An effective dose of ketamine for eliminating pain during injection of propofol: a dose response study.
Ketamine can completely eliminate pain associated with propofol injection. However, the effective dose of ketamine to eliminate propofol injection pain has not been determined. The purpose of this study was to determine the effective dose of ketamine needed to eliminate pain in 50% and 95% of patients (ED50 and ED95, respectively) during propofol injections. This study was conducted in a double-blinded fashion and included 50 patients scheduled for elective gynecological laparoscopy under general anesthesia. The initial dose of ketamine used in the first patient was 0.25mg/kg. The dosing modifications were in increments or decrements of 0.025 mg/kg. Ketamine was administered 15 seconds before injecting propofol (2.5mg/kg), which was injected at a rate of 1mL/s. Patients were asked to rate their pain during propofol injection every 5s econds using a 0-3 pain scale. The highest pain score was recorded. The ED50, ED95 and 95% confidence intervals (CI) were determined by probit analyses. The dose of ketamine ranged from 0.175 to 0.275 mg/kg. The ED50 and ED95 of ketamine for eliminating pain during propofol injection were 0.227 mg/kg and 0.283 mg/kg, respectively (95%CI: 0.211-0.243 mg/kg and 0.26-0.364 mg/kg, respectively). Ketamine at an approximate dose of 0.3mg/kg was effective in eliminating pain during propofol injection.


Prediction of liquid chromatographic retention time using quantitative structure-retention relationships to assist non-targeted identification of unknown metabolites of phthalates in human urine with high-resolution mass spectrometry.
The non-targeted analysis and identification of contaminant metabolites such as metabolites of phthalates and their alternatives in human biofluid samples constitutes a growing research field in human biomonitoring because of their importance as biomarkers of human exposure to the parent compounds. High-resolution mass spectrometry (HRMS) combined with high-performance liquid chromatography (HPLC) can provide fast separation and sensitive analysis using this application. However, the diversity of potential metabolites, especially isomers, in human samples, makes mass spectrometry-based structural identification very challenging, even with high-resolution and accurate mass. In this study, we present a retention time (tR) prediction model based on quantitative structure-retention relationship (QSRR). This model can predict the retention time of a given structure of phthalates including isomers. Twenty-three molecular descriptors were used in the development of the multivariate linear regression QSRR model. The regression coefficient (R2) between predicted and experimental retention times of 26 training set compounds was 0.9912. The combination of the retention time prediction model with identification via accurate mass search and target MS/MS spectrum interpretation can enhance the identification confidence in the lack of reference standards. Two previously unreported phthalate metabolites were identified in human urine, using this model. The results of this study showed that the developed QSRR model could be a useful tool to predict the retention times of unknown metabolites of phthalates and their alternatives in future non-targeted screening analysis. The concentration of these two unknown compounds was also estimated using a quantitative structure-ion intensity relationship (QSIIR) model.


Role of tryptophan in the pathogenesis of hepatic encephalopathy.
To monitor serum levels of total and free tyryptophan in various hepatic dysregulations. The study was conducted on 36 adult patients. All were suffering from acute or chronic liver diseases such as hepatitis (n = 12), cirrhosis (n = 12) and Hepatic Encephalopathy (HE) (n = 12). Patients of all age groups and both genders were included. Serum levels of Tyryptophan (TRP) were measured by HPLC-EC. Albumin and bilirubin were analyzed by kit method (Merck). The serum levels of total TRP (p < 0.01) was found in all patients. Free TRP significantly (p < 0.01) increased only in HE. Patients with hepatitis and cirrhosis did not show significant change in serum free TRP. The Albumin levels significantly decreased in hepatitis, cirrhosis and in HE (p < 0.01). All patients exhibited hypoalbuminaemia (p < 0.01). The results suggest that an increased ratio of free to bound TRP enhances its availability to the brain, which in turn increases 5-HT synthesis thus precipitating encephalopathy.


The effect of breastfeeding education on adolescent beliefs and attitudes: a randomized school intervention in the Canadian Ojibwa community of Sagkeeng.
Sagkeeng First Nation's adolescent breastfeeding educational session was evaluated using a randomized pretest-posttest control group design. The intervention group received the session first; the control group received the session following the posttest. A retention test to measure overall retained learning was given to all students 10 days later. Breastfeeding beliefs increased (mean +/- SD = 41.9 to 47.0, P = .0047) from pretest to posttest for intervention subjects but not for controls. There were no changes in bottle-feeding beliefs or breastfeeding attitudes. There was an increase in breastfeeding beliefs from pretest to retention test for all students (true treatment effect [TTE] = .85 standard deviation units [SDU], P = .004). Learning was gender specific, with females experiencing increases in breastfeeding beliefs (TTE = 1.12 SDU, P = .004), decreases in bottle-feeding beliefs (TTE = -.77 SDU, P = .04), and a trend to increased breastfeeding attitudes (TTE = .41 SDU, NS). Males showed small, inconsistent learning effects. Learning occurred in the areas of health, convenience, cost, and decreased embarrassment.


Current psychoanalytic theory and practice: can there be any one valid unitary approach?
In this brief presentation, I have discussed the historical continuum of present day psychoanalysis with its early antecedents. I have described some basic concepts which illustrate where seemingly diverse psychoanalytic methodologies, based on differing scientific philosophies, actually join up, namely, in the areas of empathy, empathic resonance, "optimal responsiveness," and in the understanding and technical work with transference. Space limitations precluded mentioning issues around theories of resistance and of cure. I finished by mentioning a few general points which distinguish self psychology's approach. While a comprehensive unitary scientific philosophy awaits the further development and maturation of an infant science, nevertheless, we can agree, I think, that there are unitary principles that govern psychoanalysis, and that organize the clinical approach of the most effective of its practitioners.


Codon usage in Homo sapiens: evidence for a coding pattern on the non-coding strand and evolutionary implications of dinucleotide discrimination.
This study reports the analysis of codon usage in 35 complete Homo sapiens genes. Both codon frequency and inter-codon interference exhibit patterns of evolutionary interest. There is a significant positive correlation between the frequency with which a given codon is used and the frequency with which its complement is used. Since the frequency of appearance of the complementary codon on the coding strand is equal to the frequency of appearance of the original codon on the non-coding strand, in the same phase, the non-coding strand is found to resemble the coding strand in triplet composition. The same effect has been observed in Escherichia coli. This preference for the use of certain complementary triplets as codons suggests that the evolution of the use of the genetic code depended to some extent upon the double-stranded nature of the coding material. In addition, the effect of discrimination against the use of two dinucleotides, CpG and UpA, is observed in codon usage and also in adjacent codon interference. Codons beginning with G, or A, are unlikely to be preceded by codons ending in C, or U, respectively. Consideration of codon assignment in the genetic code together with the observed CpG infrequency suggests that the evolution of the code may have been influenced by conditions in which the use of CpG dinucleotides was unfavorable. The infrequent use of UpA dinucleotides can be explained as the result of frameshift mutation during gene evolution.


Fabrication and characterization of a solid polyurethane phantom for optical imaging through scattering media.
A phantom based on a polyurethane system that replicates the optical properties of tissue for use in near-infrared imaging is described. The absorption properties of tissue are simulated by a dye that absorbs in the near infrared, and the scattering properties are simulated by TiO2 particles. The scattering and absorption coefficients of the plastic were measured with a new technique based on time-resolved transmission through two slabs of materials that have different thicknesses. An image of a representative phantom was obtained from time-gated transmission.


External Validation of the FLIPI Risk Score Measured at Diagnosis and POD24 Among Individuals With Follicular Lymphoma at the Time of Subsequent Relapse.
The Follicular lymphoma international prognostic index (FLIPI) risk score and POD24 have previously been shown to have prognostic value in follicular lymphoma (FL), but the extent to which they can inform prognosis at the time of subsequent relapse is uncertain. We conducted a longitudinal cohort study of individuals diagnosed with FL between 2004 and 2010 in Alberta, Canada who received front-line therapy and subsequently relapsed. FLIPI covariates were measured prior to the initiation of front-line therapy. Median overall survival (OS), progression-free survival (PFS2), and time to next treatment (TTNT2) were estimated from the time of relapse. A total of 216 individuals were included. The FLIPI risk score was highly prognostic at the time of relapse for OS (c-statistic = 0.70; HR[High vs. Low] = 7.38; 95% CI: 3.05-17.88), PFS2 (c-statistic = 0.68; HR[High vs. Low] = 5.84; 95% CI: 2.93-11.62) and TTNT2 (c-statistic = 0.68; HR[High vs. Low] = 5.72; 95% CI: 2.87-11.41). POD24 was not prognostic at the time of relapse for either OS, PFS2, or TTNT2 (c-statistic = 0.55). The FLIPI score measured at diagnosis may help with the risk stratification of individuals with relapsed FL.


Subcutaneous fat in normal and diseased states: 1. Introduction.
In recent years, our understanding of adipose tissue physiology and function has undergone an enormous transformation. Once considered a passive storage receptacle with a fixed number of cells and limited purpose, adipose tissue is now recognized as a complicated organ with important endocrine and metabolic functions. It is now known that both increased and decreased adipose tissue mass, as seen in obesity, anorexia, and lipodystrophy, have profound effects on multiple body systems, including immune, reproductive, and hematopoietic. The study of adipose tissue, therefore, is important not only for those who treat obesity, lipoatrophy, and their associated metabolic and endocrine derangements, but also for those dermatologists who specialize in the medical and surgical treatment of disorders within the body's largest adipose tissue subdivision, the subcutaneous fat. This introductory article is the first in a series about adipose tissue in normal and diseased states.


Meta-learning for fake news detection surrounding the Syrian war: An interview with co-author Roaa Al Feel.
Roaa Al Feel, an early-career researcher, discusses her passion for using data science for social good. She uses data to reflect living conditions of society, and in the paper published with Patterns in November, the team explores machine learning techniques for the detection of fake news around the Syrian war, demonstrating the efficacy of meta-learning techniques when tackling datasets of a modest size.


[Follow-up of children after toxoplasmosis infection in pregnancy].
A vival toxoplasmosis infection was diagnosed in 188 cases (3,8%) out, of 49,582 pregnant women routinely screened. 4 children live with congenital toxoplasmosis. Follow-up studies showed that 33 children have specific antibodies, 5 are with suspect clinical findings. Therefore is the conclusion that more late signs of connatal toxoplasmosis are to be detected by follow-up investigations.


