Evaluation of Cynara cardunculus L. and municipal solid waste compost for aided phytoremediation of multi potentially toxic element-contaminated soils.
The suitability for aided phytoremediation of Cynara cardunculus L. var. altilis and municipal solid waste compost (MSWC) applied at 2% and 4 % rates was evaluated in a multi potentially toxic element (PTE)-contaminated mining soil (Pb ~ 15,383 mg kg-1, Zn ~ 4076 mg kg-1, As ~ 49 mg kg-1, Cd ~ 67 mg kg-1, Cu ~ 181 mg kg-1, and Sb ~ 109 mg kg-1). The growth of C. cardunculus significantly increased with compost amendment and followed the order: MSWC-4% > MSWC-2% > Control. PTE concentrations in the roots of plants grown on amended soils decreased compared with control plants (i.e., less than ~ 82, 94, and 88% for Pb, Zn, and Cd respectively). PTE translocation from roots to shoots depended on both PTE and amendment rate but values were generally low (i.e., < 1). However, PTE mineralomasses were always higher for plants grown on MSWC-amended soils because of their higher biomass production, which favored an overall PTE bioaccumulation in roots and shoots. After plant growth, labile As and Sb increased in amended soils, while labile Pb, Zn, Cu, and Cd significantly decreased. Likewise, dehydrogenase and urease activities increased significantly in planted soils amended with MSWC. Also, the potential metabolic activity and the catabolic versatility of soil microbial communities significantly increased in planted soils amended with MSWC. Overall, our results indicate that C. cardunculus and MSWC can be effective resources for the aided phytoremediation of multi PTE-contaminated soils.


Leishmaniasis: early diagnosis is key.
A patient presents with nasal congestion, a history of nosebleed, and painful lesions on his body and in his mouth. What questions should you ask to ensure that you make an accurate diagnosis?


Terbium luminescence sensitized through three-photon excitation in a self-assembled unlinked antenna.
The organic-terbium hybrid compound designed with the azido molecule L, 2-methoxy benzoic acid tris-(2-methoxybenzoyl)hydrazide, exhibits three-photon-excited green emission as well as second-harmonic generation even though the antenna is unlinked from the metal center.


Orally administered microencapsulated lysozyme downregulates serum AGE and reduces the severity of early-stage diabetic nephropathy.
Diabetic nephropathy is the leading cause of end-stage kidney disease in developed countries and is related to chronic hyperglycaemia. The increased production and tissue deposition of advanced glycation end products (AGE) are known to play a major role in the pathogenesis of diabetic kidney damage. This study was undertaken to determine if lysozyme (LZ), microencapsulated in orally administrable chitosan-coated alginate microspheres (MS), is effective against the early changes seen in the initial stages of diabetic nephropathy. LZ-containing MS (MSLZ) and an equivalent dose (equidose) of nonencapsulated LZ were given as oral treatments. LZ was administered to Wistar rats for seven weeks after diabetes induction with streptozotocin. The results showed that microencapsulated LZ treatment significantly reduced the concentration of serum AGE in the circulation and their deposition in the kidneys. Likewise, MSLZ significantly prevented the development of microalbuminuria compared with untreated diabetic rats. Furthermore, MSLZ significantly prevented the development of glomerular and renal hypertrophy as well as overexpression of AGE receptors (RAGE). An equidose of free LZ had little or no effect whatsoever. Our study supports a relationship between serum AGE and nephropathy in diabetes, and suggests that orally administered microencapsulated LZ can exert kidney-protective activity in a diabetic animal model.


Long-term treatment with metoprolol after myocardial infarction: effect on 3 year mortality and morbidity.
The effects of metoprolol treatment in patients surviving acute myocardial infarction have been investigated in a double-blind randomized study. The patients were stratified according to age, infarct size and type of ventricular arrhythmias before administration of metoprolol, 100 mg twice daily (n = 154), or placebo (n = 147). All patients were followed up for 36 months. There were 31 (29 cardiac) and 25 (20 cardiac) deaths in the placebo and metoprolol groups, respectively. Subgroup analyses showed a significant reduction of cardiac death in patients with a large infarct (32.1% with placebo versus 12.5% with metoprolol, p less than 0.05) as a result of active treatment. Sudden death rates were 14.7% in the placebo versus 5.8% in the metoprolol group (p less than 0.05). The incidence of nonfatal reinfarction was 21.1% in the placebo versus 11.7% in the metoprolol group (p less than 0.05). The reduction in nonfatal reinfarction was similar in all pretreatment risk strata. The difference between the two groups in cumulative number of cardiac deaths and patients experiencing nonfatal reinfarction increased throughout the study. Furthermore, cerebrovascular events (p less than 0.05) and coronary bypass surgery (p = 0.058) were more frequent in the placebo group. In conclusion, after 36 months of metoprolol treatment after myocardial infarction, there was a significant reduction of nonfatal reinfarction and sudden death in all patients and a reduction of cardiac death in those with a large infarct.


Reliability of respiratory event detection with continuous positive airway pressure in moderate to severe obstructive sleep apnea - comparison of polysomnography with a device-based analysis.
Monitored polysomnography (PSG) is considered the gold standard technique to diagnose obstructive sleep apnea (OSA) and titrate continuous positive airway pressure (CPAP), the accepted primary treatment method. Currently, the American Academy of Sleep Medicine (AASM) considers automatic PAP therapy initiation at home comparable to laboratory titration and recommends telemonitoring-guided interventions. Advanced CPAP devices evaluate and report the residual apnea-hypopnea index (AHI). However, in order to control the effectiveness of the prescribed therapy outside of a PSG setting, the automatic event detection must provide reliable data. A CPAP titration was performed in the sleep laboratory by PSG in patients with OSA. The residual event indices detected by the tested device (prismaLine, Loewenstein Medical Technology) were compared to the manually scored PSG indices. Results of the device (AHIFLOW) were compared according to the AASM scoring criteria 1A (AHI1A, hypopneas with a flow signal reduction of ≥ 30% with ≥ 3% oxygen reduction and/or an arousal) and 1B (AHI1B, hypopneas with a flow signal decrease by ≥ 30% with a ≥ 4% oxygen desaturation). In 50 patients with OSA, the mean PSG AHI1A was 10.5 ± 13.8/h and the PSG AHI1B was 7.4 ± 12.6/h compared to a mean device AHIFlow of 8.4 ± 10.0/h. The correlation coefficient regarding PSG AHI1A and AHIFlow was 0.968. The correlation regarding central hypopneas on the other hand was 0.153. There were few central events to be compared in this patient group. The device-based analysis showed a high correlation in the determination of residual obstructive AHI under therapy. The recorded residual respiratory event indices in combination with the data about leakage and adherence of the studied device provide reliable information for the implementation and follow-up of CPAP therapy in a typical group of patients with OSA. ClinicalTrials.gov Identifier: NCT04407949, May 29, 2020, retrospectively registered.


Realization of firefly bioluminescence cycle in vitro and in cells.
The quantum yield (Q) of the "cold light" of firefly bioluminescence (BL) is remarkably high due to its nonradiative decay is extremely minimized. Thus, an artificial firefly represents the new generation of biomimetic "cold light" source with highest energy utilization. However, to manufacture a firefly-biomimetic "cold light" in vitro, one has to overcome several challenges including realization of the firefly BL cycle by incorporating the two important enzymes (i.e., firefly luciferase (Fluc) and luciferin-regenerating enzyme (LRE)) in one system. Here in this work, using self-prepared Fluc, LRE, and the main substrates, we realized the firefly BL cycle both in vitro and in cells. Moreover, using combinational analyses of HPLC and nESI-CID-MS/MS, we identified the main chemicals in the metabolic pathways underlying the firefly BL cycle. Using theoretical simulations, we revealed an optimum chemical route which balances the reaction cycle to achieve the highest BL intensity with the least chemical supplies. We anticipate that this pioneering study of the firefly cycle would provide industry with the opportunity to design tunable, economical, biomimetic "cold light" device in near future.


Association between ustekinumab trough concentrations and biochemical outcomes in patients with Crohn's disease. A real life study.
numerous studies have shown a positive correlation between serum biologic drug concentrations and favorable therapeutic outcomes during the induction and maintenance period in patients with Crohn's disease (CD). To our knowledge, only a few and contradictory studies have determined the association between ustekinumab (UST) trough concentrations and biological outcomes. This study aimed to investigate the relationship between ustekinumab trough concentrations and biological outcomes in a real-world setting. a cross-sectional cohort study was performed. All adult patients with CD who received maintenance therapy (≥ 24 weeks) with ustekinumab were included in the study. Clinical response was determined using the Harvey-Bradshaw Index. Biochemical remission was defined as a fecal calprotectin level < 150 µg/g in feces and a biochemical response as > 50 % reduction of fecal calprotectin. a total of 58 CD patients were included in the study and the median UST trough concentration was 1.78 µg/ml (IQR: 2.56). Differences in ustekinumab trough concentrations were observed for clinical (2.25 µg/ml vs 0.65 µg/ml; p = 0.006) and biochemical remission (2.33 µg/ml vs 1.03 µg/ml; p = 0.047). According to ROC analysis, a cut-off of 1.4 µg/ml (AUC: 077) and 2.0 µg/ml (AUC: 0.65) were identified for predicting clinical and biochemical remission, respectively. Likewise, ustekinumab trough levels were also higher in "composite clinical/biochemical remission" (2.38 µg/ml vs 1.08 µg/ml; p = 0.042). The trough level that was best associated with composite clinical/biochemical remission was 2.2 µg/ml (AUC: 0.69). this real-life study shows the association between ustekinumab trough concentration and clinical and biochemical remission and we suggest an optimal cut-off point higher than 2.2 µg/ml. Further studies are needed to confirm the findings and to identify the optimal cut-off in different disease outcomes and disease phenotypes.


Treatment of shigellosis: IV. Cefixime is ineffective in shigellosis in adults.
To compare the efficacy of cefixime with that of pivamdinocillin in the treatment of adults with acute dysentery caused by Shigella infection. Randomized, double-blind clinical trial. A diarrhea treatment center in Dhaka, Bangladesh. 30 men with dysentery lasting 72 hours or less. Patients were randomly assigned to receive either 400 mg of cefixime every 24 hours (n = 15) or 400 mg of pivamdinocillin every 6 hours (n = 15) for 5 days. All patients were hospitalized for 6 days. Patients in whom initial drug therapy failed received alternative antimicrobial therapy. Physical examinations were done and symptoms were recorded daily, and body temperatures were measured every 6 hours. Stools were counted and examined for consistency and for the presence of blood and mucus. Therapy failed if symptoms of dysentery persisted for more than 72 hours or if, on study day 5, a patient had six stools, one watery or bloody-mucoid stool, or an oral temperature higher than 37.8 degrees C. Bacteriologic failure of therapy occurred if Shigella could be isolated from a stool sample on or after study day 3. Therapy failed in seven (47%) patients given cefixime but in none of the patients given pivamdinocillin (P = 0.006). Patients given cefixime had longer duration of fever (median, 6 hours compared with 0 hours, P = 0.019), longer duration of the period with dysenteric stools (median, 4 days compared with 1 day, P = 0.001), and more stools during the 6 study days (median, 65 compared with 28, P = 0.002) than patients treated with pivamdinocillin. Bacteriologic failure of therapy occurred in 60% of patients (9 of 15) given cefixime and 13% of those (2 of 15) given pivamdinocillin (P = 0.009). Cefixime is ineffective in treating shigellosis in adults when used in the standard recommended dosage.


