Novel Telephone-Based Interactive Voice Response System for Incident Reporting.
The voluntary reporting of medical errors and near misses is a well-established patient safety reporting mechanism. However, studies suggest that these incident reporting systems (IRSs) detect less than 10% of all adverse events. Improving the process of reporting can facilitate more informative and timely data capture while providing more opportunities to improve health care quality and safety. The purpose of this study was to understand the barriers to incident reporting via the existing Web-based IRS and develop solutions to increase the ease and efficiency of reporting. A survey of staff in a diagnostic imaging department in St. Catharines, Ontario was performed to identify barriers to incident reporting. Based on the barriers identified, two methods of incident reporting were tested in successive phases: (1) a phone-based voice message mailbox, in the computed tomography suite; and (2) a phone-based structured interactive voice response system (IVRS), across the entire department. We measured the rate of incident reports/day and time required to complete reports. The three most common barriers to reporting identified were lack of time, complexity of reporting system, and lack of feedback. There was a significant difference in reports per day for the IVRS (mean [M] = 3.43, standard deviation [SD] = 2.71) compared to the IRS (M = 0.99, SD = 0.55); t(31) = 4.58, p ≤ 0.00001. There was also a significant difference in the average time to make a report for the IVRS (M = 97 seconds [s], SD = 30 s) compared to the IRS (M = 644 s, SD = 90 s); t(4) =13.55, p = 0.00025. IVRS is an innovative approach to incident reporting that may prove to be more efficient than Web-based approaches and encourage higher reporting rates.


Four-fraction ultra-accelerated minimal breast irradiation in early breast cancer: The initial feasibility results of an institutional experience.
To evaluate the feasibility, early toxicity, and clinical outcomes of early-breast cancer patients in a single-arm, phase I/II study of an ultra-accelerated, four-fraction schedule of minimal breast irradiation (4f-AMBI) using a multicatheter, minimally-invasive, intraoperative tumor bed implant (MITBI) during breast-conserving surgery (BCS). Eligible women aged >40 years with clinically and radiologically confirmed, unifocal invasive or in situ ≤3 cm tumors were considered as potential candidates for MITBI during BCS. After the pathology report, patients who met APBI criteria received ultra-accelerated four-fractions irradiation (6.2 Gy BID x 4fx over 2 days) with perioperative HDR-brachytherapy (PHDRBT). Early complications, toxicity, clinical outcomes, and cosmetic results were analyzed. Of 89 patients initially implanted, 60(67.4%) were definitively included in the 4f-AMBI-protocol. The median age was 64.4 years; the median CTV was 32.1 cc (6.9-75.4 cc), and the external-V100 was 43.1 cc (12.87-107 cc), representing 5% of the breast tissue irradiated with a median CTV D90 of 6.2 Gy (5.6-6.28 Gy). The entire local treatment (BCS&MITBI-4f-AMBI) was completed at a median of 8 days (4-10 days). The rate of early complications was 11%. There were no major complications. Acute skin-subcutaneous G1 toxicity was reported in 11.7%, and late G1 toxicity on 36.7%. After a median follow-up of 27 months (11-51 months), the local, elsewhere, locoregional and distant-control rates were 100%, 98.3%, 100%, and 100% respectively. The early-cosmetic evaluation was excellent-good in 94.5% of patients evaluated. Ultra-accelerated, four-fraction, minimal breast irradiation (4f-AMBI) using a minimally-invasive tumor bed implant procedure is safe, dosimetrically feasible, and shows small irradiated volumes. This program provides low toxicity rates and excellent short-term clinical and cosmesis outcomes.


New normal: two aspects of adipose tissue in COVID-19-treat and threat?
Adipose-derived stromal cells (ADSCs) can be an important alternative in COVID-19 prevention, treatment, and subsequent sequelae repair. However, ACE-2 plays a common role in the pathogenesis of adipocyte hypertrophy and COVID 19. In this 'Perspective,' the author would like to emphasize the use of adipose tissue-derived stromal cells in COVID 19 and the issues that clinicians should pay attention to in fat graft applications in terms of adipose tissue-RAS relationship. The new normal for adipose tissue in COVID 19 will be highlighted. ADSCs may potentially be used in COVID-19. However, it has been speculated that ACE2 receptors are responsible for the pathogenesis of adipose tissue overgrowth and may be a potential danger in terms of the relationship between ACE2 receptors and COVID19. We speculate that reducing the size of overgrown fat tissue by ultra-sharp blades and using near-normal adipocytes will create a 'new normal.'


