Photodiagnosis and treatment of condyloma acuminatum using 5-aminolevulinic acid and homemade devices.
The objective of this study was to improve the feasibility of applying topic 5-aminolevulinic acid (ALA) in photodiagnosis (PD) and treatment of condyloma caused by human papillomavirus (HPV) using two homemade handheld devices and to discuss the photodynamic therapy (PDT) as a suitable alternative for each of the cases studied. Both, protoporphyrin IX production and photodegradation were analyzed, and the pain experienced during the illumination was correlated with the light intensities. A total of 40 women with different grades of lesions caused by HPV were chosen from patients of the School of Medicine of Ribeirão Preto (University of Sao Paulo) and of the Unit of Public Health of Araraquara, Sao Paulo. We did not encounter any unexpected difficulties using our devices during the treatment. The existence of an easily observable reddish fluorescence with large intensity concentrated on the lesions is the clinical indication of the penetration and the selective concentration of protoporphyrin IX in the clinical and subclinical lesions rather than in the healthy tissue. The aesthetic results were much better than those obtained by conventional techniques as surgery or cryogenics, with no recurrence reported after two years of treatment. Our results are proof for the various advantages using ALA cream for the PD and PDT in many different cases of condyloma by HPV. This study will be continued to investigate the PpIX photobleaching and the irradiance and fluence rate to optimize conducting the clinical trials, to improve the devices and therefore increase the treatment response.


Effect of antihypertensive treatment on the increased beta 2-adrenoceptor density in patients with essential hypertension.
The effect of different antihypertensive drugs on the increased surface beta 2-adrenoceptor density in essential hypertension was evaluated to elucidate whether the possible effect of the treatment on these receptors was secondary to blood pressure decreases or a specific effect of the drugs. Thirty-nine untreated essential hypertensive patients and 28 normotensive control subjects were studied in basal conditions. Hypertensive patients were randomly assigned to three treatment groups: bisoprolol (10 mg/day, n = 15), enalapril (20 mg/day, n = 12), and verapamil SR (240 mg/day, n = 12), and were studied before and after 1 month of treatment. Plasma catecholamines were determined by a radioenzymatic assay. Surface beta 2-adrenoceptors were measured in intact lymphocytes by radioligand binding assay using the hydrophilic ligand [3H]-CGP12177. beta 2-adrenoceptor density was increased in hypertensive patients (P < .01). After treatment, mean blood pressure decreased similarly in the three groups, while plasma catecholamines showed no significant changes in any group. beta 2-adrenoceptor number decreased only in bisoprolol-treated patients (P < .05). Mean blood pressure decreases correlated with beta 2-adrenoceptor decrements only in bisoprolol-treated patients (r = 0.65, P < .05). beta 2-adrenoceptor density correlated with plasma epinephrine levels in the control group (r = -0.50, P < .01), but not in hypertensive patients before treatment. This correlation was also observed in hypertensive patients treated with bisoprolol (r = -0.52, P < .05), but not in those treated with verapamil or enalapril. Our results suggest that bisoprolol treatment reduces the increased surface beta 2-adrenoceptor density and restores its regulation by epinephrine in essential hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)


Drug-induced sleep-endoscopy in children's sleep related breathing disorders.
Drug-induced sedation endoscopy is a valid tool to assess site obstruction of the upper airway responsible for children's obstructive Sleep Apnea The aim is to show the experience of an ENT department with Drug-induced sedation endoscopy in children selected for sleep apnea surgery Includes 56 cases between 2 and 12 years old (mean age: 59,13±27,29 months) presenting at the Otorhinolaryngology consultation clinic with snoring and apnea. Prior polysomnography had been practiced and mean AHI was 6,32±8,71. The distribution of cases was 10 persistent sleep apnea (17.85%), 15 clinical disproportion (26.78%) and 31 conventional (55.35%). All sleep endoscopies were performed in the operating room and Chan classification was used to assess the areas of collapse. In cases of residual disease the most affected regions were the side walls of the oropharynx (70%) and turbinate (70%) and the most frequently applied surgery was total tonsillectomy followed by second tongue tonsil reduction and turbinate radiofrequency. In clinical cases of desproportion, the most affected regions were the oropharyngeal side walls (93.3%) and adenoids (66.6%). The most frequently applied surgery in this group was adenoidectomy and radiofrequency tonsillotomy. Drug-induced sedation endoscopy is a technique that can be incorporated easily into medical practice, mostly in children with residual sleep apnea syndrome or those suspected to have some cause other than adenotonsillar hypertrophy.


Clindamycin phosphate 1% gel in acne vulgaris.
A 12-week study compared Clindagel, a unique water-based gel formulation of clindamycin phosphate 1%, administered once daily, and Cleocin T, a slightly different gel formulation indicated for twice-daily use, in the treatment of acne vulgaris. Clindagel was safe and effective and equivalent to Cleocin T gel, albeit with a better tolerability profile. Clindagel is a viable alternative to Cleocin T gel.


Ultrastructural evidence of direct synaptic contact of catecholamine terminals with oxytocin-containing neurons in the parvocellular portion of the rat hypothalamic paraventricular nucleus.
Ultrastructural evidence of the direct interaction between catecholamine (CA) terminals and oxytocin (OX)-containing neurons in the parvocellular portion of the rat hypothalamic paraventricular nucleus was demonstrated using immunohistochemistry combined with false transmitter (5-hydroxydopamine, 5-OHDA) histochemistry. At the parvocellular portion, 5-OHDA labelled CA terminals make synaptic contact with proximal dendrites or somas of OX-positive cells, suggesting that the ascending CA system monosynaptically regulates the extrahypothalamic OX system.


Effect of chronic low-level cadmium intoxication on the Haversian remodeling system in dogs.
This experiment was carried out in order to determine whether the chronic administration of low doses of cadmium resulted in an alteration of the haversian bone remodeling system in dogs. Two pairs of littermate beagles were administered 25 ppm cadmium chloride in their drinking water for 6 months. Four beagles matched for age and sex from the same colony served as controls. By means of fluorescent labeling, we measured haversian bone remodeling parameters according to the techniques described by Frost. Statistical analysis of the results showed significant changes at the 0.01 level in: activation frequency, appositional rates, and number of osteoid seams. At the 0.05 level, significant differences were found in the number of resorption spaces and the bone formation rate. In the absence of other evidence indicative of an alteration in the internal milieu of the dogs, it is concluded that a direct toxic action of cadmium on the mechanisms of activation of cells responsible for the creation and formation of new haversian systems cannot be excluded.


Haemoglobin levels following unicompartmental knee arthroplasty: influence of transfusion practice and surgical approach.
A retrospective review was undertaken of preoperative and day 3 postoperative haemoglobin (Hb) levels in all unicompartmental knee arthroplasty (UKA) procedures performed by a single surgeon. Sixty-six UKAs were performed using the same prosthesis through an open approach with patella eversion. This group was compared with 212 UKAs performed using a minimally invasive approach without patella eversion, with an implant and instrumentation specifically devised for this approach. Both groups were well matched for patient demographics, surgical and anaesthetic techniques, thromboprophylaxis, and postoperative regimes. All patients received transfusions with pre-donated blood, except the unilateral minimally invasive approach group. An analysis of covariance was undertaken to examine the influence of the surgical approach and whether surgery was unilateral or bilateral, taking into account preoperative Hb levels and units of blood transfused. The average fall in Hb following UKA, adjusted for other variables, was 2.73 g/dl with an open approach compared to 1.82 g/dl with a minimally invasive approach. This difference was significant (p=0.0044). The average postoperative Hb in the minimally invasive group was 12.05 g/dl (range, 8.8 to 15.8 g/dl). Patients undergoing unilateral minimally invasive UKA are unlikely to develop symptomatic anaemia and should not be required to predonate blood or undergo transfusion.


Laparoscopic sleeve gastrectomy induces sustained changes in gray and white matter brain volumes and resting functional connectivity in obese patients.
Obesity is associated with decreased brain gray- (GM) and white-matter (WM) volumes in regions. Laparoscopic sleeve gastrectomy (LSG) is an effective bariatric surgery associated with neuroplastic changes in patients with obesity at 1 month postLSG. To investigate whether LSG can induce sustained neuroplastic recovery of brain structural abnormalities, and whether structural changes are accompanied by functional alterations. University hospital, longitudinal study. Structural magnetic resonance imaging and voxel-based morphometry analysis were employed to assess GM/WM volumes in 30 obese participants at preLSG and 1 and 3 months postLSG. One-way analysis of variance modeled time effects on GM/WM volumes, and then alterations in resting-state functional connectivity (RSFC) were assessed. Significant time effects on GM volumes were in caudate (F = 11.20), insula (INS; F = 10.11), posterior cingulate cortex (PCC; F = 13.32), and inferior frontal gyrus (F = 12.18), and on WM volumes in anterior cingulate cortex (F = 15.70), PCC (F = 15.56), and parahippocampus (F = 17.96, PFDR < .05). Post hoc tests showed significantly increased GM volumes in caudate (mean change ± SEM .018 ± .005 and P = .001, .031 ± .007 and P < .001), INS (.027 ± .008 and P = .003, .043 ± .009 and P < .001), and PCC (.008 ± .004 and P = .042, .026 ± .006 and P < .001), and increased WM volumes in anterior cingulate cortex (.029 ± .006 and P < .001, .041 ± .008 and P < .001), PCC (.017 ± .004 and P < .001, .032 ± .006 and P < .001), and parahippocampus (.031 ± .008 and P =.001, .075 ± .013 and P < .001) at 1 and 3 months postLSG compared with preLSG. Significant increases in GM volumes were in caudate (.013 ± .006 and P = .036), PCC (.019 ± .006 and P = .006), and inferior frontal gyrus (.019 ± .005 and P = .001), and in WM volumes in anterior cingulate cortex (.012 ± .005 and P = .028), PCC (.014 ± .006 and P = .017), and parahippocampus (.044 ± .014 and P = .003) at 3 relative to 1 month postLSG. GM volumes in INS and PCC showed a positive correlation at 1 (r = .57, P = .001) and 3 months postLSG (r = .55, P = .001). GM volume in INS and PCC were positively correlated with RSFC of INS-PCC (r = .40 and P = .03, r = .55 and P = .001) and PCC-INS (r = .37 and P = .046, r = .57 and P < .001) at 1 month postLSG. GM volume in INS was also positively correlated with RSFC of INS-PCC (r = .44, P = .014) and PCC-INS (r = .38, P = .037) at 3 months postLSG. LSG induces sustained structural brain changes, which might mediate long-term benefits of bariatric surgery in weight reduction. Associations between regional GM volume and RSFC suggest that LSG-induced structural changes contribute to RSFC changes.