The Fluorosome technique for investigating membrane on- and off-loading of drugs by beta-CD and sonicated SUV.
The application of the Fluorosome technique to test drug delivery systems is described. Fluorosomes, egg phosphatidylcholine liposomes with bilayer embedded fluorophores, were employed to investigate the ability of sonicated small unilamellar vesicles (sSUV) and beta-cyclodextrins (beta-CD) to deliver drugs into or extract drugs from the fluorosome's phospholipid bilayer. The addition of phloretin to a fluorosome suspension resulted in fluorescence reduction reflecting phloretin entering the bilayer and quenching fluorophore fluorescence. Subsequent addition of sSUV to phloretin pretreated fluorosomes showed an increase in fluorescence reflecting phloretin extraction from the fluorosome membrane. Sequential additions of beta-estradiol loaded beta-CD to fluorosomes as well as the addition of beta-estradiol alone resulted in fluorescence reduction due to beta-estradiol insertion into the membrane. Further addition of pure beta-CD resulted in a fluorescence increase indicating beta-estradiol extraction from the fluorosome membrane.


Quantitative DCE-MRI: an efficient diagnostic technique for evaluating early micro-environment permeability changes in ankylosing spondylitis.
In the management of early inflammatory joint of ankylosing spondylitis (AS), there is a need for reliable noninvasive quantitative monitoring biomarker to closely assess status of synovitis progression. Cognizant to this,studies geared on improving techniques for quantitative evaluation of micro-environment permeability of the joint space are necessary. Such improved techniques may provide tissue perfusion as important biological parameters and can further help in understanding the origin of early changes associated with AS. The purpose of this study was to prospectively evaluate the diagnostic performance and determine longitudinal relationships of early micro-environment active in the joint space of the sacroiliac joint (SIJ) with a rat model by using quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Thirty wistar male rats were randomly assigned to the model (n = 15) or control (n = 15) group. All rats underwent DCE-MRI of SIJ region at fixed time points (12, 17 and 22 weeks),between September 2018 and October 2019. Differences in permeability parameters between the two groups at the same time point were compared by using an independent samples t test. Spearman correlations of DCE-MRI parameters with different time points in model group were analyzed. All statistical analyses were performed with software. At 12 weeks,the Ktrans,Kep and Ve values in the model group were slightly lower than those in control group,but all the differences were not statistically significant (p > 0.05). Compared with control group,the transfer constant (Ktrans) values increased significantly at 17 weeks and 22 weeks in model group,while the rate constant (Kep) and volume of extravascular extracellular space (Ve) significantly increased only at 22 weeks(p < 0.05). The Ktrans,Kep and Ve were positively correlated with increasing time points (r = 0.946, P<0.01 for Ktrans; r = 0.945, P<0.01 for Kep; and r = 0.832, P<0.01 for Ve). Quantitative DCE-MRI parameters are valuable for evaluating the early longitudinal relationship of micro-environment permeability changes in the joint space of SIJ.


Effect of spermine and DNase on DNA release from bacteriophage T5.
Bacterial viruses (bacteriophages) consist of nucleic acid protected by a protein envelope called capsid. At the start of infection, the phage genome is translocated into the bacterial cytoplasm. In vitro (and also in vivo), this DNA release can be triggered by binding a specific receptor protein to the phage tail. The force responsible for the release arises from energy stored in the capsid due to strong confinement of the DNA. We show that this force can be modified by adding molecules like spermine that affect DNA conformation. The tetravalent cation spermine can reduce the pressure inside the capsid and induce condensation of the released DNA. We examine the effect of spermine on DNA ejection from phage T5 by using light scattering and gel electrophoresis to measure the amount of DNA remaining in the capsid at the end of ejection. We discuss the results in terms of free energy minimization and we demonstrate that the presence of a DNA condensate outside the phage generates an additional force pulling passively on the DNA remaining inside the capsid.


Severe deficiency of alpha 1-antitrypsin associated with cutaneous vasculitis, rapidly progressive glomerulonephritis, and colitis.
The association of vasculitis with severe deficiency of alpha 1-antitrypsin is rare. This report describes a 44-year-old man with severe deficiency of alpha 1-antitrypsin associated with diffuse vasculitis involving skin, kidney (rapidly progressive glomerulonephritis), and colon (colitis). Colitis has not previously been reported in association with deficiency of alpha 1-antitrypsin. Other reported cases are reviewed and the possible immunologic mechanisms underlying the association are discussed.


Clinical similarities and differences between two large HIV cohorts in the United States and Africa.
Washington, DC, and sub-Saharan Africa are both affected by generalized HIV epidemics. However, care for persons living with HIV (PLWH) and clinical outcomes may differ in these geographically and culturally diverse areas. We compared patient and clinical site characteristics among adult persons living with HIV (PLWH) enrolled in two longitudinal HIV cohort studies-the African Cohort Study (AFRICOS) and the DC Cohort. The DC Cohort is a clinic-based city-wide longitudinal cohort comprised of PLWH attending 15 HIV clinics in Washington, DC. Patients' socio-demographic characteristics, clinical evaluations, and laboratory data are retrospectively collected from electronic medical records and limited manual chart abstraction. AFRICOS is a prospective observational cohort of PLWH and uninfected volunteers attending 12 select HIV care and treatment facilities in Nigeria, Kenya, Uganda and Tanzania. AFRICOS study participants are a subset of clinic patients who complete protocol-specific visits every 6 months with history and physical examination, questionnaire administration, and blood/sputum collection for ascertainment of HIV outcomes and comorbidities, and neurocognitive and functional assessments. Among participants aged ≥ 18 years, we generated descriptive statistics for demographic and clinical characteristics at enrollment and follow up and compared them using bivariable analyses. The study sample included 2,774 AFRICOS and 8,420 DC Cohort participants who enrolled from January 2013 (AFRICOS)/January 2011 (DC Cohort) through March 2018. AFRICOS participants were significantly more likely to be women (58.8% vs 27.1%) and younger (83.3% vs 61.1% aged < 50 years old) and significantly less likely to be MSM (only 0.1% of AFRICOS population reported MSM risk factor) than DC Cohort. Similar rates of current viral suppression (about 75% of both samples), hypertension, hepatitis B coinfection and alcohol use were observed. However, AFRICOS participants had significantly higher rates of CD4<200 and tuberculosis and significantly lower rates of obesity, DM, hepatitis C coinfection and syphilis. With similar viral suppression outcomes, but many differences between our cohorts noted, the combined sample provides unique opportunities to assess and compare HIV care and treatment outcomes in the U.S. and sub-Saharan Africa. Comparing these two cohorts may inform care and treatment practices and may pave the way for future pathophysiologic analyses.


Syphilitic placentitis: demonstration of Treponema pallidum by immunoperoxidase staining.
We report a case of early congenital syphilis in which the placenta showed diffuse proliferative villitis and Treponema pallidum was identified by indirect immunoperoxidase stain in formalin-fixed paraffin-embedded placental tissue. This is the first report demonstrating T. pallidum in placental tissue using an immunohistochemical method.


Cyclosporin A attenuates weight gain and improves glucose tolerance in diet-induced obese mice.
Inflammation is a main factor responsible for obesity induced insulin resistance and type 2 diabetes. Since immunosuppressant activity is closely related with low level of inflammation, we predict that Cyclosporin A (CsA), an immunosuppressant drug, might have a protective role for combating inflammation-associated disorders such as obesity and type 2 diabetes. To address this issue, obese or lean mice were received CsA via gavage at the dose of 10mg/kg/day for 3 weeks. Our results show that CsA treatment remarkably attenuates food intake and body weight gain in the obese mice. CsA treatment down-regulates expression of gluconeogenic gene including Pepck, G6Pase and Pgc1α, leading to a decrease in blood glucose level and an improvement of glucose tolerance in the obese animals. RT-PCR analysis of genes involved in adipocyte differentiation and lipid metabolism in white adipose tissue reveal that CsA application reduces expression of Pparγ, Fas and Scd 1. The productions of pro-inflammatory cytokines (IL-1β, IL-2, IL-12 and TNFα) and JNK activity were remarkably reduced in the CsA-treated obese animals. These results suggest that CsA treatment might play beneficial effects against obesity and obesity related hyperglycemia.


Acute inhibition of Rho-kinase attenuates pulmonary hypertension in patients with congenital heart disease.
This study aimed to determine whether the Rho-kinase-mediated pathway is involved in the pathogenesis of left-to-right shunt-induced pulmonary hypertension and whether fasudil exhibits acute beneficial effects on the hemodynamics of these patients. A total of 12 patients with a mean age of 12.3 years were enrolled in a self-controlled prospective study. All the patients had a diagnosis of congenital heart disease with slight to moderate pulmonary hypertension and were scheduled for transcatheter closure. After placement of the catheters, 30 mg/kg fasudil was injected intravenously over 30 min under room air conditions. Hemodynamic parameters including pulmonary artery systolic pressure (PASP), pulmonary vascular resistance (PVR), systemic artery pressure (SAP), systemic vascular resistance (SVR), cardiac input, and blood oxygen saturation were measured and calculated at baseline and 30 min after fasudil injection. After fasudil treatment, PASP decreased to a level 33.03 +/- 6.64% less than baseline value (p < 0.01), and maximal PVR decreased to a level 33.03 +/- 6.64% less than baseline value (p < 0.01). Cardiac input increased to a level 7.7 +/- 5.2% more than baseline value (p < 0.05), and mixed venous oxygen saturation significantly increased to a level 7.7 +/- 5.2% more than baseline value (p < 0.01). The left-to-right shunt ratio (Q(P)/Q(S)) also tended to increase (16.2 +/- 12.5% of baseline value; p < 0.01). Whereas SAP showed only a slight decrease (-1.6 +/- 3.1% of baseline value; p = 0.08), SVR significantly decreased (-10.2 +/- 12.2% of baseline value; p < 0.01), and the PVR/SVR ratio tended to decrease (-23.9 +/- 15.1% of baseline value). In conclusion, Rho-kinase is involved in the pathogenesis of left-to-right shunt-induced pulmonary hypertension, and fasudil is a novel therapeutic approach.


