Kolaviron suppresses dysfunctional reproductive axis associated with multi-walled carbon nanotubes exposure in male rats.
Reproductive toxicity associated with excessive exposure to multi-walled carbon nanotubes (MWCNTs), which are commonly used in medicine as valuable drug delivery systems, is well documented. Kolaviron, a bioflavonoid isolated from Garcinia kola seeds, elicits numerous health beneficial effects related to its anti-inflammatory, anti-genotoxic activities, anti-apoptotic, and antioxidant properties. However, information on the role of kolaviron in MWCNTs-induced reproductive toxicity is not available in the literature. Herein, we assessed the protective effects of kolaviron on MWCNTs-induced dysfunctional reproductive axis in rats following exposure to MWCNTs (1 mg/kg) and concurrent treatment with kolaviron (50 or 100 mg/kg body weight) for 15 successive days. Results showed that MWCNTs-induced dysfunctional reproductive axis as evidenced by deficits in pituitary and testicular hormones, marker enzymes of testicular function, and sperm functional characteristics were abrogated in rats co-administered with kolaviron. Moreover, co-administration of kolaviron-abated MWCNTs-induced inhibition of antioxidant enzyme activities increases in oxidative stress and inflammatory indices. This is evidenced by diminished levels of tumor necrosis factor-alpha, nitric oxide, lipid peroxidation, reactive oxygen, and nitrogen species as well as reduced activity of myeloperoxidase in testes, epididymis, and hypothalamus of the rats. Biochemical data on the chemoprotection of MWCNTs-induced reproductive toxicity were corroborated by histological findings. Taken together, kolaviron suppressed dysfunctional reproductive axis associated with MWCNTs exposure via abrogation of oxidative stress and inflammation in male rats.


Glucocorticoid induced insulin resistance impairs basal but not glucose entrained high-frequency insulin pulsatility in humans.
Type II (non-insulin-dependent) diabetes mellitus is characterized by abnormal insulin secretion, which involves a disrupted basal and glucose-entrained insulin pulsatility, and by insulin resistance. The aim of this study was to examine the influence of glucocorticoid-mediated insulin resistance on the regularity of high frequency insulin pulsatility. Eight healthy men (means +/- SD; age 24.4 +/- 0.5 years, BMI 23.2 +/- 0.7 kg/m2) were examined after prednisolone treatment (30 mg/day) or placebo for 6 days in a double-blind, placebo controlled, cross-over study with a 6-week washout period. Blood was collected every minute for 60 min during baseline and glucose-entrainment. Time-series were assessed by spectral and autocorrelation analyses and a first-phase insulin secretion test was carried out. Prednisolone treatment led to insulin resistance as expected (HOMA-S; prednisolone vs placebo; 1.85 +/- 0.26 vs 1.02 +/- 0.10; p < 0.01) with exaggerated first-phase insulin secretion (3016 +/- 468 pmol/l vs 1688 +/- 207 pmol/l; p < 0.01), suggesting a stable disposition index. During baseline, normalized spectral power of serum insulin concentration time-series was reduced during prednisolone exposure compared with placebo (8.40 +/- 0.95 vs 11.79 +/- 1.66; p < 0.05) indicating a disturbed high-frequency oscillatory insulin release. A similar trend was observed using autocorrelation analysis (0.23 +/- 0.04 vs 0.32 +/- 0.07; p = 0.12). During glucose entrainment no difference in normalized spectral power or in the autocorrelation coefficient between prednisolone and placebo (p > 0.1) was observed. Six days of prednisolone treatment resulted in a pertubed high-frequency insulin release in the fasting state whereas the ability of glucose to entrain insulin secretion was preserved. This indicates a mechanism of pertubed glucose-insulin feedback mechanism which causes irregular oscillatory insulin release.


A new method with variable injection parameters in contrast-enhanced CT: a phantom study for evaluating an aortic peak enhancement.
Contrast-enhanced CT employs a standard uniphasic single-injection method (SIM), wherein administration is based on two parameters: the iodine administration rate (mgI/s) and the injection duration (s). However, as the SIM uses a fixed iodine administration rate, only a uniform contrast enhancement can be achieved with this method. The iodine administration rate can be increased only by increasing the iodine dose or shortening the injection duration, and no arbitrary adjustments can be made to the peak enhancement characteristics of the time-enhancement curves (TECs) at the fixed injection parameters used in the SIM. To address this problem, we developed a variable injection method (VIM) with a new parameter, the variation factor (VF), to adjust the TECs. A phantom study with the VIM indicated that arbitrary adjustments to the iodine administration rate could be made without changing the injection duration or increasing the iodine load. In our study, VFs of 0.3 and 0.5, which showed earlier achievement of peak enhancements, showed better temporal separation between arterial vasculature and parenchyma or the venous vasculature than that obtained with the SIM. The higher peak enhancement provided by the VF of 0.3 was also considered to improve the contrast in qualitative diagnostic examinations. A VF of 0.5 increased the duration of the enhancement and was considered to produce stable enhancement of contrast in vascular investigations. The VF is now an essential parameter, and the VIM is useful as a reasonable contrast method that may contribute to both improved visualization and improvement in the accuracy of morphologic diagnosis.


Analgesia after Cesarean delivery: a retrospective comparison of intrathecal hydromorphone and morphine.
To compare analgesia and opioid-related side effects of intrathecal morphine and intrathecal hydromorphone after elective Cesarean delivery. Retrospective, comparative study. Labor and delivery unit of an academic hospital. 114 parturients age ≥ 18 years, presenting for elective Cesarean delivery. Patients who received 0.04 mg intrathecal hydromorphone were compared to a random sample of patients who received 0.1 mg intrathecal morphine for postoperative analgesia. The primary outcome was the presence of any opioid-related complication (pruritus, nausea or vomiting, respiratory depression) requiring treatment within 24 hours of intrathecal opioid administration. Secondary outcomes included total opioid consumption (in oral morphine equivalents) within 24 hours of intrathecal opioid administration and verbal pain score (0 = none, 10 = worst) at 4, 8, 12, 18, and 24 hours after intrathecal opioid administration. 38 patients who received intrathecal hydromorphone 0.04 mg were compared with 76 patients given 0.1 mg of intrathecal morphine for elective Cesarean delivery. No significant differences in demographics were noted between groups. There were no statistically significant differences between the intrathecal hydromorphone and intrathecal morphine groups in overall frequency of opioid-related complications (50% vs. 34.2%; P = 0.11), 24-hour opioid consumption (33 mg oral morphine equivalent [OME] vs. 8 mg OME; P = 0.27), or pain scores at any time point up to 24 hours. Overall, analgesia and incidence of opioid-related side effects after 0.04 mg of intrathecal hydromorphone did not differ statistically from 0.1 mg of intrathecal morphine.


Cancer palliation: economic and societal implications.
The lessons of these examples are clear. If physicians will not decide on how to decide, others will. This theme replicates that expressed in the discussion of cost. Oncologists charged with providing palliative cancer care are in a field rife with growing tensions imposed by increasing demands for therapy. If the profession does not develop a strategy for resolving the crisis, the courts and legislatures will become increasingly involved in making clinical decisions. Although this is not transparently ominous, it does mean that the contribution that clinical judgement makes to treatment selection will be minimized.


Adherence to World Cancer Research Fund/American Institute for Cancer Research recommendations and pancreatic cancer risk.
Pancreatic cancer is a leading cause of cancer death. A role of dietary factors in pancreatic carcinogenesis has been suggested. The World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) published 8 recommendations for cancer prevention. We evaluated the effect of adherence to the WCRF/AICR recommendations on pancreatic cancer risk. We operationalized 7 of the 8 WCRF/AICR recommendations to generate a WCRF/AICR score. We examined the association of WCRF/AICR score with pancreatic cancer in data from an Italian case-control study of 326 incident cases and 652 controls. Adherence to WCRF/AICR recommendations was associated with a significantly decreased risk of pancreatic cancer. Using a WCRF/AICR score <3.5 as a reference, the adjusted odds ratio (OR) for a score 3.5-<4 was 0.80 (95% CI 0.49, 1.28), for a score 4-<5 0.54 (95% CI 0.35, 0.82), and for score 5 or more 0.41 (95% CI 0.24, 0.68; p-value for trend 0.0002). The OR for a continuous increment of one unit of the WCRF/AICR score was 0.72 (95% CI 0.60, 0.87). Adherence to the WCRF/AICR recommendations may reduce pancreatic cancer risk.


Elongation and movement of the gutta-percha master cone during initial lateral condensation.
This study evaluated gutta-percha master cone elongation and apical movement during initial lateral condensation. A split natural tooth model was used. Measurements on photographs taken before and after initial spreading were made. The results showed that both elongation and total cone displacement occur.


Maximal force and tremor changes across the menstrual cycle.
Sex hormones have profound effects on the nervous system in vitro and in vivo. The present study examines the effect of the menstrual cycle on maximal isometric force (MVC) and tremor during an endurance task. Nine eumenorrheic females participated in five study visits across their menstrual cycle. In each menstrual phase, an MVC and an endurance task to failure were performed. Tremor across the endurance task was quantified as the coefficient of variation in force and was assessed in absolute time and relative percent time to task failure. MVC decreases 23% from ovulation to the mid luteal phase of the menstrual cycle. In absolute time, the mid luteal phase has the highest initial tremor, though the early follicular phase has substantially higher tremor than other phases after 150 s of task performance. In relative time, the mid luteal phase has the highest level of tremor throughout the endurance task. Both MVC and tremor during an endurance task are modified by the menstrual cycle. Performance of tasks and sports which require high force and steadiness to exhaustion may be decreased in the mid luteal phase compared to other menstrual phases.


COVID-19-related secretory otitis media in the omicron era: a case series.
Increased numbers of patients with secretory otitis media appeared in outpatient clinics after the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron pandemic; however, the relationship between SARS-CoV-2 Omicron variant infection and secretory otitis media is uncertain. We performed tympanocentesis and used reverse transcription-polymerase chain reaction (RT-PCR) testing to examine middle ear effusion (MEE) and nasopharyngeal secretions from 30 patients with secretory otitis media associated with SARS-CoV-2 infection. RT-PCR was performed using the open reading frame 1ab and nucleocapsid protein gene kit from Shanghai Berger Medical Technology Co., Ltd., as the sole assay method, in accordance with the manufacturer's instructions. MEEs from 5 of the 30 patients tested positive for SARS-CoV-2, including one patient with positive results for both the nasopharyngeal secretion and MEE. We report and discuss the medical records of six patients, including these five MEE-positive patients and a MEE-negative patient. SARS-CoV-2 RNA can be detected in MEE caused by coronavirus disease 2019-related secretory otitis media even when a patient's nasopharyngeal secretion tests PCR-negative for SARS-CoV-2. The virus can remain in the MEE for a long time after SARS-CoV-2 infection.