Lisinopril-lactose incompatibility.
A chemical interaction between lisinopril and lactose was demonstrated and quantified in dilute mixtures in the solid state.


Depression and substance use: The CES-D's utility in predicting treatment outcomes in a longitudinal multi-site study of residential treatment centers.
This investigation utilized a large sample of individuals undergoing substance use treatment to examine the CES-D's structural validity and establish its predictive utility relative to treatment discharge. The sample included 5750 individuals who were receiving substance abuse treatment at 19 different residential treatment facilities. The CES-D was administered to participants over the course of their time in a residential inpatient substance use treatment program. The present study used a split sample method to conduct both exploratory (EFA) and confirmatory (CFA) factor analyses. Results of both the EFA and CFA indicated that the CES-D contains three first order factors measuring negative mood, positive affect, and interpersonal interactions as well as a second-order high score factor which can be used to guide interpretation and symptom monitoring. Individuals receiving residential treatment fell into one of three distinct groups based on their CES-D scores, and that their scores (and subsequent trajectories of scores over time) were differentially related to discharge status. Implications for practice and the utility of the CES-D within substance use populations are discussed.


Radionuclide transit in patients with colon interposition.
To assess radionuclide transit in interposed segments of the colon, we examined 25 patients with colon interposition for benign esophageal disease. No such assessment has been reported previously. The most common indications for operation were esophageal strictures that developed after lye ingestion and reflux strictures not responding to other treatment. The operations were performed without thoracotomy by blunt esophageal dissection in 80% of the patients. There were 18 antiperistaltic and seven isoperistaltic colon grafts. A large-field gamma camera and computer system were used. Data were collected at time intervals of 0.5 second during the first 30 seconds and at intervals of 30 seconds up to 20 minutes. The 5% and 90% stomach filling times, times to 50% and 25% activity levels, and residual activity levels as a percentage of the maxima were calculated in the upper, middle, and lower thirds of the colon grafts and of the normal esophagus of 10 healthy control subjects. The examinations were performed with the subject in a sitting position. All parameters showed that emptying of the colon graft was markedly slower than that of the normal esophagus. The intra-abdominal third of the graft had a residual activity of 50.5% +/- 15.7% after 20 minutes' observation. No differences between antiperistaltic and isoperistaltic grafts were observed. Reconstruction with proximal cologastric anastomosis and a short intra-abdominal colon graft segments is suggested.


Ambient ionization mass spectrometry imaging for disease diagnosis: Excitements and challenges.
Tissue analysis in histology is extremely important and also considered to be a gold standard to diagnose and prognosticate several diseases including cancer. Intraoperative evaluation of surgical margin of tumor also relies on frozen section histopathology, which is time consuming, challenging and often subjective. Recent development in the ambient ionization mass spectrometry imaging (MSI) technique has enabled us to simultaneously visualize hundreds to thousands of molecules (ion images) in the biopsy specimen, which are strikingly different and more powerful than the single optical tissue image analysis in conventional histopathology. This paper will highlight the emergence of the desorption electrospray ionization MSI (DESI-MSI) technique, which is label-free, requires minimal or no sample preparation and operates under ambient conditions. DESI-MSI can record ion images of lipid/metabolite distributions on biopsy specimens, providing a wealth of diagnostic information based on differential distributions of these molecular species in healthy and unhealthy tissues. Remarkable success of this technology in rapidly evaluating the cancer margin intraoperatively with very high accuracy also promises to bring this imaging technique from bench to bedside.


Reflections of a Vaccinologist: Lessons Learned About What We Can Do to Improve Trust in Vaccines and Vaccine Programsa.
Public trust can be improved by learning from past mistakes, by establishing a standing forum for review of new concerns as they arise, and by maintaining a robust vaccine safety system. Developing standard guidelines for reporting causality assessment in case reports would help educate physicians and prevent future unnecessary concerns based on false assumptions of causal relationships.


[The growth stimulation of a cell culture of dissociated rat embryonic spinal cord under the influence of the opioid peptide dalargin and the opioid receptor blocker naloxone].
Effect of synthetic analog of [Leu]-enkephalin dalargin and naloxone as a opioid blocker on fetal rat spinal cord cells was studied. It was found that the aggregation place during dalargin action had increased on average by 1.85 compared to the control, during naloxone action had increased on average by 1.78 compared to the control. The fact that brain cells reactions on opioid and on naloxone are the same and naloxone-peptide mixture is more active by 2.5 times compared to control suggests that these agents effect the cells with the help of receptors of different types, thus these agents are growth factors for nervous tissue, they increase survival and adhesion of the cells of CNS.


CRISPR/Cas mediated base editing: a practical approach for genome editing in oil palm.
The improvement of the yield and quality of oil palm via precise genome editing has been indispensable goal for oil palm breeders. Genome editing via the CRISPR/Cas9 (CRISPR-associated protein 9) system, ZFN (zinc finger nucleases) and TALEN (transcription activator-like effector nucleases) has flourished as an efficient technology for precise target modifications in the genomes of various crops. Among the genome editing technologies, base editing approach has emerged as novel technology that could generate single base changes i.e. irreversible conversion of one target base in to other in a programmable manner. A base editor (adenine or cytosine) is a fusion of catalytically inactive CRISPR-Cas9 domain (Cas9 variants) and cytosine or adenosine deaminase domain that introduces desired point mutations. However, till date no such genetic modifications have ever been developed in oil palm via base editing technology. Precise genome editing via base editing approach can be a challenging task in oil palm due to its complex genome as well as difficulties in tissue culture and genetic transformation methods. However, availability of whole genome sequencing data in oil palm provides a platform for developing the base editing technology. Here, we briefly review the potential application and future implications of base editing technology for the genetic improvement of oil palm.


Distractors associated with reward break through the focus of attention.
In the present study, we investigated the conditions in which rewarded distractors have the ability to capture attention, even when attention is directed toward the target location. Experiment 1 showed that when the probability of obtaining reward was high, all salient distractors captured attention, even when they were not associated with reward. This effect may have been caused by participants suboptimally using the 100%-valid endogenous location cue. Experiment 2 confirmed this result by showing that salient distractors did not capture attention in a block in which no reward was expected. In Experiment 3, the probability of the presence of a distractor was high, but it only signaled reward availability on a low number of trials. The results showed that those very infrequent distractors that signaled reward captured attention, whereas the distractors (both frequent and infrequent ones) not associated with reward were simply ignored. The latter experiment indicates that even when attention is directed to a location in space, stimuli associated with reward break through the focus of attention, but equally salient stimuli not associated with reward do not.


Arrested development of sheep strongyles: onset and resumption under field conditions of Central Europe.
Two tracer tests were conducted between August 2004 and March 2007 at an ecological farm in western Bohemia. The first tracer test was performed for the summer-autumn grazing period (onset of arrested development), the second for spring (resumption of arrested development). In the first tracer test, the percentage of nematodes arresting development over the winter months reached 87.7% for Teladorsagia circumcincta, 66.7% for Haemonchus contortus, 89.9% for Nematodirus filicollis, 21.6% for Trichostrongylus axei, and 23.9% for both Trichostrongylus vitrinus and Trichostrongylus colubriformis. None of the arrested larvae were observed with species Cooperia curticei, Nematodirus battus, and Oesophagostomum venulosum. In the second tracer test, a significant increase of adult worms was discovered in March of species T. circumcincta and N. filicollis and Trichostrongylus spp. in February. Redundancy analysis and generalized linear models analyses have confirmed that environmental conditions play a crucial role in hypobiosis of sheep strongyles in the Czech Republic. The analysis of influences of various environmental factors revealed that the number of arrested larvae was negatively influenced by light-day length, sunshine, or daylight decrease (p < 0.01).


Antipsychotic potential of CCK-based treatments: an assessment using the prepulse inhibition model of psychosis.
Systemic injections of cholecystokinin (CCK), a "gut-brain" peptide, have been shown to modulate brain dopamine function and produce neuroleptic-like effects on such dopamine-regulated behaviors as locomotor activity. However, clinical trials of CCK agonists in schizophrenia patients showed mixed results. To re-examine the antipsychotic potential of CCK-based treatments, we examined systemic injections of CCK analogs in an animal model with strong face and construct validity for sensorimotor-gating deficits seen in schizophrenia patients and with strong predictive validity for antipsychotic drug activity. Prepulse inhibition (PPI) occurs when a weak acoustic lead stimulus ("prepulse") inhibits the startle response to a sudden loud sound ("pulse"). PPI is significantly reduced in schizophrenia patients and rats treated with dopamine agonists. Antipsychotics reverse decreased PPI in rats to a degree highly correlated with their clinical efficacy. Subcutaneous (s.c.) injections of caerulein (10 micrograms/kg) a mixed CCKA/B agonist, partially reversed amphetamine-induced reduction of PPI; whereas, s.c. haloperidol (0.5 mg/kg) totally reversed amphetamine-induced disruption of PPI. Caerulein's effect on PPI was blocked by pretreatment with a CCKA antagonist (devazepide) but not a CCKB antagonist (L-365,260). CCK-4, a preferential CCKB agonist, had no significant effect on PPI. These results suggest that caerulein produces a weak neuroleptic-like effect on PPI that is mediated by stimulation of CCKA receptors. Possible circuities in this effect are discussed. In a separate experiment, s.c. caerulein produced to a more potent neuroleptic-like profile on amphetamine-induced hyperlocomotion, suggesting that selection of preclinical paradigms may be important in evaluating the antipsychotic potential of CCK-based treatments.


Development and validation of a model to determine the risk of esophageal strictures after endoscopic submucosal dissection for esophageal neoplasms.
Currently, endoscopic submucosal dissection (ESD) is widely used as therapeutic methods for superficial esophageal neoplasms (SENs). However, patients are likely to develop esophageal strictures after ESD. Our study aims to explore the possible risk factors for esophageal strictures after ESD and develop and validate a risk model for predicting the progression of postoperative esophageal strictures. Clinical data of patients who underwent ESD in our hospital for suspected early esophageal squamous cell carcinoma were collected from January 2014 to March 2020. The possible risk factors for postoperative esophageal strictures were analyzed by univariate and multivariate logistic regression analysis. Eventually, a risk-scoring model was built, in which 70% of patients were used to develop the model and the remaining 30% were used for validation. A total of 553 patients who received ESD were involved, and the incidence of esophageal strictures after ESD was 16.6% (92/553). In our study, the operating time, circumferential range, lesion location, depth of infiltration, and R0 resection were independent risk factors for esophageal strictures after ESD. According to the risk of postoperative esophageal stenosis, a risk-scoring model for esophageal strictures prediction was developed. The risk score ranged from 0 to 11 points, and the risk scores were divided into low risk (0-3 points), intermediate risk (4-7 points), and high risk (8-11 points). The proportions of esophageal stenosis progression in the corresponding risk categories were 6.33%, 29.14%, and 100%. We developed a risk-scoring model based on factors including circumferential range, lesion location, depth of infiltration, and R0 resection. It stratified patients into low-, intermediate-, and high-risk groups for postoperative esophageal strictures development. This scoring model may have the potential to guide the management of patients after ESD in the future.