Biomechanical effects of steroid injections used to treat pyogenic flexor tenosynovitis.
A recent study from our laboratory has demonstrated improved range of motion in the toes of broiler chickens afflicted with pyogenic flexor tenosynovitis when treated with local antibiotic and corticosteroid injections, without surgical drainage. However, the use of corticosteroids as an adjunct treatment raised peer concern, as steroids are thought to have deleterious effects on tendon strength. The purpose of this study was to compare the tensile strength of the aforementioned steroid treated tendons, to a group of tendons administered with the current standard treatment: systemic antibiotics, surgical drainage and no corticosteroids. Twenty-three tendons' structural and material properties were investigated (fifteen receiving the standard treatment, eight receiving the steroid treatment). The measurements from each group were interpreted via Student's unpaired t-test and a post-hoc power analysis. The steroid treated tendons did demonstrate a trend toward decreased mechanical properties when compared with the standard treatment group, but the results were not statistically significant. Treatment of septic tenosynovitis with local corticosteroid and local antibiotic injections resulted in better digital motion, without a significant loss of tendon strength, over a twenty-eight day recovery period.


Nocardia asteroides isolated from three patients with cystic fibrosis.
Over a 7-year period, three patients with cystic fibrosis had multiple sputum specimens that were smear- and culture-positive for Nocardia asteroides. Two of the patients had received long-term, low-dose inhalational corticosteroid therapy. Although all three patients were treated with cotrimoxazole, resulting in eradication of the organism from the sputum, there was no change in their clinical state, radiological findings, or pulmonary function. The isolation of Nocardia asteroides from the respiratory tract of cystic fibrosis patients is an unusual finding. Its presence does not necessarily imply disease, and in these three cases, it most likely represented colonisation. The clinical significance of Nocardia spp. isolated from the respiratory tract of cystic fibrosis patients needs to be considered in the context of the individual clinical picture.


Type C Niemann-Pick disease: a murine model of the lysosomal cholesterol lipidosis accumulates sphingosine and sphinganine in liver.
We have determined the levels of free sphingoid bases in livers of normal and cholesterol lipidotic Niemann-Pick type C mice. Hepatic sphingosine and sphinganine levels in affected mice (593 pmol/mg protein) were elevated more than 20-fold when compared to levels in age-matched normal mice (26 pmol/mg protein). Upon fractionation of mutant liver homogenates by differential centrifugation, most of the sphingoid bases sedimented with beta-hexosaminidase in the 9000 x g pellet. Co-sedimentation of sphingoid bases with a lighter beta-hexosaminidase peak in Percoll gradients suggests that these bases accumulate in lipid laden lysosomes. A cytosolic sphinganine kinase is the first enzyme in the degradative pathway of sphingoid base metabolism. Activity of this enzyme was partially deficient in crude mutant liver cytosolic extracts due to the presence of an inhibitory substance. Following molecular sieving of mutant cytosolic extracts on Sepharose 4B, sphinganine kinase, with normal levels of activity, was resolved from a complex higher-molecular-weight inhibitor fraction. The Km values for either sphinganine or ATP-Mg substrates with partially purified sphinganine kinase from normal and mutant mouse liver extracts, were similar. These findings indicate that accumulation of free sphingoid bases is not due to a direct inherent deficiency in the catalytic activity of sphinganine kinase. The possible cause and effect relationship between the accumulation of these endogenous hydrophobic amines and the lesion in intracellular cholesterol trafficking in Niemann-Pick type C disease is discussed.


Development and validation of a vitiligo-specific quality-of-life instrument (VitiQoL).
Vitiligo significantly affects a person's health-related quality of life (HRQL). Although a small number of generic, and disease-specific, dermatologic HRQL measures exist, currently no vitiligo-specific instrument is available to capture disease-targeted concerns and issues. We sought to develop and validate a vitiligo-specific self-report instrument for HRQL. A pool of vitiligo-specific items was created based on in-depth interviews with patients with vitiligo (n = 16) and their responses to items in several previously validated HRQL measures. These items comprising our new instrument, VitiQoL, along with Skindex-16 and Dermatology Life Quality Index were administered to patients with vitiligo (n = 90) at two academic centers. This new instrument was validated using psychometric analysis. The VitiQoL items showed high internal consistency (Cronbach alpha = 0.935). Exploratory factor analysis demonstrated 3 factors: participation limitation, stigma, and behavior. Concurrent validity was evidenced by large correlations between self-reported severity and VitiQoL scores (r = 0.51). Known groups validity was demonstrated for the VitiQoL behavior subscale between individuals with exposed and unexposed patches (P = .01). Convergent validity was shown by strong correlations between VitiQoL and outside dermatology scales measuring similar constructs (Skindex-16, r = 0.82; Dermatology Life Quality Index, r = 0.83). Potential selection bias was a limitation as most patients were recruited from academic centers. Reliability of the instrument was tested only with internal consistency and not reproducibility. Responsiveness of the instrument was not tested because of the prolonged time course necessary to observe clinically significant change in vitiligo. VitiQoL is a reliable and valid HRQL instrument.


A complex system of ligaments and a muscle keep the crystalline lens in place in the eyes of bony fishes (teleosts).
The suspension of the crystalline lens in the eye was studied in 11 species of teleost (bony fish) from 10 families and 7 orders by light and electron microscopy. In all species there were 4-5 ligaments in about the equatorial plane of the eye, in which also the tendon of the retractor lentis muscle attaches to the lens. In two cichlid species two additional ligaments were found running from the mid-posterior surface of the lens to the optic nerve head, where they attach to the falciform process. Lens suspension in teleosts is more complex than previously described and well-suited to firmly keep the heavy spherical lens in position for well-focused vision.


Satratoxin G from the black mold Stachybotrys chartarum evokes olfactory sensory neuron loss and inflammation in the murine nose and brain.
Satratoxin G (SG) is a macrocyclic trichothecene mycotoxin produced by Stachybotrys chartarum, the "black mold" suggested to contribute etiologically to illnesses associated with water-damaged buildings. Using an intranasal instillation model in mice, we found that acute SG exposure specifically induced apoptosis of olfactory sensory neurons (OSNs) in the olfactory epithelium. Dose-response analysis revealed that the no-effect and lowest-effect levels at 24 hr postinstillation (PI) were 5 and 25 microg/kg body weight (bw) SG, respectively, with severity increasing with dose. Apoptosis of OSNs was identified using immunohistochemistry for caspase-3 expression, electron microscopy for ultrastructural cellular morphology, and real-time polymerase chain reaction for elevated expression of the proapoptotic genes Fas, FasL, p75NGFR, p53, Bax, caspase-3, and CAD. Time-course studies with a single instillation of SG (500 microg/kg bw) indicated that maximum atrophy of the olfactory epithelium occurred at 3 days PI. Exposure to lower doses (100 microg/kg bw) for 5 consecutive days resulted in similar atrophy and apoptosis, suggesting that in the short term, these effects are cumulative. SG also induced an acute, neutrophilic rhinitis as early as 24 hr PI. Elevated mRNA expression for the proinflammatory cytokines tumor necrosis factor-alpha, interleukin-6 (IL-6) , and IL-1 and the chemokine macrophage-inflammatory protein-2 (MIP-2) were detected at 24 hr PI in both the ethmoid turbinates of the nasal airways and the adjacent olfactory bulb of the brain. Marked atrophy of the olfactory nerve and glomerular layers of the olfactory bulb was also detectable by 7 days PI along with mild neutrophilic encephalitis. These findings suggest that neurotoxicity and inflammation within the nose and brain are potential adverse health effects of exposure to satratoxins and Stachybotrys in the indoor air of water-damaged buildings.


Transpubic access using pedicle tubularized labial urethroplasty for the treatment of female urethral strictures associated with urethrovaginal fistulas secondary to pelvic fracture.
Female urethral injury is rare, and there is no accepted standard approach for the repair of urethral strictures. To evaluate the efficacy of transpubic access using pedicle tubularized labial urethroplasty for urethral reconstruction in female patients with urethral obliterative strictures and urethrovaginal fistulas. Between January 1996 and December 2006, eight cases of female urethral strictures associated with urethrovaginal fistulas were treated using pedicle labial skin flaps. A flap of approximately 3x3.5x3cm of the labia minora or majora with its vascular pedicle was tubularized over an 18-22 Fr fenestrated silicone stent to create a neourethra. This technique was used in five women. Two flaps, approximately 1.5-3.5 cm, were taken from bilateral labia minora or majora and were pieced together to create a neourethra. This technique was used in three patients. We performed voiding cystourethrography and uroflowmetry to assess postoperative results. The patients were followed up for 10-118 mo (mean 48.25 mo) after the procedure. There were no postoperative complications. Two patients complained of dysuria, which resolved spontaneously after 2 wk. One patient experienced stress incontinence that resolved after 4 wk. At 3-mo follow-up, one patient complained of difficulty voiding; the urinary peak flow was 13 ml/s, and the patient was treated successfully with urethral dilation. All other patients had normal micturition following catheter removal. Pedicle labial urethroplasty is a reliable technique for the repair of extensive urethral damage, and a transpubic surgical approach provides wide and excellent exposure for the management of complex obliterative urethral strictures and urethrovaginal fistulas secondary to pelvic fracture.


Modification of behavioral response to intra-hippocampal injections of noradrenaline and adrenoceptor agonists by chronic treatment with desipramine and citalopram: functional aspects of adaptive receptor changes.
The present study investigated the effects of acute and of chronic treatment with desipramine (DI) and citalopram (CT) on the alterations in rat behavior in the open field and in the forced swim tests produced by intra-hippocampal microinjections of noradrenaline (NA) and adrenoceptor agonists. Chronic but not acute treatment with DI potentiated the stimulatory effects of NA on the rats' behavior in the open field test and in the forced swim test as well as revealed the excitatory effect of microinjections of phenylephrine at a dose producing insignificant changes when given alone. The depressive effects of clonidine in the open field test were antagonized by acute DI administration and reversed by chronic DI. No characteristic changes in the isoproterenol-induced increase in rat locomotion were observed following chronic DI since the antagonistic interaction was found after both acute and chronic DI pretreatment. Chronic though not acute administration of CT produced effects in the forced swim test similar to those of DI, i.e. excitatory effects of phenylephrine and clonidine on behavior. The data indicate a potentiation of excitatory processes in the brain limbic structure, probably mediated via alpha 1-adrenoceptors.


CXC Chemokine Receptors in the Tumor Microenvironment and an Update of Antagonist Development.
Chemokine receptors, a diverse group within the seven-transmembrane G protein-coupled receptor superfamily, are frequently overexpressed in malignant tumors. Ligand binding activates multiple downstream signal transduction cascades that drive tumor growth and metastasis, resulting in poor clinical outcome. These receptors are thus considered promising targets for anti-tumor therapy. This article reviews recent studies on the expression and function of CXC chemokine receptors in various tumor microenvironments and recent developments in cancer therapy using CXC chemokine receptor antagonists.


