelet aggregation, vasomotor responses and inflammation through specific purinergic receptors. In the recent years, a strong association has been reported between circulating cytoplasmic-type creatine kinase and adverse clinical outcomes such as major bleeding, hypertension and obesity. Therefore, it is proposed that extracellular CK may modulate purinergic signalling through its ADP binding and/or ATP-generating effect.


Influence of hospital type on survival in stage IV colorectal cancer.
Hospital factors along with various patient and surgeon factors are considered to affect the prognosis of colorectal cancer. Hospital volume is well known, but little is known regarding other hospital factors. We reviewed data on 853 patients with stage IV colorectal cancer who underwent elective palliative primary tumor resection between January 2006 and December 2007. To detect the hospital factors that could influence the prognosis of incurable colorectal cancer, the relationships between patient/hospital factors and overall survival were analyzed. Among hospital factors, hospital type (Group A: university hospital or cancer center; Group B: community hospital), hospital volume, and number of colorectal surgeons were examined. In univariate analysis, Group A hospitals showed significantly better prognosis than Group B hospitals (p = 0.034), while hospital volume and number of colorectal surgeons were not associated with overall survival. After adjustment for patient factors in multivariate analysis, hospital type was significantly associated with overall survival (hazard ratio: 1.31; 95 % confidence interval: 1.05-1.63; p = 0.016). However, there was no significant difference in short-term outcomes between hospital types. Hospital type was identified as a hospital factor that possibly affects the prognosis of stage IV colorectal cancer patients.


Analysis of the Ability of a Distal Tibial Anatomical Locking Plate to Capture the Distal Tibial Fragments in Patients with Pilon Fractures.
Although pilon fractures are rare in clinical practice, they are difficult to treat because of their complexity. Effective fixation of the fracture fragment is the key to the treatment of pilon fractures. Plate osteosynthesis is common clinically, but there are many types of plates and the evaluation of the effect of fixation plates is not comprehensive. This study attempted to compare the capture effect of different fixation plates on the fracture fragments based on 3D modeling and fine distinctions of fracture fragments. The computed tomography (CT) images before treatment of 127 patients with pilon fractures from January 2019 to December 2021 were retrospectively collected. The fracture lines were mapped and digitally displayed as 3D images using MIMICS 21 software. APLUS distal tibia anatomical locking plate (Plate A) and ZIMMER distal tibia anatomical plate (Plate B) were placed on a pseudo-bone model and CT scans were used to determine the number of screws in the major and minor fragments of pilon fractures. The frequency of the two plates capturing the fracture fragments was recorded. Under Assumption 1 or 2, Plate A performed significantly better than Plate B in capturing the major, Chaput, Volkmann, medial malleolus, and die-punch fracture fragments. Plate A captured markedly more minor fragments than Plate B under Assumption 2 but was not significantly different from Plate B under Assumption 1. Plate A or Plate B showed no obvious difference between major and minor capture rates under the same assumption, and A1 or B1 showed a markedly higher capture rate compared with A2 or B2. In addition, there was a significant positive correlation between the major capture rate and the major fragments in B1, and a significant negative correlation between the minor capture rate and the minor fragments in Plates A and B. However, there was no correlation between the major capture rate of Plate A and the major fragments. The APLUS distal tibial anatomical locking plate is superior to the ZIMMER distal tibia anatomical plate in the ability to capture distal tibial fragments in pilon fracture cases.


Development and trial of a dried tube specimen (DTS) proficiency testing panel for dual HIV/syphilis rapid diagnostic tests.
To develop and trial a dried tube specimen (DTS) panel for proficiency testing of dual HIV/syphilis rapid diagnostic tests (RDTs) at clinical sites. DTS panels were prepared using plasma samples with known HIV and syphilis results, to give varying reactivity for syphilis and HIV test lines on RDTs. Laboratory DTS panels were stable for a minimum 4-week period at ambient temperatures with no inter-reader variability of results. Field testing of panels with Standard Diagnostics Bioline HIV/Syphilis duo showed 100% correlation with laboratory results, and excellent mean pair agreement between the two clinical sites (k = 1.0). With Chembio Dual Path Platform HIV-Syphilis, there were two false negative results for HIV and syphilis, respectively, at one site; and good mean pair agreement between the two sites (k = 0.9). It is feasible and practicable to incorporate DTS panels into a field proficiency testing scheme for dual HIV/syphilis RDTs.


Activation of muscarinic M1 receptors by acetylcholine to increase glucose uptake into cultured C2C12 cells.
Regulation of glucose metabolism by cholinergic nervous activation has been demonstrated. In an attempt to evaluate the role of cholinergic receptor subtype in this regulation of glucose metabolism, we employed cultured myoblast C2C12 cells to investigate the glucose uptake in the present study. Acetylcholine (ACh) enhanced the uptake of radioactive glucose into C2C12 cells at the concentration range of 0.001 to 1.0 micromol/l. This effect was suppressed by the muscarinic antagonist atropine. Effect of ACh on muscarinic receptors was further supported by the blockade of scopolamine, another classical antagonist. Thus, activation of muscarinic receptors to enhance the radioactive glucose uptake into C2C12 cells can be considered. Moreover, pirenzepine, the antagonist of muscarinic M1 receptors, competitively antagonized the action of ACh in C2C12 cells. However, methoctramine at concentration sufficient to inhibit the muscarinic M2 receptors failed to produce similar effect. Similarly, 4-DAMP at effective concentration to block muscarinic M3 receptors lacked the influence. An activation of muscarinic M1 receptors seems responsible for the action of ACh in C2C12 cells. Pharmacological inhibition of phospholipase C by U73312 resulted in a concentration-dependent decrease in ACh-stimulated uptake of radioactive glucose into C2C12 cells. However, treatment with U73343, the inactive congener, failed to block the action of ACh. Moreover, both chelerythrine and GF 109203X diminished the action of ACh at concentrations sufficient to inhibit protein kinase C. Therefore, the obtained data suggest that increase of the glucose uptake evoked by ACh is mainly due to the activation of muscarinic M1 receptors in cultured myoblast C2C12 cells.