Effect of pentazocine on the evoked potentials recorded in the primary somesthetic cortical areas of guinea pigs.
The influence of pentazocine on the evoked potentials registered in the primary somesthetic cortical area in guinea pigs under pentobarbital anesthesia was studied. The stimulation was applied in the contralateral lip and the evoked cortical responses from different zones on the cortex stereotaxically localized were registered. Pentazocine (5-10 mg/kg i.v.) induced a significant increase in the latency of the evoked potentials as compared with controls. Since morphine does not modify these potentials, the effect of pentazocine is interpreted as being a direct one on the primary pain pathway.


Comparison of the Survival Outcomes of Minimally Invasive Surgery with Open Surgery in Patients with Uterine-Confined and Node-Negative Cervical Cancer: A Population-Based Study.
We aimed to compare the oncological outcomes between Japanese women with uterine-confined and node-negative cervical cancer who underwent open surgery and those who underwent minimally invasive surgery (MIS). A population-based retrospective cohort study was conducted using data from the Osaka Cancer Registry that ranged from 2011 to 2018. A total of 2279 patients who underwent surgical treatment for uterine-confined and node-negative cervical cancer were identified. The patients were classified into groups according to surgery type (open and MIS groups) and year of diagnosis (group one, 2011-2014; group two, 2015-2018). The oncologic outcomes were compared between the MIS and open groups. When the MIS group (n = 225) was compared with open group (n = 2054), overall, there was no significant between-group difference in terms of overall survival. Based on Kaplan-Meier estimates, the probability of overall survival at four years was 99.5% in the MIS group and 97.2% in the open group (p = 0.1110). When examined according to the year of diagnosis, there were no significant between-group differences in the overall survival in both groups one and two. In this population-based cohort study, MIS did not compromise survival outcomes when compared with conventional open surgery in Japanese patients with uterine-confined and node-negative (FIGO 2018 stage I) cervical cancer.


Inhibition of microRNA-122 alleviates pyroptosis by targeting dual-specificity phosphatase 4 in myocardial ischemia/reperfusion injury.
Pyroptosis is a type of programmed cell death that induces myocardial ischemia-reperfusion injury (I/RI), which leads to cardiac dysfunction and even lethal reperfusion injury. MiR-122 is a liver-specific miRNA associated with coronary heart disease, but its role in pyroptosis activation in myocardial I/RI remains unclear. Thus, this study aimed to determine whether miR-122 inhibition exerts myocardial I/RI protection in in vivo and in vitro models. An I/RI model was established in vivo using C57BL/J6 male mice. MiR-122 expression was upregulated in the heart tissues from the I/RI group. Quantitative results of echocardiography parameters showed that miR-122 inhibition improved cardiac function and downregulated interleukin (IL)-1β, IL-18, caspase 1, and caspase 11. However, pretransfection with recombinant adeno-associated virus type 9 encoding a DUSP4-specific siRNA (AAV9-siDUSP4) blocked the protective effects of miR-122 inhibition. A hypoxia/reoxygenation (H/R) model was established to mimic the I/R condition in vitro using H9C2 cells. Results showed that miR-122 inhibition increased superoxide dismutase activity (SOD) and cell viability and decreased malondialdehyde (MDA) level, IL-1β, IL-18, caspase 1, caspase 11, and cell death. These protective effects were abolished by transfection with DUSP4-specific siRNA. In summary, miR-122 expression is upregulated in I/RI, and miR-122 inhibition alleviates I/RI by suppressing pyroptosis through targeting DUSP4. Thus, miR-122 may be a novel therapeutic target for treating myocardial I/RI.


Municipal wastewater treatment plant effluent-induced effects on freshwater mussel populations and the role of mussel refugia in recolonizing an extirpated reach.
Global human population and urbanization continually increase the volume of wastewater entering aquatic environments. Despite efforts to treat these effluents, they contribute a diverse suite of substances that enter watersheds at concentrations that have the potential to elicit adverse effects on aquatic organisms. The relationship between wastewater treatment plant (WWTP) effluent exposure and biological responses within aquatic ecosystems remains poorly understood, especially at the population level. To examine the effect of WWTP effluents on sentinel invertebrates, freshwater mussels were assessed in the Grand River, Ontario, in populations associated with the outfall of a major WWTP. This watershed, within the Laurentian Great Lakes basin, has a diverse community of twenty-five species of mussels, including nine Species at Risk, and is representative of many habitats that receive WWTP effluents regionally as well as globally. Surveys were conducted to assess the presence and species richness of freshwater mussels. In total, 55 sites downstream of the WWTP were examined using timed visual searches with one or 2 h of effort spent searching 100 m segments. Although seven species of mussels were found in moderate abundance (mean of 8 mussels per hour of searching across 2 sites) upstream of the WWTP outfall, no live mussels were observed for 7.0 km downstream of the WWTP. Long-term water quality monitoring data indicate that ammonia and nitrite concentrations along with large seasonal declines in diel dissolved oxygen were associated with the extirpation of mussels downstream of the WWTP. The first live mussels found downstream were below the confluence with a major tributary indicating that in addition to an improvement in water quality to a state that enables mussels (and/or their fish hosts) to survive, a nearby mussel refuge may have facilitated the recolonization of the depauperate WWTP-impacted zone.


[Formation of Fumonisin artefacts in thermal treated food].
Although it is well-known that fumonisin B1 (FB1) in corn meal decreases during baking, frying, and cooking, little is known about the formation of fumonisin artefacts during thermal treatment. In model experiments FB1, hydrolyzed fumonisin B1 (HFB1) and N-tert-butoxycarbonyl-fumonisin B1 (N-BOC-FB1) were heated with D-glucose, respectively, and samples were analyzed by liquid chromatography/electrospray ionization-tandem-spectrometry (HPLC-MS/MS). Whereas in samples containing FB1 and HFB1 stable products with mass/charge ratio (m/z) 884 and m/z 568 could be detected, no compounds were found following the reaction of N-BOC-FB1 and D-glucose. The compound with m/z 884 was identified as the Amadori rearrengement product of Schiff base formed by the reaction of FB1 with D-glucose.


The role of casein in supporting the operation of surface bound kinesin.
Microtubules and associated motor proteins such as kinesin are envisioned for applications such as bioseparation and molecular sorting to powering hybrid synthetic mechanical devices. One of the challenges in realizing such systems is retaining motor functionality on device surfaces. Kinesin motors adsorbed onto glass surfaces lose their functionality or ability to interact with microtubules if not adsorbed with other supporting proteins. Casein, a milk protein, is commonly used in microtubule motility assays to preserve kinesin functionality. However, the mechanism responsible for this preservation of motor function is unknown. To study casein and kinesin interaction, a series of microtubule motility assays were performed where whole milk casein, or its alphas1 and alphas2, beta or kappa subunits, were introduced or omitted at various steps of the motility assay. In addition, a series of epifluorescence and total internal reflection microscopy (TIRF) experiments were conducted where fluorescently labeled casein was introduced at various steps of the motility assay to assess casein-casein and casein-glass binding dynamics. From these experiments it is concluded that casein forms a bi-layer which supports the operation of kinesin. The first tightly bound layer of casein mainly performs the function of anchoring the kinesin while the second more loosely bound layer of casein positions the head domain of the kinesin to more optimally interact with microtubules. Studies on individual casein subunits indicate that beta casein was most effective in supporting kinesin functionality while kappa casein was found to be least effective.


Canine tooth size and fitness in male mandrills (Mandrillus sphinx).
Sexual selection theory explains the evolution of exaggerated male morphologies and weaponry, but the fitness consequences of developmental and age-related changes in these features remain poorly understood. This long-term study of mandrill monkeys (Mandrillus sphinx) demonstrates how age-related changes in canine tooth weaponry and adult canine size correlate closely with male lifetime reproductive success. Combining long-term demographic and morphometric data reveals that male fitness covaries simply and directly with canine ontogeny, adult maximum size, and wear. However, fitness is largely independent of other somatometrics. Male mandrills sire offspring almost exclusively when their canines exceed approximately 30 mm, or two-thirds of average adult value (45 mm). Moreover, sires have larger canines than nonsires. The tooth diminishes through wear as animals age, corresponding with, and perhaps influencing, reproductive senescence. These factors combine to constrain male reproductive opportunities to a brief timespan, defined by the period of maximum canine length. Sexually-selected weaponry, especially when it is nonrenewable like the primate canine tooth, is intimately tied to the male life course. Our analyses of this extremely dimorphic species indicate that sexual selection is closely intertwined with growth, development, and aging, pointing to new directions for sexual selection theory. Moreover, the primate canine tooth has potential as a simple mammalian system for testing genetically-based models of aging. Finally, the tooth may record details of life histories in fossil primates, especially when sexual selection has played a role in the evolution of dimorphism.


The Paleolithic Nutrition Model in Relation to Ultraviolet Light and Vitamin D.
The biology of every species has been optimized for life in the environment in which that species evolved. Humans originated in the tropics, and while some natural selection took place in response to behaviors and environments that decreased exposure to ultraviolet light, there has never been a species-wide biological accommodation. Paleolithic nutrition advocates argue that risk of disease is higher because modern diets differ from what was consumed by early humans. Early humans were the naked ape living in the tropics, exposed to high levels of ultraviolet light and vitamin D nutrition (serum 25-hydroxyvitamin D; 25(OH)D) averaging 115 nmol/L, as compared to today's population averages that are well below 70 nmol/L. Natural selection from an available gene pool cannot compensate fully to an environmental change away from the one within which the species originally evolved. Vitamin D nutrition remains a contentious area. The epidemiological evidence consistently relates lower 25(OH)D to higher disease risk. However, evidence from double-blind clinical trials looking at preventing new disease in healthy volunteers has been disappointing. But such negative trials have been the case for all nutrients except for folic acid which lowers risk of spina bifida. The Paleolithic nutrition model is based on fundamental biological concepts, but it has overlooked the environmental effects of ultraviolet light and vitamin D nutrition. This paper presents evolutionary and Paleolithic aspects of ultraviolet light and vitamin D with the aim to support pertinent research and, ultimately, public policy regarding nutrition and light exposure.