Seminal vesicle abscess: the use of computerized coaxial tomography for diagnosis and therapy.
Seminal vesicle abscesses are extremely rare and worthy of report. Computerized tomography easily verifies the diagnosis and simplifies the treatment of transurethral incision and drainage.


Ensembles of data-efficient vision transformers as a new paradigm for automated classification in ecology.
Monitoring biodiversity is paramount to manage and protect natural resources. Collecting images of organisms over large temporal or spatial scales is a promising practice to monitor the biodiversity of natural ecosystems, providing large amounts of data with minimal interference with the environment. Deep learning models are currently used to automate classification of organisms into taxonomic units. However, imprecision in these classifiers introduces a measurement noise that is difficult to control and can significantly hinder the analysis and interpretation of data. We overcome this limitation through ensembles of Data-efficient image Transformers (DeiTs), which not only are easy to train and implement, but also significantly outperform the previous state of the art (SOTA). We validate our results on ten ecological imaging datasets of diverse origin, ranging from plankton to birds. On all the datasets, we achieve a new SOTA, with a reduction of the error with respect to the previous SOTA ranging from 29.35% to 100.00%, and often achieving performances very close to perfect classification. Ensembles of DeiTs perform better not because of superior single-model performances but rather due to smaller overlaps in the predictions by independent models and lower top-1 probabilities. This increases the benefit of ensembling, especially when using geometric averages to combine individual learners. While we only test our approach on biodiversity image datasets, our approach is generic and can be applied to any kind of images.


Increased ability of murine bone marrow stromal cells immortalized with simian virus 40 (SV40) to retain haemopoietic cells and support long-term haemopoiesis in vitro.
A simple method for short-term recharge of SV40-immortalized marrow stromal cell (MSC) lines based on their specific interaction with the appropriate haemopoietic cells is described. During the first week after the recharge the production of polymorphonuclear and mononuclear blood cells is an order of magnitude higher than in the recharged primary MSC cultures. Progenitor-derived granulopoiesis is predominant. The long-term repopulating potential of the haemopoietic stem cells (HSC) in the recharged cultures is demonstrated when they are cultured in tissue culture wells (Sutherland et al., 1990). The blood cells produced in the later passages show signs of malignancy.


Sequestering from host and characterization of sequence of a ribosomal RNA operon (rrn) from "Candidatus Liberibacter asiaticus".
A 5005bp rrn DNA sequence of "Candidatus Liberibacter asiaticus" was obtained by PCR using primers conserved to Rhizobiaceae of alpha-proteobacteria. The rrn locus consisted of a 16S rRNA gene (rrs), an intergenic transcribed spacer (ITS) containing two genes of tRNA(Ile) and tRNA(Ala), a 23S rRNA gene (rrl), an ITS without tRNA gene and a 5S rRNA gene (rrf). Like rrs, rrl and rrf were also related (89-90%) to those of the members of Rhizobiaceae. Interestingly, the genes of tRNA(Ile) and tRNA(Ala) were more related to those of non-Rhizobiaceae alpha-proteobacteria. The non-tRNA gene regions of the 16S-23S ITS and 23S-5S rRNA ITS did not share significant similarity to any known non-Liberibacter DNA sequences, and could be used for specific and efficient detection of "Ca. L. asiaticus".


S-adenosylmethionine: studies on chemical and enzymatic synthesis.
Several methods for the chemical and enzymatic synthesis of (-)-S-adenosylmethionine (AdoMet) are described and compared. Studies on the effects of solvents, pH, methylating reagents, and KI on the coupling of sodium homocysteine thiolate and 5'-chloro-5'-deoxyadenosine led to an improved procedure for the synthesis of (+/-)-AdoMet. The use of trimethylsulfonium iodide as a methylating agent under acidic conditions results in a higher content of the desired (-)-epimer than does the use of CH3I. The enzymatic synthesis of (-)-AdoMet using AdoMet synthetase from an over-producing strain of Escherichia coli is demonstrated and the effect of product inhibition on preparative-scale synthesis is illustrated. A new HPLC technique for separation of the epimeric mixture of AdoMet, which allows small-scale preparation of optically pure AdoMet from the enzyme product, has been developed. With this HPLC technique, evidence that (-)-AdoMet is the sole epimer formed by the enzyme has been shown.


Pt(II) and Pd(II) complexes with a thiazoline derivative ligand: Synthesis, structural characterization, antiproliferative activity and evaluation of pro-apoptotic ability in tumor cell lines HT-29 and U-937.
Eluding apoptosis represents the hallmark of tumoral cell behavior. Cisplatin (CisPt) is a very common chemotherapeutic agent to treat cancer by reestablishing apoptotic mechanisms of cell death. However, certain patients acquire resistance to CisPt as well as suffer nephrotoxicity, neurotoxicity, nausea and vomiting. The synthesis of new Pt(II) compounds represents an alternative to CisPt to avoid resistance and undesirable side effects. Pd(II) could be a Pt(II) surrogate given the similarity of coordination chemistry between them, thus widening the spectra of available anticancer drugs. Herein, we have synthesized and characterized two Pt(II) or Pd(II) complexes with TdTn (2-(3,4-dichlorophenyl)imino-N-(2-thiazolin-2-yl)thiazolidine), a thiazoline derivative ligand, with formula [PtCl2(TdTn)] and [PdCl2(TdTn)]. The potential anticancer ability was evaluated in human colon adenocarcinoma HT-29 and human histiocytic lymphoma U-937 cell lines. To that aim, U-937 and HT-29 cells were treated with TdTn, [PtCl2(TdTn)] and [PdCl2(TdTn)] for 24 h. The microscopy monitoring indicated that TdTn, [PtCl2(TdTn)] and [PdCl2(TdTn)] arrested the cell proliferation of U-937 and HT-29 cells with respect to control, in agreement with MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) analysis. Moreover, it is noteworthy that the ligand by its own showed antiproliferative effects in both cell lines. [PtCl2(TdTn)] and [PdCl2(TdTn)] caused caspase-3 activation in U-937 cells, simultaneously with caspase-9 activation due to complexes; however, in HT-29 caspase-3 activation occurred simultaneously with caspase-8 activation induced by the ligand TdTn. Only metal complexes were able to induce ROS (Reactive Oxygen Species) generation in U-937 cells, but not TdTn. In HT-29 cells neither the metal complexes, nor the ligand induced ROS generation.


Establishing the Irish Critical Care Trials Group: 'Who wins in battle makes many calculations before the battle is fought'.
Quality research, requiring large numbers of participants, in the intensive care unit (ICU) population requires multicentre collaboration. Although logistically challenging, this methodology reduces the influence of individual units and has greater validity and broader relevance to patients and practitioners. The nascent Irish Critical Care Trials Group opens additional such opportunities. In the accompanying epidemiologic study, the group present data gathered over 10 weeks of 2006 describing 1,029 patients, from 10 Irish ICUs representing over one-half of Ireland's critical care bed capacity. The data depict a busy service, with 78% of admissions being emergent and with a moderately high (7%) readmission rate. While recognising that there were missing data, the outcomes in organ failure and sepsis - where international definitions exist - and the ICU survival rate (83%) were consistent with international standards. The achievement of this planned first epidemiological step lays the foundation for the conduct of prospective scientific studies. These studies might occur in Ireland or in cooperation with other audit/scientific groups such as the UK's Intensive Care National Audit and Research Centre, the European Critical Care Research Network, or others. This brings us a small step closer to the prospect of global, high-volume studies in critical care.


Endothelial cell loss after 4 mm cataract surgery.
To assess whether a 4 mm scleral tunnel incision with a 1.5 mm internal corneal lip (three-step procedure) causes increased endothelial cell loss and damage to the cornea, we retrospectively evaluated the outcomes of 20 patients (40 eyes) who had a standard 4 mm scleral tunnel incision (two-step procedure) in one eye followed by a three-step incision in the second eye, with in situ phacoemulsification and insertion of a foldable silicone lens in each eye. Mean phacoemulsification time was 2.4 +/- 1.1 minutes for the two-step incisions and 3.4 +/- 1.4 minutes for the three-step incisions. Preoperative and postoperative endothelial cell counts were obtained to determine the effects of surgery on the corneal endothelium. Although the three-step procedure had a trend toward increased endothelial cell loss from the central corneal region compared with the two-step incision, the result was neither clinically nor statistically significant. The difference between the three-step and two-step incisions in postoperative endothelial cell counts from the superior corneal region was statistically significant. The difference in postoperative counts from the inferior region was not statistically significant. Although the three-step 4 mm incision does seem to affect the corneal endothelium, its clinical significance is unknown.


[Value of electroencephalography in veterinary medicine. Methods of electroencephalographic recording in cattle].
No significant differences were found to exist between the potentials of the two cerebral hemispheres in clinically intact cattle. Six Frisians were tested, and frequencies obtained from scalp recording were not significantly higher than those recorded from the Lamina interna. The average rise was 1.21 Hertz or 4.06 per cent on the basis of 29.79 Hertz mean frequency. The amplitudes, however, declined on average by 4.36 microvolt per wave, that is by 18.4 per cent. These changes were significant in 50 per cent of the probands. The technique of recording cerebral potentials from the scalp of cattle appears to good information in the context of cortical rhythms. Faulty recording may cause amplitude variation, with different amplitude heights in different animals. The technique of scalp recording has proved applicable to a wide variety of examinations.


Elucidation of cellular targets and exploitation of the receptor-binding domain of SARS-CoV-2 for vaccine and monoclonal antibody synthesis.
The pandemic caused by novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has resulted in over 452 822 deaths in the first 20 days of June 2020 due to the coronavirus virus disease 2019 (COVID-19). The SARS-CoV-2 uses the host angiotensin-converting enzyme 2 (ACE2) receptor to gain entry inside the human cells where it replicates by using the cell protein synthesis mechanisms. The knowledge of the tissue distribution of ACE2 in human organs is therefore important to predict the clinical course of the COVID-19. Also important is the understanding of the viral receptor-binding domain (RBD), a region within the spike (S) proteins, that enables the entry of the virus into the host cells to synthesize vaccine and monoclonal antibodies (mAbs). We performed an exhaustive search of human protein databases to establish the tissues that express ACE2 and performed an in-depth analysis like sequence alignments and homology modeling of the spike protein (S) of the SARS-CoV-2 to identify antigenic regions in the RBD that can be exploited to synthesize vaccine and mAbs. Our results show that ACE2 is widely expressed in human organs that may explain the pulmonary, systemic, and neurological deficits seen in COVID-19 patients. We show that though the S protein of the SARS-CoV-2 is a homolog of S protein of SARS-CoV-1, it has regions of dissimilarities in the RBD and transmembrane segments. We show peptide sequences in the RBD of SARS-CoV-2 that can bind to the major histocompatibility complex alleles and serve as effective epitopes for vaccine and mAbs synthesis.