Differentiating psychotic patients from nonpsychotic patients with the MMPI-2 and Rorschach.
The goal of this study was to examine the incremental validity and the clinical utility of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2; (Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989) and Rorschach (Rorschach, 1942) with regard to differential diagnosis in a sample of adult inpatients with a primary psychotic disorder or a primary mood disorder without psychotic features. Diagnostic efficiency statistics have suggested that the Rorschach Perceptual Thinking Index (PTI; Exner, 2000a, 2000b) was better than MMPI-2 scales in discriminating psychotic patients from nonpsychotic patients. We compared the 84% overall correct classification rate (OCC) for the PTI to an OCC of 70% for the MMPI-2 scales. Adding the MMPI-2 scales to the PTI resulted in a decrease in OCC of 1%, whereas adding the PTI to the MMPI-2 resulted in an increase in OCC of 14%. Sensitivity, specificity, positive predictive power, negative predictive power, and kappa were equal or higher with only the PTI in the model.


Vestibular Dysfunction in Children Suffering from Otitis Media with Effusion: Does Grommet Help? An Observational Study Using Computerized Static Posturography.
Otitis media with effusion (OME) has a detrimental effect on balance, which may not present as a clear symptom in children. This effect can be improved by the insertion of ventilation tubes. This study assesses balance in children suffering from OME pre and post operatively using computerized static posturography. 50 children of 3-6 years, suffering from OME were included in this observational descriptive study. These patients underwent myringotomy and grommet insertion. The balance was evaluated pre and post operatively after 3 months using computerized static posturography with Modified Clinical Test of Sensory Interaction on Balance under four conditions, namely eyes open/closed on firm surface/foam. Posturography mean sway velocity was deranged in these children preoperatively and it showed statistically significant improvement post operatively at 3 months. There is occult vestibular dysfunction in children with OME as assessed by static posturography which improves significantly 3 months after myringotomy and grommet insertion.


Location, location, location: does early cancer in Barrett's esophagus have a preference?
Early cancer (high-grade dysplasia [HGD] and intramucosal carcinoma [ImCa]) associated with Barrett's esophagus (BE) may have a circumferential spatial predilection. To describe the esophageal circumferential location of early cancer in BE. Retrospective study, single tertiary referral center. One hundred nineteen patients were referred for endoscopic eradication therapy for early cancer associated with BE. Endoscopic images and reports and pathology were reviewed. Circumferential location designation of early cancer in BE by using a clock-face orientation. One hundred nineteen of 131 patients referred for endoscopic eradication therapy had a location designation for their advanced histology (91.9%). There were a total of 57 patients (47.9%) with HGD and 62 patients (52.1%) with ImCa. There was a significantly higher rate of early cancer (HGD or ImCa) in the right hemisphere (12 to 6 o'clock location) compared with the left hemisphere (84.9% vs 15.1%, P < .0001). The highest percentage of early cancer was found in the 12 to 3 o'clock quadrant (64.7%); 71.9% of HGD and 58.1% of ImCa lesions were located in the 12 to 3 o'clock quadrant. Retrospective design, single center. Early cancer associated with BE is far more commonly found in the right hemisphere of the esophagus (12 to 6 o'clock) with the highest rate in the 12 to 3 o'clock quadrant. These findings support enhanced scrutiny of the right hemisphere of the esophagus during surveillance and endoscopic treatment of patients with BE.


Rates of dyspepsia one year after Helicobacter pylori screening and eradication in a Danish population.
Helicobacter pylori (Hp) is strongly correlated with peptic ulcer and is a risk factor for gastric cancer. The aim of this study was to assess whether screening and eradication of Hp in a general population would reduce the prevalence of dyspepsia and the incidence of peptic ulcer and thus save health care resources and improve quality of life. Twenty thousand individuals aged 40 to 65 years were randomized to screening and eradication for Hp or to the control group. Hp status was assessed by a whole blood Hp test, a positive result confirmed by a (13)C-urea breath test. Hp-positive individuals were offered Hp eradication therapy. The prevalence of dyspepsia and the quality of life were assessed through a mailed questionnaire. Information on the use of endoscopies and the use of prescription medication was obtained from registers. The response rate was 62.6%. The prevalence of Hp was 17.5%. The Hp eradication rate was 95%. In the intervention group, the prevalence of dyspepsia decreased from 24.3% at inclusion to 20.5% at 1-year follow-up. The reduction was similar in Hp-negative and Hp-positive persons. In the control group, dyspepsia increased from 20.3% to 21.5%. Gastroesophageal reflux symptoms improved slightly in Hp-eradicated participants. Except for a decreased consultation rate for dyspepsia, there were no visible savings in health care. Dyspepsia was modestly reduced after the screening and treatment procedure, and the result was not sufficiently extensive to have an effect on the use of health care or to improve quality of life.


Quality of life for patients with hypopharyngeal cancer after different therapeutic modalities.
Concurrent chemoradiation therapy (CCRT) and transoral laser microsurgery (TLM) have become therapeutic selections for organ preservation in patients with hypopharyngeal cancer. Our cross-sectional, observational study assesses quality of life (QOL) in patients with hypopharyngeal cancers receiving TLM plus radiotherapy (RT) compared with those treated with CCRT only or radical open surgery (nearly all of whom also received RT or CCRT). QOL was assessed at least 6 months posttreatment. The study included 87 patients. Patients receiving open surgery reported significantly more sensory and speech disturbances than the others and more dental problems than the TLM group; the CCRT group experienced more xerostomia than the others, more weight loss, and dysphagia than the open surgery group; TLM patients experience fewer difficulties in emotional and social functioning, financial impact, and cough. TLM may provide comparable, if not better, QOL for patients relative to the other therapeutic regimens for selective advanced cases of hypopharyngeal cancer.


'How to do': digital-interactive-interpretation course for stress echocardiography.
To improve stress echocardiography interpretation standards, we introduced a structured 5-day interpretation course in 2017. In order to deliver the course during the world-wide pandemic, we transformed the existing boardroom style, workstation-based, interactive course into a cloud-based digital entity maintaining the same features. On completion of 6 lectures via live webinars, 15 participants performed, fully GDPR compliant, 80 recorded case analysis using a web-based reporting system over the course of 5 days. After self-reporting and generating preliminary reports the joint case review with the faculty, resulted in finalization of the reports and provided individual feedback for the participants. By the 5th day, participants had collected 80 reports for their e-logbook and were ready to sit the digital interpretation exam. Eighty-eight percent of participants passed the e-exam and received a certificate of completion with 15 re-accreditation and 30 CPD points by the British Society of Echocardiography and Federation of the Royal Colleges of Physicians, UK, respectively. The feedback by the participants was praising the pre-course provision of lectures and digital aids, the conduct of the course by the faculty and the technical support with an average score of 4.7 for each, on a scale from 1 to 5. Our experience proved that interactive, multi-day; hands-on reporting course can be delivered using the digital platform. Online interpretation courses have great potential to improve the competency of imaging specialists. This digital teaching model could be suitable in other imaging-based training courses like cardiac CT and MRI.


[Immunization with monovalent oral vaccine against rotavirus in Mexico. Evaluation of the data of two years of the system of temporarily adverse event reports associated to vaccination (ETAV)].
The gastrointestinal manifestations are the adverse events mainly studied to the application of the vaccine against rotavirus. In order subsequent to consider the risk of associated events taken care of the vaccination against rotavirus in infants, we realized a retrospective study of 2 years, evaluating 7,691,757 distributed doses of oral vaccine, in 2008 and 2009. The risk considered of an event associated after the application of the oral vaccine against rotavirus is of 2.9 events by 1,000,000 distributed doses. The taken care of associated events were little common subsequent to the vaccination against rotavirus.


GABAergic innervation of the Mauthner cell and other reticulospinal neurons in the goldfish.
The Mauthner cells are pair of identifiable hindbrain neurons that participate in the escape response of fishes. Membrane excitability in these cells is regulated by inhibitory neurons that use glycine as a transmitter. We examined the possibility that the inhibitory transmitter gamma-amino butyric acid (GABA) may also act on the Mauthner cells. We used immunocytochemical methods involving an antibody against glutamic acid decarboxylase (GAD), the synthesizing enzyme for GABA. Our study revealed dense GAD immunoreactive terminals surrounding the Mauthner cells. Puncta counts showed that the distribution of GAD immunoreactivity was densest at the distal lateral dendrite of the Mauthner cells; the distribution of puncta tapers gradually in regions closer to the soma. The axon cap was devoid of GABAergic immunoreactivity. We also performed unilateral lesions of the octaval nuclei to evaluate the origin of the GAD immunoreactive terminals. Following the lesions, we found marked decreases in GAD immunoreactive terminals on the proximal lateral dendrite, soma, and proximal ventral dendrite of both Mauthner cells. These results suggest that the octaval region contributes to bilateral inhibition of the Mauthner cells. The distal lateral dendrite of the ipsilateral Mauthner cell also showed a reduction in GAD immunoreactive terminals. This suggests that GABA mediates remote dendritic inhibition of this cell. GAD immunoreactive puncta also surrounded other large reticulospinal neurons, some of which are serially reiterated along the anterior-posterior axis of the hindbrain. Thus, GABA may also exert an influence not only on the Mauthner cells, but also on other reticulospinal neurons.


Electron microscopy as a means for carrier detection and genetic counselling in families at risk of tuberous sclerosis.
In otherwise asymptomatic parents of two unrelated children severely affected with tuberous sclerosis (TS), the ultrastructure of hypomelanotic skin lesions was investigated. In the hypomelanotic macules of both mothers of the two families, the population density of melanocytes was normal, melanization, however, was markedly suppressed. Therefore, these macules represent typical "white leaf-shaped macules" characteristic of tuberous sclerosis. Especially by applying the dihydroxyphenylalanine (DOPA) reaction to the ultrastructural level, it was possible to separate the TS-macules from the vitiliginous lesions of one father with a decrease of functional melanocytes as well as from other congenital circumscribed hypomelanoses. Thus electron microscopy in combination with the DOPA reaction may be helpful in recognizing a "forme fruste" of the dominantly inherited tuberous sclerosis (i.e. identification of white leaf-shaped macules) to enable genetic counselling and family planning by marking carriers of the mutant TS gene amongst the relatives of a patient and to exclude a sporadic mutation.