Outcomes of parathyroidectomy in renal hyperparathyroidism in patients with No access to renal transplantation in Singapore.
Total parathyroidectomy with autotransplantation (TPTX + AT) and subtotal parathyroidectomy (SPTX) are considered standard surgical treatments for refractory renal hyperparathyroidism. However, there is little data available comparing their outcomes in an area with poor access to renal transplant and calcimimetics. Patients with renal hyperparathyroidism who underwent TPTX + AT and SPTX in a tertiary institution from 2006 to 2013 were studied. Patient characteristics, pre- and post-operative biochemical marker levels, and outcomes including recurrence rates, post-operative morbidity and mortality were analysed. 87 patients underwent parathyroidectomy for renal hyperthyroidism. Transplant patients were excluded in this study. 81 patients were on long-term dialysis, with a median time of 7 years from initiation of haemodialysis to parathyroidectomy. 57 patients (70.4%) underwent TPTX + AT while 24 (29.6%) underwent SPTX. Post-operatively, there was significant decrease in parathyroid hormone (PTH), calcium and phosphate levels in both groups. PTH and phosphate levels were significantly lowered with TPTX compared to SPTX (p = 0.004, 0.003). Symptomatic hypocalcaemia was seen in both groups. In a median follow-up of 4 years, 11 patients developed biochemical recurrence, with a median time of 29 months to recurrence. Median PTH at recurrence was 67.1 pmol/L. Rate of recurrence was higher in patients who underwent SPTX (20.8% vs 10.5%), with a shorter median time to recurrence (median 62.1 vs 81.3 months). 2 patients required resection of the autograft. Cohort mortality was 11 patients (13.4%), with 3 deaths secondary to cardiovascular events. Total parathyroidectomy with autoimplantation is superior to subtotal parathyroidectomy in the short to intermediate term.


SYNTHESIS, REACTIONS, AND BIOLOGICAL ACTIVITY OF SOME TRIAZINE DERIVATIVES CONTAINING SULFA DRUG MOIETIES.
Thienyl-triazine-sulphonamide conjugates were prepared from their precursor amines using triethyl orthoformate or ethyl chloroformate as cross coupling reagents. The progress of these reactions was investigated by spectral (IR, NMR, MS) and microanalytical techniques. The synthesized compounds were in vitro screened for antibacterial, antifungal, antioxidant, and anticancer activity. 4-[({[3-Mercapto-5-oxo-6-[2-(2-thienyl)yinyl]-1,2,4-triazin- 4(5H)-yl]imino}methyl)amino]-benzenesulfonamide turned out to be a powerful antibacterial agent, while all the compounds prepared were inactive against fungal species tested. 4-{[({8-Cyano-4-oxo-3-[2-(2-thienyl)vinyl- 4H,8H-[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-7-yl}amino)(ethoxy)methyl]amino}benzenesulfonamide displayed in vitro promising cytotoxicity against Ehrlich ascites carcinoma cell line with concurrent attenuation of malonodinitrile and it was unique among other compounds being unable to increase glutathione S-transferase and reduced glutathione S-transferase activities. This compound exhibited also good antioxidant properties that together with its cytotoxicity nominated it for further investigation in cancer research.


Deep mitigation of CO2 and non-CO2 greenhouse gases toward 1.5 °C and 2 °C futures.
Stabilizing climate change well below 2 °C and towards 1.5 °C requires comprehensive mitigation of all greenhouse gases (GHG), including both CO2 and non-CO2 GHG emissions. Here we incorporate the latest global non-CO2 emissions and mitigation data into a state-of-the-art integrated assessment model GCAM and examine 90 mitigation scenarios pairing different levels of CO2 and non-CO2 GHG abatement pathways. We estimate that when non-CO2 mitigation contributions are not fully implemented, the timing of net-zero CO2 must occur about two decades earlier. Conversely, comprehensive GHG abatement that fully integrates non-CO2 mitigation measures in addition to a net-zero CO2 commitment can help achieve 1.5 °C stabilization. While decarbonization-driven fuel switching mainly reduces non-CO2 emissions from fuel extraction and end use, targeted non-CO2 mitigation measures can significantly reduce fluorinated gas emissions from industrial processes and cooling sectors. Our integrated modeling provides direct insights in how system-wide all GHG mitigation can affect the timing of net-zero CO2 for 1.5 °C and 2 °C climate change scenarios.


HIF-1α- and HIF-2α-Immunopositive Neurons and Capillaries in the Prefrontal Cerebral Cortex of Rats with Experimental Myocardial Infarction.
The quantitative content of HIF-1α- and HIF-2α-immunopositive brain neurons in Wistar rats was studied 1, 15, and 30 days after modeling of myocardial infarction. In rats of the control group, the immunohistochemical markers HIF-1α and HIF-2α in the prefrontal cortex of the brain were determined in few pale-colored neurons and capillaries. One day after myocardial infarction simulation, the number of HIF-1α+ neurons increased, and on day 15 it reached the maximum level: the concentration of immunopositive neurons and capillaries increased by 24.7 and 18.4%, respectively, in comparison with the control. After 30 days, the number of HIF-1α+ structures decreased, but remained above the control values. The number of neurons and capillaries positively stained for HIF-2α peaked only on day 30 of the postinfarction period.


Does the addition of earplugs improve adherence to a reduced eating rate protocol?
Eating slowly has been associated with low body mass and greater cephalic phase response. This study hypothesised that the novel addition of earplugs -that block the ear canal-to a previously developed slow eating protocol would increase postprandial satiety. 12 healthy young participants [(6 M, 6F) mean age (± SD) 24.58 ± 6.64 years, mean BMI 22.23 ± 3.13 kg/m2] were randomised to a one way crossover study. Following anthropometric measurements an isocaloric meal was consumed and participants' normal eating rates (NER) were recorded. Participants received instruction on a slow eating rate protocol on 2 occasions with (SERIn) and without (SER-Out) earplugs. Perceived satiety was measured at the start of the meal, t = 0 and then at 15, 30, 45, 60, 90 and 120 min. Total area under the curve (TAUC) was calculated from visual analogue data to compare the different eating conditions. Perceived hunger (p = 0.034) and desire to eat (p = 0.005) were significantly lower and perceived fullness significantly greater (p = 0.03) in SER-In compared to NER, with no significant differences between SER-In and SER-Out. Although there was a positive effect on perceived satiety for the SER-In group only, this study showed that there is no added effect in perceived satiation when earplugs are combined with a SER protocol.


Reduction in gastric mucosal hemorrhage and ulceration with chronic high-level dosing of enteric-coated aspirin granules two and four times a day.
When administered on a chronic high-dosage regimen, enteric-coated aspirin granules produced significantly less gastric damage than plain aspirin or aspirin-antacid combinations. Clinically meaningful damage occurred in all subjects receiving plain aspirin, 93% of those receiving aspirin-antacid combination and only 27% and 20% of those receiving enteric-coated aspirin granules qid and bid, respectively. All three aspirin formulations were taken as 1 g qid (4 g/day) and an additional group received enteric granules administered as 2 g bid (4 g/day). Gastric damage was assessed by means of endoscopy carried out after seven days of treatment. Enteric granules are equally safe when administered on a bid or qid regimen (at same total daily dosage) and, in a bid regimen, should provide a compliance advantage for patients on high-dose therapy for diseases such as rheumatoid arthritis.


Comparative In Vivo Study of Solid-Type Pure Hyaluronic Acid in Thread Form: Safety and Efficacy Compared to Hyaluronic Acid Filler and Polydioxanone Threads.
Although various products are commonly used for skin rejuvenation, solid-type hyaluronic acid (HA) as an injectable form has not been researched or utilized. This study aimed to demonstrate the safety and efficacy of solid-type HA in thread form, which differs from the conventional gel-type HA commonly used. Solid-type HA threads, conventional HA fillers, and polydioxanone (PDO) threads were inserted into the dorsal subcutaneous layer of mice. Photographs were taken on days 0, 1, 3, and 7, and on day 7, the samples were harvested for histological analysis. Inflammatory reactions and detection of collagen were confirmed through tissue staining, and real-time PCR was conducted to quantify collagen synthesis. In the histological analysis, the PDO threads exhibited a greater inflammatory response compared to the HA threads. Masson's trichrome staining revealed a higher degree of collagen synthesis in the HA thread group compared to the HA filler group. While collagen type 1 expression was significantly higher in the PDO thread group than in the HA thread group, the HA thread group showed higher expression levels of collagen type 3. Furthermore, the PDO thread group demonstrated a statistically significant increase in TGF-β1 compared to the HA group. This in vivo study demonstrated the stable application of solid-type pure HA threads and their potential for inducing collagen production, while also yielding a low inflammatory response. The findings highlight the promising applications of solid-type HA in the field of cosmetic dermatology. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


[Ethical issues in primary care during the coronavirus (SARS-CoV-2) pandemic].
Public health emergencies, such as the current SARS-CoV-2 coronavirus pandemic, have led to tragic resource constraints that prevent lives from being saved. This has led to tensions in patient-centered care as the backbone of the system in normal conditions and the same care in emergencies originating in the COVID-19. In this review we address some of the healthcare, organizational and ethical problems that this scenario has caused in primary care such as: cancellation of programmed activities; scarce home care and follow-up of elderly, chronically ill and immobilized patients; shortage of PPE and the exposure to risk of healthcare professionals, and finally the problems associated with telemedicine and telephone attention to patients.


Mutagenicity and toxicity of chloroethylene oxide and chloroacetaldehyde.
Exposure of several trp-auxotrophic Escherichia coli strains, carrying base-pair substitutions, to chloroethylene oxide or chloroacetaldehyde (two metabolites of vinyl chloride) increased the mutation frequency to tryptophan prototrophy. Strong cytotoxic and mutagenic effects were observed with 2.5 mM chloroethylene oxide, while a higher concentration of chloroacetaldehyde (100 mM) exhibited a mutagenic effect which was 400 times lower.