Early repolarization: Electrocardiographic cues to distinguish benign from malignant variants.
Historically, early repolarization (ER) has been considered a marker of good health as it is more prevalent in athletes, younger persons, and at slower heart rates. However, contemporary reports, largely based on data from resuscitated sudden cardiac arrest patients, suggest an association between ER and an increased risk for sudden cardiac death and the development of malignant ventricular arrhythmias. Therefore, after we present a brief-case presentation, we intend to review a challenging topic in recognition of malignant variants and propose a four-step comprehensive approach to simplify ECG discrimination when assessing ER changes.


Preparation, purification, and stability of high specific activity 125I-labeled thyronines.
A modified chloramine-T method is described for the preparation of several radioiodothyronines by an exchange reaction, which results in low specific activity preparations, or by an addition reaction, which yields radioiodothyronines with specific activities up to 7 mCi/microgram. Purification by paper chromatography is shown to be more convenient than by LH-20 chromatography and provides better resolution among the various thyronines. Radioiodothyronines with only a single iodine atom in the outer (3,5,3'-triiodothyronine and 3,3'-diiodothyronine) are stable for several months when stored in organic solvents. The least stable radioiodothyronines are those with two 125I atoms in the outer ring (3,3',5'-triiodothyronine (rT3) produced from 3-iodothyronine and thyroxine (T4) from 3,5-diiodothyronine). The stability of rT3 and T4 stored in human plasma at 4 C is much greater than when stored in buffer at the same pH. The use of high specific activity [125I]rT3 has permitted the development of a radioimmunoassay with a sensitivity of 1 pg rT3/ml incubation volume.


Distribution of Osteochondral Lesions in Patients With Simple Elbow Dislocations Based on MRI Analysis.
The clinical relationship between osteochondral lesions and long-term outcomes and patterns in the elbow joint has not yet been established. A sole evaluation from plain standard radiography may underestimate the severity of bony lesions in patients with simple dislocations. It has been suggested that the mechanism of a posterior elbow dislocation could be inferred from the pattern of bony contusions and osteochondral lesions visible on magnetic resonance imaging (MRI) in patients with simple elbow dislocations. The purpose of this study was to describe the incidence and distribution of osteochondral lesions based on MRI findings in patients with simple elbow dislocations. We hypothesized that (1) osteochondral lesions are consistently found in patients with simple elbow dislocations and (2) the distribution and severity of osteochondral lesions may explain the mechanism of the simple elbow dislocation. Cohort study; Level of evidence, 3. A retrospective review of 43 patients with simple elbow dislocations was performed in tertiary-level hospitals from January 2010 to August 2019. Two orthopaedic surgeons separately assessed the initial plain radiographs and MRI scans. Osteochondral lesions were evaluated and categorized based on whether they were located (1) on the lateral side (posterolateral capitellum and radial head; type 1) or (2) on the medial side (posterior trochlea and anteromedial facet of the coronoid; type 2). The severity of the osteochondral lesions was assessed according to the Anderson classification. Of the 43 patients, 21 (48.8%) presented with osteochondral lesions on MRI. The type 1 pattern of osteochondral lesions was the most frequently observed on MRI in patients with simple elbow dislocations (69.8% of cases), and these were confirmed by simple radiography. Posterolateral capitellum osteochondral lesions were found in 13 patients. Among them, 10 (76.9%) were advanced-stage lesions (stages III and IV according to the Anderson classification). Osteochondral lesions were found on MRI after simple elbow dislocations at a rate of 48.8%. Osteochondral lesions in the posterolateral capitellum were associated with an advanced stage. Clinically, these findings may help surgeons in the diagnosis of osteochondral lesions and in determining how to manage patients with the progression of arthritic changes.


Health-related quality of life in adults after repair of congenital diaphragmatic defects--a questionnaire study.
Long-term respiratory, gastrointestinal, and vertebral sequelae are common after repair of congenital diaphragmatic defects (CDDs). The aim of this study was to assess the effect of these sequelae on the health-related quality of life (HRQoL) of adult survivors after CDD repair. A questionnaire, including 36-Item Health Survey Form (SF-36), 36-item Gastrointestinal Quality of Life Index (GIQLI), 55-item Psychosocial Survey, 9-item survey for Respiratory Symptoms-Related Quality of Life Index, and a symptoms query, was sent to 94 adult survivors of CDD and to 400 healthy control subjects. One SD lower than the age-adjusted national average in the 36-Item Health Survey Form score for physical or mental health was considered as low HRQoL. Sixty-nine patients with CDD (72%) and 162 (41%) control subjects returned the questionnaire. The initial presentation was critical in less than 10% of patients with CDD. Forty-five patients with diaphragmatic hernia had primary closure; in 1 patient with diaphragmatic hernia, a patch was used. Twenty-four patients had plication of diaphragmatic eventration. The incidence of gastroesophageal reflux (20% vs 2%), recurrent intestinal obstruction (7% vs 0%), and recurrent abdominal pain (12% vs 2%) was significantly higher in patients with CDD than in control subjects, whereas no difference in the incidence of respiratory, musculoskeletal, or other health problems not associated with CDD was found. Scores in GIQLI, Psychosocial Survey, and Respiratory Symptoms-Related Quality of Life Index did not differ between patients with CDD and control subjects. Health-related quality of life was low in 17 (25%) of 69 patients with CDD, which exceeded 1.5 times the expected value. There was no correlation between the type or severity of the primary defect and HRQoL at the time of the study. Most adults with repaired CDD have good or satisfactory HRQoL. Congenital diaphragmatic defect-associated symptoms with or without acquired diseases significantly impair HRQoL in one fourth of the patients.


Poor patient knowledge regarding family history of colon polyps: implications for the feasibility of stratified screening recommendations.
In 2008, the American College of Gastroenterology (ACG) modified its colorectal screening guidelines regarding patients with family histories of colorectal polyps, specifically highlighting the importance of obtaining detailed history that includes the number, type, and size of adenomas found in a patient's relative. This information is then used to guide screening recommendations for these patients. To assess the proportion of patients undergoing screening colonscopy for a family history of polyps who have knowledge of their family members' colonoscopy findings. Retrospective, single-center cohort pilot study. Tertiary care medical center. Patients who presented for screening colonoscopy between 2008 and 2010 with an indication of family history of polyps. Obtain detailed history regarding patient's family history of polyps, including which family member, age of family member at diagnosis, size, type and number of polyps found. Knowledge of family history. Seventy-three patients were included in the study. Their knowledge of their family histories of polyps showed the following: 23.2% (17/73; 95% CI, 14%-35%) did not know which family member had polyps, 42.5% (31/73; 95% CI, 31%-55%) did not know the age at diagnosis, 71.2% (52/73; 95% CI, 59%-81%) did not know the polyp type, 90.4% (66/73; 95% CI, 81%-96%) did not know the number of polyps found, and 97.3% (71/73; 95% CI, 90%-100%) did not know the polyp size. Retrospective study at a single tertiary referral center. Patients' knowledge regarding the details of their family histories of polyp data appears often unknown or incomplete. Thus, at present, it may not appear feasible or practical to incorporate this level of information in colon cancer screening guidelines.


The role of the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PIGF) - ratio in clinical practice in obstetrics: diagnostic and prognostic value.
Analyze the diagnostic and prognostic value of the sFlt-1/PlGF ratio in pregnant women with at least one sign/symptom of suspected/diagnosed pre-eclampsia. This retrospective observational study included 170 pregnant women with at least one sign/symptom of pre-eclampsia, who had sFlt-1/PlGF ratio values. The following information was evaluated: pregnant women's demographic data and clinical history; laboratory data (urine protein/creatinine ratio; sFlt-1/PlGF ratio); signs and symptoms presented; clinical outcome; fetal complications; data related to childbirth. Statistical analysis was performed by R Software Version 3.5.2. Among the 170 patients, 78 presented pre-eclampsia. The median sFlt-1/PlGF ratio was significantly higher [143.1 (2.2-2,927.1)] for women who presented pre-eclampsia than for women without pre-eclampsia [33.5 (0.8-400.2)]. The negative predictive value of sFlt-1/PlGF ratio <38 was 83.9 % (95 % CI, 71.7-92.4 %) and the positive predictive value of sFlt-1/PlGF ratio >85 or 110 (for late onset pre-eclampsia) was 76.4 % (95 % CI, 66.2-84.8 %). sFlt-1/PlGF >85 or 110 was associated with pre-eclampsia clinical development, fetal complications, shorter gestational age at birth, higher number of caesarean deliveries and lower birth weight. The sFlt-1/PlGF ratio, together with the standard diagnostic criteria, can be used to rule out pre-eclampsia, identify high-risk patients and predict the occurrence of adverse outcomes.


Primary squamous cell carcinoma with sarcomatoid differentiation of the kidney associated with ureteral stone obstruction: A case report.
Primary squamous cell carcinoma (SCC) with sarcomatoid differentiation of the kidney was rarely reported. This disease is usually related to renal stones, and due to a lack of symptoms and radiological features, patients usually attend the hospital with late stage disease. A 54-years-old female presented with left flank pain and an abdominal mass for 6 mo. Imaging studies revealed that the left kidney was enlarged and massive hydronephrosis was present. A stone was seen in the ureteropelvic junction. The patient subsequently underwent left radical nephrectomy, and histopathological examination of the mass revealed a poorly differentiated renal SCC with sarcomatoid differentiation. After primary surgery, the patient received four cycles of tirelizumab. Four months later, the patient developed adrenal, lymph, and uterine appendage metastases. SCC of the kidney has a poor prognosis, and should be considered in patients with a renal mass, long-standing urinary calculi and massive hydronephrosis.


Salivary cortisol and cortisone by LC-MS/MS: validation, reference intervals and diagnostic accuracy in Cushing's syndrome.
The Endocrine Society recommends late-night salivary cortisol (LNS-F) as a first-line screening test for Cushing's syndrome (CS). In the parotid gland, 11β-hydroxysteroid dehydrogenase type 2 inactivates cortisol (F) to cortisone (E), a known source of interference in the more frequently used immunoassays. A highly specific method is mandatory in determining salivary F and E: it is widely accepted that liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the best available technique for this purpose. A LC-MS/MS method with SPE of saliva samples was developed and validated. Appropriate awakening and bedtime reference ranges were established. The diagnostic performance for F, E and the ratio at bedtime was evaluated in 25 cases of CS. The method was linear, with up to 55.4 nmol/L and 51.0 nmol/L, LLOQ of 0.51 nmol/L and 0.55 nmol/L, for F and E, respectively. Within-run and between-run imprecisions were <10% for both analytes. No ion suppression was observed. A cut-off of 2.4 nmol/L for LNS-F yielded a sensitivity of 100% and a specificity of 98% in the diagnosis of CS. The analytical performance of this method justifies its introduction into clinical practice, thus allowing clinicians the opportunity to further investigate CS and other endocrine diseases.