Present status of the diagnosis and treatment of gallbladder carcinoma.
Because early carcinoma of the gallbladder causes no specific signs or symptoms, most patients with this disease are diagnosed with advanced-stage tumors. High-resolution ultrasonography and a low index of suspicion for polypoid masses or asymmetric gallbladder thickening represent the best method of early detection. Despite regular preoperative gallbladder imaging, many cancers are only detected intraoperatively or incidentally on pathologic examination. All known or suspected gallbladder cancers should be definitively treated with a laparotomy, not laparoscopic surgery. For early gallbladder cancers (Tis and T1 cancers), simple cholecystectomy is adequate therapy. More advanced-stage carcinomas without distant metastases should routinely be managed with a radical cholecystectomy, which includes partial hepatectomy and regional lymphadenectomy. Any adherent organs should be resected en bloc with the cancer. Pancreatoduodenectomy has been performed in several Japanese centers, but is rarely performed in the West for locally advanced gallbladder cancers. Most patients who undergo curative resection will develop recurrent disease, but there is currently no proven effective adjuvant therapy.


Prophylactic use of anticoagulation and hemodilution for the prevention of venous thromboembolic events following meningioma surgery.
Brain tumors may be associated with postoperative venous thromboembolic (VTE) events with possible devastating consequences. Meningioma has the highest incidence of postoperative VTE events among all brain tumors. Hemodilution and anticoagulation both proved efficacy in deep venous thrombosis (DVT) prophylaxis that is why we theorized that this regimen would be beneficial for VTE prophylaxis in operated intracranial meningioma patients without added risk to the patients. A retrospective double-blinded study, where the records of consecutive intracranial meningioma patients were revised comparing the efficacy of two regimens of postoperative VTE prophylaxis. Patients were divided into 2 groups; group A was submitted to the use of compressive stockings, low-molecular weight heparin (LMWH) administration and hemodilution, while group B was submitted only to the use of compressive stockings. The study included 194 patients. Mean age of patients was 55 years (range from 27 to 78 years). VTE events were diagnosed in 16 patients (8.2%) all of them belonged to group B. The median time for VTE events was 12 days. Older age (P=.0001), larger size tumor (p=0.0438), delayed ambulation postoperatively (p=0.0351) as well as skull base location of meningioma (p=0.0163) were associated with higher incidence of postoperative VTE. Overall, group A patients showed more favorable outcome as compared to group B. In addition to the use of elastic stockings, we recommend starting hemodilution at the outset of surgery, LMWH administration starting 12h postoperatively as well as refraining from the use of diuretics during and after intracranial meningioma surgery till the patient became fully ambulatory to reduce the incidence of postoperative VTE events.


Urothelial damage and tumor initiation by urinary metabolites of sodium o-phenylphenate in the urinary bladder of female rats.
Intravesical instillation of 2-phenyl-1,4-benzoquinone (PBQ), a metabolite of sodium o-phenylphenate (Na-OPP), at a concentration of 0.1% in saline caused acute epithelial injury, prolonged inflammation and epithelial hyperplasia in female F344 rats. Ten such instillations of PBQ within 5 weeks resulted in the development of preneoplastic lesions of the urinary bladder epithelium when followed by 5% sodium saccharin feeding for 31 weeks. Since neither urothelial damage nor tumor-initiating activity was observed with either Na-OPP itself or another metabolite, phenylhydroquinone, PBQ may play an essential role in Na-OPP urinary bladder carcinogenesis.


Electromyographic analysis of infraspinatus and scapular muscles during external shoulder rotation with different weight loads and positions.
Strengthening the infraspinatus is important in shoulder rehabilitation. Changes in infraspinatus activity with changing load and position have not been quantified. We sought to determine the most appropriate load and posture for early infraspinatus strengthening by assessing for changes in electromyographic activity in the healthy infraspinatus and other shoulder girdle muscles during isometric external rotational exercise under different loads with the shoulder adducted in the supine and seated positions. Sixteen healthy adults (30 shoulders) performed isometric shoulder external rotation in the sitting and supine positions, starting with the shoulder and forearm in neutral position and the elbow flexed 90°. Loads (0.5 kg, 1 kg, and 2 kg) were applied at rest. We assessed the infraspinatus, upper trapezius, posterior deltoid, and biceps brachii. For analysis, we used the mean percentage of maximum voluntary muscle contraction (%MVC) value measured during each isometric contraction divided by the maximum voluntary muscle contraction (MVC) of each muscle. In the infraspinatus and posterior deltoid, significant interaction was observed between body position and load. Compared to the sitting position, an increase in activity in the supine position was attenuated as load increased, especially at 2 kg. The supine values of the upper trapezius and biceps brachii were always significantly lower than those in the sitting position regardless of load. The activity of the infraspinatus can be increased gradually during rehabilitation by beginning in the supine position, which assures low activity of the upper trapezius and biceps brachii. Exercise with the shoulder adducted in the supine position can strengthen the infraspinatus gradually and avoid compensatory mobility. Level 3.


Impact of patient selection on outcomes of PDA in very low birth weight infants.
The aim of this study was to observe whether our patient selection maximized the benefits of PDA ligation by comparing the outcomes in a surgically ligated group of PDA to a medically closed group. If a hemodynamically significant ductus arteriosus (HSDA) was found to meet both clinical and echocardiographic criteria (stage≥3), as proposed by NcNamara and Hellman, medical treatment was initiated with oral ibuprofen (maximum 2 courses). If the PDA of these patients failed to close medically, timed surgical closure was performed. Medical treatment was effective in 75 (72%) cases, and 29 (28%) patients required surgical ligation. The mean gestational age and birth weight were each significantly lower and the initial PDA shunt size was significantly larger in the surgically treated group. Additionally, the mean durations of mechanical ventilation, oxygen dependence and hospital admission were significantly longer in the surgically ligated group. However, our logistic regression analysis demonstrated no statistically significant difference in the outcomes of hospitalization (CLD, NEC, ARF, sepsis, IVH, ROP, PVL and death) between the two groups. Comprehensive HSDA patient selection may maximize the benefits of timed PDA ligation without adverse outcomes in very low birth weight infants.


Whole genome sequence analysis of antimicrobial resistance genes, multilocus sequence types and plasmid sequences in ESBL/AmpC Escherichia coli isolated from broiler caecum and meat.
Plasmid-encoded extended-spectrum β-lactamase and AmpC gene-carrying Escherichia coli (ESBL/AmpC E. coli) is an increasing cause of human infections worldwide. Increasing carbapenem and colistin resistance further complicate treatment of these infections. The aim of this study was to assess the occurrence of ESBL/AmpC E. coli in different broiler flocks and farms, as well as in broiler meat, in a country with no antimicrobial usage in broiler production. An additional goal was to assess the genetic characteristics of ESBL/AmpC E. coli isolates by using whole genome sequencing (WGS). Altogether 520 caecal swabs and 85 vacuum-packed broiler meat samples were investigated at the slaughterhouse level. WGS of the bacterial isolates revealed acquired antimicrobial resistance (AMR) genes, multilocus sequence types (MLST) and plasmid sequences. ESBL/AmpC E. coli was identified in 92 (18%) of the caecum and 27 (32%) of the meat samples. ESBL/AmpC E. coli-carrying birds derived from six (33%) out of 18 farms. Of the two blaESBL/AmpC genes detected by PCR, blaCMY-2 (96%) was predominant over blaCTX-M-1 (4%). Furthermore, WGS revealed an additional AMR gene sul2. Carbapenemase, colistin, and other AMR genes were not detected from the isolates of either the caecal or meat samples. Altogether seven MLSTs (ST101, ST117, ST212, ST351, ST373, ST1594 and an unknown ST) and a variety of different plasmid sequences (IncB/O/K/Z, IncI1, IncFII, IncII, IncFIB, IncFIC, IncX1 and an additional set of Col-plasmids) were detected. This is the first study on genomic epidemiology of ESBL/AmpC E. coli on broiler farms and flocks with no antimicrobial usage, by using WGS analysis. Results show that ESBL/AmpC E. coli occurrence is common both in the caecum and in the packaged meat. However, compared to other European countries, the occurrence is low and the presence of AMR genes other than blaCMY-2 and blaCTX-M-1 is rare. More studies are needed to understand the ESBL/AmpC E. coli occurrence in broiler production to prevent the meat from contamination during slaughter and processing, thereby also preventing zoonotic transmission of ESBL/AmpC E. coli. Additionally, more studies are needed to understand the ecology and fitness cost of Enterobacteriaceae plasmids in animal production in order to prevent their acquisition of plasmid-encoded antimicrobial resistance genes such as carbapenem and colistin resistance genes, as this would pose a great hazard to food safety.


Immune checkpoint inhibitor-induced cutaneous toxicities: a review of histopathologic and clinical features.
Immune checkpoint inhibitors (ICIs) represent an emerging treatment option for a variety of cancer types. Through inhibition of programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), and/or cytotoxic lymphocyte-associated antigen-4 (CTLA-4), ICIs activate the host's immune system causing a heightened anti-tumor response. However, off-target effects of ICIs can result in numerous different immune-related cutaneous adverse events (irCAEs). Beyond impacting quality of life, irCAEs can lead to dose limitations or discontinuation of anti-cancer therapies. Correct diagnosis is necessary for expedient and appropriate management. Skin biopsies are often performed to increase diagnostic accuracy and guide clinical management. An extensive literature review was performed using the PubMed database to identify the reported clinical and histopathologic features of irCAEs. This comprehensive review primarily details the histopathologic features of various irCAEs reported to date. Clinical presentation and immunopathogenesis are also discussed in relation to histopathology.


Body sodium blood volume state in essential hypertension: abnormal relation of exchangeable sodium to age and blood pressure in male patients.
The circulatory volume and exchangeable sodium (NaE) were measured by the Berne group in 110 normal subjects and 12 patients with benign untreated essential hypertension. Total plasma volume (PV) and blood volume (BV) correlated with total NaE (r = 0.64-0.75, p less than 0.001); these correlations were similar in normal and hypertensive subjects. PV, BV, and NaE related to body surface area averaged normal in the hypertensive population. PV and BV were unrelated to age or blood pressure in both normal and hypertensive subjects; NaE correlated positively with age (r = 0.25, p less than 0.02) and arterial pressure (r = 0.25, p less than 0.02) in essential hypertensive but not in normal subjects. These relationships in essential hypertension confirmed a previous observation by the Glasgow group. Moreover, a combined analysis of both study populations, with a total of 211 hypertensive patients, revealed significant correlations between NaE and age (r = 0.38, p less than 0.001) or arterial pressure (r = 0.40, p less than 0.001) in male but not in female subjects. The NaE was significantly decreased in hypertensive males less than 35 years old as compared with appropriate controls (95.8 +/- 5.1 vs 99.1 +/- 6.5%, p less than 0.02). BV and body sodium content are on average normal in patients with benign essential hypertension. The NaE may even be decreased in young male patients. These observations do not support the concept that body sodium and fluid volume expansion represent the initial event leading to high blood pressure in patients with essential hypertension.