Clinical characteristics and molecular analysis of hepatitis B virus reactivation in hepatitis B surface antigen-negative patients during or after immunosuppressive or cytotoxic chemotherapy.
Reactivation of hepatitis B virus (HBV) in hepatitis B surface antigen (HBsAg)-positive patients treated with immunosuppressive or cytotoxic chemotherapy is well known and has emerged as an important clinical issue. The risk is low, but reactivation of HBV in HBsAg-negative patients after resolution of HBV infection also occurs; however, the clinical and virological characteristics remain somewhat unclear. We investigated HBsAg-negative patients who developed HBV reactivation during or after immunosuppressive or cytotoxic chemotherapy to clarify the clinical and virological features. Reactivation of HBV in 30 previously infected that is HBsAg-negative patients during or after immunosuppressive or cytotoxic chemotherapy was examined. Direct sequencing at the time of reactivation was used to evaluate 11 patients. The majority of patients had diffuse large B cell lymphoma treated by rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Fulminant hepatic failure developed in three patients, who did not survive. HBV subgenotypes A2/Ae (n = 1), B1/Bj (n = 2), and C2/Ce (n = 8) were detected. There were no significant differences in the prevalence of BCP/PC variants between HBV reactivation and acute self-limited hepatitis patient groups. BCP and PC variants were not associated with development of fulminant hepatic failure from HBV reactivation. The prevalence of HBV S region variants, including immune-escape mutants, among reactivation patients was significantly higher than that in acute self-limited hepatitis patients. Reactivation risk factors included male sex, advanced age, and hematological malignancy. HBV S gene immune-escape mutants were frequently found in the HBsAg-negative reactivation patients during or after immunosuppressive or cytotoxic chemotherapy.


Interactions between intracellular free Ca2+ and cyclic AMP in neuroendocrine cells.
Calcium ions and cyclic adenosine monophosphate (cAMP) are virtually ubiquitous intracellular signaling molecules in mammalian cells. This paper will focus on the cross-talk between Ca(2+) and cAMP mobilizing signaling pathways and summarize the underlying molecular mechanisms. Subsequently, workings of adenohypophyseal corticotrope cells will be reviewed to highlight the physiological relevance of a Ca(2+) cAMP interactions in neuroendocrinology.


Effects of pseudomonas aeruginosa colonization on lung function and anthropometric variables in children with cystic fibrosis.
The aim of this study was to evaluate how lung function and growth changed over time in children with cystic fibrosis (CF) colonized with pseudomonas aeruginosa (Pa) compared with those free of the organism. A total of 192 children attended our cystic fibrosis clinic between 1982 and 1992. Sixty-two of these had three or more annual assessments for lung function, and 117 had three or more annual assessments for height and weight. When lung function was expressed as a standard deviation score (SDS), forced expiratory volume in 1 second (FEV1) and forced expiratory flow at 25% of vital capacity (FEF25) decreased significantly more with respect to height in colonized compared with noncolonized children: FEV1, -0.052 verses -0.015 SDS/cm (P < 0.05); FEF25, -0.060 verses -0.007 SDS/cm (P < 0.05); forced vital capacity (FVC), -0.034 versus -0.012 (NS). In actual values those patients colonized with Pa increased their FEV1 by 16.4 versus 31.6 mL/cm (P < 0.01); FVC by 28.8 versus 41.4 mL/cm, P < 0.01; and FEF25 by -0.001 versus 0.015 L/s/cm, P < 0.01. In terms of height, colonized children grew at 5.63 versus 6.96 cm/yr, P < 0.001, and height SDS decreased in colonized compared with noncolonized children at -0.031 verses 0.08 SDS/yr, P < 0.05. Clinically, most children with CF, with or without Pa, grew within +/- 1 SD of the norm for weight and height. However, in terms of lung function despite optimum pulmonary management colonized children deteriorated significantly faster.