Dynamic brain activation patterns for face recognition: a magnetoencephalography study.
The present study used magnetoencephalography (MEG) to investigate the spatiotemporal profile of neurophysiological activity associated with recognition of recently encountered human faces in seventeen healthy right-handed adults. Activity sources modeled as instantaneous equivalent current dipoles were found in ventral occipito-temporal regions during the early stages of stimulus processing and in lateral temporal cortices during later stages. Hemispheric asymmetries in regional activity were restricted to ventral occipitotemporal areas. The magnitude of magnetic flux originating in these regions was greater in the right hemisphere during the first 350 ms post-stimulus onset. In addition, the duration of neurophysiological activity was greater in the right hemisphere after 600 ms post-stimulus onset. The results indicate right hemisphere predominance in the degree of engagement of neurophysiological processes involved in both the pre- and post-recognition phases of face processing.


Review article: the pathophysiology of thrombocytopenia in hepatitis C virus infection and chronic liver disease.
The pathophystology of thrombocytopenia in patients with chronic liver disease resulting from hepatitis C virus (HCV) infection is complex and involves several complementary mechanisms that likely act in concert. To summarize the available data on the etiology of thrombocytopenia in patients with chronic liver disease. In patients with untreated hepatitis C, both prevalence and severity of thrombocytopenia increase in parallel with the extent of disease, usually becoming clinically relevant when patients develop extensive fibrosis and/or cirrhosis. Pathogenetic mechanisms include hypersptenism secondary to portal hypertension, bone marrow suppression resulting from either HCV itself or interferon treatment, aberrations of the immune system resulting in the formation of anti-platelet antibodies and/or immune-complexes that bind to platelets and facilitate their premature clearance, development of immunologically-mediated extrahepatic manifestations including mixed cryoglobulinemia with or without associated joint, renal, or cutaneous involvement, and thrombopoietin (TPO) deficiency secondary to liver dysfunction. In chronic liver disease, the natural inverse relationship between TPO and platelet levels is not maintained; therefore, blood TPO levels fail to have clinical relevance or predictive value in assessing the thrombocytopenic status of a given patient. The development of thrombocytopenisa in patients with chronic liver disease is complex and multifactorial.


A simple blood-culture bacterial pellet preparation for faster accurate direct bacterial identification and antibiotic susceptibility testing with the VITEK 2 system.
An ammonium chloride procedure was used to prepare a bacterial pellet from positive blood cultures, which was used for direct inoculation of VITEK 2 cards. Correct identification reached 99% for Enterobacteriaceae and 74% for staphylococci. For antibiotic susceptibility testing, very major and major errors were 0.1 and 0.3% for Enterobacteriaceae, and 0.7 and 0.1% for staphylococci, respectively. Thus, bacterial pellets prepared with ammonium chloride allow direct inoculation of VITEK cards with excellent accuracy for Enterobacteriaceae and a lower accuracy for staphylococci.


Resection of lateral temporal lobe arteriovenous malformations.
Cerebral arteriovenous malformations (AVMs) can be formidable lesions to treat. There are four modalities available for treatment: expectant management, radiosurgery, embolization, and microsurgery. In order to make a decision about treatment, the surgeon must consider the natural history of the lesion versus the rate of treated morbidity and mortality. Characteristics of temporal lobe AVMs such as their location, the potential for deep-seated arterial feeders and deep venous drainage, increase the risk of early clinical onset, hemorrhage, and overall morbidity and mortality (Fleetwood and Steinberg; Lancet 359:863-873, 3) and provide an additional challenge to surgeons attempting to remove the lesion while preserving eloquent local structures. In this paper, we demonstrate our technique for the microsurgical resection of lateral temporal lobe AVMs. In order to maximize access to the lesion for safe resection, a large craniotomy is utilized, with the malformation separated from the MCA feeding arteries and underlying cortex, with care taken not to compromise en passage vessels. The entire nidus is resected and intraoperative angiography confirms appropriate resection. Microsurgical resection remains an important part of the treatment paradigm for temporal lobe AVMs. In appropriately selected patients, this can be done with minimal morbidity.


Erythropoietic drive is the strongest predictor of hepcidin level in adults with sickle cell disease.
Levels of hepcidin, a key modulator of iron metabolism, are influenced by erythropoiesis, iron, and inflammation, all of which may be increased in patients with sickle cell disease (SCD). The objectives of this study were to determine: 1) the variation in hepcidin level, and 2) the relative contribution of erythropoietic drive, iron, and inflammation to differences in hepcidin level in an adult cohort with SCD. In a prospective study, cross-sectional measurements of hepcidin, reticulocyte percentage, erythropoietin, ferritin, and high-sensitivity CRP were obtained. A regression tree analysis was used to measure the association between these interacting factors and hepcidin level. The cohort was comprised of 40 adults with SCD. Median age was 26years, 68% were female, and all had HbSS. Hepcidin values ranged from 30ng/ml to 326ng/ml, with a median of 87ng/ml. Regression tree analysis demonstrated that reticulocyte percentage, erythropoietin, ferritin and hs-CRP all were associated with hepcidin. The highest hepcidin values were found in subjects with low reticulocyte percentage and erythropoietin. In conclusion, erythropoietic drive, iron status, and inflammation all contribute to variation in hepcidin level. The strongest contributor is erythropoietic drive. Future studies could determine whether suppression of erythropoiesis with chronic transfusion influences hepcidin level.


Quality assurance and outcomes in outpatient parenteral antibiotic therapy.
The quality improvement process in outpatient parenteral antibiotic therapy (OPAT) is driven by outcome measurement. Collection and analysis of outcome data will be an essential component of an OPAT program. Data collected must be measurable, consistently defined and transformed through analysis into understandable results that can be used to improve care.


Personalized therapy for chronic viral hepatitis C in the naive patient: How can we optimize treatment duration as a function of viral genotype?
Pegylated interferon plus ribavirin is the standard treatment for chronic hepatitis C (CHC). It yields sustained virological response (SVR) rates of 42-52% for genotype 1, 66-72% for genotype 4, and 76-80% for genotypes 2 and 3. Hence, the patient's genotype appears to be a determining predictive factor for the SVR. We have reviewed the literature in order to determine whether a genotype-specific treatment duration should be envisaged. The largest study to date of patients infected with HCV genotype 2 or 3 confirmed the value of the standard treatment duration of 24 weeks. Shorter treatments exposed the patients to a greater risk of relapse. For genotype 1, it was possible to offer a shorter, 24-week course of treatment to the 35% of patients with an initial viral load below 600,000 IU/mL and an early virological response (EVR) at week 4 (negative PCR), resulting in an SVR of 89%. For the remaining two-thirds of genotype 1 patients with a high viral load, the treatment duration should remain at 48 weeks. A subgroup of patients - the "slow virological responders" (positive PCR at week 12 but with less than 6000 IU/mL; negative PCR at week 24) - benefited from the extension of the treatment to 72 weeks, with an SVR of 88%. For patients infected with genotype 4 virus, combination therapy should feature a ribavirin dose of more than 1000 mg/day for an optimal duration of 48 weeks.


Change in depression predicts change in bladder symptoms for women with urinary incontinence undergoing pelvic-floor muscle training.
To examine the relationship between depression and bladder symptoms, especially the impact of change in depression on changes in bladder symptoms, for women with urge and stress urinary incontinence undergoing a course of PFMT. 106 adult females with pelvic-floor dysfunction (PFD), consecutively referred to an outpatient pelvic-floor muscle training (PFMT) programme for either urge, stress, or mixed incontinence, participated in a prospective observational study. Participants reported subjective views of their pelvic floor problems (Queensland), and their levels of depression (HADS_D), and data relating to age and BMI were collected. The trial was registered on clinicaltrials.gov (NCT02549157). There was a positive relationship between depression and bladder symptoms at intake. Levels of initial depression significantly predicted levels of bladder symptoms at completion of PFMT, and ability to complete the PFMT programme. Change in depression significantly predicted change in bladder symptoms, over and above intake patient characteristics and symptoms. These data imply a multidisciplinary focus, including psychological input, for PFD may be a highly effective strategy for its management.


COVID-19 pneumonia: Diagnostic and prognostic role of CT based on a retrospective analysis of 214 consecutive patients from Paris, France.
To evaluate the diagnostic and prognostic performance of CT in patients referred for COVID19 suspicion to a French university hospital, depending on symptoms and date of onset. From March 1st to March 28th, 214 patients having both chest CT scan and reverse transcriptase polymerase chain reaction (RT- PCT) within 24 h were retrospectively evaluated. Sensitivity, specificity, negative and positive predictive values of first and expert readings were calculated together with inter reader agreement, with results of RT-PCR as standard of reference and according to symptoms and onset date. Patient characteristics and disease extent on CT were correlated to short-term outcome (death or intubation at 3 weeks follow-up). Of the 214 patients (119 men, mean age 59 ± 19 years), 129 had at least one positive RT-PCR result. Sensitivity, specificity, negative and positive predictive values were 79 % (95 % CI: 71-86 %), 84 %(74-91 %), 72 %(63-81 %) and 88 % (81-93 %) for initial CT reading and 81 %(74-88 %), 91 % (82-96 %), 76 % (67-84 %) and 93 % (87-97 %), for expert reading, with strong inter-reader agreement (kappa index: 0.89). Considering the 123 patients with symptoms for more than 5 days, the corresponding figures were 90 %, 78 %, 80 % and 89 % for initial reading and 93 %, 88 %, 86 % and 94 % for the expert. Disease extent exceeded 25 % for 68 % and 26 % of severe and non-severe patients, respectively (p < 0.001). CT sensitivity increased after 5 days of symptoms. A disease extent > 25 % was associated with poorer outcome.


Isolation and characterisation of the acetyl-CoA carboxylase gene from Aspergillus nidulans.
The putative gene encoding acetyl-CoA carboxylase, accA, has been isolated from Aspergillus nidulans. This single-copy gene has an open reading frame (ORF) of 6864 bp and contains two small introns near the 5'-end. A short ORF upstream of the ATG start codon has been identified in this gene by RT-PCR. Based on sequence homology to acetyl-CoA carboxylases from other organisms, putative biotin-, ATP-, HCO3-- and acetyl-CoA- binding sites have been assigned. Northern data and ACC enzyme-activity measurements from A. nidulans suggested that expression of accA was higher in media containing nitrate than ammonia as a sole nitrogen source. Deletion of accA in A. nidulans was unsuccessful. The failure of A. nidulans to grow in the presence of the ACC-specific inhibitor, soraphen A, supplemented with C16-18 fatty acids suggested that ACC is an essential enzyme.