A comparison of triclosan and chlorhexidine preparations with 60 per cent isopropyl alcohol for hygienic hand disinfection.
Four detergent preparations containing triclosan; two alcoholic products, containing triclosan and chlorhexidine respectively, and a detergent preparation containing chlorhexidine were compared with 60 per cent isopropyl alcohol following a single hand wash using Escherichia coli as the test organism. In vitro tests indicated that all had a high activity against hospital pathogens. The triclosan-containing preparations exhibited a significant pathogens. The triclosan-containing preparations exhibited a significant residual activity. Experiments in volunteers showed that 0.5 per cent alcoholic triclosan was significantly more effective than all other preparations tested. All the detergent preparations had an effect similar to that of 60 per cent isopropyl alcohol. None of the seven products evaluated was significantly less bactericidal than 60 per cent isopropyl alcohol.


Update on hepatocellular carcinoma breakthroughs: poly(ADP-ribose) polymerase inhibitors as a promising therapeutic strategy.
Hepatocellular carcinoma is the most common form of primary liver cancer which is the fifth most common cancer in men and the seventh in women and the third most common cause of cancer-related death worldwide. Only 10-20% of patients are eligible for curative treatments that result in a 5-year survival rate of 40% to 70%. Therefore, the development of novel treatment options is necessary for the majority of patients and remains a considerable challenge. Conformal radiotherapy is used in certain circumstances and preliminary data obtained from phase 1/2 trials are showing promising curative effects. There is thus an interest in identifying drugs that can be exploited to enhance radiation sensitivity that could be used in therapy and might improve clinical outcome. Small molecules inhibitors of poly(ADP-ribose) polymerases (PARP) are an example of a radio- and chemo-sensitizing drug, as well as being an efficient single agent treatment in certain genetic backgrounds. In this review, we discuss the role of PARP-1 in hepatocellular carcinoma and present the results of preclinical studies that have assessed the potential of PARP inhibition as a single treatment or combined with chemotherapy or radiotherapy for the treatment of hepatocellular carcinoma.


Homology modeling, active site prediction, and targeting the anti hypertension activity through molecular docking on endothelin - B receptor domain.
In cardiovascular system, activation of Endothelin receptors causes vasoconstriction which leads to Pulmonary Arterial Hypertension (PAH). Endothelin receptor antagonism has emerged as an important therapeutic strategy in pulmonary arterial hypertension. Bosentan is intended to affect vasoconstriction, hypertrophic and fibrotic effects by blocking the actions of receptors ET(A) and ET(B). In this study we identified the action of Bosentan on endothelin B receptor using docking studies with homology modeled endothelin B receptor. Through the modeled protein, the flexible Docking study was performed with Bosentan and its derivatives with theoretically predicted active sites. The results indicated that amino acid ARG82, ARG84 and HIS197 present in endothelin B receptor are core important for binding activities and these residues are having strong hydrogen bond interactions with Bosentan. We have investigated the Bosentan and its derivatives interactions and scoring parameters using gold docking package. Among the docked compounds, one of the Bosentan derivatives BD(6) shows better interaction than Bosentan with endothelin B receptor. Our results may be helpful for further investigations in both in vivo and in vitro conditions.


Collaborative neurodynamic optimization for solving nonlinear equations.
A distributed optimization method for solving nonlinear equations with constraints is developed in this paper. The multiple constrained nonlinear equations are converted into an optimization problem and we solve it in a distributed manner. Due to the possible presence of nonconvexity, the converted optimization problem might be a nonconvex optimization problem. To this end, we propose a multi-agent system based on an augmented Lagrangian function and prove that it converges to a locally optimal solution to an optimization problem in the presence of nonconvexity. In addition, a collaborative neurodynamic optimization method is adopted to obtain a globally optimal solution. Three numerical examples are elaborated to illustrate the effectiveness of the main results.


A stochastic approach for the interpretation of single pulse experiments in morphological multicompartments of renewing and exponentially growing cell populations.
A general approach for the interpretation of single pulse experiments in multicompartment systems is presented. It allows an extension of the classical single compartment Barret's methodology, and has been detailed in the pipeline model case to show its capabilities. FLM, FLC, grain count curves, labelling indices and compartment size ratios of each compartment, are fitted into a coherent scheme that fully describes the statistical aspects of the phase durations including possible losses. It is shown that if the compartments are identical, irrespective of the feedback coupling between them, the system may be treated as a single compartment. It is also shown that the FLC information is necessary to identify the existence of losses in the system, and how to correct the "apparent" transit times if losses are present. The pipeline model is treated and a suggestion is made to reconcile the "British" and "American" interpretations of the erythroid system. As a corollary, simple formulae are derived in the deterministic case through a coupling matrix describing the interaction between compartments. Computer codes are described and have been implemented in the J.E.N. Thermoecology Laboratory.


Compatibility screening of linezolid injection during simulated Y-site administration with other drugs and infusion solutions.
To evaluate the physical compatibility of linezolid injection (Zyvox-Pharmacia) during simulated Y-site administration with 8 infusion solutions and 110 selected other drugs. Controlled experimental trial. Laboratory. Five-milliliter samples of linezolid injection 2 mg/mL were mixed with 5 mL samples of the selected infusion solutions and the selected other drugs diluted in 5% dextrose injection, or, if necessary to avoid incompatibility with the diluent, 0.9% sodium chloride injection. Visual examinations of the samples were performed in normal fluorescent light with the unaided eye and using a Tyndall beam (high-intensity monodirectional light source) to enhance visualization of small particles and low-level haze. The turbidity of each sample was measured, and for samples that did not exhibit visible precipitation, the particle content was measured, as well. All of the samples were assessed initially and at 1 and 4 hours. All of the infusion solutions and most of the test drugs were physically compatible with linezolid injection during the 4-hour observation period. Physical incompatibilities resulted when linezolid injection was combined with five of the drugs: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, and phenytoin sodium. Precipitation, turbidity formation, and/or unacceptable changes in measured haze levels were observed. Linezolid 2 mg/mL was physically compatible for 4 hours at room temperature with all 8 infusion solutions tested and 105 of the drugs tested. Simultaneous Y-site administration of linezolid injection with the five drugs resulting in physical incompatibilities should be avoided.


Application of a Systems Pharmacology-Based Placebo Population Model to Analyze Long-Term Data of Postmenopausal Osteoporosis.
Osteoporosis is a progressive bone disease characterized by decreased bone mass resulting in increased fracture risk. The objective of this investigation was to test whether a recently developed disease systems analysis model for osteoporosis could describe disease progression in a placebo-treated population from the Early Postmenopausal Intervention Cohort (EPIC) study. First, we qualified the model using a subset from the placebo arm of the EPIC study of 222 women who had similar demographic characteristics as the 149 women from the placebo arm of the original population. Second, we applied the model to all 470 women. Bone mineral density (BMD) dynamics were changed to an indirect response model to describe lumbar spine and total hip BMD in this second population. This updated disease systems analysis placebo model describes the dynamics of all biomarkers in the corresponding datasets to a very good approximation; a good description of an individual placebo response will be valuable for evaluating treatments for osteoporosis.


Survival trend after invasive cervical cancer diagnosis in Sweden before and after cytologic screening. 1960-1984.
Cytologic screening can reduce mortality from cervical cancer by detection and removal of premalignant lesions. Conceivably, mortality is further reduced because more women with invasive disease are diagnosed at an earlier, curable stage. This hypothesis can be assessed in Sweden, where population-based screening programs were introduced successively over about a decade starting in 1964. Record linkages permitted complete follow-up through 1986 of all 17,377 patients with invasive cervical cancer diagnosed in Sweden from 1960 through 1984. We analyzed relative survival rates that describe the survival of patients after elimination of the effects of causes of death other than cancer of the cervix. Prognosis improved substantially in patients younger than age 50 years at diagnosis; from 1960-1964 to 1980-1984, the 5-year relative survival rate increased from 69.8% to 88.8% at age 20-29 years, from 71.7% to 85.5% at age 30-39 years, and from 68.6% to 77.9% at age 40-49 years. The excess mortality was thus reduced by more than half in patients diagnosed when younger than 40 years. In contrast, only slight or no improvement was noted in those diagnosed at older ages when screening was less extensive. In all time periods, a strong association was found between older age at diagnosis and poorer prognosis. Although alternative explanations for our findings must be seriously considered, the most obvious interpretation is that cytologic screening reduces mortality from cervical cancer by earlier diagnosis of invasive disease.


Favorable outcome of retreatment by direct-acting antivirals for hepatitis C patients with daclatasvir plus asunaprevir combination therapy failure.
In patients with hepatitis C virus, treatment failure of daclatasvir plus asunaprevir combination therapy (DCV + ASV) seems to become intractable due to the induction of resistance-associated substitutions. This study aimed to investigate the outcomes of retreatment with direct-acting antivirals (DAAs) in patients with DCV + ASV therapy failure, as well as changes in drug resistance mutations. We retrospectively analyzed 44 patients re-treated with DAAs after DCV + ASV failure between December 2015 and April 2018. All patients were analyzed for amino acid substitutions, and additional treatment regimens were selected based on the results and current treatment guidelines. The sustained virological response rate with second-line treatment was 81.8% (36/44), and relapse occurred in five of 16 patients who received sofosbuvir/ledipasvir and three of seven patients who received DCV/ASV/beclabuvir. Third- and fourth-line treatments were also tried in relapsed cases, and the overall sustained virological response rates were 90.9% (40/44) and 93.2% (41/44), respectively. A high rate of viral clearance was eventually observed. Before second-line treatment, the prevalence of mutations in the NS5A and NS3/4A regions was 100% (44/44) and 86.4% (38/44), respectively. There was no significant increase in the number of amino acid substitutions in patients for whom second-line treatment failed. Amino acid substitutions were frequently observed in patients with DCV + ASV failure, but most patients achieved a sustained virological response after retreatment with DAAs. Although the spread of drug-resistant viruses due to unsuccessful DAA treatment was a matter of concern, most cases of DCV + ASV failure were overcome with additional treatment.