Conflicts in the treatment of chronic ulcers in drug addicts--case series and discussion.
Vascular access in intravenous drug abusers may become compromised by the repeated injection of toxic substances. In such circumstances abusers are driven by their addiction to seek alternative routes of drug delivery. We report a series of individuals with chronic ulcers, which were cultivated and maintained for the administration of heroin. We advise that practitioners should be wary of granulation tissue being promoted in this way and suggest that the patients' desire for wound healing may be overridden by their addiction and that successful treatment of these wounds is reliant upon cessation of drug abuse and patient compliance. In our experience this is most easily achieved in a multidisciplinary environment.


Cloning of GLUT3 cDNA from Atlantic cod (Gadus morhua) and expression of GLUT1 and GLUT3 in response to hypoxia.
A putative facilitative glucose transporter, GLUT3, cDNA was cloned from Atlantic cod. It is ubiquitously expressed, with substantial levels in kidney. The 519 aa protein has the highest sequence identity (66.3%) to grass carp GLUT3. Atlantic cod were exposed to a hypoxic challenge (45% DO2) for 24 h and the effects on GLUT1 and GLUT3 expression assessed. GLUT1 expression in gill is upregulated; however, in spleen, there is a significant decrease in both GLUT1 and GLUT3 expression. The increase in GLUT1 mRNA is considered to be associated with an increased energy demand on gill, whereas, the decrease in gene expression in spleen potentially reflects a general decrease in rates of transcription.


[Effect of electroacupuncturing heart meridian on arterial blood pressure with myocardial ischemia in rabbits].
To explore the relationship between Heart Meridian (HM) and cardiac function. Forty-eight rabbits with acute myocardial ischemia resulting from intravenous pituitrin injection was conducted. Electroacupunture(EA) on the HM and the Lung meridian, 3 points for each, was applied and their change of arterial pressure was observed. The distinct difference existed in the improvement of arterial pressure on the HM and Lung Meridian with EA. The regulatory action of EA in HM on the cardiac function was significantly better than that of EA in Lung Meridian. HM was closely related to the cardiac function.


The right auricle tunnel as intercaval tunnel in total cavopulmonary connection may prevent atrial flutter.
Total cavopulmonary connection (TCPC) is a routine operation for palliation of children with cardiac anomalies in whom biventricular repair is impossible. The original technique consists of the creation of a semi-prosthetic intercaval tunnel. A substantial proportion of these patients develop atrial flutter. We developed a technique for creating an intercaval tunnel that uses the tissue of the right auricle as intercaval tunnel. This technique avoids suture lines in the neighbourhood of the blood supply of the sinus node and leaves the terminal crest free. Since atrial flutter frequently occurs after Mustard and Senning operations in which suture lines are similar as for creating the lateral tunnel in TCPC we postulated that our technique for creating the intercaval tunnel without prosthetic material might prevent atrial flutter. All the children that qualified for a TCPC were included. Whenever possible our operative technique was applied. In the other cases a semi-prosthetic conduit was used for creating the intercaval tunnel. Of 47 consecutive patients 30 (64%) had a tunnel of right auricle tissue, 12 (26%) had a tunnel of prosthetic material. Five patients did not need an intercaval tunnel and were omitted in this study. Only surviving patients were included in this study. Patients that needed more atrial surgery then necessary for TCPC were also omitted. Postoperative ECG's and Holter monitorings were studied. Overall mortality was 7 of 47 patients (14.9% 70% CL 9.4-22.2%). There was no mortality due to rhythm disturbances. Atrial flutter occurred in 3 of 31 included patients (9.7, 70% CL 4.3-18.5%). In the right auricle group 1 of 22 patients (4.5, 70% CL 0.6-14.6%) had atrial flutter compared to 2 of 9 patients (22.2, 70% CL 7.5-45.0%) in the prosthesis group (P=0.13). The use of the right auricular technique for creating the intercaval tunnel TCPC is applicable in the majority of patients qualifying for a TCPC. Mortality and morbidity are equal comparing the two techniques. However, markedly less atrial flutter occurs in the group where the right auricle was used as intercaval tunnel. Therefore, we recommend the use of our technique for total cavopulmonary connection.