Effects of alpha lipoic acid supplementation on serum levels of IL-8 and TNF-α in patient with ESRD undergoing hemodialysis.
Chronic renal failure is a progressive and irreversible loss of kidney function, and the hemodialysis (HD) is one of the most common modalities in this regard. Oxidative stresses [like interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α)] and inflammation are the main risk factors associated with cardiovascular diseases and other complications in many organs in hemodialysis patients; meanwhile, antioxidants like alpha lipoic acid (ALA) may reduce the oxidative stress markers and the levels of inflammatory cytokines, so can improve of the patient's quality of life. In this randomized clinical trial study, 60 HD patients were randomly categorized in two case and control groups. Case group received a daily capsule of 600 mg of ALA supplementation for 8 weeks, and the control group received placebo capsules daily. The serum level of IL-8 and TNF-α was measured in both groups before and after the intervention. There were no significant differences in age, gender, duration of dialysis, and causative factor for dialysis between both groups (P > 0.05). The mean of IL-8 and TNF-α after the intervention in case group was 26.20 ± 15.34 and 21.25 ± 9.61, respectively; the difference between both groups was not statistically significant (P > 0.05). Based on the better feeling and other beneficial effects of ALA were found in our study; we can conclude that it is a beneficial and recommended supplement, especially, for diabetic and dialysis patients.


The central inhibitory effect of interleukin-1 on gastric acid secretion.
The effect of interleukin-1 (IL-1) on gastric secretory functions was examined in pylorus-ligated conscious rats. Intracisternal (i.c.) injection of IL-1 beta (1-100 ng) induced dose-related, long-lasting inhibition of gastric acid output, which was due to the reductions of both the amount and the acid concentration of the gastric juice. A much higher dose of IL-1 alpha was required to achieve identical effects on gastric acid secretion when it was given by intravenous routes. The i.c. injection of IL-1 alpha also had an inhibition of gastric secretion. This inhibitory effect of i.c. applied IL-1 beta on gastric acid secretion was completely abolished in indomethacin-pretreated animals but not in reserpine-pretreated ones. These results suggest that IL-1 may have an inhibitory action on the regulation of gastric secretory functions by its central action which is dependent on the eicosanoid metabolism.


Current level of fish and omega-3 fatty acid intakes and risk of Type 2 diabetes in China.
Whether fish and marine omega-3 polyunsaturated fatty acid (PUFA) intakes are linked to type 2 diabetes (T2D) risk remains unclear in China. We aimed to assess the long-term associations in a nationwide cohort. Overall 15,100 Chinese adults, aged ≥20 years, were included from China Health and Nutrition Survey. The cumulative averages of fish and marine omega-3 PUFA intakes were evaluated based on 3-day 24-h records. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of T2D risk. Overall 1017 T2D cases were documented over a median of 14 years of follow-up. Compared with non-fish consumers, low and moderate fish consumption were associated with higher T2D risk whereas high fish consumption was not associated. Multivariable-adjusted HRs (95% CIs) for low and moderate fish consumption were 1.43 (1.09, 1.86) and 1.42 (1.07, 1.85) respectively in men, and were 1.58 (1.22, 2.02) and 1.39 (1.08, 1.83) respectively in women. In meat substitution analyses, low and moderate fish consumption was related to 55% and 69% higher T2D risk for men, and was associated with 68% and 54% higher T2D risk for women, respectively. Fried but not non-fried fish intake was associated with higher T2D risk. Intake of marine omega-3 PUFAs was dose-dependently associated with higher T2D risk for both men and women (P-trend<0.001). Overall low and moderate intakes of fish, especially fried fish, and marine omega-3 PUFAs were associated with higher T2D risk. Current level of fish and marine omega-3 PUFA consumption is not protective against T2D incidence among Chinese people.


Impact of changing the ovarian hyperstimulation protocol in the sequental cycle on ICSI outcomes in the same patient population.
Whether to use the same ovarian stimulation protocol or change it after a failed in vitro fertilization cycle is still a controversial issue. In this study we aimed to investigate the effect of changing the stimulation protocol in the sequental cycle of the same patient population on intracytoplasmic sperm injection (ICSI) outcomes. This retrospective study included two sequental fresh ICSI cycles of 941 infertile women attended in a period of one year. Group A was composed of patients who failed to have clinical pregnancy with a GnRH agonist and group B was composed of patients who failed to have clinical pregnancy with a GnRH antagonist protocol cycle. In both groups the study group was composed of patients whose stimulation protocol was changed in the sequential cycle and the control group was composed of patients who proceeded with the same stimulation protocol. The clinical pregnancy and live birth rates were primary outcomes. In group A, the clinical pregnancy rates were comparable between the study and the control groups, but the live birth rate was higher in the study group (p=0.03). In group B, there was no difference in terms of clinical pregnancy and live birth rates between the study and control groups (p=0.740 and p=0.842 respectively). Changing the ovarian stimulation protocol after a failed ICSI cycle downregulated with a GnRH agonist increased the live birth rate. After a failed cycle stimulated with a GnRH antagonist protocol, protocol change did not have any impact on the clinical pregnancy and live birth rates.


Dosimetric impact of different CT datasets for stereotactic treatment planning using 3D conformal radiotherapy or volumetric modulated arc therapy.
The purpose of this study was to assess the impact on dose to the planning target volume (PTV) and organs at risk (OAR) by using four differently generated CT datasets for dose calculation in stereotactic body radiotherapy (SBRT) of lung and liver tumors. Additionally, dose differences between 3D conformal radiotherapy and volumetric modulated arc therapy (VMAT) plans calculated on these CT datasets were determined. Twenty SBRT patients, ten lung cases and ten liver cases, were retrospectively selected for this study. Treatment plans were optimized on average intensity projection (AIP) CTs using 3D conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT). Afterwards, the plans were copied to the planning CTs (PCT), maximum intensity projection (MIP) and mid-ventilation (MidV) CT datasets and dose was recalculated keeping all beam parameters and monitor units unchanged. Ipsilateral lung and liver volumes and dosimetric parameters for PTV (Dmean, D2, D98, D95), ipsilateral lung and liver (Dmean, V30, V20, V10) were determined and statistically analysed using Wilcoxon test. Significant but small mean differences were found for PTV dose between the CTs (lung SBRT: ≤2.5 %; liver SBRT: ≤1.6 %). MIPs achieved the smallest lung and the largest liver volumes. OAR mean doses in MIP plans were distinctly smaller than in the other CT datasets. Furthermore, overlapping of tumors with the diaphragm results in underestimated ipsilateral lung dose in MIP plans. Best agreement was found between AIP and MidV (lung SBRT). Overall, differences in liver SBRT were smaller than in lung SBRT and VMAT plans achieved slightly smaller differences than 3D-CRT plans. Only small differences were found for PTV parameters between the four CT datasets. Larger differences occurred for the doses to organs at risk (ipsilateral lung, liver) especially for MIP plans. No relevant differences were observed between 3D-CRT or VMAT plans. MIP CTs are not appropriate for OAR dose assessment. PCT, AIP and MidV resulted in similar doses. If a 4DCT is acquired PCT can be omitted using AIP or MidV for treatment planning.


Human embryonic stem cell-derived hematoendothelial progenitors engraft chicken embryos.
To investigate whether human embryonic stem cells (hESC) committed in culture into hematopoietic/endothelial cell progenitors can be further developed into mature blood and vascular cells following transplantation into chicken embryos. The yolk sac of 42- to 44-hour chicken embryos received yolk sac injections of unfractionated human embryoid body (hEB) cells, CD34-positive hEB cells, or CD34+CD45+ granulocyte colony-stimulating factor-mobilized human peripheral blood hematopoietic stem-progenitor cells. Human cells in the host were detected by flow cytometry and immunohistochemistry. All injected cell populations engrafted chicken hematopoietic organs, as assessed by detection of CD45+ cells in the spleen, bursa of Fabricius, and thymus. CD34+ day -10 hEB cells showed the highest efficiency for producing human CD45+ cells in the hosts and yielded human glycophorin A+ erythroid, CD13+ myeloid, and CD19+ lymphoid cells in the spleen and bursa of Fabricius. Spleen cells from chimeric embryos also contained human colony-forming units-granulocyte macrophage, as assessed in methylcellulose colony-forming assays. Human endothelial cells expressing vascular endothelial-cadherin, von Willebrand factor, CD31, and the receptor for the Ulex europaeus lectin were also observed in the yolk sac vasculature following injection of either unfractionated or CD34+ day -10 hEB cells. Primitive angiohematopoietic stem cells (total and CD34+ day -10 hEB cells) as well as adult hematopoietic stem cells could home to intraembryonic blood-forming organs following injection into the yolk sac. These observations demonstrate the utility of the avian embryo as a convenient and reliable host to model the angiohematopoietic development of human embryonic, or other early stem cells.


High-dose oral glutamine supplementation reduces elevated glutamate levels in cerebrospinal fluid in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome.
Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous disorder caused by mitochondrial DNA mutations. There are no disease-modifying therapies, and treatment remains mainly supportive. It has been shown previously that patients with MELAS syndrome have significantly increased cerebrospinal fluid (CSF) glutamate and significantly decreased CSF glutamine levels compared to controls. Glutamine has many metabolic fates in neurons and astrocytes, and the glutamate-glutamine cycle couples with many metabolic pathways depending on cellular requirements. The aim was to compare CSF glutamate and glutamine levels before and after dietary glutamine supplementation. It is postulated that high-dose oral glutamine supplementation could reduce the increase in glutamate levels. This open-label, single-cohort study determined the safety and changes in glutamate and glutamine levels in CSF after 12 weeks of oral glutamine supplementation. Nine adult patients with MELAS syndrome (66.7% females, mean age 35.8 ± 3.2 years) were included. After glutamine supplementation, CSF glutamate levels were significantly reduced (9.77 ± 1.21 vs. 18.48 ± 1.34 μmol/l, p < 0.001) and CSF glutamine levels were significantly increased (433.66 ± 15.31 vs. 336.31 ± 12.92 μmol/l, p = 0.002). A side effect observed in four of nine patients was a mild sensation of satiety. One patient developed mild and transient elevation of transaminases, and another patient was admitted for an epileptic status without stroke-like episode. This study demonstrates that high-dose oral glutamine supplementation significantly reduces CSF glutamate and increases CSF glutamine levels in patients with MELAS syndrome. These findings may have potential therapeutic implications in these patients. ClinicalTrials.gov Identifier: NCT04948138. Initial release 24 June 2021, first patient enrolled 1 July 2021. https://clinicaltrials.gov/ct2/show/NCT04948138.