Hormone responses to methylamphetamine in depression: a new approach to the noradrenaline depletion hypothesis.
The corticosteroid response to methylamphetamine was lower in ten patients when they were depressed than when they were recovered (P less than .026). The growth hormone responses to the same injection in the depressed and recovered states were not significantly different. This pattern of responses is seen in normal subjects after blockade of alpha adrenergic receptors. These findings may indicate a functional deficiency of noradrenaline at alpha adrenergic receptors in these patients during the time they are depressed.


Two more steps to add to your eye drops care procedure.
The article on 'How to administer eye drops and eye ointment' omitted two important parts of the procedure (art & science, May 25).


Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species.
It is well established that tumor growth is associated with accumulation of immature myeloid cells (ImC). They play an important role in tumor-associated immune suppression. ImC accumulate not only in tumor-bearing hosts but also in immunized, tumor-free hosts or hosts infected with bacterial pathogens. The kinetics of ImC in these mice is different. If in tumor-bearing mice, the number of ImC continues to increase with tumor progression in tumor-free mice after an initial spike, it decreases to the control level. Here, we have investigated the mechanisms of ImC accumulation in tumor-bearing hosts by comparing differentiation of ImC obtained from tumor-free and tumor-bearing mice. In the presence of appropriate growth factors, ImC isolated from tumor-free mice quickly differentiated in vitro into mature dendritic cells (DC), macrophages, and granulocytes. In contrast, differentiation of ImC from tumor-bearing mice was significantly delayed. Similar results were obtained in vivo after adoptive transfer of ImC into naïve, congeneic mice. ImC transferred into tumor-bearing recipients failed to differentiate into DC or macrophages. ImC from tumor-bearing mice had significantly higher levels of reactive oxygen species (ROS) than ImC obtained from tumor-free mice. Hydrogen peroxide (H(2)O(2)) but not superoxide radical anions was found to be the major part of this increased ROS production. In vitro experiments demonstrated that scavenging of H(2)O(2) with catalase induced differentiation of ImC from tumor-bearing mice into macrophages. Thus, this is a first demonstration that tumors may prevent differentiation of antigen-presenting cells by increasing the level of endogenous H(2)O(2) in immature myeloid cells.


Glycobiology: drifting toward polymer perfection.
The addition of polysialic acid to proteins and cells is emerging as a promising therapeutic strategy. Polysialyltransferases synthesize polymers of widely varying lengths not optimal for therapeutic reagents, but the development of enzyme variants using neutral genetic drift offers a new way to overcome this problem.


Pre-treatment with chloroquine and parasite chloroquine resistance in Ghanaian children with severe malaria.
Self-medication with anti-malarial drugs is widespread, and chloroquine (CQ) resistance is increasing. The effect of these factors on the incidence and presentation of severe malaria is uncertain. To investigate subtype of severe malaria, duration of illness, previous CQ treatment and prevalence of Plasmodium falciparum CQ-resistance markers among children presenting with severe malaria to a teaching hospital in Ghana. Prospective clinical study. Consecutive patients (n = 189) presenting with severe malaria were examined clinically, and blood was taken for routine haematology and malaria films. Plasma and blood cells were stored and subsequently analysed by ELISA for CQ levels (n = 168) and by PCR and restriction digest for P. falciparum chloroquine resistance transporter gene (pfcrt) mutations (n = 139). Of 47 presenting with cerebral malaria, 21 had severe anaemia and 13 respiratory distress (RDS). Twenty-nine had prostration or RDS alone, 41 severe anaemia with prostration or RDS, and 72 severe anaemia not associated with coma, prostration or RDS. Of the patients studied, 77% had CQ in their plasma, and 88% were carrying P. falciparum with a CQ-resistance genotype. Significant associations were found (i) between the CQ-resistance genotype of parasites and plasma CQ levels, (ii) between the presence of CQ in plasma and the reported duration of illness, and (iii) between the reported duration of illness and the occurrence of severe but otherwise uncomplicated anaemia. There was extensive prior CQ use in our patients presenting with severe malaria, and a high prevalence of parasites with the CQ-resistance genotype. CQ resistance in P. falciparum may contribute to the development of severe but otherwise uncomplicated anaemia in this setting.