Surface glycoproteins of cultured human keratinocytes from normal and uninvolved psoriatic epidermis.
Surface glycoproteins of cultured human keratinocytes from normal skin and uninvolved psoriatic epidermis, isolated by the suction blister method, were studied by two different methods. Cells were cultured on collagen-coated culture dishes and showed a fibrillar keratin-specific staining by immunofluorescence. Surface labelling experiments using the neuraminidase/galactose oxidase/sodium borohydride method (which labels the penultimate galactose moieties of glycoproteins) revealed one major glycoprotein with Mr 53 kD (kilodaltons) both in normal keratinocytes and in keratinocytes from uninvolved psoriatic skin. The periodate/sodium borohydride method (which labels the terminal sialic acids in glycoproteins) by contrast revealed three major glycoproteins, with Mr 53 kD to 63 kD, in normal keratinocytes but only a single major glycoprotein, with Mr 53 kD, in keratinocytes from uninvolved psoriatic skin. Treatment of cultured keratinocytes with etretinate appeared to restore the normal pattern of surface glycoproteins in uninvolved psoriatic keratinocytes.


Proximity-dependent protein detection based on enzyme-assisted fluorescence signal amplification.
In this paper, we develop a sensitive fluorescence method for protein detection based on proximity extension and enzyme-assisted signal amplification. In this novel method, pairs of proximity probes are designed, and the recognition elements are integrated into the proximity probes. Then proteins are detected by transforming aptamer or antibody-protein binding signals into DNA detection based on proximity effect. In addition, nick sites are introduced into the proximity probes to amplify the detectable signal. As proof of concept, detection of human α-thrombin and human IgG are demonstrated in this study. The aptamers and antibodies are coupled in the proximity probes as recognition elements for human α-thrombin and human IgG respectively. In the presence of target protein, aptamer or antibody-protein binding signals are transformed into detectable signals by the proximity effect, and can be further amplified by enzyme-assisted strand displacement. The above mentioned strategies consequently bring the limit of detection (LOD) to as low as 1 pM for human α-thrombin and 6 pM for human IgG. Furthermore, this method might be extended to sensitive detection of other proteins by changing recognition elements of proximity probes.


PRMT5 promotes chemotherapy-induced neuroendocrine differentiation in NSCLC.
In response to therapeutic treatments, cancer cells can exhibit a variety of resistance phenotypes including neuroendocrine differentiation (NED). NED is a process by which cancer cells can transdifferentiate into neuroendocrine-like cells in response to treatments, and is now widely accepted as a key mechanism of acquired therapy resistance. Recent clinical evidence has suggested that non-small cell lung cancer (NSCLC) can also transform into small cell lung cancer (SCLC) in patients treated with EGFR inhibitors. However, whether chemotherapy induces NED to confer therapy resistance in NSCLC remains unknown. We evaluated whether NSCLC cells can undergo NED in response to chemotherapeutic agents etoposide and cisplatin. By Knock-down of PRMT5 or pharmacological inhibition of PRMT5 to identify its role in the NED process. We observed that both etoposide and cisplatin can induce NED in multiple NSCLC cell lines. Mechanistically, we identified protein arginine methyltransferase 5 (PRMT5) as a critical mediator of chemotherapy-induced NED. Significantly, the knock-down of PRMT5 or pharmacological inhibition of PRMT5 suppressed the induction of NED and increased the sensitivity to chemotherapy. Taken together, our results suggest that targeting PRMT5 may be explored as a chemosensitization approach by inhibiting chemotherapy-induced NED.


Association between perceived public stigma and suicidal behaviors among college students of color in the U.S.
Suicide is the 2nd leading cause of death among college students and 10 to 34-year-olds in the U.S. While rates of suicide among young people of color have increased, less is known about factors that contribute to suicidality among racial minority students who are sorely underrepresented within existing research. Thus, we sought to explore the association between perceived public stigma of receiving mental health treatment and suicidality among Black, Asian Domestic, Asian International, Latinx, Multiracial, Arab/Arab American, American Indian/Alaska Native, and White college students. We analyzed cross-sectional survey responses from racially diverse sample of 153, 635 college students who participated in the Healthy Minds Study from years 2007-2018. Multivariable logistic regression was used to examine associations between perceived public stigma and suicide ideation, suicide planning, and suicide attempt. Perceived public stigma was significantly associated with greater odds of suicide ideation, planning, and attempt. Odds of having attempted suicide within the past year were significantly greater among Asian International and Black college students. Sexual minority students broadly, and bisexual students specifically, were also at elevated risk for suicidal behavior. Cross-sectional survey responses were assessed and causality cannot be determined. Students who endorsed more perceived public stigma also reported significantly greater odds of having experienced suicide ideation, planning, and attempt within the past 12 months. Subsequent interventions should account for concerns surrounding public perceptions of stigma when working to prevent suicide among students of color.


Preconception tests at advanced maternal age.
Pregnancies at an advanced reproductive age are increasingly common. However, the safety of pregnancy remains a concern as maternal age is a recognized independent factor for various obstetric complications. Also, age is a risk factor for most systematic health problems and older women are more likely to enter into pregnancy with pre-existing conditions. At the moment there is no separate, structured guidance on preconception tests at advanced maternal age. However, the preconceptual period offers an ideal window to recognize and address underlying health issues, social issues and harmful lifestyle behaviours in order to optimize maternal health ultimately reducing infertility, perinatal morbidity and mortality. Preconception tests should be clinically relevant aiming to identify risk factors and address them to predict and prevent infertility and pregnancy complications. The importance of preconception care is magnified for women of advanced age for whom the risks are higher and the potential benefits greater.


Unintended consequences: Disrupting microbial communities of Nilaparvata lugens with non-target pesticides.
Insects are frequently exposed to a range of insecticides that can alter the structure of the commensal microbiome. However, the effects of exposure to non-target pesticides (including non-target insecticides and fungicides) on insect pest microbiomes are still unclear. In the present study, we exposed Nilaparvata lugens to three target insecticides (nitenpyram, pymetrozine, and avermectin), a non-target insecticide (chlorantraniliprole), and two fungicides (propiconazole and tebuconazole), and observed changes in the microbiome's structure and function. Our results showed that both non-target insecticide and fungicides can disrupt the microbiome's structure. Specifically, symbiotic bacteria of N. lugens were more sensitive to non-target insecticide compared to target insecticide, while the symbiotic fungi were more sensitive to fungicides. We also found that the microbiome in the field strain was more stable under pesticides exposure than the laboratory strain (a susceptible strain), and core microbial species g_Pseudomonas, s_Acinetobacter soli, g_Lactobacillus, s_Metarhizium minus, and s_Penicillium citrinum were significantly affected by specifically pesticides. Furthermore, the functions of symbiotic bacteria in nutrient synthesis were predicted to be significantly reduced by non-target insecticide. Our findings contribute to a better understanding of the impact of non-target pesticides on insect microbial communities and highlight the need for scientific and rational use of pesticides.


Hospitalizations among HIV controllers and persons with medically controlled HIV in the U.S. Military HIV Natural History Study.
HIV controllers (HICs) experience relatively low-level viraemia and CD4 preservation without antiretroviral therapy (ART), but also immune activation that may predispose to adverse clinical events such as cardiovascular disease and hospitalization. The objective of this study was to characterize the rates and reasons for hospitalization among HICs and persons with medically controlled HIV. Subjects with consistently well-controlled HIV were identified in the U.S. Military HIV Natural History Study. ART prescription and HIV-1 RNA data were used to categorize subjects as HICs or medically controlled as defined by ≥ 3 HIV-1 RNA measurements ≤ 2000 or ≤ 400 copies/mL, respectively, representing the majority of measurements spanning ≥ 12 months. Hospitalizations were tallied and assigned diagnostic categories. All-cause hospitalization rates were compared between groups using negative binomial regression. Of 3106 subjects followed from 2000 to 2013, 221 were HICs, including 33 elite (1.1%) and 188 viraemic (6.0%) controllers, who contributed 882 person-years (PY) of observation time. An additional 870 subjects with medically controlled HIV contributed 4217 PY. Mean hospitalization rates were 9.4/100 PY among HICs and 8.8/100 PY among medically controlled subjects. Non-AIDS-defining infections were the most common reason for hospitalization (2.95/100 PY and 2.70/100 PY, respectively) and rates of cardiovascular hospitalization were similar in both groups (0.45/100 PY and 0.76/100 PY). There was no difference in hospitalization rate for HICs compared with subjects with medically controlled HIV (adjusted incidence rate ratio 1.15 [95% confidence interval 0.80 to 1.65]). All-cause and cardiovascular hospitalization rates did not differ between HICs and persons with medically controlled HIV. Non-AIDS defining infections were common in this young, healthy, predominantly male cohort of military personnel and beneficiaries.


Safety evaluation of curative gastrectomy for gastric cancer patients who underwent liver transplantation: a comparative study with conventional gastrectomy for gastric cancer patients.
We aimed to examine the technical and oncological safety of curative gastrectomy for gastric cancer patients who underwent liver transplantation. In this study, we compared the surgical and oncological outcomes of two groups. The first group consisted of 32 consecutive patients who underwent curative gastrectomy for gastric cancer after liver transplantation (LT), while the other group consisted of 127 patients who underwent conventional gastrectomy (CG). In addition, a subgroup analysis was performed to evaluate the impact of the background differences and the surgical outcomes on the involvement of a specialized liver transplant surgery team. The mean operative time was significantly longer in the LT group (p < 0.05). Furthermore, there were more frequent cases of postoperative transfusion in the LT group compared to the CG group (p < 0.05). However, there were no significant differences in the overall complications between the groups (25.00 vs 23.62%, p = 0.874). The 5-year overall survival rates of the LT and CG groups were 76.7% and 90.1%, respectively (p < 0.05). The results of the subgroup analysis demonstrated no statistically significant difference in various early surgical outcomes, such as time to transfusion during surgery, first flatus, time to first soft diet, postoperative complications, hospital stay after surgery, and the number of harvested lymph nodes except for operation time. Despite one's medical history of undergoing LT, our study demonstrated that curative gastrectomy could be a surgically safe treatment for gastric cancer. However, further study should be conducted to identify the reason gastric cancer patients who underwent liver transplant surgery have lower overall survival rate.