Intra-ovarian infusion of autologous platelet-rich plasma in women with poor ovarian reserve: A before and after study.
Female ovarian reserve progressively declines with increasing age. Intraovarian injection of platelet-rich plasma (PRP) seems to be an alternative treatment to increase fertility in women. Therefore, this study aimed to evaluate the effect of intra-ovarian infusion of PRP in treating women with poor ovarian reserve. In this before-and-after study, 22 infertile women with a poor ovarian reserve who underwent in vitro fertilization with the GnRH antagonist protocol were enrolled. After the oocyte retrieval undergoing vaginal ultrasound guide, PRP was injected into the ovary with a puncture needle under general anesthesia. Finally, the levels of anti-Müllerian hormone (AMH) and antral follicle counts (AFCs) were compared in all participants before and three months after the PRP injection. Our findings showed that AMH significantly increased after the intra-ovarian infusion of PRP (P < 0.001) in these women, while no significant changes were observed in AFC (P = 0.140) at the end of the study. In addition, logistic regression indicated that body mass index (BMI) and maternal age had no significant effect on ovarian response to PRP injection. However, the duration of infertility > 5 years was associated with a 20-fold increase in the probability of AFC < 7 in women with poor ovarian reserve. PRP can increase the chance of fertility in women with poor ovarian reserve by significantly increasing AMH levels.


[Cognitive impact of mitoxantrone and methylprednisolone in multiple sclerosis: an open label study].
Interferons beta have shown some positive effects on cognitive function in multiple sclerosis (MS). The potential immunosuppressive impact of mitoxantrone on cognitive dysfunction in MS has never been evaluated. We assessed changes in cognitive dysfunction in patients with very active MS treated with mitoxantrone combined with methylprednisolone. We assessed a non randomized controlled trial including successively 15 consecutive MS patients. Very active MS was defined by a progression of at least two EDSS points or more than two relapses during the previous year and at least one enhanced lesion after gadolinium infusion on MRI. All patients received a monthly intravenous pulse of mitoxantrone (20mg) for six months with methylprednisolone (1g). Global cognitive efficiency, memory and executive function were assessed before treatment (M0) and after six months (M6) and 12 months (M12) of treatment. To evaluate the learning effect, 15 healthy subjects also participated. A significant improvement in global cognitive efficiency was observed at M6 and was sustained at M12, as a few parameters on memory and executive functions. We suggest that mitoxantrone combined with methylprednisolone has a potential positive effect on cognitive functions.


Superoxide produced by Kupffer cells is an essential effector in concanavalin A-induced hepatitis in mice.
Although concanavalin A (Con-A)-induced experimental hepatitis is thought to be induced by activated T cells, natural killer T (NKT) cells, and cytokines, precise mechanisms are still unknown. In the current study, we investigated the roles of Kupffer cells, NKT cells, FasL, tumor necrosis factor (TNF), and superoxide in Con-A hepatitis in C57BL/6 mice. Removal of Kupffer cells using gadolinium chloride (GdCl(3)) from the liver completely inhibited Con-A hepatitis, whereas increased serum TNF and IFN-gamma levels were not inhibited at all. Unexpectedly, anti-FasL antibody pretreatment did not inhibit Con-A hepatitis, whereas it inhibited hepatic injury induced by a synthetic ligand of NKT cells, alpha-galactosylceramide. Furthermore, GdCl(3) pretreatment changed neither the activation-induced down-regulation of NK1.1 antigens as well as T cell receptors of NKT cells nor the increased expression of the CD69 activation antigen of hepatic T cells. CD68(+) Kupffer cells greatly increased in proportion in the early phase after Con-A injection; this increase was abrogated by GdCl(3) pretreatment. Anti-TNF antibody (Ab) pretreatment did not inhibit the increase of Kupffer cells, but it effectively suppressed superoxide/reactive oxygen production from Kupffer cells and the resulting hepatic injury. Conversely, depletion of NKT cells in mice by NK1.1 Ab pretreatment did suppress both the increase of CD68(+) Kupffer cells and Con-A hepatitis. Consistently, the diminution of oxygen radicals produced by Kupffer cells by use of free radical scavengers greatly inhibited Con-A hepatitis without suppressing cytokine production. However, adoptive transfer experiments also indicate that a close interaction/cooperation of Kupffer cells with NKT cells is essential for Con-A hepatitis. Superoxide produced by Kupffer cells may be the essential effector in Con-A hepatitis, and TNF and NKT cells support their activation and superoxide production.


Organ-specific susceptibility of p53 knockout mice to N-bis(2-hydroxypropyl)nitrosamine carcinogenesis.
To elucidate which is the major determinant of susceptibility of p53 deficient mice, the carcinogen or the target organ, N-bis(2-hydroxypropyl)nitrosamine was administered to induce tumors in multi-organs. In a 15-week experiment, the incidences of both lung and hepatic vascular tumors were found to be significantly higher in p53 nullizygous (-/-) than in heterozygous (+/-) and wild-type (+/+) mice, indicating universal susceptibility of p53 (-/-) mice. In a 40-week experiment, p53 (+/-) mice showed increased susceptibility only with regard to vascular tumors, coinciding with significantly more frequent (60%) p53 gene mutations, in comparison with lung tumors with their low mutation rate (10.8%) (P<0.005). These results indicate that the target organ may be a more important factor than the carcinogen in determining susceptibility of p53 (+/-) mice.


Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents: synthesis and structure-activity relationships of novel series of sulfonamides, acylphosphonamides and acylphosphoramidates.
Sulfoacetic acid, phosphoramidate, and phosphoramide analogs of the ACAT inhibitors, CI-999 and CI-1011 were synthesized. The structure-activity relationships of these compounds as ACAT inhibitors are described.


Co-occurrence of HBsAg and anti-HBs: two consecutive infections or a sign of advanced chronic liver disease?
Simultaneous presence of hepatitis B surface antigen (HBsAg) and antibodies to the surface antigen (anti-HBs) was detected in 32 out of 89 Dutch chronic hepatitis patients of Caucasian race. HBsAg was subtyped ad in 28 and ay in four cases. Anti-HBs could be subtyped in 25 cases using reference antigens discriminating between d, y, and w1-4 subdeterminants. In 20 patients HBsAg subtype ad (HBsAg/ ad) was accompanied by antibody to subdeterminant y (anti-y), whereas HBsAg/ ay and anti-d were simultaneously detected in the serum of one patient. The antibody pattern in sera from the remaining patients was complex. Eighteen anti-HBs-positive patients were matched for age, histology, and hepatitis B e antigen (HBeAg) status with 18 anti-HBs-negative patients. Differences in risk factors for acquiring a hepatitis B infection were not found. These results do not support the hypothesis that co-occurrence of HBsAg and anti-HBs is due to two consecutive infections with hepatitis B virus. The frequency of the co-occurrence of HBsAg and anti-HBs was found to be related to the degree of progressive liver disease, since anti-HBs was found in three out of 23 asymptomatic carriers, in four out of 20 chronic persistent hepatitis patients, in 20 out of 41 chronic active hepatitis patients, and in all five patients with chronic active hepatitis and cirrhosis. The high frequency of anti-HBs in advanced liver disease may be the result of a disturbed immunologic response mechanism.


Intergenic sequences of clustered tRNA genes: new type of genetic marker for phylogenetic studies, with application to the taxonomy of liverworts.
We have established a new type of genetic marker in Pellia liverworts that can be used to differentiate between closely related species within this genus. The Pellia intergenic sequences spanning the tandemly repeated nuclear tRNA(Leu) genes were amplified using the PCR technique and, in the case of Pellia neesiana, the tRNA(Leu) tandem region was cloned and sequenced. The length comparison of the intergenic regions allowed for the identification of a number of Pellia species. Additional experiments suggest that this marker can be used to differentiate other species of liverworts and mosses.


The biologic significance of the aldosterone concentration in saliva.
Salivary aldosterone measurements can be used to study aldosterone secretion and metabolism noninvasively. Salvia and plasma aldosterone concentration were highly correlated during all periods of study; during adrenocorticotrophic hormone (ACTH) administration, a relatively greater amount of aldosterone appeared in saliva; during dexamethasone administration, a relatively smaller amount of aldosterone appeared in saliva. As plasma cortisol increased with ACTH administration there was an increased relative amount of aldosterone in saliva. DOC (11-deoxycorticosterone) was found in saliva only during ACTH administration. Corticosterone was identified during baseline periods. Salivary aldosterone concentrations were independent of flow. The data indicate that saliva is an accessible bodily fluid which may be used to monitor the changes in nonprotein bound plasma steroid hormone concentration in children.


Lead exposure from households and school settings: influence of diet on blood lead levels.
Lead is known as a potent toxicant to human health, particularly for children while their central nervous system is developing. The aim of this study was to investigate the associations between blood lead levels (BLLs) and lead exposure in the children's diet, home, and school environments. A cross-sectional study was conducted with 153 children aged 1-4 years, in four day care centers (DCCs), where a high prevalence of lead exposure was previously found. Lead determination by graphite furnace atomic absorption spectrometry (GF-AAS) was performed for venous blood, drinking water collected in the DCCs, and the 24-h diet (n = 64). Environmental screenings were conducted to evaluate lead concentrations in the tableware, buildings, and playground items in all DCCs and children's homes (n = 18) by using a field-portable X-ray fluorescence analyzer (FP-XRF). The BLL mean was 2.71 μg dL-1. Means for 24-h lead concentrations in the diet were 1.61 and 2.24 μg kg-1 of body weight (BW) in two DCCs. Lead concentrations in the water supply were lower than 2 μg L-1. More than 11% of the DCCs' environmental analyses presented lead concentrations higher than or equal to 1 mg cm-2, as defined by the USEPA. The diet was not found to be a risk factor for lead exposure, but households and DCC settings raised concern. Children's exposure to lead in DCC environments, where they spend the most part of their weekdays, appeared to be relevant. Graphical abstract .