Persistent organochlorine pollutants in surface sediments and economic shellfish of Minjiang Estuary-Mazu and Xiamen-Jinmen sea areas.
Samples of surface sediment and shellfish were collected from Minjiang Estuary-Mazu and Xiamen-Jinmen sea areas and were analyzed for hexachlorocyclohexanes (HCHs), dichlorodiphenyl-trichlorophenyl (DDT) and its degraded derivatives dichloro-diphenyl-dichloroethane (DDT) and dichloro-dichlorophenyl-ethylene (DDE), and polychlorinated biphenyls (PCBs) by gas chromatography. Concentration ranges of HCHs, DDTs, and PCBs in the sediments were 0.03-0.48, 1.10-14.3, and ND to 0.76 ng/g dw, respectively; those for shellfish samples were ND to 1.5, 21.5-892, dw and ND-3.7 ng/g dw, respectively. The results showed that the concentrations of such oganochlorine compounds (OCs) in the sediments were usually low as compared with other sea areas and estuaries, and the organochlorines were accumulated in marine bivalve mollusks, particularly in oyster. With respect to the concentrations of HCHs, DDTs, and PCBs in the samples of either sediment or shellfish, DDTs were higher than HCHs and PCBs. The concentrations of OCs in shellfish samples varied with the sampling locations and organism species but were generally higher than those in the sediments. The concentration distributions, compositions, and residue levels of these OCs are extensively discussed and evaluated.


Interim results of adaptive functioning and neurodevelopment in BUTTERFLY - An observational study of children and adolescents with Dravet syndrome.
The purpose of this study is to evaluate adaptive functioning and neurodevelopment study assessments in a prospective study of patients with Dravet syndrome (DS). We present 3-month interim adaptive functioning and neurodevelopment data from the prospective, observational BUTTERFLY study in patients with DS aged 2-18 years. BUTTERFLY enrolled thirty-six patients divided 1:1:1 across three age groups (2-7: 8-12: and 13-18 years). Most enrolled patients were female (61.1%), white (94.4%), and non-Latino (83.3%) with a mean (standard deviation; SD) age of 10.8 (5.2) years and a mean (range) age of seizure onset of 0.4 (0.2-1.0) years. Patients used a mean (SD) of 3.5 (1.63) anti-seizure therapies at baseline. Regression analysis of the baseline Vineland Adaptive Behavior Scale - third edition (VABS-III) composite score indicated that the gap in adaptive function between patients with DS (n = 33) and neurotypical children widens with age. Similarly, developmental quotients calculated for patients who completed all Bayley Scales of Infant Development - third edition (BSID-III) subtests at baseline (n = 15) highlighted a gap in intellectual functioning between patients with DS and neurotypical children that widens with age. More patients in the two older age groups were able to validly complete the Wechsler Preschool and Primary Scale of Intelligence - fourth edition (WPPSI-IV) at baseline compared with the youngest age group. There were trends towards higher raw scores, albeit of low magnitude, in the oldest age group compared with the younger age two groups across multiple VABS-III domains and WPPSI-IV subtests. All three measures showed no significant change in the all-patients analyses and demonstrated relatively low intra-patient variability from baseline to Month 3. Three-month interim data from BUTTERFLY demonstrated the feasibility of utilizing the VABS-III, BSID-III, and WPPSI-IV for the assessment of adaptive function and neurodevelopment in future clinical studies of DS. Moreover, many patients with DS appear to gain neurodevelopmental and adaptive function skills over time, although at a slower rate and lower magnitude than that seen in the neurotypical population.


Rhinocerebral mucormycosis and internal carotid artery thrombosis in a previously healthy patient.
Mucormycosis is a very serious fungal infection caused by habitual saprophytes of the human organism, in many cases concomitant with various pathological conditions marked by immunodepression. The rhinocerebral variant habitually accompanies ketoacidotic diabetes. We report a case of rhinocerebral mucormycosis in a subject free from immunodepression and non-diabetic, in apparently normal health. Following treatment with amphotericin B combined with 5-fluorocytosine and surgery, remission of the disease was finally secured and about one year after the last operation there are no sign of resumption.


DNA methylation in normal and malignant hematopoiesis.
The study of DNA methylation has been a rapidly expanding field since its dawn in the 1960s. DNA methylation is an epigenetic modification that plays a crucial role in guiding the differentiation of stem cells to their destined lineage, and in maintaining tissue homeostasis. Moreover, aberrant DNA methylation has been well characterized as a significant contributing factor in the pathogenesis of a variety of cancers. Hematopoiesis is a process that is uniquely susceptible to epigenetic changes due to the small pool of actively cycling stem cells that give rise to the entire mature immune-hematopoietic system. Mutations in DNA methyltransferase enzymes have been shown to be initiating events in the development of hematological malignancies such as acute myeloid leukemia and, therefore, have become targets for improved diagnostics and therapy. The spatial and temporal regulation of DNA methylation in the hematopoietic developmental hierarchy is critical to hematopoietic homeostasis. An improved understanding of the roles that DNA methylation plays in normal and malignant hematopoiesis will have a significant impact on the future of regenerative stem cell therapy and clinical treatment of hematopoietic malignancies. This review aims to highlight current developments in the field and prioritize future research directions.


Profile of biochemical traits influencing tenderness of muscles from the beef round.
The objective of this study was to define the biochemical differences that govern tenderness and palatability of economically important muscles from the beef round using cuts with known tenderness differences. At 24h postmortem, the longissimus dorsi (LD), gracillus (GR), adductor (AD), semimembranosus (SM), sartorius (SAR), vastus lateralis (VL), and vastus intermedius (VI) muscles were removed from ten market weight beef cattle. Sensory and biochemical characteristics were determined in each cut and compared with the LD. The GR, SAR and VI had sensory traits similar to the LD while the SM, AD and VL differed. The GR, SAR, AD, and SM all had multiple biochemical characteristics similar to the LD, while the VI and AD had numerous biochemical differences. While no one biochemical characteristic can be used to predict tenderness across all muscles, analysis of the biochemical characteristics revealed that in most beef round cuts postmortem proteolysis provided a good indication of the tenderization occurring during aging.