A new concept for DRG-based reimbursement of services in German intensive care units: results of a pilot study.
To evaluate LOS in developing a concept of borderline ICU LOS for a realistic reimbursement of intensive care. Retrospective analysis of LOS and cost data extracted from patients' electronic records. Surgical ICU of the University Hospital Göttingen, Germany. All adult ICU admissions with LOS >24 h over a 24-month period (1 January 2000 to 31 December 2001; n=1631.) None. Cluster analysis partitioned the ICU population into three homogeneous groups based on ICU LOS and total direct costs: cluster 1 (n=1405; mean LOS=2.8; mean cost= Euro 2399); cluster 2 (n=190; mean LOS=13.4; mean cost=Euro 12,754); cluster 3 (n=36; mean LOS=34.9; mean cost= Euro 34,173). Cost distribution between cluster 1 and clusters 2 and 3 combined was 48 vs 52%. Upper 95 percentile LOS of 6.7 allowed cluster 1 to be replaced by an LOS profile population of < or = 7 days population (n=1355; 96% population and 91% total ICU cost overlap with cluster 1) representing 83% of total ICU population and 44% of total ICU costs. Stratification of >7 day population into LOS less than or >20 days (n=220; n=56) were further differentiated by mortality (11 vs 23%) and sepsis incidence (33 vs 79%). It may be feasible to formulate a LOS-based reimbursement scheme for ICU services in Germany based on the selection of (appropriate) patients' ICU LOS profiles.


Effect of organic/inorganic composites as soil amendments on the biomass productivity and root architecture of spring wheat and rapeseed.
Organic and inorganic soil amendments are used to increase crop yields and fertilizer efficiency, as well as to improve the physical and biological properties of soil, increase carbon sequestration, and restore contaminated and saline soils. The present study aimed to evaluate the effect of various zeolite composites mixed with either lignite or leonardite on the biomass production of spring wheat and rapeseed and their root morphology. A pot experiment involved the application of the following treatments: zeolite-carbon, zeolite-vermiculite composites, both mixed with lignite or leonardite, and a control treatment with no amendments. Inorganic composites were applied in a dose of 3% and 6%. The study also included an analysis of the root morphometric parameters and aboveground biomass of spring wheat and rapeseed. The lowest productivity was observed when both crops were not enriched with fertilizers or other amendments, 24.92 g per pot and 29.83 g per pot for spring wheat and rapeseed, respectively. The application of mineral fertilizers in combination with zeolite-carbon composite gave the highest aboveground biomass of spring wheat, 110.11 g per pot. Both zeolite-carbon and zeolite-vermiculite composites modified the morphological parameters of roots, with the control treatment showing the lowest root length and dry matter. Although mineral fertilization was found to have a positive impact root development in relation to untreated control, the treatment amended with zeolite-carbon composite and leonardite exhibited the highest root length and biomass of spring wheat. No other soil amendments improved the properties of rapeseed roots.


Long-term outcomes of the Endurant endograft in patients undergoing endovascular abdominal aortic aneurysm repair.
To investigate the long-term outcomes after endovascular aneurysm repair (EVAR) in a real-world setting using the Endurant endograft (EG). 184 EVAR candidates treated with the Endurant family EGs in a single vascular center were prospectively enrolled from January 2009 to December 2016. Kaplan-Meir estimates of long-term standardized primary and secondary outcome measures were performed. Per protocol, subgroup comparison analysis was performed in three groups: patients treated within instructions for use (in-IFU) vs patients treated outside IFU (outside-IFU), EVAR in patients receiving the Endurant proximal diameter 32 or 36 mm EG vs those receiving the <32 mm diameter EG and EVAR with various Endurant EG versions. The mean follow-up was 75.09 ± 37.9 months (range: 4.1-172 months). The median age of the patients was 72.96 ± 7.03 years (range: 55-88 years). A total of 177 patients were male (96.2%). Compliance with IFU was followed in 107 patients (58.2%). Overall survival was 69.5% and 48% at 5 and 8 years, respectively. Of the 102 all-cause deaths, 7 (6.9%) were aneurysm related. Six of these postimplant deaths occurred in patients presented with aneurysm rupture from type Ia or/and type Ib endoleak. At 5, 8, and 10 years of observation, freedom from aneurysm rupture, open surgical conversion, type I/III endoleak, any type of endoleak, aneurysm-related secondary intervention probabilities, and neck-related events were as follows: 98.1%, 95%, and 89.4%; 95.1%, 91.2%, and 85.7%; 93.6%, 87.3%, and 83.9%; 83.4%, 74%, and 70.9%; 89.8%, 76.7%, and 72%; and 96.3%, 90%, and 87.6%, respectively. Corresponding clinical success was 90%, 77.4%, and 68.4%, respectively. Patients treated outside-IFU had significantly higher risk of aneurysm rupture, open surgical conversion probability, occurrence of type I/III endoleak, and chance of reinterventions and lower clinical success probabilities compared with the in-IFU counterparts at 5 and 8 years. This statistical difference remained when type Ia endoleak or endoleak of any type was considered independently. In addition, it was stronger in patients having extreme anatomic boundaries (>1 hostile anatomic condition), when aneurysm-related death, aneurysm rupture, and clinical success at 5 years were considered. Overall proximal migration and limb occlusion were recorded in 1.1% and 4.9% of the patients, respectively. Overall reintervention rate was 17.4%. An increase in aneurysm sac diameter was observed in 12.5% of patients and was not related to IFU status. The Endurant version or the proximal EG diameter had no significant association with the chance of any complication or adverse event. The data confirmed the durability of the Endurant EG, achieving promising long-term outcomes in a real-world setting. However, its positive performance must be interpreted with caution in patients treated off-label especially those with extreme anatomic boundaries. In this cohort, some of EVAR advantages might be lost in the late future. Further similar studies are warranted.


High scavenger receptor class B type I expression is related to tumor aggressiveness and poor prognosis in breast cancer.
Scavenger receptor class B type I (SR-BI) has been linked to the development and progression of breast cancer. However, its clinical significance in breast cancer remains unclear. Here, we evaluated SR-BI expression in a well-characterized breast cancer tissue microarray by immunohistochemistry. High SR-BI expression was observed in 54 % of all breast cancer cases and was significantly associated with advanced pTNM stage (P = 0.002), larger tumor size (P = 0.023), lymph node metastasis (P = 0.012), and the absence of ER (P = 0.014). The Kaplan-Meier survival analysis revealed that patients with high SR-BI expression had significantly shorter overall survival (OS) (P = 0.004). Moreover, multivariate analysis with adjustment for other prognostic factors confirmed that SR-BI was an independent prognostic factor for patient outcome (P = 0.017). Overall, our study demonstrated that high SR-BI expression was related to conventional parameters indicative of more aggressive tumor type and may serve as a new prognostic marker for poor clinical outcome in human breast cancer.


Duplication at Xq28 involving IKBKG is associated with progressive macrocephaly, recurrent infections, ectodermal dysplasia, benign tumors, and neuropathy.
Duplications on Xq28 are common, although quite variable in size, but usually include the MECP2 gene. Here, we present a patient with a unique, small, 167-kb duplication at Xq28, not including MECP2. The most important gene in the duplicated region was IKBKG, mutations in which can cause a variety of distinct syndromes. Our patient's symptoms overlapped with different IKBKG-associated phenotypes, including hypohidrotic ectodermal dysplasia, incontinentia pigmenti, immunodeficiency, recurrent isolated invasive pneumococcal disease and anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, and lymphedema. In addition, she also had peripheral neuropathy, gastroparesis and various benign tumors, but no intellectual disability. Mixed syndromal presentation in several patients with IKBKG defect implies that IKBKG-related phenotypes are more like a spectrum, rather than distinct syndromes. We also suggest our patient's multisystem phenotype to be a novel contiguous gene syndrome, in which the key features include immune deficiency, macrocephaly, skin abnormalities, gastroparesis, peripheral small-fiber neuropathy, and benign tumors.


Enhanced survival and decreased mutation frequency after photoreactivation of UV damage in rat kangaroo cells.
The effect of pyrimidine dimers on cytotoxicity, DNA repair and mutagenesis was studied in cells, derived from the rat kangaroo, which possess photoreactivating capabilities. A significant enhancement in colony-forming ability was achieved after UV irradiation in exponentially growing cells if photoreactivating light treatment followed the UV irradiation. If photoreactivation treatment was delayed 24 h after UV irradiation, no significant increase in survival was observed. Assays of pyrimidine dimers, unscheduled DNA synthesis, and survival in contact-inhibited cells all confirmed a minor role of dark excision repair and a major role of photoreactivation. Photoreactivation decreased the frequency of mutations to 6-thioguanine resistance to a greater extent than the alteration seen in survival. Approximately 1.6 times the dose must be given to get equal killing in photoreactivated cells, whereas 4 times the dose must be given to obtain equal mutation frequencies in light-treated cells. This suggests that the removal of dimers is more effective in mutant reduction than enhancement of survival.


Genomic-wide identification and expression analysis of R2R3-MYB transcription factors related to flavonol biosynthesis in Morinda officinalis.
The R2R3-MYB transcription factors are a crucial and extensive gene family in plants, which participate in diverse processes, including development, metabolism, defense, differentiation, and stress response. In the Lingnan region of China, Morinda officinalis is extensively grown and is renowned for its use as both a medicinal herb and food source. However, there are relatively few reports on the R2R3-MYB transcription factor family in M.officinalis. In this study, we identified 97 R2R3-MYB genes in the genome of Morinda officinalis and classified them into 32 subgroups based on phylogenetic comparison with Arabidopsis thaliana. The lack of recent whole-genome duplication events in M.officinalis may be the reason for the relatively few members of the R2R3-MYB family. We also further analyzed the physical and chemical characteristics, conserved motifs, gene structure, and chromosomal location. Gene duplication events found 21 fragment duplication pairs and five tandem duplication event R2R3-MYB genes in M.officinalis may also affect gene family expansion. Based on phylogenetic analysis, cis-element analysis, co-expression analysis and RT-qPCR, we concluded that MoMYB33 might modulate flavonol levels by regulating the expression of 4-coumarate-CoA ligase Mo4CL2, chalcone isomerase MoCHI3, and flavonol synthase MoFLS4/11/12. MoMYB33 and AtMYB111 showed the highest similarity of 79% and may be involved in flavonol synthase networks by the STRING database. Moreover, we also identified MoMYB genes that respond to methyl Jasmonate (MeJA) and abscisic acid (ABA) stress by RT-qPCR. This study offers a thorough comprehension of R2R3-MYB in M.officinalis, which lays the foundation for the regulation of flavonol synthesis and the response of MoMYB genes to phytohormones in M.officinalis.