A highly predictive autoantibody-based biomarker panel for prognosis in early-stage NSCLC with potential therapeutic implications.
Lung cancer is the leading cause of cancer-related death worldwide. Surgical resection remains the definitive curative treatment for early-stage disease offering an overall 5-year survival rate of 62%. Despite careful case selection, a significant proportion of early-stage cancers relapse aggressively within the first year post-operatively. Identification of these patients is key to accurate prognostication and understanding the biology that drives early relapse might open up potential novel adjuvant therapies. We performed an unsupervised interrogation of >1600 serum-based autoantibody biomarkers using an iterative machine-learning algorithm. We identified a 13 biomarker signature that was highly predictive for survivorship in post-operative early-stage lung cancer; this outperforms currently used autoantibody biomarkers in solid cancers. Our results demonstrate significantly poor survivorship in high expressers of this biomarker signature with an overall 5-year survival rate of 7.6%. We anticipate that the data will lead to the development of an off-the-shelf prognostic panel and further that the oncogenic relevance of the proteins recognised in the panel may be a starting point for a new adjuvant therapy.


Association Between Difficult Airway Predictors and Failed Prehosptial Endotracheal Intubation.
Difficult airway predictors (DAPs) are associated with failure of endotracheal intubation (ETI) in the emergency department (ED). The purpose of this study was to determine if DAPs are associated with failure of prehospital ETI. This retrospective study compared the prevalence of DAPs in cases of failed prehospital ETI successfully intubated in the ED (FPH/SED) with cases with no prehospital attempt that were successfully intubated in the ED on the first attempt by a physician using direct laryngoscopy (NPH/SED). All cases were transported by ground or air to an academic, level-1 trauma center. A total of 1377 ED ETIs were performed; 161 FPH/SED and 530 NPH/SED were identified. The odds ratios with 95% confidence intervals (CIs) of finding DAPs in the FPH/SED group compared with the NPH/SED group was blood = 5.80 (95% CI, 3.89-8.63), vomit = 2.01 (95% CI, 1.25-3.21), short neck = 2.67 (95% CI, 1.39-5.03), neck immobility = 2.52 (95% CI, 1.72-3.67), airway edema = 10.52 (95% CI, 4.15-29.92), facial trauma = 4.64 (95% CI, 2.91-7.39), and large tongue = 3.08 (95% CI, 1.75-5.40). When grouped by the number of DAPs per case (0, 1, 2, 3, or ≥ 4), the odds of multiple DAPs in cases of FPH/SED compared with NPH/SED ranged from 2.89 (95% CI, 1.71-4.90) with 1 DAP to 24.55 (95% CI, 10.60-56.90) with ≥ 4 DAPs. Cases of FPH/SED have more DAPs than NPH/SEDs.


Variation of bone layer thicknesses and trabecular volume fraction in the adult male human calvarium.
The human calvarium is a sandwich structure with two dense layers of cortical bone separated by porous cancellous bone. The variation of the three dimensional geometry, including the layer thicknesses and the volume fraction of the cancellous layer across the population, is unavailable in the current literature. This information is of particular importance to mathematical models of the human head used to simulate mechanical response. Although the target geometry for these models is the median geometry of the population, the best attempt so far has been the scaling of a unique geometry based on a few median anthropometric measurements of the head. However, this method does not represent the median geometry. This paper reports the average three dimensional geometry of the calvarium from X-ray computed tomography (CT) imaging and layer thickness and trabecular volume fraction from micro CT (μCT) imaging of ten adult male post-mortem human surrogates (PMHS). Skull bone samples have been obtained and μCT imaging was done at a resolution of 30 μm. Monte Carlo simulation was done to estimate the variance in these measurements due to the uncertainty in image segmentation. The layer thickness data has been averaged over areas of 5mm(2). The outer cortical layer was found to be significantly (p < 0.01; Student's t test) thicker than the inner layer (median of thickness ratio 1.68). Although there was significant location to location difference in all the layer thicknesses and volume fraction measurements, there was no trend. Average distribution and the variance of these metrics on the calvarium have been shown. The findings have been reported as colormaps on a 2D projection of the cranial vault.


Closing the loop on adrenal health, dysfunction, and disease.
A wearable microdialysis device measures ultradian patterns of adrenal hormone secretion in humans at minute scale (Upton et al.).


A novel framework for understanding reduced awareness of dyskinesias in Parkinson's Disease.
Although dyskinesias-reduced-self-awareness (DRSA) in Parkinson's disease (PD) is related to deficit in metacognition, other factors, such as "Theory of Mind" (ToM), could operate. Forty-one PD patients were assessed using the Global Awareness of Movement Disorders (GAM) and the Dyskinesias Subtracted-Index (DS-I). To study whether GAM and DS-I scores could be influenced by second-type ToM or Reading the Mind in the Eyes (RME) tasks, we conducted two multiple logistic regression analyses. The association between the GAM, the DS-I and RME task were highly significant. The association between DS-I and Trail Making Test B-A version was also verified. DRSA was related with affective component of ToM and executive functions, thus caused by a complex interplay between specific neuropsychological and motor factors.


Efficacy and Quality of Life with the Modified Versus the Traditional Thoraco-Laparoscopic McKeown Procedure for Esophageal Cancer: A Multicenter Propensity Score-Matched Study.
This study aimed to compare the efficacy and postoperative quality of life for patients with esophageal cancer treated by either the modified or the traditional thoracolaparoscopic McKeown procedure. This retrospective case-control study included 269 patients with esophageal cancer admitted to three medical centers in China from February 2020 to August 2022. The patients were divided according to surgical method into the layered hand-sewn end-to-end invagination anastomosis group (modified group) and the traditional hand anastomosis group (traditional group). Propensity score-matching (PSM) was used to maintain balance and comparability between the two groups. The differences in age and tumor location between the patients in the traditional and modified groups were statistically significant. After PSM, the aforementioned factors were statistically insignificant. After PSM, each group had 101 patients. The modified group showed the greater advantage in terms of postoperative hospital stay (P = 0.036), incidence of anastomotic leak (P = 0.009), and incidence of gastroesophageal reflux (P < 0.001), and the difference was statistically significant. The results of the Quality of Life Questionnaire Core 30 (QLQ-C30) and Quality of Life Questionnaire Oesophageal Cancer Module 18 (QLQ-OES18) scales showed that the modified group also had the advantage over the traditional group in terms of physical function, overall health status, loss of appetite, eating, reflux, obstruction, and loss of appetite scores at the first and third months after surgery. The modified thoraco-laparoscopic McKeown procedure is a safe and effective surgical approach that can significantly reduce the incidence of postoperative anastomotic leak and gastroesophageal reflux, shorten the postoperative hospital stay, and improve the postoperative quality of life for patients with esophageal cancer.


Induction of an MLKL mediated non-canonical necroptosis through reactive oxygen species by tanshinol A in lung cancer cells.
Recent discoveries revealed several types of programmed necrosis, such as necroptosis, ferroptosis, pyroptosis, etc. Necroptosis is mediated by signaling complexes with receptor-interacting protein kinases (RIPs) and mixed lineage kinase domain-like protein (MLKL). Here, we described an MLKL mediated non-canonical necroptosis through reactive oxygen species (ROS) in lung cancer cells triggered by a natural compound, tanshinol A (TSA). Morphologically, TSA-induced necrotic cell death is characterized by increased cell volume, transparent of cytoplasm, and rupture of the cell membrane. Biochemically, it induces intracellular ATP depletion and PI penetration. Molecularly, TSA-induced cell death is mediated by MLKL but independent of RIP1 and RIP3. Furthermore, TSA induces MLKL phosphorylation and membrane translocation, and cytosolic calcium accumulation. However, calcium shows no effect on TSA-induced cell death. Especially, TSA induces intracellular ROS generation, which was found to be the upstream of MLKL. Collectively, our data indicated that TSA triggers a novel type of programmed necrosis mediated by MLKL in lung cancer cells, which might have therapeutic potentials for lung cancer treatment.


Activity-dependent neuroprotective protein: a novel gene essential for brain formation.
We have recently cloned the novel homeobox-containing activity-dependent neuroprotective protein (ADNP). In the current study, mouse ADNP was shown to be expressed at the time of neural tube closure, detected at E7.5 and increased on E9.5. Expression was augmented in the brain (E12.5), sustained throughout embryogenesis and regulated by VIP. To assess the function of ADNP, knockout mice were established. Detailed analysis revealed cranial neural tube closure failure and death on E8.5-9.0 of the ADNP-knockout embryos. The expression of Oct4, a gene associated with germ-line maintenance was markedly augmented in the knockout embryos. In contrast, the expression of Pax6, a gene crucial for cerebral cortex formation, was abolished in the brain primordial tissue of the knockout embryos. Thus, Pax6 and Oct4 constitute a part of the mechanism of action of ADNP on brain formation, inhibiting germ-line division while activating morphogenesis. In conclusion, ADNP is identified here as a new key gene essential for organogenesis in the developing embryo and may be implicated as a clinical target associated with proper neurodevelopment.


2,4,6-Tri-amino-1,3,5-triazin-1-ium 3-(prop-2-eno-yloxy)propano-ate acrylic acid monosolvate monohydrate.
The asymmetric unit of the title salt, C3H7N6 (+)·C6H7O4 (-)·C3H4O2·H2O, contains a 2,4,6-tri-amino-1,3,5-triazin-1-ium cation, a 3-(prop-2-eno-yloxy)propano-ate anion and acrylic acid and water solvent mol-ecules in a 1:1:1:1 ratio and with each species in a general position. In the crystal, the components are linked into a supra-molecular layer in the bc plane via a combination of O-H⋯O, N-H⋯N and N-H⋯O hydrogen bonding. The crystal studied was a non-merohedral twin, the minor component contribution being approximately 26%.


Design and optimization of new piperidines as renin inhibitors.
The discovery of a new series of piperidine-based renin inhibitors is described herein. SAR optimization upon the P3 renin sub-pocket is described, leading to the discovery of 9 and 41, two bioavailable renin inhibitors orally active at low doses in a transgenic rat model of hypertension.


The jamming avoidance response in Rhamphichthys rostratus: an alternative principle of time domain analysis in electric fish.
A Jamming Avoidance Response was found in the weakly electric fish Rhamphichthys rostratus, a South American pulse-Gymnotid. The analysis of the response suggests that it requires a key stimulus which is fundamentally different from that in previously described harmonic Gymnotids. It relies on a sensitivity for the direction of phase shifts of stimulus pulses relative to the fish's own electric organ discharge rather than on a sensitivity for beating frequencies.