Management of adverse effects of intrathecal opioids in acute pain.
Intrathecal opioids have been used for several decades in different clinical settings. They are easy to administer and provide many benefits in clinical practice, such as better quality of spinal anaesthesia, prolonged postoperative analgesia, decreased postoperative analgesic requirements and early mobilisation. Several lipophilic and hydrophilic opioids are available for intrathecal administration, either in combination with general anaesthesia or as adjuncts to local anaesthetics. Adverse effects after intrathecal lipophilic opioids administration are predominantly short-lived and benign. In contrast, intrathecal hydrophilic opioids may have potentially serious adverse effects, the most feared of which is respiratory depression. In this review, we will focus on the contemporary evidence regarding intrathecal hydrophilic opioids and present their adverse effects and how to manage them.


Evaluation and Management of Venous Thoracic Outlet Syndrome.
Venous thoracic outlet syndrome (TOS) is uncommon but occurs in young, healthy patients, typically presenting as subclavian vein (SCV) effort thrombosis. Venous TOS arises through chronic repetitive compression injury of the SCV in the costoclavicular space with progressive venous scarring, focal stenosis, and eventual thrombosis. Diagnosis is evident on clinical presentation with sudden spontaneous upper extremity swelling and cyanotic discoloration. Initial treatment includes anticoagulation, venography, and pharmacomechanical thrombolysis. Surgical management using paraclavicular decompression can result in relief from arm swelling, freedom from long-term anticoagulation, and a return to unrestricted upper extremity activity in more than 90% of patients.


Structural analyses of polymorphic transitions of sn-1, 3-distearoyl-2-oleoylglycerol (SOS) and sn-1, 3-dioleoyl-2-stearoylglycerol (OSO): assessment on steric hindrance of unsaturated and saturated acyl chain interactions.
Polymorphic transformations in two saturated-unsaturated mixed acid triacylglycerols, SOS (sn -1,3-distearoyl-2-oleoylglycerol) and OSO (sn -1,3-dioleoyl-2-stearoylglycerol), have been studied by FT-IR spectroscopy using deuterated specimens in which stearoyl chains are fully deuterated. A reversible phase transition between sub alpha and alpha and a series of irreversible transitions (alpha-->gamma-->beta'-->beta (beta2, beta1) for SOS and alpha-->beta'-->beta for OSO) were studied with an emphasis on the conformational ordering process of stearoyl and oleoyl chains. The alpha-->sub alpha reversible transition was due to the orientational change of stearoyl chains in the lateral directions from the hexagonal subcell to a perpendicularly packed one. As the first stage of the series of irreversible transitions from alpha to beta, the conformational ordering of saturated chains took place in the alpha-->gamma transition of SOS and in the alpha-->beta' transition of OSO; one stearoyl chain in SOS and OSO takes the all-trans conformation and the second stearoyl chain in SOS takes the bent conformation like those observed in the most stable beta-type. As the final stage, the ordering of unsaturated chains occurred in the beta'-->beta transition both for SOS and OSO. A conversion in the layered structure from bilayer to trilayer was also accompanied by the conformational ordering in the alpha-->gamma transition of SOS and in the beta'-->beta transition of OSO.


The vesicle content of catecholamine-containing axons in the rectum of the domestic fowl: effect of permanganate and chromaffin fixations.
The ultrastructural appearance of catecholamine-containing (CA) axon profiles in the rectum of the domestic fowl was compared following fixation using the chromaffin reaction or potassium permanganate. As described previously, after chromaffin fixation CA-axons in the perivascular plexuses contained many small granular vesicles (SGV) and variable numbers of large granular vesicles (LGV), whereas those in the non-vascular sites contained few small vesicles and were characterised by the presence of elongated LGV. Following fixation in potassium permanganate, CA-axons in both the non-vascular and vascular sites contained many SGV. The SGV were accompanied by variable numbers of large round vesicles which were often devoid of a core. Large vesicles comprised 16 and 26%, respectively, of total vesicles in the vascular and non-vascular axon profiles. The total number of vesicles per CA-axon profile in both the vascular and non-vascular site was not dependent on fixation procedure. It is concluded that the vesicle content of CA-axon profiles in the rectum of the domestic fowl is dependent on the fixative employed.


Psychosocial factors associated with adherence to non-insulin antidiabetes treatments.
To discern psychosocial factors of non-insulin antidiabetes drug (NIAD) adherence. A cross-sectional study based on the theory of planned behavior (TPB). Adults with type 2 diabetes (T2D) who were members of Diabète Québec, a provincial association of persons with diabetes, and were prescribed at least one NIAD were invited to complete a web-based questionnaire. We measured variables ascertaining TPB constructs and other factors potentially associated with NIAD adherence (e.g., habit, social support, and mental health). NIAD adherence was assessed using the 8-item Morisky Medication Adherence Scale. Factors were identified using a multivariate logistic regression model. In our study, 901 participants (373 women; 515 retired; mean age: 62.7 years) with T2D for a mean of 10 years, completed the questionnaire. Participants exhibited a high intention to adhere to their NIAD treatment (mean score=5.8/6), positive attitudes toward adherence (mean score=5.5/6), and elevated perceived behavioral control in taking their medication (mean score=5.7/6). Only 405 (45%) participants reported high adherence (score=8/8). Perceived behavioral control, habit, older age, no perceived side effects, a longer period since T2D diagnosis and a lower number of NIAD daily doses were significantly associated with adherence (p<0.05). We identified several factors that may be modified for NIAD adherence and thereby provided insight into future adherence-enhancing intervention targets.