Patient-derived organoids as a platform for modeling a patient's response to chemoradiotherapy in esophageal cancer.
3D patient-derived organoids (PDOs) have been utilized to evaluate potential therapies for patients with different cancers. However, the use of PDOs created from treatment-naive patient biopsies for prediction of clinical outcomes in patients with esophageal cancer has not yet been reported. Herein we describe a pilot prospective observational study with the goal of determining whether esophageal cancer PDOs created from treatment naive patients can model or predict clinical outcomes. Endoscopic biopsies of treatment-naive patients at a single tertiary care center were used to generate esophageal cancer PDOs, which were treated with standard-of-care chemotherapy, gamma-irradiation, and newer non-standard approaches, such as proton beam therapy or two small molecule inhibitors. Clinical outcomes of patients following neoadjuvant treatment were compared to their in vitro PDO responses, demonstrating the PDO's ability to mirror clinical response, suggesting the value of PDOs in prediction of clinical response to new therapeutic approaches. Future prospective clinical trials should test the use of pre-treatment PDOs to identify specific, targeted therapies for individual patients with esophageal adenocarcinoma.


Mapping the timecourse of goal-directed attention to location and colour in human vision.
Goal-directed attention prioritises perception of task-relevant stimuli according to location, features, or onset time. In this study we compared the behavioural timecourse of goal-directed selection to locations and colours by varying the stimulus-onset asynchrony (SOA) between cue and target in a strategic cueing paradigm. Participants reported the presence or absence of a target following prior information regarding its location or colour. Results revealed that preparatory selection by colour is more effective at enhancing perceptual sensitivity than selection by location, even though both types of cue provided equivalent overall information. More detailed analysis revealed that this advantage arose due a limitation of spatial attention in maintaining a sufficiently broad focus (>2°) for target detection across multiple stimuli. In contrast, when target stimuli fell within 2° of the spatial attention spotlight, the strategic advantages and speed of spatial and colour attention were equated. Our findings are consistent with the conclusion that, under spatially optimal conditions, prior spatial and colour information are equally proficient at guiding top-down selection. When spatial locations are ambiguous, however, colour-based selection is the more efficient mechanism.


Role of liver function tests in predicting common bile duct stones in acute calculous cholecystitis.
The role of liver function tests (LFTs) in evaluating common bile duct (CBD) stones in patients with cholelithiasis has been studied widely. However, it is not clear whether these predictive models are useful in inflammatory gallstone disease. A review was undertaken of 385 consecutive patients admitted as an emergency for acute calculous gallbladder disease. The diagnosis of calculous cholecystitis was confirmed by ultrasonography or histological confirmation of acute or chronic inflammation of the gallbladder. Patients with obvious jaundice, defined as a bilirubin level above 80 micromol/l, and gallstone pancreatitis were excluded. Some 216 patients met the inclusion criteria, of whom 28 (13.0 per cent) were found to have CBD stones. LFT results were not significantly different in patients with chronic, acute or complicated acute cholecystitis. Using several cut-off levels, gamma-glutamyl transpeptidase (GGT) had the highest specificity, positive predictive value and negative predictive value, comparable to a scoring system that combined all LFTs. Bilirubin was the least specific and predictive. A cut-off point for GGT at 90 units/l produced a sensitivity of 86 per cent (24 of 28), specificity of 74.5 per cent (140 of 188), and positive and negative predictive values of 33 per cent (24 of 72) and 97.2 per cent (140 of 144) respectively. This represented a one in three chance of CBD stones when the GGT level was above 90 units/l and a one in 30 chance when the level was less than 90 units/l. Selection criteria based on GGT can be used in acute calculous cholecystitis to identify high-risk patients who would benefit most from further imaging to exclude choledocholithiasis.


Reproductive strategy in Drosophila melanogaster: Significance of a genetic divergence between temperate and tropical populations.
Reproductive capacities of tropical and temperate populations of D. melanogaster were compared using three complementary techniques: (1) measure of egg production by females grown in the laboratory under uncrowded conditions and provided as adults with abundant food; (2) study of egg production of flies of unknown ages, collected in nature and then kept in similar conditions; and (3) analysis of ovarian activity of wild females dissected just after their capture.Tropical populations showed a lower fecundity in the laboratory and this was also observed in laboratory reared adults. On the average, flies also appeared to be older in the tropics than in temperate countries. These data, together with ecological observations showing that tropical populations live in a more predictable and stable environment, suggest that temperature populations are r-selected, while tropical ones are K-selected. The study of ovarian activity of wild females failed however to confirm this expectation. Tropical flies, which have a lower genetic fecundity, generally appeared to produce more propagules than did temperate flies. Such a contradiction shows how the ideas of r- and K-selection are difficult to apply to natural populations of Drosophila. Population density and interindividual competition are probably not the main selective forces in nature. Attention must also be paid to the necessity of exploring the environment to find resources, to the role of predation and parasitism, and to the occurrence in temperate countries of seasonal fluctuations with different selective pressures on successive generations.


Integrative medicine using East Asian herbal medicine for inflammatory pain in patients with rheumatoid arthritis: A protocol for systematic review and meta-analysis integrated with multiple data mining for core candidate discovery.
Rheumatoid arthritis is a chronic inflammatory autoimmune disease characterized by a wide range of clinical symptoms affecting various bodily functions, including skeletal, vascular, metabolic, and cognitive functions. This review aimed to evaluate the efficacy and safety of integrative medicine (East Asian herbal medicine combined with conventional medicine) used for the treatment of inflammatory pain in rheumatoid arthritis and to identify key candidate drugs based on the data. A comprehensive literature search will be conducted in 4 core databases (PubMed, Excerpta Medica database, Cochrane Library, and Cumulative Index to Nursing & Allied Health Literature) 4 Korean databases (Oriental Medicine Advanced Searching Integrated System, Korean Studies Information Service System, Research Information Service System, and Korea Citation Index), 2 Chinese databases (Chinese National Knowledge Infrastructure Database and Wanfang data), and 1 Japanese database (Citation Information by National Institute of Informatics) for randomized controlled trials from December 13, 2022. Statistical analysis will be performed using R version 4.1.2 and R Studio program. The American College of Rheumatology 20/50/70 score and rate of adverse events will be the primary outcomes. All outcomes will be analyzed using a random-effects model to produce more statistically conservative results. Sensitivity, meta-regression, and subgroup analyses will be used to identify the sources of any heterogeneity in the study. The revised tool for assessing the risk of bias in randomized trials, version 2.0, will be used to evaluate methodological quality. The overall quality of evidence will be assessed according to the Grading of Recommendations Assessment, Development, and Evaluation Pro Framework. There are no ethical issues, as no primary data will be collected directly from the participants. The results of this review will be reported in a peer-reviewed scientific journal. PROSPERO registration number: CRD42023412385.


Sewer epidemiology mass balances for assessing the illicit use of methamphetamine, amphetamine and tetrahydrocannabinol.
In sewer epidemiology, mass balances are used to back-extrapolate measurements of wastewater influent concentrations of appropriate drug residues to assess the parent illicit drug's level of use in upstream populations. This study focussed on developing and refining mass balances for the use of illicit methamphetamine, amphetamine and tetrahydrocannabinol. As a first step, a multi-criteria evaluation was used to select unchanged methamphetamine, unchanged amphetamine and 11-nor-9-carboxy-tetrahydrocannabinol as the most appropriate drug residues to track a selected population's use of illicit methamphetamine, amphetamine and tetrahydrocannabinol, respectively. For each of these selected drug residues, mass balances were developed by utilizing all disposition data available for their release from all their respective sources, incorporating route-of-administration considerations where relevant, and accounting for variations in the metabolic capacity of users of the various relevant licit and illicit sources. Further, since the selected drug residues for the use of methamphetamine and amphetamine cannot only result from their use but numerous other licit and illicit sources, comprehensive general source models were developed for their enantiomeric-specific release to sewers. The relative importance of the sources identified in the general source model was evaluated by performing national substance flow analyses for a number of countries. Results suggested that licit sources of methamphetamine are expected to be only of significance in populations where its illicit use is minor. Similarly, in populations where the use of illicitly produced amphetamine is currently of relevance, licit contributions to the sewer loads of amphetamine are likely to be of negligible importance. Lastly, the study of tetrahydrocannabinol back-extrapolation mass balances suggested that further research is required to assess the importance of fecal elimination of 11-nor-9-carboxy-tetrahydrocannabinol.


Abbé Felice Fontana (1730-1805): founder of modern toxinology.
One of the great experimentalists in toxinology, Felice Fontana, worked in Tuscany on the venom of the European viper; his classic text Traité sur le Vénin de la Vipère was published in 1781. Fontana identified fundamental questions which he proceeded to test experimentally using as quantitative an approach as possible within the technical confines of the mid to late eighteenth century. Amongst his findings are the discoveries that the constituents of viper venom can be precipitated by alcohol, that the action of the venom is myotoxic and that it produces not only coagulation of blood, but paradoxically, fluidity as well. After more than 200 years, it is time to honour his name and recall his work once more.


A possible gene silencing mechanism: hypermethylation of the Keap1 promoter abrogates binding of the transcription factor Sp1 in lung cancer cells.
Hypermethylation often leads to gene silencing; however, the mechanism responsible for the low expression resulting from hypermethylation of the tumor suppressor gene Kelch-like ECH-associating protein 1 (Keap1) in human lung cancer cell lines remains unclear. In this study, using promoter deletion and site mutagenesis assays, we determined that one transcription factor stimulating protein-1 (Sp1) regulatory element in the Keap1 promoter region was important for the transcription of Keap1 in A549 cells. We demonstrated that the transcription factor Sp1 can directly bind to this element in the normal bronchial epithelial BEAS-2B cell line but not in A549 cells, as assessed with chromatin immunoprecipitation (ChIP). EMSAs and supershift assays also showed that CpG island methylation could abrogate Sp1 binding to the Keap1 promoter. Moreover, Keap1 mRNA decreased by 50% after the knock-down of Sp1 with siRNA in BEAS-2B cells, whereas the over-expression of Sp1 led to a dramatic increase in Keap1 promoter activity. The treatment of A549 cells with 5-aza-2'-deoxycytidine restored the binding of Sp1 to the promoter and Keap1 expression. Our results indicate that Sp1 is essential for Keap1 expression and that promoter methylation blocks Sp1 binding in A549 cells. These results demonstrate that hypermethylation may act as an epigenetic gene silencing mechanism, i.e., the inhibition of Sp1 binding to the hypermethylated Keap1 promoter in lung cancer cells, which suggests new approaches to lung cancer treatment.