The human homolog of murine Evi-2 lies between two von Recklinghausen neurofibromatosis translocations.
Von Recklinghausen neurofibromatosis (NF1) is one of the most common inherited human disorders. The genetic locus that harbors the mutation(s) responsible for NF1 is near the centromere of chromosome 17, within band q11.2. Translocation breakpoints that have been found in this region in two patients with NF1 provide physical landmarks and suggest an approach to identifying the NF1 gene. As part of our exploration of this region, we have mapped the human homolog of a murine gene (Evi-2) implicated in myeloid tumors to a location between the two translocation breakpoints on chromosome 17. Cosmid-walk clones define a 60-kb region between the two NF1 translocation breakpoints. The probable role of Evi-2 in murine neoplastic disease and the map location of the human homolog suggest a potential role for EVI2 in NF1, but no physical rearrangements of this gene locus are apparent in 87 NF1 patients.


Arrhythmogenic effect of epinephrine during correction of dyslipidemia.
In rats with dyslipidemia epinephrine decreased HR and suppressed automaticity of the sinus node. This effect was not eliminated by LBK-149, dibunol, and glutabiance despite normalization of the plasma lipid spectrum. LBK-149 prevented the development of heart rhythm disturbances during epinephrine administration.


Goblet cell tumors of the appendix: A review.
Goblet cell tumors are rare tumors of the appendix that exhibit both neuroendocrine and mucinous differentiation. This dual differentiation has led to a controversy regarding the proper classification of these neoplasms as to whether they should be considered neuroendocrine tumors or adenocarcinomas. Multiple grading systems have been proposed that were able to segregate these tumors into prognostically significant groups. Many of these grading systems rely on identifying and/or quantifying the carcinomatous growth pattern. Goblet cell tumors show patchy and focal expression of neuroendocrine markers and are characterized by a mutational profile that is different from both appendiceal adenocarcinomas and neuroendocrine tumors. They exhibit a more aggressive behavior than neuroendocrine tumors, and as such, many authors recommend that they be approached and treated as adenocarcinomas.


Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype.
Peroxisome biogenesis factor 10 (PEX10) is involved in the import of peroxisomal matrix proteins, and the mutation of this gene causes 3 subtypes of peroxisome biogenesis disorders, namely Zellweger syndrome (severe), neonatal adrenoleukodystrophy (moderate) and an ataxic form (mild). Here, we report 3 siblings of the ataxic form with cerebellar ataxia, mild mental retardation, and 3 additional characteristic features: mydriasis, hyperreflexia and involuntary head movement. All 3 siblings are compound heterozygous for a previously reported mutation, c.2T>C (p.M1T), and a novel mutation, c.920G>A, causing a missense change (p.C307Y) located in the RING finger domain of PEX10. The present cases suggest that these PEX10 mutations involve not only cerebellar but also more multiple nervous systems including pupillary autonomic, pyramidal and extrapyramidal systems.


Polymorphism in cathelicidin gene (CAMP) that alters Hypoxia-inducible factor (HIF-1α::ARNT) binding is not associated with tuberculosis.
Polymorphisms in the CAMP gene (cathelicidin) have not been tested in tuberculosis susceptibility. We tested polymorphisms rs9844812 (HIF-1α::ARNT binding site) and rs56122065 (CAMP) plus rs1800972 (DEFB1). SNP rs1800972 was associated with extrapulmonary tuberculosis (EPTB) in a codominant model (genotype CG, P = 0.037, OR 4.82; 95% CI: 0.92-47.42; statistical power, 82%), but not PTB (P = 0.101) in a Mexican population.


SCA17 caused by homozygous repeat expansion in TBP due to partial isodisomy 6.
An expanded polyglutamine domain in the TATA-binding protein (TBP) has been described in patients with spinocerebellar ataxia type 17 (SCA17) characterized by cerebellar ataxia associated with dementia. TBP is a general transcription initiation factor that regulates the expression of most eukaryotic genes transcribed by RNA polymerase II. SCA17, as an autosomal dominantly inherited progressive neurodegenerative disorder, is caused by heterozygous expansion of a CAG repeat coding for glutamine. Alleles with 27 to a maximum of 44 glutamine residues were found as the normal range, whereas expansions above 45 repeat units were considered pathological. Here, we present a patient with a very severe phenotype with a late onset but rapidly progressing ataxia associated with dementia and homozygous 47 glutamine residues caused by an apparent partial isodisomy 6. This extraordinary case has important implications for the insights of TBP and SCA17. The expanded polyglutamine domain in both TBP copies is not correlated with embryonic death indicating that the normal function of the protein is not disrupted by this kind of mutation but may account for the dementia seen in this patient.


The surface activity of PVP and other polymers and their antihemolytic capacity.
The polymeric cryoprotective agents polyvinylpyrrolidone, dextran, and hydroxyethyl starch do not penetrate the cell membrane and are not present in high osmotic concentrations. Thus, they can exert little of the "antifreeze" behavior generally attributed to glycerol or dimethyl sulfoxide, and must protect cells from freezing injury by some action external to the cell surface. Surface energy measurements of droplets of hemoglobin solution immersed in solutions of cryoprotective polymers indicate that these polymers lower the surface energy of the solution below that of the hemoglobin droplets and form a stable interface. In injured cells, these polymers will therefore hide membrane defects by forming an interface across which hemoglobin cannot easily pass. When freezing is slow, the polymers have little if any true cryoprotective effect but interfere with hemoglobin release as an assay of injury.


Use of microdose phenotyping to individualise dosing of patients.
Administering the right amount of the right drug at the right time is a key mission of clinical medicine. This comprises dose adaptation according to a patient's intrinsic and extrinsic factors influencing drug disposition. Several biomarkers are available for dose adaptation; still, prediction of individual drug disposition may be improved. Phenotyping is the quantification of drug metabolism with probe substrates specific to drug-metabolising enzymes. This allows measurement of baseline metabolism and changes after modulation of drug metabolism. This article explores the concept of phenotyping using pharmacologically ineffective microdoses of probe substrates to obtain information on drug metabolism. Several probe drugs such as midazolam for cytochrome P450 3A have already been used, but validation of other microdosed probe drugs, analytical procedures and drug formulations still face some challenges that have to be overcome. Since microdosed probe drugs have no risk of adverse drug reactions or interference with therapy, more widespread use is possible. This allows drug-drug interaction data to be safely obtained during first-in-man studies, enhancing the clinical safety of human healthy volunteers and patients in clinical trials, and, most importantly, allows determination of the drug-metabolising phenotype in severely ill patients. With harmless probe drugs at hand quantifying drug metabolism and adapting the dose accordingly, a phenotyping-based dosing strategy could become reality, offering the possibility of individualised drug therapy with reduced adverse effects and fewer therapeutic failures.


[A rare case of Friedreich's atoxia with cardiac involvement: the torsade de pointe (author's transl)].
The Authors describe a case of Friedreich's ataxia complicated by an unusual arrhythmia, torsade de pointes, the only manifestation of cardiac involvment in this patient. Then some hypothesis of etiopathogenetic mechanism of this rhythm disturbance in patients affected with Friedreich's ataxia are proposed.


Hypoxia-induced soluble CD137 in malignant cells blocks CD137L-costimulation as an immune escape mechanism.
Hypoxia is a common feature in solid tumors that has been implicated in immune evasion. Previous studies from our group have shown that hypoxia upregulates the co-stimulatory receptor CD137 on activated T lymphocytes and on vascular endothelial cells. In this study, we show that exposure of mouse and human tumor cell lines to hypoxic conditions (1% O2) promotes CD137 transcription. However, the resulting mRNA is predominantly an alternatively spliced form that encodes for a soluble variant, lacking the transmembrane domain. Accordingly, soluble CD137 (sCD137) is detectable by ELISA in the supernatant of hypoxia-exposed cell lines and in the serum of tumor-bearing mice. sCD137, as secreted by tumor cells, is able to bind to CD137-Ligand (CD137L). Our studies on primed T lymphocytes in co-culture with stable transfectants for CD137L demonstrate that tumor-secreted sCD137 prevents co-stimulation of T lymphocytes. Such an effect results from preventing the interaction of CD137L with the transmembrane forms of CD137 expressed on T lymphocytes undergoing activation. Indeed, silencing CD137 with shRNA renders more immunogenic tumor-cell variants upon inoculation to immunocompetent mice but which readily grafted on immunodeficient or CD8+ T-cell-depleted mice. These mechanisms are interpreted as a molecular strategy deployed by tumors to repress lymphocyte co-stimulation via CD137/CD137L.


HIV cure: knocking on the door.
Although major advances in drug development and public health are helping to control the HIV/AIDS epidemic, there is a strong rationale for pursuing a more definitive cure. Several bold but unproven strategies for HIV eradication are reviewed in this issue of CPT, including novel drugs, gene therapy, and bone marrow transplantation (BMT). Early results, including one probable case of HIV eradication in a leukemia patient, are intriguing but raise many questions.


Capturing Meaningful Outcomes in -Pediatric Neurology: Further Reflections on Principles, Challenges, and Opportunities.
Patient and public involvement in health care is considered indispensable in the way we conduct daily pediatric neurology practice, and in the development and utilization of health outcome measurements. This essay examines what meaningful quality evaluations and measurements are, describes the development of approaches to measuring health and outcomes, explores the potential applications of patient-reported outcome measures in pediatric neurology, and identifies opportunities and challenges in using patient-reported outcome measurements in our daily clinical practice. Recent developments have transformed our attitude on how to help children with neurological and developmental conditions and their families: specifically, (1) the recognition of the fundamental rights of children with disabilities; (2) the application of the framework of the International Classification of Functioning, Disability and Health by the World Health Organization that views health from the perspective of both biopsychosocial strengths and functional abilities; (3) the application of qualitative research methodologies to children with neurological conditions and their caregivers to elucidate what they consider essential for their own good health and well-being; and (4) the development of core outcome measurements sets for children and adults with various neurological and developmental conditions. In summary, supporting patients in their role as full partners in clinical care and research enables them to contribute their experiential knowledge and helps ensure that results are relevant and address patient needs, preferences, and priorities. Recognizing the importance of involving young people in their health management decisions has become central in contemporary medicine and needs to be part of the curriculum of all health care professionals.


Traumatic retinal pigment epithelial edema.
A 17-year-old girl was struct in the right eye by a mortarboard tossed into the air during high school graduation exercises. She suffered commotio retinae with damage to the retinal pigment epithelium and macular hole formation. Fluorescein angiography in the acute stages revealed diffuse staining at the level of the pigment epithelium. Five months later, the areas of abnormal staining had undergone depigmentation and dye no longer accumulated in the pigment epithelial layer. The fluorescein findings in traumatic retinal pigment epithelial edema are unusual.