Nano-enabled agrochemicals/materials: Potential human health impact, risk assessment, management strategies and future prospects.
Nanotechnology is a rapidly developing technology that will have a significant impact on product development in the next few years. The technology is already being employed in cutting-edge cosmetic and healthcare products. Nanotechnology and nanoparticles have a strong potential for product and process innovation in the food industrial sector. This is already being demonstrated by food product availability made using nanotechnology. Nanotechnologies will have an impact on food security, packaging materials, delivery systems, bioavailability, and new disease detection materials in the food production chain, contributing to the UN Millennium Development Goals targets. Food products using nanoparticles are already gaining traction into the market, with an emphasis on online sales. This means that pre- and post-marketing regulatory frameworks and risk assessments must meet certain standards. There are potential advantages of nanotechnologies for agriculture, consumers and the food industry at large as they are with other new and growing technologies. However, little is understood about the safety implications of applying nanotechnologies to agriculture and incorporating nanoparticles into food. As a result, policymakers and scientists must move quickly, as regulatory systems appear to require change, and scientists should contribute to these adaptations. Their combined efforts should make it easier to reduce health and environmental impacts while also promoting the economic growth of nanotechnologies in the food supply chain. This review highlighted the benefits of a number of nano enabled agrochemicals/materials, the potential health impacts as well as the risk assessment and risk management for nanoparticles in the agriculture and food production chain.


Biographical disruption or cohesion?: How parents deal with their child's autism diagnosis.
Currently, we are witnessing a precipitous rise in autism diagnoses among children, and several bodies of sociological research are attempting to explain this development. However, the experiences within parental contexts have been inadequately examined; that is, how parents feel about and act upon the awareness of their child's autism diagnosis. Drawing upon a qualitative study among Danish parents of 20 children recently diagnosed with autism, this paper contributes with situated insights into parents' experiences. We identify a spectrum of feelings towards the autism diagnosis, including both relief and grief. In the absence of theoretical notions drawing attention to how a child's diagnosis influences parents' self-conceptions and understandings of their child, we develop the concept of 'parent-biographical disruption': the parents' rethinking of themselves and their child that might be caused by a chronic condition such as autism. Based on the variety of findings, we discuss what we call 'parent-biographical cohesion' as a counterpart to 'disruption'. By 'cohesion' we refer to the diagnostic awareness potentially creating clarification for parents about the past, present and future parenting of their child instead of disrupting their self-understandings as parents. In this way, through the notion of a parental-biographical spectrum of disruption and cohesion, we emphasize the diversity in how parents deal with a child's autism diagnosis and the variety of needs for rethinking parental biographies in the wake of a diagnosis.


Influences of marital conflict on child adjustment: review of theory and research.
This review summarizes the literature on the relationship between marital conflict and child maladjustment with an emphasis on variables that qualify, explain the association, or both. Following a historical review, the modest findings on the strength of the association between marital conflict and child maladjustment is explored. The definition of marital conflict is clarified through specification of its various dimensions (frequency, intensity, content, resolution). The role of variables that serve to moderate and/or mediate the relationship between marital conflict and child maladjustment are elaborated. Mediating models include exposure theories (Modeling, Cognitive-Contextual effects: appraisal of threat and blame, and Emotional Insecurity) and changes in the parent-child relationship (Spillover). Variables that moderate or qualify the relationship include children's cognitions and behaviors, contextual factors, and demographic differences. A model is presented summarizing these mechanisms. Research recommendations are proposed and the clinical implications of this literature are addressed.


Zinc binding to the NH2-terminal domain of the Wilson disease copper-transporting ATPase: implications for in vivo metal ion-mediated regulation of ATPase activity.
Mutations in the Wilson disease copper transporting, P-type ATPase lead to the accumulation of toxic levels of copper in the liver, brain, and kidney causing extensive tissue damage and eventual death. The NH(2)-terminal domain ( approximately 70 kDa), which contains six copies of the heavy metal-associated repeat GMT/HCXXC, is also able to bind zinc. We have used circular dichroism (CD) and x-ray absorption spectroscopy (XAS) to characterize zinc binding to the NH(2)-terminal metal-binding domain. These studies have revealed that zinc is able to bind to this domain with a stoichiometry of 6:1, and upon binding, induces conformational changes in the NH(2)-terminal domain. These conformational changes are completely different from those previously observed for copper binding to the domain and lead to an overall loss of secondary structure in the domain. The XAS spectra indicate that zinc is ligated primarily by nitrogen atoms and therefore has low affinity for the heavy metal-associated repeats where copper has been shown to bind. The differences between zinc and copper binding may serve as the basis for the metal-ion mediated regulation of the ATPase in vivo.


Deleted in colorectal carcinoma and differentially expressed integrins mediate the directional migration of neural precursors in the rostral migratory stream.
Precursors of the olfactory interneurons migrate from the subventricular zone via the rostral migratory stream (RMS). To investigate the molecular mechanisms by which RMS cells migrate, we used a slice preparation, which allows the migrating cells to be imaged at very high temporal and spatial resolution in the presence of added inhibitors. Using immunohistochemistry, we first determined that the alpha1-, beta8-, and beta1-integrin subunits and the alpha5- and gamma1-laminin subunits are expressed during embryonic day 16 to the early postnatal stage. During early postnatal days, alpha(v)- and beta6-integrins appeared, and their expression persisted throughout adulthood. The migrating cells also expressed the netrin receptors neogenin and Deleted in Colorectal Carcinoma (DCC). Netrin-1 is expressed in olfactory mitral cells. Anti-integrin antibodies inhibited the production of protrusions as well as cellular translocation. In contrast, anti-DCC antibodies primarily altered the direction of the protrusions; consequently, the migration was no longer unidirectional, and the speed was reduced. Thus, the interaction of DCC, possibly through an interaction with netrin-1, contributes to the direction of migration by regulating the formation of directed protrusions. In contrast, the integrins function in production of protrusions and cellular translocation, with different integrins participating at different developmental stages.


Vulnerability to chosen-cyphertext attacks of optical encryption schemes based on double random phase keys.
We show how optical encryption methods based on double random phase keys are vulnerable to an organized attack of the chosen-ciphertext type. The decryption key can be easily obtained by an opponent who has repeated access to either the encryption or decryption machines. However, we have also devised a solution that prevents the attack. Our results cast doubts on the present security of these techniques.


Enzymatic characterization of a maltogenic amylase from Lactobacillus gasseri ATCC 33323 expressed in Escherichia coli.
A gene corresponding to a maltogenic amylase (MAase) in Lactobacillus gasseri ATCC 33323 (lgma) was cloned and expressed in Escherichia coli. The recombinant LGMA was efficiently purified 24.3-fold by one-step Ni-NTA affinity chromatography. The final yield and specific activity of the purified recombinant LGMA were 68% and 58.7 U/mg, respectively. The purified enzyme exhibited optimal activity for beta-CD hydrolysis at 55 degrees C and pH 5. The relative hydrolytic activities of LGMA to beta-CD, soluble starch or pullulan was 8:1:1.9. The activity of LGMA was strongly inhibited by most metal ions, especially Zn(2+), Fe(2+), Co(2+) and by EDTA. LGMA possessed some unusual properties distinguishable from typical MAases, such as being in a tetrameric form, having hydrolyzing activity towards the alpha-(1,6)-glycosidic linkage and being inhibited by acarbose.


Muscle K+, Na+, and Cl disturbances and Na+-K+ pump inactivation: implications for fatigue.
Membrane excitability is a critical regulatory step in skeletal muscle contraction and is modulated by local ionic concentrations, conductances, ion transporter activities, temperature, and humoral factors. Intense fatiguing contractions induce cellular K(+) efflux and Na(+) and Cl(-) influx, causing pronounced perturbations in extracellular (interstitial) and intracellular K(+) and Na(+) concentrations. Muscle interstitial K(+) concentration may increase 1- to 2-fold to 11-13 mM and intracellular K(+) concentration fall by 1.3- to 1.7-fold; interstitial Na(+) concentration may decline by 10 mM and intracellular Na(+) concentration rise by 1.5- to 2.0-fold. Muscle Cl(-) concentration changes reported with muscle contractions are less consistent, with reports of both unchanged and increased intracellular Cl(-) concentrations, depending on contraction type and the muscles studied. When considered together, these ionic changes depolarize sarcolemmal and t-tubular membranes to depress tetanic force and are thus likely to contribute to fatigue. Interestingly, less severe local ionic changes can also augment subtetanic force, suggesting that they may potentiate muscle contractility early in exercise. Increased Na(+)-K(+)-ATPase activity during exercise stabilizes Na(+) and K(+) concentration gradients and membrane excitability and thus protects against fatigue. However, during intense contraction some Na(+)-K(+) pumps are inactivated and together with further ionic disturbances, likely precipitate muscle fatigue.


Some considerations on the ion transport properties of the rod disc membrane.
The ion transport properties of the disc membranes in rod outer segments are discussed on the basis of available data. The properties of an air-water interface film of spectroscopically intact and chemically regenerable rhodopsin are presented, and results of studies of ion binding to these films are reported.


Reversible derivatization to enhance enzymatic synthesis: chemoenzymatic synthesis of doxorubicin-14-O-esters.
An efficient three-step, chemoenzymatic synthesis of unprotected doxorubicin-14-O-esters from doxorubicin hydrochloride salt is described. The key step is a lipase-catalyzed regioselective transesterification/esterification using commercially available acyl donors and doxorubicin reversibly derivatized with N-alloc to improve substrate loadings. The overall yield is ca. 60% and chromatographic purification is not required, thereby making the process more amenable to scale-up.


First-order Wiener kernel visually evoked potentials obtained from multiple sclerosis patients.
Visually evoked potentials (VEP) were measured in multiple sclerosis patients with five sizes of reversing check stimuli. The VEPs were obtained using random binary sequence triggered check reversals. The random binary sequence was cross-correlated with scalp potential responses to obtain the estimates of the linear response of the system. For each evaluation a series of five VEPs, one for each of five check sizes, was done. A correlation coefficient was calculated to evaluate check size versus amplitude of the major negative wave. A tabulation was made to compare Snellen chart visual acuity with these correlation coefficients. For the eyes with a Snellen acuity of 20/20, 63% of the VEP amplitudes increased as the check size was decreased with correlation coefficients of -0.6 to -1. For the eyes with a Snellen acuity of 20/70 or less the amplitude decreased with the check size decrease, showing a correlation coefficient of +0.6 to +1 in 45% of the evaluations. The check size giving the largest amplitude was also tabulated with respect to the visual acuity, but did not appear to have as strong a relationship to visual acuity.