Studies on rationales for an expert system approach to the interpretation of protein sequence data. Preliminary analysis of the human epidermal growth factor receptor.
The molecular modelling of larger proteins benefits from a preliminary analysis of the sequence to identify regions of potential structural and functional importance. In this study the sequence of the epidermal growth factor receptor has been analysed using a variety of established methods and novel procedures developed for the study of weak internal and external homologies and for the use of homologous sequences in the prediction of secondary and super-secondary structures. The procedures explored here are potentially suitable for incorporation into an expert system for the initial investigation of protein sequence data.


A cognitive approach to Korsakoff's syndrome.
Ten Korsakoff and ten alcoholic subjects were compared on their ability to take advantage of meaningful and linguistic factors in five verbal memory experiments. Korsakoff subjects were deficient in the use of visual imagery, in remembering random letters and in learning relatively easy paired-associates; there was a suggestion that they did not benefit from variation in word class. The effect of word frequency, the ability to remember very easy paired-associates, and possibly the effect of pronounceability were preserved. These findings were interpreted as supporting a model which emphasised the disruption of some higher cognitive structure whilst leaving intact simpler memory functions.


Set-up of large laboratory-scale chromatographic separations of poly(ethylene glycol) derivatives of the growth hormone-releasing factor 1-29 analogue.
In this paper we report the scale-up of the purification of poly(ethylene glycol) (PEG) derivatives of the growth hormone-releasing factor 1-29, from laboratory scale (100 mg of bulk starting material) to larger scale (3 g of bulk), through the use of a cation-exchange TSK-SP-5PW chromatographic column. A one-step purification process capable of purifying large amounts of mono-PEGylated GRF species from the crude reaction mixture was developed. A simple, straightforward stepwise gradient elution separation was developed at laboratory scale and then scaled up with a larger column packed with a chromatographic resin with the same chemistry which maintained the laboratory-scale separation profile. Active material recovery and material purity remained constant through the scale-up from the 13-microm stationary phase to the 25-microm larger column. Overall, the gram GRF equivalent/batch process scale showed to be quite reproducible, and could be considered as a good platform for scale up to production scale.


Deleterious mis-splicing of STK11 caused by a novel single-nucleotide substitution in the 3' polypyrimidine tract of intron five.
Pathogenic variants in STK11, also designated as LKB1, cause Peutz-Jeghers syndrome, which is a rare autosomal dominant disorder characterized by mucocutaneous pigmentation changes, polyposis, and a high risk of cancer. A male meeting the clinical diagnostic criteria for Peutz-Jeghers syndrome underwent next-generation sequencing. To validate the predicted splicing impact of a detected STK11 variant, we performed RNA-Seq on mRNA extracted from patient-derived Epstein-Barr virus-transformed lymphocytes treated with cycloheximide to inhibit nonsense-mediated decay ex vivo. Blood testing identified a novel single-nucleotide substitution, NM_000455.4:c.735-10C>A, at the end of the 3' polypyrimidine tract of intron five in STK11. RNA-Seq confirmed a predicted eight base pair insertion in the mRNA transcript. Following inhibition of nonsense-mediated decay, the out-of-frame insertion was detected in 50% of all RNA-Seq reads. This confirmed a strong, deleterious splicing impact of the variant. We characterized a novel likely pathogenic germline variant in intron five of STK11 associated with Peutz-Jeghers syndrome. The study highlights RNA-Seq as a useful supplement in hereditary cancer predisposition testing.


Toxicology of newer insecticides in small animals.
In the broadest definition, a pesticide (from fly swatters to chemicals) is a substance used to eliminate a pest. Newer insecticides are much safer to the environment, humans and non target species. These insecticides are able to target physiologic differences between insects and mammals, resulting in greater mammalian safety. This article briefly reviews toxicity information of both older insecticides like organophosphates (OPs), carbamates, pyrethrins, and pyrethroids, as well as some newer insecticides.


Thin flap laser in situ keratomileusis: flap dimensions with the Moria LSK-One manual microkeratome using the 100-microm head.
To determine the predictability and consistency of corneal flap thickness, flap diameter, and hinge length with the modern 100 microm head of the Moria LSK-One manual microkeratome. Private clinic, office-based practice. Forty-two consecutive eyes with no previous surgery having thin flap laser in situ keratomileusis with the Moria LSK-One manual microkeratome had a new 100 microm (predicted flap thickness) head used for flap creation. Flap thickness was measured intraoperatively by subtraction ultrasound pachymetry (difference between central corneal thickness before flap cutting and residual stromal bed thickness after flap lifting). Vertical flap diameter and nasal hinge length were measured with calipers. Mean flap thickness was 107 microm +/- 14 (SD) (range 82 to 137 microm). Standard deviation for mean vertical flap diameter was +/-0.24 mm. The cord length of the nasal hinge was variable with a mean of 4.26 +/- 0.63 mm (range 3.12 to 5.75 mm) in length. Postoperatively, there were no slipped flaps, flap striae, diffuse lamellar keratitis, or epithelial defects; there was 1 epithelial slide. At 1 day, the visual acuity was 20/20 or better in 76% of eyes. The 100 microm head of the Moria LSK-One manual microkeratome cut a very predictable flap thickness and diameter but with variable length hinges. This flap thickness predictability was superior to that in other series with thicker intended flaps cut with mechanical microkeratomes and is comparable to that reported with the IntraLase FS femtosecond laser. Visual recovery was rapid, epithelial risks minimal, efficiency superior, and cost nominal relative to femtosecond laser technology.


Nerve injury in lower limb vascular surgery.
Nerve injury is one of the most common complications of varicose vein surgery and is a frequent cause for litigation but its incidence following lower limb arterial surgery has not been well documented. This study was undertaken to determine the incidence of nerve injury following lower limb arterial surgery. This was addressed in relation to long saphenous or femoral vein harvesting, or re-operative surgery. A total of one hundred patients who had undergone lower limb arterial reconstruction in the previous five years were invited to participate in this study. Seventy-eight patients responded, of which 44 patients (66 operated legs) agreed to participate. They underwent neurological assessment of the lower limbs. 66.7% of limbs had objective evidence of sensory deficit following lower limb arterial surgery but none had motor deficit. Redo surgery or superficial femoral vein harvest had no influence on the incidence of nerve injury. Below knee incisions had a higher incidence of nerve injury than other approaches. Long saphenous vein harvest significantly increased the rate of nerve injury. There is a high incidence of sensory nerve damage following lower limb arterial surgery. In the present climate of increasing litigation it is important to know the likely incidence of post-operative nerve damage so that patients can be counselled appropriately during the process of obtaining informed consent.


Axial protocadherin (AXPC) regulates cell fate during notochordal morphogenesis.
The separation and specification of mesoderm into the notochord and somites involves members of the non-clustered δ-protocadherins. Axial (AXPC) and paraxial (PAPC) protocadherins are expressed in the early dorsal mesoderm and later become refined to the developing notochordal and somitic mesoderm, respectively. The role of PAPC in this process has been studied extensively, but the role of AXPC is poorly understood. Partial knockdown of AXPC causes a specific bent-axis phenotype, while more severe knockdown results in the loss of notochord formation. The inability of these embryos to develop a notochord is not due to a cell-sorting event via changes in cell adhesion during gastrulation, but rather this defect is manifested through the loss of axial mesoderm specification, but not general mesoderm induction. The results presented here show that AXPC functions in notochord morphogenesis by directing cell-fate decisions rather than cell-cell adhesion.


Integrated excitatory response to microinjections of L-glutamic acid into the reticular system of the toad.
Microinjections of L-glutamic acid into the mesencephalic tegmentum and diencephalon of anesthetized toads evoked an excitatory response consisting of electrocephalographic and electromyographic activation, and a rise in arterial blood pressure. Electromyographic responses were reduced or absent in diencephalically injected toads. Except for this case, all other components of the response always appeared together and presented the same time course. L-glutamic acid was able to activate a group of neurons at different levels of the reticular system involved in an integrated response of ergotropic nature.


Colorectal carcinoma evaluated by incremental dynamic CT: comparison of CT density, histology, and tumor size.
Evaluation of incremental dynamic CT scan and histologic findings were compared in order to clarify the cause of the differences in colorectal carcinoma as observed on CT after administration of contrast medium. In 48 cases demonstrated on postcontrast dynamic CT scan, the CT density of the tumor was homogeneous (Type 1) in 26 (54.2%) cases and heterogeneous (Type 2) in 22 (45.8%) cases. Well differentiated adenocarcinoma was seen as Type 1 in 11 of 13 (84.6%) cases while moderately differentiated adenocarcinoma was of Type 1 in 15 of 29 (51.7%) cases. Poorly differentiated and mucinous adenocarcinoma were detected as Type 2 in all cases. A comparison of CT types and tumor size showed that as tumor size increased, the number of Type 1 cases decreased while Type 2 cases increased. Histologically, high density areas consisted mainly of well-developed tubular, branching glands of adenocarcinoma, while low density areas were composed of fibrous or mucinous stroma or necrosis. Dynamic CT scans for colorectal cancer are useful not only for preoperative staging but also for tissue characterization.


Gamma-aminobutyric acid- and picrotoxin-induced changes in c-wave and light peak of retinal potentials in the chick.
Retinal potentials were recorded from the eyes of anesthetized and immobilized chicks by a standard direct current method. The amplitude of the electroretinogram (ERG) c-wave was measured 2 and 5 sec after the onset of the light stimulus, as indexes of the fast-rise c-wave (cF-wave) and the slow-rise c-wave (cS-wave), respectively. An intravitreal injection of gamma-aminobutyric acid (GABA) at an estimated intravitreal concentration of 10(-9)-10(-7) M resulted in an increase of the amplitude of the cS-wave, a less remarkable change in the a- and cF-waves, and a slight decrease in the b-wave. The light peak of the retinal standing potential increased in amplitude following GABA administration (10(-7)-10(-4) M). Following an intravitreal injection of picrotoxin (10(-5)-10(-3) M), the polarity of the cS-wave changed from positive to negative and a significant decrease and deformation in the light peak was observed. The amplitude of the a-wave, however, increased in the range of the higher dose, while that of the b- and cF-waves decreased markedly but no polarity reversal of the cF-wave was found. The results may suggest that the GABA-ergic synapse plays a significant role in production of the cS-wave and the light peak, along with that of the pigment epithelium.