Recurrent schilder's disease.
Schilder's disease is a rare and aggressive central nervous system demyelinating disorder that is typically monophasic and steroid responsive. Here, we present an unusual case of a teenager with Schilder's disease who was treated with corticosteroids and had a clinical and radiographic recurrence nearly one year after the initial presentation.


Multidisciplinary team counseling for fetal anomalies.
Prenatal management of fetal anomalies requires a cooperative effort of the family, obstetrician, ultrasonographer, neonatologist, pediatric subspecialists, nursing staff, geneticists, and social workers. Our approach to these patients is to convene all team members and the family shortly after an anomaly is identified to review the diagnosis, prognosis, plans, and alternatives. Team counseling offers a clear definition of the problem, avoids unnecessary confusion and anxiety for the family, and provides a supportive environment during this family crisis. Our experience with 28 families has been favorable and is described herein.


ILAE-defined epilepsy syndromes in children: correlation with quantitative MRI.
The role of quantitative magnetic resonance imaging (MRI) in evaluation of childhood epilepsy remains poorly defined, with minimal published data. Previous work from our center questioned the specificity of hippocampal asymmetry (HA) in an outpatient group whose epilepsy was defined by using clinical and interictal data only. By using childhood volunteer controls and defining epilepsy syndromes using video-EEG monitoring, we readdressed the utility of HA in differentiating mesial temporal lobe epilepsy (MTLE) from other partial and generalized epileptic syndromes in children. Seventy children were enrolled; entry criteria were age younger than 18 years with predominant seizure type recorded on video-EEG telemetry with volumetric MRI in all cases. Thirty healthy child volunteers had volumetric MRI. Epilepsy syndrome classification was according to ILAE. Control data revealed symmetric hippocampi, mean smaller/larger ratio of 0.96 (0.95-0.97, 95% CI) with no gender or right/left predominance. Overall 23% of patients had significant HA. Mean hippocampal ratio for MTLE was 0.78 (95% CI, 0.70-0.86), significantly lower than controls and from all other epilepsy syndromes. HA was highly specific (85%) to the syndrome of MTLE. Other potential epileptogenic lesions were found in 27 (39%) patients, lowest yield in frontal and mesial temporal syndromes. Dual pathology was present in 10% of patients. There was no significant association between HA and risk factors. In this study, we found that HA in children with a well-defined epilepsy syndrome is highly sensitive and specific for MTLE. Whether this will correlate with surgical outcome, as in adults, is the subject of ongoing study.


Key elements and regulation strategies of NRPSs for biosynthesis of lipopeptides by Bacillus.
Lipopeptides are a group of second metabolites of Bacillus and have multiple activities such as inhibiting fungi, bacteria, viruses, and tumors, showing a great potential application in agricultural and biomedical fields. However, low production severely restrained their application in practice. Deeply understanding the key elements of lipopeptide synthesis and the regulatory strategies is essential to target the improvement of lipopeptide production. The synthetic pathways of different lipopeptides are different, but closely and mutually interfered. The loading of fatty acid chains and the extension of peptide chains are two key steps for the synthesis of different lipopeptides by Bacillus. The selection of fatty acid chains, the loading order of amino acids, and the recognition of the final cyclization site are the critical steps to determine the end products of different lipopeptides. In order to find the key elements for precisely directing the formation of different lipopeptides by Bacillus, the key structural elements and possible regulatory strategies that have been reported in the production of different lipopeptides, mainly surfactin, iturin, and fengycin by Bacillus, were summarized and compared. The possible ways to improve the production of different targeted lipopeptides were proposed. KEY POINTS: • The selectivity of fatty acids is determined by specific domains. • The COM domain and the PKS docking domain determine the order of amino acids. • The regulation patterns of different domains for lipopeptide synthesis are different. • The regulation of different lipopeptide products overlaps each other.