Complement activation by antibodies to DNA in systemic lupus erythematosus measured by enzyme immunoassay.
An enzyme immunoassay to detect complement-fixing antibodies to DNA (CF-antiDNA) was developed. Of SLE sera, 64% had these antibodies as did 6% of 50 rheumatoid arthritis and 3.2% of 93 normal human sera. The mean CF-antiDNA level was higher in the sera of SLE patients with renal disease than those SLE patients who had no renal disease (P less than 0.0001), and higher in those SLE patients with active rather than inactive renal disease (P = 0.006). CF-antiDNA was more closely associated with renal activity than total IgG-antiDNA or CH50. These observations suggest that both the quality and quantity of anti-DNA antibodies play a role in the pathogenesis of renal disease, and that modern enzyme immunoassays help distinguish the relative importance of complement-fixing antibodies to anti-DNA from that of total anti-DNA.


Endothelial injury, an intriguing effect of methotrexate and cyclophosphamide during hematopoietic stem cell transplantation in mice.
Elevated circulating endothelial cells (EC) in peripheral blood are an important indicator of endothelial damage and graft-versus-host disease (GVHD). However, the injured endothelial vasculature may in turn promote GVHD. In this study, we investigated whether methotrexate or cyclophosphamide, two conventional chemotherapeutic agents used in hematopoietic stem cell transplantation, caused endothelial injury and what were the functional consequences of this injury on GVHD. Six to 8-week-old female mice were randomly separated into three groups, including methotrexate (15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11), cyclophosphamide (60 mg/kg; days 1, 2), and PBS saline alone (control). Circulating EC (CD31+CD133(-)CD45low) and the CD4+/CD8+ T lymphocytes in the peripheral blood were estimated by flow cytometry on days 1, 3, 5, 7, 9, 11, 16, 21, and 26. The morphologic changes of the endothelium were examined by phase contrast light microscopy to determine the integrity of the endothelial vasculature. Elevated EC were detected at day 1 or 3 in mice receiving cyclophosphamide or methotrexate, respectively, with a peak increase at day 5 or day 3, respectively. The ratio of CD4+/CD8+ T lymphocytes showed a delayed increase in the peak to day 11 for both groups. In the cyclophosphamide group, there was significant apomorphosis with necrosis/thrombosis under light microscopy, whereas only apomorphosis was noticed in the methotrexate group. In both groups, EC showed hydropsia and cytomembrane damage. Circulating EC increase during the early phases of cyclophosphamide or methotrexate conditioning, suggesting that both chemotherapeutic drugs induce endothelial damage, which occurs a little earlier than suppression of the immune system.


From staff nurse to nurse consultant - Clinical leadership part 12: series summary.
John Fowler, independent education consultant, summarises his series which has explored the importance of leadership for clinically based nurses.


The lipoxygenase pathway of Tupaia belangeri representing Scandentia. Genomic multiplicity and functional characterization of the ALOX15 orthologs in the tree shrew.
The tree shrew (Tupaia belangeri) is a rat-sized mammal, which is more closely related to humans than mice and rats. However, the use of tree shrew to explore the patho-mechanisms of human inflammatory disorders has been limited since nothing is known about eicosanoid metabolism in this mammalian species. Eicosanoids are important lipid mediators exhibiting pro- and anti-inflammatory activities, which are biosynthesized via lipoxygenase and cyclooxygenase pathways. When we searched the tree shrew genome for the presence of cyclooxygenase and lipoxygenase isoforms we found copies of functional COX1, COX2 and LOX genes. Interestingly, we identified four copies of ALOX15 genes, which encode for four structurally distinct ALOX15 orthologs (tupALOX15a-d). To explore the catalytic properties of these enzymes we expressed tupALOX15a and tupALOX15c as catalytically active proteins and characterized their enzymatic properties. As predicted by the Evolutionary Hypothesis of ALOX15 specificity we found that the two enzymes converted arachidonic acid predominantly to 12S-HETE and they also exhibited membrane oxygenase activities. However, their reaction kinetic properties (KM for arachidonic acid and oxygen, T- and pH-dependence) and their substrate specificities were remarkably different. In contrast to mice and humans, tree shrew ALOX15 isoforms are highly expressed in the brain suggesting a role of these enzymes in cerebral function. The genomic multiplicity and the tissue expression patterns of tree shrew ALOX15 isoforms need to be considered when the results of in vivo inflammation studies obtained in this animal are translated into the human situation.


Real-time isothermal detection of Abalone herpes-like virus and red-spotted grouper nervous necrosis virus using recombinase polymerase amplification.
Abalone herpes-like virus (AbHV) and Red-spotted grouper nervous necrosis virus (RGNNV) are two serious viruses that infect animal populations in aquaculture. Both viruses cause diseases associated with high mortality rates, resulting in dramatic economic losses in the aquaculture industry. There are currently no effective treatments for either of these two viral diseases. Thus, early, rapid, and accurate diagnosis plays a fundamental role in disease prevention and control in aquaculture. Traditional methods of diagnosis, such as virus culture, enzyme-linked immunoassay, and polymerase chain reaction (PCR), are either time consuming or require sophisticated temperature control devices. In this study, one sets of specific primers and probes were designed for the real-time quantitative recombinase polymerase amplification (qRPA) detection of AbHV and RGNNV separately. The sensitivity and specificity of detection were evaluated by comparison with detection by conventional PCR and quantitative PCR. The optimal reaction temperature and time for virus detection is 37°C for 20min. The detection limit is 100 copies per reaction, making this approach faster and more sensitive than qPCR in this study. In a field application, the detection percentage of qRPA was higher than that of qPCR for both AbHV and NNV. Additionally, good correlation was found between qRPA and qPCR detection (R2>0.8). The methods presented here can be used as alternatives to qPCR for quick and quantitative detection of pathogens infecting aquaculture species.


Correlation of mutagenic and dermal carcinogenic activities of mineral oils with polycyclic aromatic compound content.
Mutagenicity, polynuclear aromatic compound content, and skin carcinogenicity were compared for a series of complex oil mixtures derived from the refining and processing of petroleum. Mutagenicity in a modified Ames Salmonella assay showed an excellent correlation with carcinogenicity, as determined in a mouse skin-painting bioassay, for oil samples with median boiling points (defined as the temperature at which 50%/volume of an oil sample is recovered as condensate during distillation--50% recovered) above approximately 500 degrees F. A significant correlation was also observed between the 3-7 ring polycyclic aromatic compound (PAC) content and both mutagenic and carcinogenic potencies for samples ranging from those with median (50% recovered) boiling points above approximately 500 degrees F to those with initial boiling points of approximately 1070 degrees F. These results show that both PAC content and mutagenicity are predictive of dermal carcinogenic activity and indicate that PAC components are largely if not entirely responsible for both the carcinogenic and mutagenic activities.


Acute effects of moderate-intensity cycling exercise on endothelial function in young healthy men: An investigation using the reactive hyperemia index.
Endothelial cells play an important role in the prevention of cardiovascular disease. In this study, we examined the effects of transient aerobic exercise on peripheral endothelial function. Twenty-seven healthy male college students were selected as subjects and randomly divided into two groups: 13 in the control group and 14 in the exercise group. The subjects in the exercise group had a 15-minute supine rest, followed by 30 minutes of cycling exercise at moderate intensity, while measuring the reactive hyperemia index (RHI), an indicator of endothelial function, before and after exercise. The subjects in the control group had a 40-minute rest, during which RHI was measured with the same timing as in the exercise group. Two-factor analysis of variance revealed a statistically significant interaction effect. In the exercise group, RHI increased significantly after exercise. However, no significant change was observed in the control group. When RHI before exercise was compared between the two groups, no significant difference was found. However, RHI after exercise was significantly higher in the exercise group. The results of this study suggest that 30 minutes of moderate-intensity exercise may have a favorable impact on peripheral endothelial function.


Enzymatic formation of inosine 3',5'-monophosphate and of 2'-deoxyguanosine 3',5'-monophosphate. Inosinate and deoxyguanylate cyclase activity.
Enzymes in particulate fractions from sea urchin sperm and in soluble fractions from rat lung were shown to catalyze the formation of inosine 3',5'-monophosphate (cyclic IMP) and of 2'-deoxyguanosine 3',5'-monophosphate (cyclic dGMP) from ITP and dGTP, respectively. With sea urchin sperm particulate fractions, Mn2+ was an essential metal cofactor for inosinate, deoxyguanylate, guanylate and adenylate cyclase activities. Heat-inactivation studies differentiated inosinate and deoxyguanylate cyclase activities from adenylate cyclase, but indicated an association of these activities with guanylate cyclase. Preincubation of sea urchin sperm particulate fractions with trypsin altered in a very similar manner guanylate, inosinate, and deoxyguanylate cyclase activities, and various metals and metal-nucleotide combinations protected the three cyclase activities to comparable degrees against trypsin. The relative guanylate, deoxyguanylate and inosinate cyclase activities at 0.1 mM nucleoside triphosphate were 1.0, 0.5 and 0.08, respectively. With these three cyclase activities, plots of reciprocal velocities against reciprocal Mn2+-nucleoside triphosphate concentrations were concave upward, suggesting positive homotropic effects. With rat lung soluble preparations, relative guanylate, deoxyguanylate, inosinate and adenylate cyclase activities at 0.09 mM nucleoside triphosphate were 1.0, 1.7, 0.1 and 0, respectively. MnGTP was a competitive inhibitor of deoxyguanylate cyclase activity (Ki equals 12.2 muM) and MndGTP was a competitive inhibitor of guanylate cyclase activity (Ki equals 16.2 muM). Inhibition studies using ITP were not conducted. When soluble fractions from rat lung were applied to Bio-Gel A 1.5 m columns, elution profiles of guanylate, deoxyguanylate and inosinate cyclase activities were similar. These results suggest that deoxyguanylate, guanylate and inosinate cyclase activities reside within the same protein molecule.


Temperature alternation by an on-chip microheater to reveal enzymatic activity of beta-galactosidase at high temperatures.
A method to measure enzymatic activity at high temperatures by rapid temperature alternation of a microreactor with a microheater is proposed. On-chip microreactor and microheater were integrated on a glass plate by MEMS technology; this microheater can control the temperature of the microreactor with a response speed of 34.2 and 31.5 K/s for temperature rise and fall, respectively, with an accuracy of 3 degrees C. The enzyme, beta-galactosidase, was revealed to survive short exposure (4-s pulses) to temperatures above that which would "normally" denature them. Its activity at 60 degrees C was revealed to be approximately 4 times greater than that at room temperature. This method not only gives new kinetic information in biochemistry but also enables application in highly sensitive biosensors.