Validation of predictive equations for resting energy expenditure in children and adolescents with different body mass indexes.
Accurate estimation of resting energy expenditure (REE) in children and adolescents is important to establish estimated energy requirements. The objective of this study was to assess the validity of existing equations in literature and a newly developed equation in estimating REE in children and adolescents. 275 participants (148 boys, 127 girls) aged 6-18 years included in the study were classified as normal-weighted, overweight, obese based on BMI z-scores for age according to WHO-2007 growth curves for 5-19 years of age. REEs were measured using an indirect calorimeter, with various equations, and a newly established equation [REE = 505.412+(24.383*FFM);Adjusted R2 = 0.649] were compared with REE measured using Bland-Altman and further validation parameters. When the predicted REEs were compared with the measured REEs, the highest prediction accuracy was achieved using the new Eq. (64.8%) and IOM (63.8%) for normal-weight participants, Müller FFM and new Eq. (59.6%) for overweight participants and Lazzer (44.9%) for obese participants. In normal and overweight participants, lowest root mean squared error (RMSE) values were acquired from Schmelzle's equation (respectively 136.2;159.9 kcal/d), and the highest values were found in Kim's Eq. (315.2; 295.2 kcal/d respectively). RMSE value of the new equation was 174.7 kcal/d for normal-weight children and adolescents, and 201.9 kcal/d for overweight ones. In obese participants, the lowest RMSE value was obtained from Schmelzle's Eq. (305.4 kcal/d) and the new Eq. (317.4 kcal/d), while the highest value was obtained from IOM Eq. (439.9 kcal/d). RMSE was higher in obese groups compared to the other BMI groups. Indirect-calorimeter is the most suitable method for REE measurement in especially obese children and adolescents. The new equation and Schmelzle's equation appear to be most accurate equations for normal and overweight children and adolescents.


Association of air pollutants and hospital admissions for respiratory diseases in Lanzhou, China, 2014-2019.
The aim of this study was to assess the effects of air pollutants on hospital admissions for respiratory disease (RD) by using distributed lag nonlinear model (DLNM) in Lanzhou during 2014-2019. In this study, the dataset of air pollutants, meteorological, and daily hospital admissions for RD in Lanzhou, from January 1st, 2014 to December 31st, 2019, were collected from three national environmental monitoring stations, China meteorological data service center, and three large general hospitals, respectively. A time-series analysis with DLNM was used to estimate the associations between air pollutants and hospital admissions for RD including the stratified analysis of age, gender, and season. The key findings were expressed as the relative risk (RR) with a 95% confidence interval (CI) for single-day and cumulative lag effects (0-7). A total of 90, 942 RD hospitalization cases were identified during the study period. The highest association (RR, 95% CI) of hospital admissions for RD and PM2.5 (1.030, 1.012-1.049), and PM10 (1.009, 1.001-1.015), and NO2 (1.047, 1.024-1.071) were observed at lag 07 for an increase of 10 μg/m3 in the concentrations, and CO at lag07 (1.140, 1.052-1.236) for an increase of 1 mg/m3 in the concentration. We observed that the RR estimates for gaseous pollutants (e.g., CO and NO2) were larger than those of particulate matter (e.g., PM2.5 and PM10). The harmful effects of PM2.5, PM10, NO2, and CO were greater in male, people aged 0-14 group and in the cold season. However, no significant association was observed for SO2, O38h, and total hospital admissions for RD. Therefore, some effective intervention strategies should be taken to strengthen the treatment of the ambient air pollutants, especially gaseous pollutants (e.g., CO and NO2), thereby, reducing the burden of respiratory diseases.


Assisting Hand Assessment and Children's Hand-Use Experience Questionnaire -Observed Versus Perceived Bimanual Performance in Children with Unilateral Cerebral Palsy.
To explore the differences, relationship, and extent of agreement between the Assisting Hand Assessment (AHA), measuring observed ability to perform bimanual tasks, and the Children's Hand-Use Experience Questionnaire (CHEQ), assessing experienced bimanual performance. This study investigates a convenience sample of 34 children (16 girls) with unilateral cerebral palsy aged 6-18 years (mean 12.1, SD 3.9) in a cross-sectional design. The AHA and CHEQ subscales share 8-25% of their variance (R2). Bland-Altman plots for AHA and all three CHEQ subscales indicate good average agreement, with a mean difference approaching zero but large 95% confidence intervals. Limits of agreement were extremely wide, indicating considerable disagreement between AHA and CHEQ subscales. AHA and CHEQ seem to measure different though somewhat related constructs of bimanual performance. Results of this investigation reinforce the recommendation to use both instruments to obtain complementary information about bimanual performance including observed and perceived performance of children with unilateral cerebral palsy.


Novel self-protective phosphorescence from crystalline nanoparticles assembled by 3-bromo- and 3-iodo-carbazoles based on halogen-halogen interaction in suspension solutions.
The crystalline nanoparticles can be assembled by 3-bromo- and 3-iodo-carbazole (3-BrC and 3-IC) based on the halogen-halogen interaction in suspension aqueous solutions. As the colloid-like suspension was dropped onto film the particles further aggregate as rod-like structures with size of 3 microm in length and 1 microm in width. The halogen-halogen interaction are well proved by single crystal X-ray data, and the data reveal that each bromine atom interacts with the neighboring two, and each iodine atom interacts with the neighboring five and I-I interaction is stronger than that of Br-Br. Both 3-BrC and 3-IC can emit novel self-protective room temperature phosphorescence (RTP) in the range of 480 to near 800 nm at the excitation of 338 nm, and 3-BrC shows additionally the delayed fluorescence emission from 350 to 480 nm, both possessing the charge-transfer character caused by halogenations. RTP decay possesses the bi-exponential property and RTP lifetimes are 3.37, 31.16 ms (with ethanol) and 1.52, 30.83 ms (with THF) for 3-BrC or 3.53, 14.95 ms (with ethanol) and 1.68 ms, 13.74 ms (with THF) for 3-IC, showing " heavier atom ", I, makes intersystem crossing rate k(ISC) from both S1 to T1 and T1 to S(0) faster. For the results, the detection limits of 3-BrC and 3-IC can reach 2.4 x 10(-7) and 9.0 x 10(-8)mol L(-1), respectively, with wider linear range and higher precision compared with other systems.


Localization and characterization of the acrosomal antigen recognized by GB24 on human spermatozoa.
GB24, a mouse monoclonal antibody, recognizes a trophoblast-leukocyte cross-reactive antigen (TLX), which is likely identical to the membrane cofactor protein (MCP), a complement regulatory protein. GB24 reacts also with a human acrosomal sperm antigen (Fénichel et al.: J Reprod Fertil 87:699-706, 1989). By immunofluorescence or immunoperoxidase, testicular, epididymal, and ejaculated spermatozoa were found to be positive after fixation by acetone. Motile, suspended spermatozoa became positive only through conditions known to induce acrosome reaction (A23187, follicular fluid, contact with oocytes). Ultrastructural studies with immunogold staining localized this protein on the inner acrosome membrane and in the acrosomal content. By SDS-polyacrylamide gel electrophoresis, GB24 immunoprecipitated a unique protein of 48 kDa from capacitated and A23187-induced spermatozoa under reducing conditions. No cross-reactivity was found with mouse, boar, or ram spermatozoa. Localization of this human sperm antigen recognized by GB24 and its similarity with the TLX-MCP family antigens would suggest a possible role of this molecule during fertilization in sperm-egg binding or immune protection.


Limits to lifespan.
It has long-been accepted that normal somatic cells have intrinsic mechanisms that limit their proliferative lifespan. Recent work has now challenged this view by demonstrating that extrinsic factors might be determining proliferative potential.


Direct Myosin Activation by Omecamtiv Mecarbil for Heart Failure with Reduced Ejection Fraction.
Myosin is the indispensable molecular motor that utilizes chemical energy to produce force for contraction within the cardiac myocyte. Myosin activity is gated by intracellular calcium levels which are regulated by multiple upstream signaling cascades that can be altered for clinical utility using inotropic medications. In contrast to clinically available cardiac inotropes, omecamtiv mecarbil is a novel direct myosin activator developed to augment left ventricular systolic function without the undesirable secondary effects of altered calcium homeostasis. Its identification and synthesis followed high-throughput screening of a reconstituted sarcomere, deliberate optimization, exquisite biochemical evaluation, and subsequently promising effects in animal models were demonstrated. Physiologically, it prolonged the duration of left ventricular systole in animal models, healthy adults, and patients with heart failure with reduced ejection fraction (HFrEF) without changing the velocity of pressure development, as assessed in animal models. It has been formulated for both intravenous and oral administration, and in both acute and chronic settings produced similar alterations in the duration of systole associated with beneficial increases in cardiac output, improvements in left ventricular volumes, and reductions in heart rate and often of natriuretic peptides. Small, asymptomatic increases in troponin were also observed in the absence of clinically evident ischemia. Clinically, the question remains as to whether the possible harm of this minimal troponin release is outweighed by the potential benefits of reduced neurohormonal activation, increased stroke volume and cardiac output, and improved ventricular remodeling in patients treated with omecamtiv mecarbil. The resolution of this question is being addressed by a phase III outcomes trial of this potential novel therapy for heart failure.


The impact of orthodontic-surgical treatment on facial expressions-a four-dimensional clinical trial.
The objective of this clinical trial was to compare facial expressions (magnitude, shape change, time, and symmetry) before (T0) and after (T1) orthognathic surgery by implementing a novel method of four-dimensional (4D) motion capture analysis, known as videostereophotogrammetry, in orthodontics. This prospective, single-centre, single-arm trial included a total of 26 adult patients (mean age 28.4 years; skeletal class II: n = 13, skeletal class III: n = 13) with indication for orthodontic-surgical treatment. Two reproducible facial expressions (maximum smile, lip purse) were captured at T0 and T1 by videostereophotogrammetry as 4D face scan. The magnitude, shape change, symmetry, and time of the facial movements were analysed. The motion changes were analysed in dependence of skeletal class and surgical movements. 4D motion capture analysis was feasible in all cases. The magnitude of the expression maximum smile increased from 15.24 to 17.27 mm (p = 0.002), while that of the expression lip purse decreased from 9.34 to 8.31 mm (p = 0.01). Shape change, symmetry, and time of the facial movements did not differ significantly pre- and postsurgical. The changes in facial movements following orthodontic-surgical treatment were observed independently of skeletal class and surgical movements. Orthodontic-surgical treatment not only affects static soft tissue but also soft tissue dynamics while smiling or lip pursing. To achieve comprehensive orthodontic treatment plans, the integration of facial dynamics via videostereophotogrammetry provides a promising approach in diagnostics. DRKS00017206.


The chemically dependent physician: clinical and legal considerations.
The medical community has made great advances in recognizing chemical dependence in the physician community. However, difficulties remain in terms of the clinician treating this disease and maintaining a liaison between legal and clinical aspects.