A case of renal cell carcinoma with multiple lung metastases refractory to interferon-alpha showing complete remission by interleukin-2 monotherapy.
We report a case in which a regimen of interleukin-2 (IL-2) achieved pathologically complete remission against renal cell carcinoma with multiple lung metastases. A 63-year-old man was admitted to the Osaka University Hospital with a right renal tumor and multiple lung metastases. Right radical nephrectomy was performed and the histological diagnosis was clear cell carcinoma, G3 > G2, INFbeta, pT3a, pN0. Postoperatively, despite treatment with interferon-alpha, the lung metastases progressed. Consequently, intravenous administration of IL-2 was started at a dose of 70 x 10(4) JRU/day five times per week. After 16 weeks of IL-2 therapy, most of the multiple lung metastases completely vanished and the largest metastatic lung mass was reduced in size. Resection of this residual lung mass was performed and pathological examination revealed no viable cancer cells.


Task modulation of the effects of brightness on reaction time and response force.
Van der Molen and Keuss [van der Molen, M.W., Keuss, P.J.G., 1979. The relationship between reaction time and intensity in discrete auditory tasks. Quarterly Journal of Experimental Psychology 31, 95-102; van der Molen, M.W., Keuss, P.J.G., 1981. Response selection and the processing of auditory intensity. Quarterly Journal of Experimental Psychology 33, 177-184] showed that paradoxically long reaction times (RT) occur with extremely loud auditory stimuli when the task is difficult (e.g. needs a response choice). It was argued that this paradoxical behavior of RT is due to active suppression of response prompting to prevent false responses. In the present experiments, we demonstrated that such an effect can also occur for visual stimuli provided that they are large enough. Additionally, we showed that response force exerted by participants on response keys monotonically grew with intensity for large stimuli but was independent of intensity for small visual stimuli. Bearing in mind that only large stimuli are believed to be arousing this pattern of results supports the arousal interpretation of the negative effect of loud stimuli on RT given by van der Molen and Keuss.


Skin hyperreactivity of Behçet's patients (pathergy reaction) is also positive in interferon alpha-treated chronic myeloid leukaemia patients, indicating similarly altered neutrophil functions in both disorders.
Typical manifestations of Behcet's disease (BD) and a positive pathergy reaction were observed in a few patients with chronic myeloid leukaemia (CML) on interferon alpha (IFN-alpha) therapy and the significance of this observation was assessed in a prospective study. The skin pathergy test was applied to 15 patients with CML prior to IFN-alpha therapy, 29 patients with CML following IFN-alpha therapy and 30 patients with BD. Twenty-five patients with inflammatory arthropathies (IA), 20 patients with recurrent oral ulcers (ROU), 23 patients treated with IFN-alpha for various disorders and 20 normal individuals were also studied as control groups. The pathergy reaction was positive in nearly a quarter of IFN-alpha-treated CML cases (24%) as well as one-half of the patients with BD (50%). All CML patients prior to IFN-alpha treatment and all patients using IFN-alpha for other diseases were negative for the pathergy reaction. These results may indicate a similarly altered neutrophil function in both BD and IFN-alpha-treated CML patients.


Patterns of physiological parameters and nitrogen partitioning in flag leaf explain differential grain protein content in rice.
The grain protein content (GPC) in rice is low, and more efforts with agronomic and molecular approaches were performed to increase them. However, the rice research focusing on the plant physiological behaviour that modulates the phenomenon of grain protein filling is very scarce. This work contains physiological parameters related to photosynthetic activity in the flag leaf in the grain filling period and N partitioning assays of high (Nutriar) and traditional (Camba) GPC cultivars. Results indicated a higher photosynthetic capacity, a better capacity to provide CO2 to the chloroplast and a healthier PSII structure in Camba relative to Nutriar. Chlorophyll fluorescence parameters decreased more steeply over time in the high protein variety, and a strong negative correlation was observed between GPC and PSII structure parameters. N content in the flag leaf at anthesis showed lower values and higher remobilisation during the grain filling period in Nutriar compared to Camba. The results of this work suggested that the inactivation of some PSII structures in higher GPC cultivars is associated with N remobilisation and would contribute to an increase in the free N available to be translocated to the grain.


Functional outcomes and gait analysis of patients after periacetabular sarcoma resection with and without ischiofemoral arthrodesis.
Treatment of periacetabular sarcomas remains a difficult challenge. Many reconstruction options are fraught with high complication and failure rates. Little is known about patients' functional outcomes, and there have been no studies that examine how these reconstructions affect patients' gait parameters. The purpose of this study is to evaluate gait parameters and functional outcome in patients whom have undergone periacetabular resections with either an ischiofemoral pseudoarthrodesis or soft tissue reconstruction only. Ten patients with sarcoma of the periacetabular region were identified from our database. Functional outcome was assessed using the Musculoskeletal Tumor Society Scores (MSTS) and Toronto extremity salvage score (TESS) scoring systems. Gait analysis was performed on all subjects. Patients in both surgical groups had average functional scores. All patients were ambulatory. Cadence and velocity in the surgical group were significantly slower than the control group, however, the remainder of the gait parameters examined were similar to controls. Patients who underwent minimal reconstruction following periacetabular resections demonstrated average functional scores, comparable to those undergoing more extensive reconstructions. With the exception of speed, gait parameters were not significantly different than controls. Complication rates were low. Pseudoarthrodesis or even no bone reconstruction following periacetabular resection is reasonable and functional options for many of these patients.