Risk factors analysis for clinical symptoms of prenatally diagnosed choledochal cysts: a retrospective study.
This study aimed to screen the impact factors for clinical symptoms of prenatally diagnosed choledochal cysts (CDCs), to warn about the occurrence of clinical symptoms and the timing of surgery. Medical records of patients with prenatally diagnosed CDCs admitted to our hospital from April 2013 to April 2018 were retrospectively reviewed. Fetal hilar or abdominal cysts were found by prenatal ultrasonogram. All patients underwent laparoscopic cyst excision and hepaticojejunostomy in our center. Univariate analysis and multivariate logistic regression analysis were performed to screen the factors related to clinical symptoms intimately. Two hundred eighteen cases were included. One hundred thirty-four patients (134/218, 61.5%) presented clinical symptoms before surgery. The results of univariate analysis showed that patients with clinical symptoms had earlier time of prenatal diagnosis (P = 0.002), higher values of GGT, TBIL, DBIL (P < 0.001, P < 0.001, P < 0.001, respectively) and larger maximum diameter of cyst before surgery (P = 0.012). Multivariate logistic regression analysis suggested that the time of prenatal diagnosis (P = 0.001, OR = 0.898, 95% CI: 0.845 ~ 0.955) and the GGT value within one week of life (P = 0.028, OR = 1.002, 95% CI: 1.000 ~ 1.003) were independent influencing factors for symptoms. For children with prenatally diagnosed CDCs, approximately 2/3 patients presented noticeable clinical symptoms before surgery. The time of prenatal diagnosis and the GGT value within 1 week of life were independent impact factors for the occurrence of clinical symptoms.


Bidirectional modulatory effect of 17β-estradiol on NMDA receptors via ERα and ERβ in the dentate gyrus of juvenile male rats.
The neurosteroid 17β-estradiol (E2) is synthesized by aromatase in both male and female hippocampi and is known to modulate hippocampal synaptic functions. However, as some contradictory findings regarding the modulatory effects of E2 have been reported in the literature, its physiological role and mechanism of action in the hippocampus remain controversial. Our recent study showed that a low E2 dose (1 nM) increased the amplitude of NMDA receptor-mediated EPSCs (NMDAR-EPSCs) and lowered the threshold for the induction of NMDA receptor-dependent long-term potentiation (NMDAR-LTP), while a high E2 dose (7 nM) exerted opposite effects in the dentate gyrus of juvenile male rat hippocampal slices. The present study is a follow-up that explores the underlying mechanism of this bidirectional effect of E2. We found that the ERα agonist PPT reproduced the actions of the low E2 dose on NMDAR-EPSCs and NMDAR-LTP, while the ERβ agonist DPN reproduced the actions of the high E2 dose. Moreover, PPT, but not DPN, restored the decrease in NMDAR-EPSCs induced by the aromatase inhibitor letrozole, suggesting that E2 synthesized constitutively in the hippocampus enhances NMDA receptor function via ERα. The PPT-induced enhancement in NMDAR-EPSCs was mediated by Src family kinase, but was not caused by NR2B modulation. These findings demonstrate that E2 exerts condition-dependent bidirectional effects on NMDA receptor-mediated transmission and, thus, synaptic plasticity via ERα and ERβ in the dentate gyrus of juvenile male rats.


Selection of myocardial electrogram features for use by implantable devices.
Implantable devices that terminate ventricular tachycardia must be capable of correctly classifying heart rhythms to a high degree of reliability. We evaluated the relative discriminating power of several myocardial electrogram (ME) features in six human subjects by reducing the order of their corresponding feature spaces using three different optimization methods: 1) minimizing univariate Bayes error rates (univariate parametric), 2) maximizing the Kullback divergence (multivariate parametric), and 3) pruning classification trees (nonparametric). We found that although the composition of the optimal subspaces varied considerably from one subject to another, one frequency domain feature was common to most of the optimal subspaces.


Mapping of the linkage group GLO--Bf--HLA-B,C,A--PGM3. 2. Segregation analysis.
Segregation analysis of informative families for chromosome 6 markers confirmed the map order GLO--Bf--HLA-(B, C)--HLA-A, and, surprisingly, implies that PGM3 is more probably located on the HLA-A than on the HLA-B side of the linkage group. Therefore the map position of PGM3 should be reconsidered, i.e., more informative families should be tested for all the relevant marker loci available.


Longitudinal Sex-Specific Physical Function Trends by Age, Race/Ethnicity, and Weight Status.
There is a need to assess longitudinal trends in physical function and to understand the prevalence of physical function status in the older population using objectively measured physical function. Therefore, the primary purpose of this study was to examine longitudinal sex-specific physical function trends and prevalence of physical function status by age, race/ethnicity, and weight status in older adults, aged 65 years and older. The present study used longitudinal data from the National Health and Aging Trends Study. Physical function was measured annually from 2011 to 2018 using the Short Physical Performance Battery, and classified as poor (0-6), fair (7-9), or good (10-12). Mixed effect regression and generalized estimating equation models were used to estimate unadjusted trends and annual changes in physical function, adjusting for confounders and accounting for complex sampling. Respondents' physical function declined over time regardless of sex, age, race/ethnicity, and weight status (P < .001). Respondents aged 75 to 84 years (males: β = -.18; 95% confidence interval (CI) = -.22 to -.13; females: β = -.23; 95% CI = -.27 to -.20) and 85 years and older (males: β = -.39; 95% CI = -.47 to -.30; females: β = -.33; 95% CI = -.39 to -.28) had a greater annual physical function rate of decline than respondents aged 65 to 74 years. Respondents aged 75 years and older also had a greater annual increase in the proportion classified as having poor physical function than respondents aged 65 to 74 years (P < .001), regardless of sex. Compared with non-Hispanic whites, Hispanic females had a lower annual physical function rate of decline (β = .14; 95% CI = 0.07-0.20), and Hispanic and/or non-Hispanic blacks had slower annual changes in the proportion classified as having good physical function (P < .05). Compared with normal weight males, overweight males had lower annual changes in physical function (P = .003) and proportion of those with poor physical function (P = .004), but no differences between weight status were observed in females. Physical function declines with age, but temporal changes in physical function and physical function status varied by sex, age, race/ethnicity, and weight status. J Am Geriatr Soc 68:2270-2278, 2020.


Bilateral adrenal neuroblastoma in the infant: Is it an image-defined risk factor?
The treatment of neuroblastoma is based on the International Neuroblastoma Risk Group stratification considering life-threatening symptoms, image-defined risk factors (IDRFs), presence and site of metastases, biology, and histopathology. The authors present an infant with bilateral nonmetastatic adrenal neuroblastoma with favorable biology. Both tumors were resectable and without IDRFs, but bilateral resection was considered mutilating, so it was decided to operate one side only. The authors suggest considering bilaterality among IDRFs.


A preliminary study of uterine scar tissue following cesarean section.
To compare smooth muscle cells, type I collagen, and apoptosis of the lower uterine segment of women who had/without a prior cesarean delivery. Alpha smooth muscle actin (α-SMA), type I collagen, and nuclear apoptosis were compared between the groups from lower uterine segment. Twenty-eight controls and 82 with one prior cesarean delivery were included. The women with a prior cesarean section were classified by time since the surgery: ≤3 years, >3 and ≤5 years, >5 and ≤7 years, >7 and ≤9 years, and >9 years. Smooth muscle volume density (VD) % was significantly lower in women who had cesarean sections in first three groups than in the controls (all, P<0.01). Type I collagen VD% was similar among all groups and the controls. The number of apoptotic nuclei in the lower uterine segment of the scarred group was greater up to 3 years after surgery and less than in the control at 7-9 years. The number of non-apoptotic nuclei in the scarred group was greater than controls up to 7 years after surgery. The lower uterine segment scar becomes stable at 3 years after cesarean delivery, and by 9 years, the scar is mature.


Age-related changes in binding to excitatory amino acid uptake site in temporal cortex of human brain.
The binding of D-[3H]aspartate to the specific uptake site for the excitatory amino acids glutamate and aspartate was measured in homogenates of temporal lobe cortex taken at postmortem from 76 human infant and adult brains. Binding levels were very low in brains of preterm and term infants but increased rapidly during the first 20 postnatal weeks to reach levels which exceeded those in adult brains. Linear regression analysis which compared the amount of D-[3H]aspartate binding with the age of the infant, showed a positive correlation up to 25 postnatal weeks. Saturation analysis showed that the maximum number of D-[3H]aspartate binding sites (Bmax) in temporal cortex from infants aged 20 postnatal weeks was 3 times greater than the number of sites in adult brain. The findings show that the number of excitatory amino acid uptake sites, which may be associated in part with presynaptic terminals, increase in number rapidly after birth. Furthermore, the data may indicate that a slow regression of excitatory amino acid terminals occurs during the later stages of brain development.


Investigation of dissolved organic matter's influence on the toxicity of cadmium to the cyanobacterium Microcystis aeruginosa by biochemical and molecular assays.
Rapid economic development has increased the accumulation of dissolved organic matter (DOM) and heavy metals in aquatic environments. In addition, Microcystis aeruginosa can cause the outbreak of cyanobacteria bloom and can produce microcystin, which poses a threat to human water safety. Therefore, this study analyzed the biochemical and molecular assays of DOM (0, 1, 3, 5, 8, 10 mg C L-1) extracted from four different sources on the toxicity of cadmium (Cd) to M. aeruginosa. The results showed that the addition of different concentrations of DOM from sediment, biochar, and humic acid alleviated the toxicity of Cd to M. aeruginosa. But the addition of rice hulls DOM at high concentrations (8 and 10 mg L-1) significantly reduced the normal growth and metabolic activities of M. aeruginosa. DOM from four different sources promoted the expression level of microcystin-related gene mcyA and the production of microcystin-leucine-arginine (MC-LR), and mcyA was positively correlated with MC-LR. DOM from biochar, sediment, and humic acid were able to bind Cd through complexation. The results will help to understand the toxic effects of heavy metals on toxic-producing cyanobacteria in the presence of DOM, and provide certain reference for the evaluation of water environmental health.