Central administration of alloxan impairs glucose tolerance in rats.
By means of oral glucose tolerance test (OGTT), we investigated glucose tolerance in rats pre-treated with intracerebroventricular and subcutaneous non-diabetogenic dose of betacytotoxic drug alloxan 7 days before OGTT. Being normoglycemic and normoinsulinemic pre-OGTT, at 30 minutes post-OGTT, alloxan intracerebroventricularly-treated rats had a lower glucose and a higher insulin plasma levels in comparison with controls or alloxan subcutaneously treated animals. Centrally administered alloxan seems to have brain related effect on the regulation of peripheral glucose tolerance and insulin secretion.


Relationship between static and dynamic balance tests among elite Australian Footballers.
Research assessing the direct relationship between static and dynamic balance ability of athletes is sparse. The aim of this project was to determine the relationship between a static balance task on a firm surface with a stepping balance task on an unstable surface. Thirty-seven Australian male professional footballers participated in the study. The static test involved maintaining single limb stance on a force platform. The other balance test involved stepping on to a balance mat on top of the force platform and maintaining single limb stance. The centre of pressure was monitored and the maximum excursion in the medial-lateral direction was recorded and used as the balance value. It was found that the magnitude of the maximum centre of pressure excursion was significantly greater (53%) for the stepping balance task. There were significant but low correlations for the centre of pressure excursion values between the two balance tests for the right limb and average of both limbs. There was no significant correlation between the test values for the left limb. Only a small proportion of the variance could be explained by each test: 16% for right limb values, 7% for left limb values and 11% for the average of both limbs. Given the overall weak associations between the two balance test values, it was concluded that performance in the static balance test was not reflective of performance in the dynamic balance test. Attempting to infer dynamic balance ability based on static balance ability should be avoided.


Pyrazolopyrimidine metabolism in the pathogenic trypanosomatidae.
Pyrazolopyrimidines are purine analogues. These compounds are metabolized by the pathogenic hemoflagellates and other members of the family Trypanosomatidae as though they were purines. This metabolic sequence does not exist in man or other mammals. In the hemoflagellates, the pyrazolopyrimidine base, of which allopurinol is the paradigm, undergoes ribosylphosphorylation to the ribonucleotide. This ribonucleotide may remain as such or be aminated to the amino analogue and further converted to the aminopyrazolopyrimidine ribonucleoside triphosphate. The latter is incorporated into RNA. This metabolic sequence has been demonstrated in the genera Leishmania and Trypanosoma.


[Phenomenology and systemic approaches in socio-anthropological studies of illness: a brief critical review].
This paper aims to identify the ways by which the principal frames of reference in the social sciences explain the structure of social actors' knowledge, practices, values, and behaviors regarding health care. The article begins by examining some of the assumptions underlying studies produced within what are called systemic theories. It then proceeds to discuss phenomenological approaches to the health and illness experience. The goal is to clarify how these approaches focus on experience and depart from prevailing systemic models.


Downsizing food: a systematic review and meta-analysis examining the effect of reducing served food portion sizes on daily energy intake and body weight.
Portion sizes of many foods have increased over time. However, the size of effect that reducing food portion sizes has on daily energy intake and body weight is less clear. We used a systematic review methodology to identify eligible articles that used an experimental design to manipulate portion size served to human participants and measured energy intake for a minimum of 1 d. Searches were conducted in September 2020 and again in October 2021. Fourteen eligible studies contributing eighty-five effects were included in the primary meta-analysis. There was a moderate-to-large reduction in daily energy intake when comparing smaller v. larger portions (Standardised Mean Difference (SMD) = -0·709 (95 % CI: -0·956, -0·461), approximately 235 kcal (983·24 kJ)). Larger reductions to portion size resulted in larger decreases in daily energy intake. There was evidence of a curvilinear relationship between portion size and daily energy intake; reductions to daily energy intake were markedly smaller when reducing portion size from very large portions. In a subset of studies that measured body weight (four studies contributing five comparisons), being served smaller v. larger portions was associated with less weight gain (0·58 kg). Reducing food portion sizes may be an effective population-level strategy to prevent weight gain.