A comparison of the cardiovascular effects and subjective tolerability of binedaline and amitriptylene in healthy volunteers.
Binedaline is a new antidepressant drug which is not a tricyclic compound. In animal investigations it showed a greater therapeutic index than imipramine and amitriptylene and a smaller ED50. It also showed less anticholinergic and antihistaminic activity. In this study the effects of 100 mg (females) and 150 mg (males) of binedaline was compared with 50 mg and 75 mg of amitriptylene and placebo in healthy volunteers. Binedaline was better tolerated than amitriptylene and produced less sedation and fewer instances of dry mouth. Binedaline was devoid of the marked postural hypotension produced by amitriptylene but caused the same degree of tachycardia as amitriptylene at rest, when subjects were tilted and when subjected to ergometry. It was concluded that binedaline causes less alpha-adrenergic blockade than amitriptylene but that the sympathomimetic effects were similar. At the doses employed no major changes in electrocardiogram or systolic time intervals occurred.


Ca2+ entry in T cells is activated by emptying the inositol 1,4,5-triphosphate sensitive Ca2+ pool.
Using alpha-linolenic acid (ALA), one of several polyunsaturated fatty acids (PUFAs) that have previously been shown to both mobilize intracellular Ca2+ from the inositol 1,4,5-trisphosphate (IP3)-sensitive Ca2+ pool independently of IP3 production and inhibit Ca2+ influx, the relationship between Ca2+ mobilization from intracellular stores and Ca2+ influx in T cells (JURKAT) was studied. JURKAT cells were treated with 30 microM ALA to deplete the IP3-sensitive Ca2+ pool. When the intracellular free Ca2+ concentration [( Ca2+]i) returned to basal level, fatty acid free bovine serum albumin (BSA) was added to remove extracellular and membrane bound ALA. This resulted in a sustained increase in [Ca2+]i in the absence of inositol phosphates' formation. This sustained increase in [Ca2+]i was insensitive to protein kinase C activation but was inhibited by Ni2+ ions. The extent of Ca2+ influx was found to be correlated to the amount of Ca2+ initially discharged from the IP3-sensitive Ca2+ pool by sub-optimal concentrations of ALA. Ligation of the CD3 complex of the T cell antigen receptor with an anti-CD3 antibody (OKT3) during the sustained [Ca2+]i increased (induced by a sub-optimal concentration of ALA), produced a greater response. No increase in the sustained response was observed when the CD3 complex was activated in cells pretreated with an optimal concentration of ALA. In summary, Ca2+ entry in T cells is activated by emptying of the IP3-sensitive Ca2+ pool which can be dissociated from inositol phosphate production. The rate of Ca2+ influx appears to be closely correlated to the initial discharge of Ca2+ from the IP3-sensitive Ca2+ pool, suggesting that Ca2+ may first enter the depleted pool and then is released into the cytosol.


Peripheral canine CD4(+)CD8(+) double-positive T cells - unique amongst others.
T lymphocytes co-expressing CD4 and CD8 ("double-positive T cells") are commonly associated with a thymic developmental stage of T cells. Their first description in humans and pigs as extrathymic T cells with a memory phenotype almost 30 years ago came as a surprise. Meanwhile peripheral double-positive T cells have been described in a growing number of different species. In this review we highlight novel data from our very recent studies on canine peripheral double-positive T cells which point to unique features of double-positive T cells in the dog. In contrast to porcine CD4(+)CD8(+) T cells forming a homogenous cellular population based on their expression of CD4 and CD8α, canine CD4(+)CD8(+) T cells can be divided into three different cellular subsets with distinct expression levels of CD4 and CD8α. Double-positive T cells expressing CD8β are present in humans and dogs but absent in swine. Moreover, canine CD4(+)CD8(+) T cells can not only develop from CD4(+) single-positive T cells but also from CD8(+) single-positive T cells. Together, this places canine CD4(+)CD8(+) T cells closer to their human than porcine counterparts since human double-positive T cells also appear to be heterogeneous in their CD4 and CD8α expression and have both CD4(+) and CD8(+) T cells as progenitor cells. However, CD4(+) single-positive T cells are the more potent progenitors for canine double-positive T cells, whereas CD8(+) single-positive T cells are more potent progenitors for human double-positive T cells. Canine double-positive T cells have an activated phenotype and may have as yet unrecognized roles in vivo in immunity to infection or in inflammatory diseases such as chronic infection, autoimmunity, allergy, or cancer.


Stage-specific activity in vitro on the Theileria infection process of serum from calves treated prophylactically with buparvaquone.
An in vitro method for testing activity of buparvaquone in serum on the infection and development of Theileria in its bovine host mononuclear cells is described and results compared with the effect exhibited in vivo. Serum samples were collected over a time course from calves in a clinical trial of 5 mg kg(-1) buparvaquone prophylaxis on Theileria annulata or T. parva experimental infection. To evaluate drug levels and persistence in each animal for a period of 14 days and its effect on the early infection stages, the sera were tested on established macroschizont infected cell lines and against the in vitro infection and development process of the sporozoite and trophozoite stages of the two Theileria species. Results from the in vitro assays show that buparvaquone in serum can completely prevent the establishment of Theileria infection during the first 48 h after administration at 5 mg kg(-1). After seven days, levels are sufficient to delay the establishment of infection. The drug is more effective in the prevention of the de novo development of the parasite in cells than against established macroschizont infected cell culture. At low concentrations, it is more effective against T. parva than against T. annulata. Drug effect peaks during the first 24 h but residual effect persists for 14 days, particularly against T. parva infection. These novel findings demonstrate how high doses of buparvaquone could over-protect calves if used in the 'infection-and-treatment' method of immunisation when drug is administered prophylactically at the same time as infection with live sporozoites. It is suggested that in certain high Theileria risk situations there may be potential for the immunoprophylactic use of buparvaquone without simultaneous infection. The in vitro assay itself has been shown to be of value as a model for Theileria establishment in cattle.