Citation classics in critical care medicine.
The number of citations an article receives after its publication reflects its impact on the scientific community. Our purpose was to identify and examine the characteristics of the most frequently cited articles in the field of critical care medicine. The 74 top-cited articles in critical care journals were identified by a computer search using the database of the Science Citation Index Expanded (SCI-EXPANDED, 1945 to present) and the Web of SCIENCE. The 45 top-cited critical care articles in all other biomedical journals were identified using the database SciSearch (1974 to present) with the key word "Critical Care". The most cited articles received 3402 and 2860 citations, respectively. The citation classics in critical care journals were published between 1968 and 1999 in six high-impact journals, led by Critical Care Medicine (37 articles), followed by the Journal of Trauma (21), and American Journal of Respiratory and Critical Care Medicine (9). Seventy articles were original publications, two were reviews or guidelines, and two were editorials. The top 45 classic articles in non-critical care journals were published in 13 different journals, led by the New England Journal of Medicine (11 articles), followed by JAMA and Lancet (6 articles each). The United States of America contributed most of the classic articles. Pathophysiology of the lung, sepsis and scoring systems were the primary focus of classic publications. Our analysis gives a historical perspective on the scientific progress of critical care medicine and allows for recognition of important advances in this specialty.


Inconsistent response of soil bacterial and fungal communities in aggregates to litter decomposition during short-term incubation.
Soil aggregate-size classes and microbial communities within the aggregates are important factors regulating the soil organic carbon (SOC) turnover. However, the response of soil bacterial and fungal communities in aggregates to litter decomposition in different aggregate-size classes is poorly understand. Soil samples from un-grazed natural grassland were separated into four dry aggregate classes of different sizes (2-4 mm, 1-2 mm, 0.25-1 mm and <0.25 mm). Two types of plant litter (leaf and stem) of Leymus chinensis were added to each of the four aggregate class samples. The CO2 release rate, SOC storage and soil microbial communities were measured at the end of the 56-day incubation. The results showed that the 1-2 mm aggregate had the highest bacterial Shannon and CO2 release in CK and leaf addition treatments, and the SOC in the <0.25 mm aggregate was higher than that in the others across the treatments. The relative abundance of Ascomycota was higher in the 2-4 mm and <0.25 mm aggregates than in the 1-2 mm and 0.25-1 mm aggregates in the treatment without litter addition, and the relative abundance of Aphelidiomycota was lower in the 2-4 mm and <0.25 mm aggregates than in the 1-2 mm and 0.25-1 mm aggregates. Also, litter addition increased the relative abundance of Proteobacteria and Bacteroidetes, but decreased the relative abundance of Acidobacteria, Gemmatimonadetes, and Actinobacteria. The relative abundance of Ascomycota and Aphelidiomycota increased by more than 10% following leaf litter addition. The bacterial Shannon index had a significantly positive and direct effect on SOC concentration and CO2 release, while the fungal Shannon index was significantly correlated with SOC concentration. Our results indicate that the soil bacterial diversity contributes positively to both carbon emissions and carbon storage, whereas soil fungal diversity can promote carbon storage and decrease carbon emissions.


Compartments in the striatum of the cat observed by retrograde cell labeling.
The distribution of neurons giving rise to striatal efferent projections has been studied in the cat by the aid of Mesulam's histochemical methods following large injections of horseradish peroxidase into the pallidum and substantia nigra. The findings suggest that neurons of medium size form a major fraction of the efferent neurons of the striatum and that these neurons are grouped into geometrically complex, three-dimensional networks.


Differential blockade of estrogen-induced uterine responses by the antiestrogen nafoxidine.
We have used an experimental design described by Gardner et al. [6] for dissociating early and late uterine responses to estradiol, involving pretreatment of immature rats with 5 micrograms nafoxidine (Upjohn U-11, 100 A, UA) for 24 h, before administrating estradiol. In these conditions the authors showed that responses occurring 4-h after estradiol administration were not blocked, while 24-h responses were abolished. These findings were defined and extended in the present investigation which shows that: (1) The overall wet weight response of the uterus to estradiol in UA-pretreated animals is decreased when compared to saline pretreated rats. (2) The early increase in cGMP content induced at 2-4 h by estrogen is also decreased but not abolished by the pretreatment with UA, contrary to the late increase in cGMP, which is abolished. (3) The late estrogen-induced proliferative response, measured by the [3H]thymidine labeling index, in the myometrium, stroma and luminal epithelium is maintained after pretreatment with UA. It is remarkable that this occurs in the absence of any estrogen induced uterine hypertrophy as measured by the 24-h increase in uterine weight and RNA or protein content. These results strongly support the hypothesis proposed by Gardner et al. [6] that different control mechanisms might regulate early and late uterine responses to estrogen. Our data suggest the existence of the following dissociable groups of response: (1) Wet weight increase and early increase in cGMP content, (2) Late hypertrophy and second rise in cGMP content and (3) Proliferative response; which are respectively, moderately depressed, abolished or unaffected by UA pretreatment.


Effects of central and peripheral administration of an acute-phase protein, α-1-acid-glycoprotein, on feed intake and rectal temperature in sheep.
In rodents, an acute-phase protein, α-1-acid-glycoprotein (AGP), was shown to provide a link between inflammation and suppression of feed intake by acting as a leptin receptor agonist. The objective of this study was to determine the effects of AGP on feed intake and rectal temperature in sheep. Ewes were ovariectomized, implanted with a cannula into a lateral ventricle of the brain, and kept indoors in individual pens. Feed intake and rectal temperature were determined for sheep in all experiments. In the first experiment, ewes (n = 4) received 1 of 4 treatments [0 (control), 0.012 (low), 0.06 (medium), or 0.30 (high) mg/kg BW AGP] into the lateral ventricle (ICV). All sheep received all treatments in a Latin square design balanced for carryover effects with 10 d between treatments. In the second experiment, ewes (n = 10) received 1 of 2 treatments (0 and 3 mg/kg BW of AGP) intravenously (IV) in a completely randomized design. In the third experiment, ewes (n = 19) received peripheral treatments (IV) of an antipyretic [0 (control) or 2.2 mg/kg BW flunixin meglumine (FLU)] 30 min before receiving central AGP [0 (control) or 0.3 mg/kg BW of AGP] in a completely randomized design. All data were analyzed using a mixed model analysis of variance and tested for effects of treatment, time, and the interaction of treatment and time. Cumulative 48-h feed intake after administration of treatments was also determined. In the first experiment, there was no effect of ICV treatment (P = 0.37) on feed intake rate or on cumulative feed intake (P = 0.31). There was an effect of ICV treatment (P = 0.002) on rectal temperatures, which were greater (P < 0.05) after the high dose of centrally administered AGP. In the second experiment, there was no effect of AGP administration IV on feed intake rate (P = 0.98), on cumulative feed intake (P = 0.41) or on rectal temperature (P = 0.71). In the third experiment, there was an effect of central AGP treatment (P < 0.0001) and an interaction of central AGP and time (P < 0.0001) on rectal temperature, whereas FLU had no effect (P = 0.93), demonstrating that AGP increased rectal temperatures regardless of antipyretic treatment. These results indicate that central AGP increases rectal temperature in sheep by pathways that do not involve prostaglandins. Further research is needed to determine whether AGP may be an important integrator of energy balance and inflammation.


The minus end in sight.
Microtubules are intrinsically polar structures. A consequence of this polarity is that the two ends of the microtubule polymer exhibit different properties. The more dynamic plus ends and the mechanisms that regulate their behavior have been the focus of much recent attention. Here, we concentrate on the dynamics and regulation of minus ends, which play distinct but equally critical roles in microtubule function. In the first part of this review, we compare the in vitro and in vivo behavior of microtubules from a minus end perspective. This comparison suggests that cells possess conserved mechanisms to specifically inhibit minus end polymerization, and perhaps also to actively promote depolymerization. In the second part, we focus on the spatial positioning of minus ends, which is achieved by localized microtubule nucleation, minus end capping and minus end anchoring as well as by motor-dependent sorting. These mechanisms are used in different biological contexts to generate the diversity of organized microtubule arrays in cells.


Avoidance of social threat: Evidence from eye movements during a public speaking challenge using 360°- video.
Social anxiety (SA) is thought to be maintained in part by avoidance of social threat, which exacerbates fear of negative evaluation. Yet, relatively little research has been conducted to evaluate the connection between social anxiety and attentional processes in realistic contexts. The current pilot study examined patterns of attention (eye movements) in a commonly feared social context - public speaking. Participants (N = 84) with a range of social anxiety symptoms gave an impromptu five-minute speech in an immersive 360°-video environment, while wearing a virtual reality headset equipped with eye-tracking hardware. We found evidence for the expected interaction between fear of public speaking and social threat (uninterested vs. interested audience members). Consistent with prediction, participants with greater fear of public speaking looked fewer times at uninterested members of the audience (high social threat) compared to interested members of the audience (low social threat) b = 0.418, p = 0.046, 95% CI [0.008, 0.829]. Analyses of attentional indices over the course of the speech revealed that the interaction between fear of public speaking and gaze on audience members was only significant in the first three-minutes. Our results provide support for theoretical models implicating avoidance of social threat as a maintaining factor in social anxiety. Future research is needed to test whether guided attentional training targeting in vivo attentional avoidance may improve clinical outcomes for those presenting with social anxiety.


Central action of new derivatives of tetrahydropirimidinedione-4,6.
The central action and LD50 of 11 new 2,5-substituted derivates of tetrahydropirimidinedione-4,6 with an aryl group at C2 were investigated. The most favorable action was exerted by 2-furfurylamine derivatives with an alkil or benzyl group at C5. These compounds acted in doses of 0.0025--0.01 of their LD50 synergistically with chloral hydrate and strongly with hexobarbital, delayed convulsions induced with pentetrazole and potentiated the central action of DOPA in mice pargyline-inhibited MAO activity. They did not antagonize electrogenic convulsions, amphetamine potentiated motility and the action of reserpine, and had no analgetic action. Their LD50s were 670-- 1660 mg/kg.


No time to fear: new nurse assists patients following Joplin tornado. Interview by Sandy Painter.
A new nurse is interviewed after working with patients following the May 22, 2011 Joplin, Missouri, Tornado.


Notulae seminologicae. 1. New combinations of Kartagener's syndrome.
In this note new consequences of the Kartagener's syndrome are described. In males the syndrome involved a diffused sperm immaturity; in one female severe skeletal defects were present probably resulting from bad organization of the renal apparatus.


Antidepressant action of imipramine and iprindole in mice is enhanced by inhibitors of enkephalin-degrading peptidases.
The implication that opioid peptides are involved in the action of the antidepressants imipramine and iprindole was investigated in mice by using the forced swimming test as an experimental model of depression. Both the drugs were found to shorten the immobility time in this test. This effect of imipramine and iprindole was reversed by the opiate antagonist naloxone. Moreover, when subeffective doses of either imipramine or iprindole were given together with an intracerebroventricular injection of an inhibitor of their degradation (thiorphan or bestatin), the immobility time was again decreased. Interestingly, the reduction of the time of immobility was found to be not related to the effect of the drugs on locomotor activity. These data might be taken as further evidence for the involvement of opioid peptides in the pharmacological action of antidepressant drugs.