Life under lockdown: Notes on Covid-19 in Silicon Valley.
This article is a preliminary exploration of the effects of Covid-19 in Silicon Valley, one of three pandemic 'hotspots' on America's west coast. In particular, it describes how the crisis has deepened and magnified social and economic inequalities in a region where poverty, homelessness and gentrification are rife. Despite the fact that many technology firms are reaping massive profits in the wake of 'shelter in place' orders, many Silicon Valley workers have lost their jobs and are struggling to cope with the consequences of Covid-19. The article also analyzes the different meanings of 'lockdown' by comparing examples from China, Brazil, Taiwan and the United States. The authors conclude that anthropologists have a significant role to play in helping to understand how and why communicable diseases emerge, the underlying social and environmental conditions that fuel them and cross-cultural strategies for the effective mitigation of epidemics and pandemics.


Ubiquitous presence of calciferin-like and cathepsin D-like activities in the sera (vertebrates) and humoral fluids (invertebrates).
1. Sera (or humoral fluids) from various animals (vertebrates and invertebrates) were assayed for calciferin-like and cathepsin D-like activities, indicating the ubiquitous presence of the latter and the former (with a few exceptions). Animals other than the mammals appeared to contain an organophilic calciferin-like activity in addition to a hydrophilic component (calciferin). 2. A correlation was found between the levels of calciferin and acid protease in most of the mammalian sera. An age-dependent decrease in calciferin (but not acid protease) was found in human sera. The possible presence of an acid protease-inhibitor was suggested.


A different kind of medical home.
Primary care physicians were supposed to lead this patient-centered model. Now specialists want in, too. Good idea?


Perceptual sequence learning in a serial reaction time task.
In the serial reaction time task (SRTT), a sequence of visuo-spatial cues instructs subjects to perform a sequence of movements which follow a repeating pattern. Though motor responses are known to support implicit sequence learning in this task, the goal of the present experiments is to determine whether observation of the sequence of cues alone can also yield evidence of implicit sequence learning. This question has been difficult to answer because in previous research, performance improvements which appeared to be due to implicit perceptual sequence learning could also be due to spontaneous increases in explicit knowledge of the sequence. The present experiments use probabilistic sequences to prevent the spontaneous development of explicit awareness. They include a training phase, during which half of the subjects observe and the other half respond, followed by a transfer phase in which everyone responds. Results show that observation alone can support sequence learning, which translates at transfer into equivalent performance as that of a group who made motor responses during training. However, perceptual learning or its expression is sensitive to changes in target colors, and its expression is impaired by concurrent explicit search. Motor-response based learning is not affected by these manipulations. Thus, observation alone can support implicit sequence learning, even of higher order probabilistic sequences. However, perceptual learning can be prevented or concealed by variations of stimuli or task demands.


Zoning of precipitation regimes on the Qinghai-Tibet Plateau and its surrounding areas responded by the vegetation distribution.
Compared with other factors influencing vegetation patterns, such as light and temperature, precipitation has relatively large variability, especially on the Qinghai-Tibet Plateau (QTP), where the natural environment is extremely fragile and sensitive. However, the impact of precipitation regimes, rather than precipitation amount, on vegetation has seldom been revealed. This study characterised the precipitation regimes by both the amount and temporal distribution of precipitation and zoned the QTP as different precipitation regimes accordingly. The response of vegetation to such precipitation regimes was then investigated. The results indicate that the vegetation patterns are quite consistent with zoning, that is, there is a certain type or a few dominant types of vegetation in each sub-region divided by the precipitation regimes. The areas where the precipitation became more uniform within a year were concentrated in grassland and bare land, which benefits the restoration and improvement of the ecological environment of the plateau. The increase in precipitation variability in the south-eastern part of the plateau may lead to natural disasters such as floods and mudslides. This study provides a novel perspective to understand the distribution of vegetation patterns.


Dimensional indicators of generalized anxiety disorder severity for DSM-V.
For DSM-V, simple dimensional measures of disorder severity will accompany diagnostic criteria. The current studies examine convergent validity and test-retest reliability of two potential dimensional indicators of worry severity for generalized anxiety disorder (GAD): percent of the day worried and number of worry domains. In study 1, archival data from diagnostic interviews from a community sample of individuals diagnosed with one or more anxiety disorders (n = 233) were used to assess correlations between percent of the day worried and number of worry domains with other measures of worry severity (clinical severity rating (CSR), age of onset, number of comorbid disorders, Penn state worry questionnaire (PSWQ)) and DSM-IV criteria (excessiveness, uncontrollability and number of physical symptoms). Both measures were significantly correlated with CSR and number of comorbid disorders, and with all three DSM-IV criteria. In study 2, test-retest reliability of percent of the day worried and number of worry domains were compared to test-retest reliability of DSM-IV diagnostic criteria in a non-clinical sample of undergraduate students (n = 97) at a large west coast university. All measures had low test-retest reliability except percent of the day worried, which had moderate test-retest reliability. Findings suggest that these two indicators capture worry severity, and percent of the day worried may be the most reliable existing indicator. These measures may be useful as dimensional measures for DSM-V.


Influence of Venezuelan equine encephalomyelitis virus on catecholamine metabolism in mouse CNS: early changes in turnover rates and content.
The influence of two strains of Venezuelan equine encephalomyelitis virus on catecholamine metabolism in the central nervous system (CNS) of the mouse was studied by the intracranial inoculation of NMRI-IVIC mice, 24 days old. Doses of 300 LD50 of the moderately virulent Pixuna strain and 10(4) LD50 of the nonvirulent TC-83 strain were used. The animals were sacrificed 4, 7, 12, and 18 days after the inoculation, and the CNS contents of dopamine, norepinephrine, and adrenaline were determined by a radioenzymatic method. The turnover of these compounds was studied with the aid of the enzymatic inhibitors pargyline and alpha-methyl tyrosine. With the Pixuna strain a decrease in the level and turnover of catecholamines was observed in all eight brain areas studied: cerebellum, pons-medulla, hypothalamus, mesencephalon, striatum, olfactory bulb-tuberculum, hippocampus, and cerebral cortex. In some regions the levels returned to normal in 12-18 days, but in the striatum, mesencephalon, hypothalamus, and olfactory bulb-tuberculum, recovery was slower and required at least 18 days after inoculation. The levels of catecholamines in the brain of mice inoculated with the nonvirulent TC-83 strain were not modified, but there was a decrease in the turnover.


Unexpected finding of a rare pathogenic germline BRCA1 variant in an intrahepatic cholangiocarcinoma using the Oncomine Focus DNA assay: clinical and diagnostic implications.
Cholangiocarcinoma (CCA) is a malignant tumor arising from the epithelial cells of the bile ducts and is the second most common liver cancer after hepatocellular carcinoma. Recently, our Institution launched a Comprehensive Genomic Profiling (CGP) program (named FPG500 program), set up to provide a complete molecular characterization through the TruSight Oncology 500 High Throughput (TSO500HT) solution and samples that do not reach pre-set sample quantity and/or quality thresholds required for TSO500HT, are addressed to Oncomine Focus DNA Assay (OFA) and the Archer's FusionPlex Lung Panel (AFL). Here we report the case of a patient with iCCA enrolled in the FPG500 program and screened by the orthogonal workflow (OFA/AFL). Although BRCA1 is not among the genes declared in the OFA panel, we unexpectedly detected a pathogenic variant in this gene (c.5278-2del, rs878853285). This case highlights the diagnostic capabilities of CGP, now widely used in both clinical practice and academic setting. The incidental involvement of BRCA1 focuses attention on the role of BRCA genes in biliary tract cancers. Finally, as an orthogonal test confirmed the germline origin of BRCA1 c.5278-2del variant, the germline implications of CGP need to be considered.


Environmental factors in the etiology of neural tube defects: a negative study.
A case-control study was made on women who had an infant with a neural tube defect and twice as many controls. Cases and controls were selected from a national medical birth registry from which prospectively collected data on previous pregnancy, contraceptive use, and smoking were also retrieved. Women's occupation was either retrieved from that registry or from census information which was partially checked with direct interview. Information on environmental characteristics of the place of living of the women in early pregnancy was given by field workers who were unaware of the status of case or control. Cases and controls showed no statistically significant difference with regard to previous pregnancies and use of contraceptives at or the month before the time of conception. Case women smoked 10 cigarettes or more a day slightly more often than control women did but the difference was not statistically significant. No statistically significant difference in occupation distribution was seen between cases and controls (but cases had slightly more occupations where chemical exposure is likely), and no differences in home environment could be found. It is concluded that the factors studied play no major etiological role for the origin of neural tube defects in Sweden.


STAT1 requirement for PKR-induced cell cycle arrest in vascular smooth muscle cells in response to heparin.
Interferons (IFNs) are a family of cytokines that exhibit antiviral, antiproliferative, and immunomodulatory properties. PKR (protein kinase, RNA activated) is of central importance in mediating the antiproliferative actions of IFNs. Our research has established that PKR inhibits vascular smooth muscle cell (VSMC) proliferation by regulating G1 to S transition. Many cardiovascular diseases result from complications of atherosclerosis, a chronic and progressive inflammatory condition often characterized by excessive proliferation of VSMC. Thus, an effective method for inhibiting VSMC proliferation is likely to arrest atherosclerosis and restenosis at early stages. Our research establishes that PKR activation in VSMC leads to a G1 arrest brought about by an inhibition of cyclin-dependent kinase 2 (Cdk2) activity by p27(kip1). In quiescent VSMC, p27(kip1) levels are high and when stimulated by serum/growth factors, p27(kip1) levels drop by destabilization of the protein. Under conditions that lead to activation of PKR, there is a marked inhibition of p27(kip1) down-regulation due to increased stability of p27(kip1) protein. In order to understand the mechanism of heparin-induced stabilization of p27(kip1) in VSMC, we examined the involvement of the Signal Transducer and Activator of Transcription-1 (STAT1), which is an important player in mediating antiproliferative effects of IFNs. Our results demonstrate that PKR overexpression in VSMC leads to an increase in p27(kip1) protein levels and this increase requires the catalytic activity of PKR. PKR activation induced by antiproliferative agent heparin leads to phosphorylation of STAT1 on serine 727, which is essential for the cell cycle block. STAT1 null VSMCs are largely defective in heparin-induced cell cycle arrest and in PKR null cells the STAT1 phosphorylation in response to heparin was absent. These results establish that heparin causes STAT1 phosphorylation on serine 727 via activation of PKR and that this event is required for the G1 arrest in VSMC.