Inhibition of Insulin Degrading Enzyme to Control Diabetes Mellitus and its Applications on some Other Chronic Disease: a Critical Review.
This review aims to provide a precise perceptive of the insulin-degrading enzyme (IDE) and its relationship to type 2 diabetes (T2D), Alzheimer's disease (AD), obesity, and cardiovascular diseases. The purpose of the current study was to provide clear idea of treating prevalent diseases such as T2D, and AD by molecular pharmacological therapeutics rather than conventional medicinal therapy. To achieve the aims, molecular docking was performed using several softwares such as LIGPLOT+, Python, and Protein-Ligand Interaction Profiler with corresponding tools. The IDE is a large zinc-metalloprotease that breakdown numerous pathophysiologically important extracellular substrates, comprising amyloid β-protein (Aβ) and insulin. Recent studies demonstrated that dysregulation of IDE leads to develop AD and T2D. Specifically, IDE regulates circulating insulin in a variety of organs via a degradation-dependent clearance mechanism. IDE is unique because it was subjected to allosteric activation and mediated via an oligomer structure. In this review, we summarised the factors that modulate insulin reformation by IDE and interaction of IDE and some recent reports on IDE inhibitors against AD and T2D. We also highlighted the latest signs of progress of the function of IDE and challenges in advancing IDE- targetted therapies against T2D and AD.


Serum markers of collagen metabolism in patients with diseases of the respiratory system.
The variations of the serum markers of collagen metabolism such as total and free hydroxyproline and hydroxylysine and collagen-like protein were studied in patients with chronic bronchitis, pneumonia and emphysema as compared to healthy controls. The values found in diseased subjects were significantly higher than in controls.


Pre- and probiotic overview.
The dynamic relationship between gut microbiota and its human host is also known as a trophic association that might range from commensalism, where only the microbe enjoys a positive effect from the relationship, to intestinal symbiosis where both host and microbe benefit from their interaction. In the last years, we have started to understand how alterations of the gut microbiota composition leading to the disruption of host-microbial interactions are associated and/or predispose individuals to disease conditions ranging from inflammatory bowel diseases to allergy and functional gastrointestinal disorders, such as irritable bowel syndrome. While we await important insights in this field, the microbiota is already a therapeutic target. Based on the actual definitions, prebiotics are defined as substrates that are selectively utilized by host microorganisms conferring a health benefit, while probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. Although their health promoting activities encompasses numerous effects, including immunostimulation, competitive exclusion of pathogens, and gut barrier enhancement, the exact mechanism of action by which these compounds exert their beneficial actions in humans is only partially known. In this review, we highlight the current insights into the clinical applications of prebiotics and probiotics in gastroenterology.


Role of norepinephrine in the dorsomedial hypothalamic panic response: an in vivo microdialysis study.
Blockade of gamma-aminobutyric acid-A (GABA(A)) receptors in the dorsomedial hypothalamus (DMH) elicits a panic-like response that includes increases in heart rate (HR), blood pressure (BP), respiration rate (RR), and anxiety. Norepinephrine (NE) has been postulated to be critical in regulating panic and anxiety responses. Therefore, the first study sought to determine changes in extracellular NE levels within the DMH following acute blockade of GABA(A) receptors in the DMH using in vivo microdialysis. Rats were implanted with femoral arterial catheters and microdialysis probes into the DMH. Following recovery, the DMH of conscious rats were perfused with 100, 150, or 200 microM solutions of the GABA(A) receptor antagonist bicuculline methiodide (BMI) via the microdialysis probe. HR and BP responses were recorded and the changes in extracellular levels of NE in the dialysate samples from the DMH were determined by HPLC. Rats receiving BMI injections showed dose-dependent increases in both the extracellular NE levels in the DMH as well as HR and BP. The second study was conducted to test the functional importance of NE in the DMH to the BMI-induced physiological responses. The effects of BMI microinjection into the DMH were measured at baseline and 10 days after local injection of either vehicle or two doses of 6-hydroxydopamine (6-OHDA), a neurotoxin known to lesion NE terminals. There was a significant loss of tissue NE levels as well as BMI-induced HR, BP and RR responses in the 6-OHDA-treated but not vehicle-treated rats. Thus, blockade of GABA(A) receptors in the DMH results in NE release and the presence of NE appears to be necessary for eliciting the physiological components of the panic-like responses in this region.