L-asparaginase fatal toxic encephalopathy during consolidation treatment in an adult with acute lymphoblastic leukemia.
Male, 51 FINAL DIAGNOSIS: Encephalopaty toxic Symptoms: Confusion • disorientation • drowsiness • fever L-asparaginase Clinical Procedure: - Specialty: Oncology. Unknown ethiology. Novel therapies have improved survival in malignancies of lymphoid origin. This improvement, however, has been at the cost of chemotherapy-related toxicities. L-asparaginase is frequently included in combination chemotherapies for acute lymphoblastic leukemia. Its use is frequently limited by significant adverse effects, such as coagulation abnormalities and cerebrovascular complications. L-asparaginase-associated encephalopathy is most often observed during the induction phase of chemotherapy and usually carries a favorable prognosis. We describe the profile of an adult with acute lymphoblastic leukemia treated with L-asparaginase, who developed toxic leukoencephalopathy during the second phase of consolidation treatment. He presented with decreased level of consciousness, which progressed to deep coma and finally brain death. MRI disclosed extensive lesions, consistent with toxic encephalopathy. Even mild neurological symptoms should raise suspicion of these possibly fatal chemotherapy related toxicities.


Reliability of the acid phosphatase test for the identification of seminal fluid.
Data from 100 cases of alleged rape victims demonstrate why the author believes the AP test to be a reliable tool, when employed by an expert for the identification of seminal fluid.


Protein requirement of young adult Nigerian females on habitual Nigerian diet at the usual level of energy intake.
A short-term N balance study was conducted in twelve healthy female adults aged 21-32 years to determine their protein requirement. Four dietary protein levels (0.3, 0.4, 0.5 and 0.6 g protein/kg per d) were used. Energy intake of the subjects was kept constant at 0.18 MJ/kg per d. All subjects maintained their normal activity throughout the study period. N excretion was determined from the measurements of N in a total collection of urine, faeces, sweat and menstrual fluid for each dietary period. N balance during the four protein levels were -15.15 (SD 5.95), -5.53 (SD 6.71), +6.15 (SD 4.76) and +12.05 (SD 8.63) mg N/kg per d for 0.3, 0.4, 0.5 and 0.6 g protein/kg per d respectively. The calculated average N requirements from regression analysis was 76.0 (SD 3.37) mg N/kg per d (0.48 g protein/kg per d). The estimate of allowance for individual variation to cover the 97.5% population was 95 mg N/kg per d (0.6 g protein/kg per d). The net protein utilization (NPU) of the diet was 0.55. When compared with a similar study with men, there was a significant difference in the protein requirement between sexes. Thus, the unjustifiable sex difference in the protein allowance recommended by the Food and Agriculture Organization/World Health Organization/United Nations University (1985) Expert Consultation group must be reviewed.


The Peptidome of Behçet's Disease-Associated HLA-B*51:01 Includes Two Subpeptidomes Differentially Shaped by Endoplasmic Reticulum Aminopeptidase 1.
To characterize the peptidome of the Behçet's disease-associated HLA-B*51:01 allotype as well as the differential features of major peptide subsets and their distinct endoplasmic reticulum aminopeptidase 1 (ERAP-1)-mediated processing. The endogenous B*51:01-bound peptidome was characterized from 721.221 transfectant cells, after affinity chromatography and acid extraction, by tandem mass spectrometry. Recombinant ERAP-1 variants were used to digest synthetic B*51:01 ligands. HLA and transporter associated with antigen processing (TAP) binding affinities of peptide ligands were calculated with well-established algorithms. ERAP-1 and ERAP-2 from 721.221 cells were characterized by genomic sequencing and Western blotting. The B*51:01 peptidome consisted of 29.5% octamers, 61.7% nonamers, 4.8% decamers, and 4.0% longer peptides. The major peptide motif consisted of Pro and Ala at position 2, aliphatic/aromatic position 3 residues, and Val and Ile at the C-terminal position. The ligands with Pro or Ala at position 2 constituted 2 distinct subpeptidomes. Peptides with Pro at position 2 showed higher affinity for B*51:01 and lower affinity for TAP than those with Ala at position 2. Most important, both peptide subsets differed drastically in the susceptibility of their position 1 residues to ERAP-1, revealing a distinct influence of this enzyme on both subpeptidomes, which may alter their balance, affecting the global affinity of B*51:01-peptide complexes. ERAP-1 has a significant influence on the B*51:01 peptidome and its affinity. This influence is based on very distinct effects on the 2 subpeptidomes, whereby only peptides in the subpeptidome with Ala at position 2 are extensively destroyed, except when their position 1 residues are ERAP-1 resistant. This pattern provides a mechanism for the epistatic association of ERAP-1 and B*51:01 in Behçet's disease.


Closed head injury-related information processing deficits: an event-related potential analysis.
Event-related potentials (ERPs) can elucidate aspects of sensory and cognitive processing that have been compromised due to closed head injury. We present the results of two investigations, one previously unreported, in which we used ERPs to evaluate information processing in head-injury survivors. In the first study, we used visual and auditory reaction time tasks differing in attentional demands to assess processing after head trauma. We found numerous changes in auditory processing in survivors: longer reaction times (but normal accuracy), longer N200 and P300 latencies, and reduced N100 and N200 amplitudes. In contrast, on visual tasks, only reduced N200 amplitude distinguished survivors and controls. To increase attentional demands, in a second study, we administered the continuous performance test (CPT). Survivors performed with lower accuracy than controls on visual and auditory tasks, and their ERPs were characterized by smaller visual and auditory N200s and P300s and smaller auditory N100s. We also present a synthesis, derived from a review of the literature, of closed head-injury effects on ERPs. Our own findings are in agreement with that synthesis. Namely, cognitive ERP components are more sensitive than sensory components to the effects of trauma. Specifically, in survivors, the amplitudes of N200 and P300 are often reduced, and their latencies prolonged. In general, as compared with visual ERPs, auditory ERPs may be more susceptible to the effects of closed head injury, suggesting that the auditory processing system is more vulnerable than the visual system. We conclude by discussing the potential use of ERPs to monitor clinical course and recovery in survivors of closed head injury.


Comparison of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1 gene expression profile in lymphocytes from mice, rats, and humans: most potent induction in humans.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exerts its toxicity by binding a transcription factor, the aryl hydrocarbon receptor (AhR). C57BL/6 (C57) mice express AhRs that have high affinity for TCDD, and they strongly express target genes and develop severe toxic effects upon TCDD exposure. By contrast, DBA/2 (DBA) mice have a low-affinity form of AhR, weakly express target genes, and are resistant to TCDD. Although humans express low-affinity AhRs and have been assumed to be refractory to TCDD, their sensitivity to TCDD has yet to be determined. In this study we compared the TCDD-induced CYP1A1 gene expression profiles in lymphocytes from humans, C57 mice, DBA mice, and SD rats to obtain data as a basis for estimating human sensitivity to TCDD. Lymphocyte fractions prepared from the blood of individual humans and animals were cultured with TCDD. Their mRNAs for CYP1A1 and housekeeping genes were measured by RT-PCR or real-time PCR with primers designed for regions that are 100% homologous among each of the genes of all species/strains tested to obtain similar PCR efficiency. TCDD-induced CYP1A1 expression peaked at 2h in DBA mice and SD rats and at 6h in C57 mice and humans. At the peak times human lymphocytes showed the most potent CYP1A1 mRNA induction of the four species/strains tested. These results suggest that human lymphocytes are more sensitive to TCDD than the lymphocytes of mice and rats. Since the AhR-dependent gene expression did not reflect the AhR affinity for TCDD, these results also suggest that AhR-dependent gene expression in lymphocytes is modulated by an as yet unidentified mechanism in addition to the AhR affinity.


Thalidomide for the therapy of graft-versus-host disease following allogeneic bone marrow transplantation.
The immunosuppressive effects of the sedative drug thalidomide have been utilised in a variety of immune disorders. In the present study, 6 patients were treated who developed graft-versus-host disease (GvHD) following allogeneic bone marrow transplantation (BMT) with thalidomide and in a dose range of 200-600 mg daily. Two of 3 patients with chronic GvHD showed clear improvement, whereas none of the 3 patients with acute GvHD derived unequivocal benefit. Although based on a small number of patients, these data suggest that thalidomide may find a useful place in the therapy of GvHD, perhaps specifically in the chronic form of this disorder.


Risk factors for impaired health-related quality of life in a cohort of pediatric patients with inborn metabolic diseases.
In the last decade, health-related quality of life (HrQoL) has become an increasingly important outcome parameter in children and adolescents with chronic health conditions; among them are pediatric patients with inborn metabolic diseases (IMDs). Hence, knowledge on this topic is increasing, but findings on non-medical influences on the HrQoL of IMD patients are still scarce. In the present study, we retrospectively evaluated the self-reported generic HrQoL of a cohort of pediatric patients (ages 7 to 17 years) with diverse IMDs (n = 204) and explored associations between HrQoL and psychosocial and medical characteristics of the patients. We aimed to identify risk factors for impaired HrQoL to improve and tailor support for the patients and economize resources. Generic HrQoL was assessed with the KINDL-R questionnaire. We compared the HrQoL scores to published German normative data and analyzed the impact of demographic variables and intellectual and psychosocial functioning on the HrQoL. Moreover, we examined the influence of the diagnostic category and the health impairment (as judged by the physicians) on our patients' HrQoL. Overall, the HrQoL of the adolescent patients was comparable to the HrQoL of the norm group. Disorders of intellectual development, impaired psychosocial functioning, and a severe health impairment were associated with lower HrQoL scores.Conclusion: We recommend evaluating these factors in children and adolescents with IMDs to identify patients at risk for impaired HrQoL. What is Known: • Studies on HrQoL in pediatric patients with IMDs mainly focused on subgroups with specific diagnoses and found normal HrQoL in some of those subgroups. • In healthy children and adolescents as well as in pediatric patients with various chronic diseases, associations between psychosocial factors and HrQoL are well known. What is New: • Impaired psychosocial functioning, disorders of intellectual development, and a significant disease and/or treatment burden are risk factors for impaired HrQoL in pediatric patients with IMDs. • Evaluating these factors in children and adolescents with IMDs can help identify patients and families in need of enhanced psychological support.