Accuracy of outpatient endometrial biopsy in the diagnosis of endometrial cancer: a systematic quantitative review.
To determine the accuracy of outpatient endometrial biopsy in diagnosing endometrial cancer in women with abnormal uterine bleeding. A systematic quantitative review of published research. Studies were selected if accuracy of outpatient endometrial biopsy was estimated compared with a reference standard. Diagnostic accuracy was determined by pooled likelihood ratios for positive and negative test results. There were 1013 subjects in 13 diagnostic evaluations reported in 11 primary studies. A positive test result on outpatient biopsy diagnosed endometrial cancer with a pooled likelihood ratio of 66.48 (95% CI 30.04-147.13) while a negative test result had a pooled likelihood ratio of 0.14 (95% CI 0.08-0.27). The post test probability of endometrial cancer was 81.7% (95% CI 59.7%-92.9%) for a positive test and 0.9% (95% CI 0.4%-2.4%) for a negative test. Outpatient endometrial biopsy has a high overall accuracy in diagnosing endometrial cancer when an adequate specimen is obtained. A positive test result is more accurate for ruling in disease than a negative test result is for ruling it out. Therefore, in cases of abnormal uterine bleeding where symptoms persist despite negative biopsy, further evaluation will be warranted.


Optimal conditions for titration of SV40 by the plaque assay method.
The parameters of the Simian Virus 40 (SV40) plaque assay on African green monkey kidney cells were optimized for reproducibility and maximum plaquing efficiency. Plaques were visible as early as 8 days postinfection; maximum titers were obtained with a 10- to 11-day incubation period. Titers read 12-16 days postinfection were not significantly higher than those observed after 10-11 days. Adsorption volumes greater than 0.1 ml/60 mm Petri dish decreased plaque forming units (PFUs) detected. Times greater than 60 min for adsorption of virus to the cell monolayer did not significantly increase the titer; adsorption times less than 60 min resulted in decreased titers. Under standard conditions, 3 ml of overlay medium containing 0.8% agar was applied following virus adsorption and again on days 5 and 10. Concentrations of fetal calf serum (FCS) in the overlay medium of 2.5 to 7.5% gave equal plaque formation. FCS concentrations of 1 and 10% resulted in slightly decreased and increased plaquing efficiencies respectively. Of the reagents tested, agar or agarose containing overlay media produced plaques of maximum number and size. An overlay of methyl cellulose resulted in the same number of plaques, but their size was reduced by approximately 70% relative to those observed in agar; thus longer incubation times were required. Gum tragacanth overlay medium was actually inhibitory to plaque development. DEAE-dextran, dextran sulfate, or DMSO added to agar overlay medium did not enhance plaque number or size, nor did they shorten the incubation period required for their detection.


Cytotoxic effects of vincristine on tumour subpopulations separated from pulmonary nodules.
The cytotoxic and stathomokinetic effects of vincristine (VCR) on murine fibrosarcoma (FSa) cells, grown either in vitro as primary cultures or in vivo as micro- or macroscopic pulmonary nodules, were determined and compared. FSa cells were separated and synchronized on the basis of size by centrifugal elutriation. Flow microfluorometry (FMF) was used to determine the cell-cycle parameters and the relative synchrony of the separated populations, thus allowing determination of age-dependent cytotoxicity. The colony-forming efficiencies (CFE) of these cells were determined using a lung colony assay. Synchronized cell population of FSa cells, separated by centrifugal elutriation, were injected into recipient animals and exposed 20 min later to a single dose of VCR to determine their age-specific sensitivity. Under these conditions there appeared to be a suggestion of an enhanced killing of cells enriched in the G2 + M phase. However, following prolonged VCR exposure in vitro (e.g., 2.5 micrograms ml-1; 25 ml for 24 h) to primary cultures of FSa cells or in vivo (e.g., 0.25 mg kg-1 per fraction i.p.; 5 fractions in 24 h) to macroscopic pulmonary tumour nodules, elutriated FSa cell populations most enriched with G1 phase cells exhibited the lowest CFE. If under either condition exposed cells were allowed to recover in the absence of VCR for 24 h prior to their removal and separation, FSa cell survival increased in each of the elutriated populations. In contrast, while G1 enriched cell populations from in vitro exposed cultures still exhibited a significant reduction in CFE, no such age-specific response was observed for in vivo exposed macroscopic pulmonary nodules. The stathomokinetic effect of VCR on FSa cells was also readily observed in vitro using FMF analysis (e.g., an increase of from 20 to 38% in the G2 + M phase compartment). While no such effect was observed in vivo using FMF analysis, cluster of mitotic figures were observed. The mitotic indices (MI) of the in vivo exposed FSa cells increased from 2.5 to 8.4%.


Target position variability throughout prostate radiotherapy.
To quantify the variability in prostate and seminal vesicle position during a course of external beam radiotherapy, and to measure the proportion of target variability due to setup error. Forty-four weekly planning computerized tomography (CT) studies were obtained on six patients undergoing radiotherapy for prostate cancer. All patients were scanned in the radiotherapy treatment position, supine with an empty bladder, with no immobilization device. All organs were outlined on 3-mm-thick axial CT images. Anterior and lateral beam's eye view digitally reconstructed radiographs and multiplanar reformatted images were generated. The position of the prostate and seminal vesicles relative to the isocenter location as set that day was recorded for each CT study. Target position relative to a bony landmark was measured to determine the relative contribution of setup error to the target position variability. The seminal vesicle and prostate position variability was most significant in the anterior-posterior (AP) direction, followed by cranial-caudal (CC) and mediolateral (ML) directions. Setup error contributed significantly to the total target position variability. Rectal filling was associated with a trend to anterior movement of the prostate, whereas bladder filling was not associated with any trends. Although most deviations from the target position determined at the initial planning CT scan were within 10 mm, deviations as large as 15 mm and 19 mm were seen in the prostate and seminal vesicles respectively. Target position variations were evenly distributed around the initial target position for some patient studies, but unpredictable patterns were also seen. From a simulation based on the observed variability in target position, the AP, CC, and ML planning target volume (PTV) borders around the clinical target volume (CTV) required for target coverage with 95% certainty are 12.4 mm, 10.3 mm, and 5.6 mm respectively for the prostate and 13.8 mm, 8.6 mm, and 3.9 mm respectively for the seminal vesicles. Target position variability is significant during prostate radiotherapy, requiring large PTV borders around the CTV. This target position variability may be potentially reduced by improving the setup accuracy.


2'-Hydroxy-4',5'-dimethoxyacetophenone Exhibit Collagenase, Aldose Reductase Inhibition, and Anticancer Activity Against Human Leukemic Cells: An In Vitro, and In Silico Study.
Diabetes is a serious growing concern that affects many parts of the body including the skin due to high sugar levels. Moreover, diabetic patients are at risk of developing cancer and are prone to a higher risk of hematological malignancies. In the present study, the inhibitory effect of 2'-Hydroxy-4',5'-dimethoxyacetophenone was investigated on aldose reductase and collagenase enzymes, along with docking and ADMET analysis. MTT assay was also conducted to investigate the anti-leukemic effect of 2'-Hydroxy-4',5'-dimethoxyacetophenone on human acute leukemia cells (32D-FLT3-ITD, Human HL-60/vcr, MOLT-3, and TALL-104 cell lines) and DPPH assay for establishing activity against oxidative stress. The 2'-Hydroxy-4',5'-dimethoxyacetophenone showed potent inhibition of both the above tested enzymes with numerous strong interactions with the key catalytic residues in the active site of the enzymes. The MTT assay showed strong anti-cancer activity against entire tested human acute leukemia cells and was found non-toxic to normal (HUVEC) at the tested concentration. In DPPH free radical scavenging assay, 2'-Hydroxy-4',5'-dimethoxyacetophenone showed strong inhibitory activity with IC50 of 157 µg/mL, which found comparable to the standard BHT. Our study demonstrated prominent pharmacological benefit of 2'-Hydroxy-4',5'-dimethoxyacetophenone, against various leukemic cell lines, aldose reductase and collagenase enzymes, and free radical scavenging activity.


Aphidicolin inhibits growth and DNA synthesis in halophilic arachaebacteria.
Aphidicolin, a specific inhibitor of eucaryotic alpha DNA polymerase, inhibits the growth of halophilic arachaebacteria. In Halobacterium halobium, aphidicolin prevents cell division and DNA synthesis. These results suggest that arachaebacterial replicases are of the eucaryotic type.


Cord blood-derived Vδ2+ and Vδ2- T cells acquire differential cell state compositions upon in vitro expansion.
Human cord blood-derived γδ T cells (CBγδ) display a highly diverse TCRγδ repertoire and have a unique subtype composition different from fetal or adult peripheral blood counterparts. We expanded CBγδ in vitro using an irradiated Epstein-Barr virus-transformed feeder cell-based modified rapid expansion protocol (REP). Single-cell RNA sequencing tracked progressive differentiation of naïve CBγδ into cells expressing neoantigen-reactive tumor-infiltrating lymphocyte as well as tissue-resident memory precursor-like and antigen-presenting cell-like gene signatures. TCRγδ clonal tracing revealed a bias toward cytotoxic effector differentiation in a much larger proportion of Vδ2- clones compared to Vδ2+ clones, resulting in the former being more cytotoxic at the population level. These clonotype-specific differentiation dynamics were not restricted to REP and were recapitulated upon secondary nonviral antigen stimulations. Thus, our data showed intrinsic cellular differences between major subtypes of human γδ T cells already in operation at early postnatal stage and highlighted key areas of consideration in optimizing cell manufacturing processes.


Status epilepticus induces p53 sequence-specific DNA binding in mature rat brain.
Previous studies have implicated the tumor suppressor gene, p53, in neuronal apoptosis due to excitotoxin treatment. To test whether p53 protein functions as a transcription factor during excitotoxic cell death, we used electrophoretic mobility shift assays to measure p53 sequence-specific DNA-binding activity following kainic acid (KA)-induced seizures. A rapid and significant increase in p53 DNA-binding activity was observed in extracts from kainate-vulnerable brain regions at 2.5 h after seizure onset, an effect which lasted up to 16 h after seizure-onset. DNA binding activity returned to normal by 30 h after KA injection. Pre-treatment with the protein synthesis inhibitor cycloheximide, as well as pre-incubation with PAb421, a p53 monoclonal antibody, significantly attenuated p53 DNA-binding activity induced by KA treatment. These results indicate that p53 protein may function as a transcription factor, following KA treatment, to regulate the expression of p53-responsive genes involved in neuronal apoptosis.