The thymus in "bare lymphocyte" syndrome: significance of expression of major histocompatibility complex antigens on thymic epithelial cells in intrathymic T-cell maturation.
Thymic biopsies from two patients with combined immunodeficiency and defective expression of HLA class I and class II antigens on blood mononuclear cells ("bare lymphocyte" syndrome) were investigated. This made possible an evaluation of the significance of HLA antigen expression in a detailed (immuno)histologic study. Both thymuses showed a normal lobular architecture with distinct cortex-medulla areas, well-differentiated epithelium, including ultrastructurally defined subtypes, and Hassall's corpuscles. Normal numbers of lymphoid cells were present and normal T-cell phenotype was found. Using anti-HLA-A,B,C antisera, confluent staining of the medulla (stroma and lymphocytes) was observed. One of the thymuses was found to be negative for HLA class II antigen expression: the other revealed only HLA-DR positivity of nonlymphoid cells in the medulla. These cells were not of epithelial nature as judged from double staining with anti-keratin antibody. There was no expression of HLA-DC/DS. These observations differ from findings in the normal thymus, wherein epithelial cells in the cortex carry HLA class I and class II antigens, and epithelial cells in the medulla express HLA class I, and for a minor part class II antigens. The results indicate a normal sequential acquisition of T-cell differentiation antigens in the thymus of both cases. It is suggested that the expression of HLA class I and class II antigens on epithelial cells in the normal thymus cortex does not play a significant role in the sequential acquisition of differentiation antigens on T lymphocytes.


Activation by ATP of a P2U 'nucleotide' receptor in an exocrine cell.
1. We employed the perforated patch whole-cell technique to investigate the effects of ATP and other related nucleotides on membrane conductances in avian exocrine salt gland cells. 2. ATP (10 microM-1 mM) evoked an increase in maxi-K+ and Cl- conductances with a reversal potential of -35 mV. At lower concentrations of ATP (< or = 100 microM) responses were generally oscillatory with a sustained response observed at higher concentrations (> or = 200 microM). 3. Both oscillatory and sustained responses were abolished by the removal of bath Ca2+. In cells preincubated in extracellular saline containing reduced Ca2+, the application of ATP resulted in a transient increase in current. 4. As increasing concentrations of ATP (and related nucleotides) evoked a graded sequence of events with little run-down we were able to establish a rank order of potency in single cells. The order of potency of ATP analogues and agonists of the various P2-receptor subtypes was UTP > ATP = 2-methylthio-ATP > ADP. Adenosine (1 microM-1 mM), AMP (1 microM-1 mM), alpha,beta-methylene-ATP (1 microM-1 mM) and beta,gamma-methylene-ATP (1 microM-1 mM) were without effect. 5. In conclusion, although unable to preclude a role for a P2Y-receptor, our results suggest that ATP binds to a P2U-receptor increasing [Ca2+]i and subsequently activating Ca(2+)-sensitive K+ and Cl- currents.


Cardiac MRI Left Atrial Strain Associated With New-Onset Atrial Fibrillation in Patients With ST-Segment Elevation Myocardial Infarction.
Left atrial (LA) strain is associated with structural remodeling of the LA. Whether there is an association between LA strain obtained by cardiac magnetic resonance imaging (MRI) and new-onset atrial fibrillation (AF) after ST-segment elevation myocardial infarction (STEMI) is unclear. To investigate the relationship between LA strain and new-onset AF after STEMI. Retrospective. Three hundred and seventy-nine STEMI patients were enrolled, of which 26 had new-onset AF. 3.0 T, balanced turbo field echo sequence. Patients were divided into w/o AF group and new-onset AF group. Cardiac MRI images were analyzed using cardiovascular imaging software CVI 42 (Circle Cardiovascular Imaging, Canada). An automatic tracing algorithm was applied to obtain strain values. The reservoir strain, conduit strain, and booster strain were included in model 1, model 2, and model 3, respectively. Student's t-test, Mann-Whiney U test, and chi-square test were performed. Variables with a P ≤ 0.05 were incorporated into the logistic regression analysis. Area under curve of receiver operating characteristic was used to assess the ability of LA strain to identify new-onset AF. Bayesian information criterion, Akaike information criterion, and C-index were used to make comparisons between three models. P < 0.05 was considered statistically significant. Three models were used to assess LA strain identification ability for new-onset AF. After including multiple factors, right coronary artery (RCA), LVEF, and reservoir strain were still risk factors for new-onset AF in model 1. In model 2, age, RCA, LVEF, and conduit strain were still risk factors for new-onset AF. In model 3, RCA, LVEF, LVEDVi, and booster strain were still risk factors for new-onset AF. Model 2 has a stronger identification ability than others. LA strain associated with new-onset AF after STEMI. The model including conduit strain was the best-fit one. 4 TECHNICAL EFFICACY: Stage 3.


Advances in the therapy of the myelodysplastic syndromes.
The study of the proliferation and differentiation of the MDS clone at the molecular level, including the details of apoptosis, may hopefully lead to more effective differentiation-induction/antiapoptotic agents. The study of the cytokines at the cellular/molecular level may lead to more effective trails of combination therapy with differentiation-induction agents, chemotherapy, and/or early-acting cytokines. Further phenotypic characterization of the MDS clone may lead to negative selection of these cells or positive selection of normal stem cells as part of an autotransplant strategy, as is presently being done in chronic-phase chronic myeologenous leukemia. The use of agents such as the topoisomerase I inhibitors (e.g., topotecan), which have mechanisms of action disparate from agents already used in MDS, may increase the efficacy of chemotherapy for MDS. The further clinical refinements in reducing treatment-related mortality and the study of T cells at the molecular level may hopefully lead to improvement in the prevention and therapy of graft-versus-host disease, in turn increasing the upper age limit of allogeneic BMT for MDS and increasing the feasibility of matched unrelated allogeneic BMT. At present, we can tailor the approach to a MDS patient based on his or her IPSS risk stratification, degree of cytopenia, and age, as outlined in Figure 2. At present, we can tailor the approach to a MDS patient based on his or her IPSS risk stratification, degree of cytopenia, and age, as outlined in Figure 2.