Genetic polymorphism of XRCC1 correlated with response to oxaliplatin-based chemotherapy in advanced colorectal cancer.
To examine the association between genetic polymorphisms of XRCC1 Arg399Gln(G→A) and response to oxaliplatin-based chemotherapy in advanced colorectal cancer. XRCC1 genotypes of totally 99 patients(37 stage III, 62 stage IV)with advanced colorectal cancer treated with oxaliplatin-based chemotherapy were detected by TaqMan-MGB probe allelic discrimination method. And clinical response of 62 patients in stage IVafter 2 to 3 cycles of chemotherapy were evaluated. Also time to progress (TTP) of all patients were evaluated. Of the genotype frequencies in all patients, up to 52.53 % were G/G genotype, 9.09 % were A/A genotype, and 38.38 % were G/A genotype. The response rate (CR+PR) of 62 patients in stage IV was 61.29 % (19/31). Patients with G/G genotype showed enhanced respond to chemotherapy compared to those with G/A+A/A (x(2) = 5.6, P = 0.029; OR = 3.845, 95 %CI = 1.231 ~ 12.01, P = 0.018). Individuals with the G/G genotype had a TTP of 10.0 (8.88-11.12) months, those with the G/A+A/A genotype had an TTP of 5.0(4.26-5.74) months. The log-rank test was marginally significant (x(2) = 29.20, P < 0.01). The Cox proportional hazards model, adjusted for stage, performance status, and chemotherapy regimen, showed that only XRCC1 G/G genotypes increases the OR significantly (OR = 3.555; 95 % CI, 2.119 ~ 5.963; P < 0.01). The results suggest that XRCC1 Arg399Gln polymorphisms is associated with the response to oxaliplatin-based chemotherapy and time to progression in advanced colorectal cancer in Chinese population. It is proposed that the XRCC1 Arg399Gln polymorphism should be routinely detected to screen patients who are more likely benefit from oxaliplatin-based treatment.


Autonomic nervous regulation of cellular processes during subchondral bone remodeling in osteoarthritis.
Osteoarthritis (OA) is the most prevalent degenerative joint disease. Besides loss of articular cartilage and synovial inflammation, OA progression is characterized by pathological changes in the subchondral bone. In early OA, subchondral bone remodeling typically shifts to an increased bone resorption. However, as the disease progresses an increased bone formation takes place, leading to higher bone density with subsequent bone sclerosis. These changes can be influenced by different local or systemic factors. Recent evidence suggests that the autonomic nervous system (ANS) plays a role in regulating subchondral bone remodeling in OA. In this review, we 1) introduce bone structure and cellular mechanisms of bone remodeling in general, 2) explain the subchondral bone changes during OA pathogenesis, 3) then describe the contribution of the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS), the two major autonomic branches, to physiological subchondral bone remodeling, 4) followed by the influence of the SNS and PNS on subchondral bone remodeling in OA, and 5) finally, discuss the potential of therapeutic approaches targeting different components of the ANS.NEW & NOTEWORTHY The autonomic nervous system (ANS) with its two major branches, the sympathetic and parasympathetic nervous systems, plays a role in osteoarthritis pathogenesis by influencing bone structure and remodeling. We here review the current knowledge on subchondral bone remodeling with special regard to different bone cell types and underlying mechanisms at the cellular and molecular level. A better understanding of these mechanisms is needed for the development of novel OA treatment strategies targeting the ANS.


The reactivity of frozen B lymphocytes to B cell mitogens and human B cell growth factor: a study of step 1 and step 2 activators.
Human B lymphocytes, purified from the peripheral blood of several different donors can be pooled, frozen, and stored in liquid nitrogen to provide an easy and reproducible source of cells for mitogenic assays. These B cell preparations did not show any reactivity to T cell mitogens, but responded to Staphylococcus aureus Cowan strain 1 (SAC) and anti-IgM antibodies to the same extent as freshly purified B cells. When stimulated with either anti-IgM antibodies or SAC, these B cells became responsive to B cell growth factor (BCGF), allowing a quantitative measurement of this important lymphokine activity. In addition, we have studied the reactivity of frozen B lymphocytes to various combinations of activators. We have confirmed that phorbol myristate acetate (PMA) was a very potent mitogenic agent for preactivated human B cells and shown that bacterial lipopolysaccharide (LPS), although not mitogenic by itself, could synergize with anti-IgM antibodies to yield increased levels of stimulation. Furthermore experiments using the lysosomotropic agent leucine methyl ester showed that the action of LPS on anti-IgM-stimulated B cells did not require the presence of functional monocytes. Neither PMA nor LPS could induce BCGF responsiveness and thus these two compounds can be considered exclusive step 2 activators for human peripheral blood B cells.


A holistic approach to promoting success on NCLEX-RN.
The nursing faculty at the State University of West Georgia views individuals as an integration of body-mind-spirit. Our program's commitment complements efforts to teach students to honor the body, mind, and spirit of patients. Within this framework, faculty recognize that factors other than nursing knowledge impact students' ability to pass NCLEX-RN. An intervention program was designed that incorporated these factors. "Preparation for Licensure" was implemented as a holistic nursing course to intervene with students' learning and testing needs. The purpose was to increase self-awareness, promote a positive attitude toward passing the NCLEX-RN, and provide specific strategies for test taking and stress reduction. Posttest raw scores and percent correct on the Mosby Assess Test were significantly higher (p < .05) than pretest scores. Qualitative analysis of journal data exploring the students' experience of participating in the course revealed three themes: Perfectionism, Self-Worth, and Consequences and Meaning of Failure.


Amino acid sequence of the calcium-binding light chain of myosin from the lower eukaryote, Physarum polycephalum.
We have established a new method for preparing Physarum myosin whose actin-activated ATPase activity is inhibited by micromolar levels of Ca2+. This Ca2+-inhibition is mediated by the Ca2+ binding to the myosin rather than by the Ca2+-dependent modification of the phosphorylated state of the myosin (Kohama, K., and Kendrick-Jones, J. (1986) J. Biochem. (Tokyo) 99, 1433-1446). Ca2+-binding light chain (CaLC) has been suggested to be primary importance in this Ca2+ inhibition (Kohama, K., Takano-Ohmuro, H., Tanaka, T., Yamaguchi, T., and Kohama, T. (1986) J. Biol. Chem. 261, 8022-8027). The amino acid sequence of CaLC was determined; it was composed of 147 amino acid residues and the N terminus was acetylated. The molecular weight was calculated to be 16,131. The homology of CaLC in the amino acid sequence with 5,5'-dithiobis-(2-nitrobenzoic acid) light chain and alkali light chain of skeletal muscle myosin were rather low, i.e., 25% and 30%, respectively. Interestingly, however, the CaLC sequence was 40% homologous with brain calmodulin. This amino acid sequence was confirmed by sequencing the cloned phage DNA accommodating cDNA coding CaLC. Northern and Southern blot analysis indicated that 0.8-kilobase pair mRNA was transcribed from a single CaLC gene. This is the first report on the amino acid sequence of myosin light chain of lower eukaryotes and nucleotide sequence of its mRNA.


Benchmarking large language models' performances for myopia care: a comparative analysis of ChatGPT-3.5, ChatGPT-4.0, and Google Bard.
Large language models (LLMs) are garnering wide interest due to their human-like and contextually relevant responses. However, LLMs' accuracy across specific medical domains has yet been thoroughly evaluated. Myopia is a frequent topic which patients and parents commonly seek information online. Our study evaluated the performance of three LLMs namely ChatGPT-3.5, ChatGPT-4.0, and Google Bard, in delivering accurate responses to common myopia-related queries. We curated thirty-one commonly asked myopia care-related questions, which were categorised into six domains-pathogenesis, risk factors, clinical presentation, diagnosis, treatment and prevention, and prognosis. Each question was posed to the LLMs, and their responses were independently graded by three consultant-level paediatric ophthalmologists on a three-point accuracy scale (poor, borderline, good). A majority consensus approach was used to determine the final rating for each response. 'Good' rated responses were further evaluated for comprehensiveness on a five-point scale. Conversely, 'poor' rated responses were further prompted for self-correction and then re-evaluated for accuracy. ChatGPT-4.0 demonstrated superior accuracy, with 80.6% of responses rated as 'good', compared to 61.3% in ChatGPT-3.5 and 54.8% in Google Bard (Pearson's chi-squared test, all p ≤ 0.009). All three LLM-Chatbots showed high mean comprehensiveness scores (Google Bard: 4.35; ChatGPT-4.0: 4.23; ChatGPT-3.5: 4.11, out of a maximum score of 5). All LLM-Chatbots also demonstrated substantial self-correction capabilities: 66.7% (2 in 3) of ChatGPT-4.0's, 40% (2 in 5) of ChatGPT-3.5's, and 60% (3 in 5) of Google Bard's responses improved after self-correction. The LLM-Chatbots performed consistently across domains, except for 'treatment and prevention'. However, ChatGPT-4.0 still performed superiorly in this domain, receiving 70% 'good' ratings, compared to 40% in ChatGPT-3.5 and 45% in Google Bard (Pearson's chi-squared test, all p ≤ 0.001). Our findings underscore the potential of LLMs, particularly ChatGPT-4.0, for delivering accurate and comprehensive responses to myopia-related queries. Continuous strategies and evaluations to improve LLMs' accuracy remain crucial. Dr Yih-Chung Tham was supported by the National Medical Research Council of Singapore (NMRC/MOH/HCSAINV21nov-0001).


ABPM Induced Alarm Reaction: A Possible Cause of Overestimation of Daytime Blood Pressure Values Reduced By Treatment with Beta-Blockers.
Alarm reaction to clinical blood pressure (BP) measurement, defined white-coat effect (WCE), can cause overestimation of true BP values. To assess whether ambulatory blood pressure monitoring (ABPM) can similarly affect BP values during the initial hours of recording. In 420 ABPMs selected for a first systolic BP (SBP) reading at least 10 mmHg higher than the mean daytime SBP, we calculated mean diurnal and 24 h SBP with and without the exclusion of the two first hours of recording defined as the WCE window (WCEw). We also calculated the magnitude and duration of WCE. These analyses were also performed separately in patients off anti-hypertensive treatment (n = 156), and on treatment with and without the inclusion of beta-blockers (respectively n = 113 and 151). Exclusion of WCEw period reduced mean diurnal and 24 h SBP respectively from 135 ± 0.5 to 133 ± 0.5 (p < 0.01) and from 131 ± 0.5 to 130 ± 0.5 (p < 0.02). As a result the percentage of patients diagnosed as having diurnal or 24 h hypertension was reduced respectively from 48 to 40 % and from 52 to 47 %. The magnitude of WCEw was similar in both genders but the duration was longer in females (66 ± 2 vs. 56 ± 2 min, p < 0.01). Treatment with beta-blockers was associated with a shorter duration of WCE in both genders but this effect was statistically significant only in males. In some patients ABPM is not free from WCE. WCE may affect the overall estimation of BP profile and is longer but less blunted by beta-blockers in females than in males.