Serum zinc in healthy Belgian children.
Many reports mention marginal zinc status in childhood. Information on serum zinc (Zn) in Belgian children since the last reports are old and feeding habits are changing. Four hundred fifty-seven healthy children (0-14 yr, 262 boys) had a venipuncture after an overnight fast during a vaccination campaign. Serum Zn, alpha-tocopherol (alpha-T), cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (Apo B), Apo A, and malondialdehyde (MDA) were determinated. The median Zn value is lower in infants than in older children (respectively 11.6 micromol/L vs 12.8 micromol/L). The type of infant feeding does not influence the serum Zn concentrations (breast-feeding, adapted, hypoallergenic, soy, or thickened). No children had increased serum MDA concentrations and the value is not influenced by the Zn concentration. Children presenting higher serum Zn values also have significantly higher serum alpha-T levels. In infants, there is a significant positive correlation between serum Zn and cholesterol, LDL-C, and Apo B. In this apparently healthy population, no signs of abnormal in vivo peroxidation of fatty acids are observed, even in the children with low serum Zn. More sensitive methods for the detection of peroxidation are necessary for determination of in vivo effects of marginal trace element status.


[Current status of treatment of appendicitis. Results of 2 prospective multicenter studies in East Germany. East German Working Group "Outcome Assessment and Quality Assurance in Surgery" of the CAQ of the German Society of Surgery].
In a period of 10 years we carried out two prospective multicentric trials to evaluate the state of the art in treatment of appendicitis. One study was performed before introduction of laparoscopy. Important criteria like new diagnostic methods (sonography, laparoscopy), frequency of operation, perforation rate, frequency of appendectomies in case of non acute inflammation and postoperative complications were compared.


An evidence-based review of current guidelines for the public health control of typhoid in Australia: a case for simplification and resource savings.
Although an uncommon disease in Australia, public health control measures for typhoid remain important to prevent further cases, however, they are labour intensive. We reviewed current guidelines from all Australian states and territories, England and the United States to ascertain whether recommended control measures for typhoid are supported by evidence from the medical literature or data from Victorian typhoid notifications. Guidelines lacked consistency and were overly complex, particularly with reference to the frequency and timing of faecal specimens required to demonstrate eradication of typhoid from cases and contacts. Data from the medical literature are limited and do not support the superiority of any one approach, or multiple approaches based on risk groups of cases or contacts. Victorian data suggest that a general approach, with a reduction in the number of specimens collected and duration of follow-up is reasonable. Potential exists for simplification and improved consistency between guidelines for the public health control of typhoid, with associated resource savings.


Novel UV filters from Pentacalia pulchella extracts with photoprotective properties and antioxidant activity.
Most of the plant species found in the high mountain ecosystems of the tropics is unique and exceptional, because they have developed complex adaptations to survive in extreme environmental conditions, such as high levels of UVR and low temperatures of these ecological environments. In an exploratory study carried out on some plants of this ecosystem, we found that one of the most promising species was the Pentacalia pulchella (Kunth) Cuatrec. (Asteraceae) an endemic plant of Colombia, which grows between 2500 and 3500 m.a.s.l. Therefore, the objective of this work was to evaluate the photoprotective, antioxidant, and chemical composition of extracts from the leaves of P. pulchella. Extracts showed good absorption coefficients in UVA-UVB, high content of total phenols, with antioxidant activity comparable to that obtained with butylhydroxytoluene (BHT). Finally, the formulation labeled "7" with 10% extract presented adequate sensory characteristics for topical use, good in vitro photoprotection values in the UVA-UVB range (SPF (Sun Protection Factor): 7.3 ± 0.9, UVAPF (Ultraviolet A Protection Factor): 5.3 ± 0.6, λc 376), and antioxidant activity. Results obtained allow us to suggest that the extract of P. pulchella has a high potential as a source of new natural solar filters.


Chlorambucil therapy in rheumatoid arthritis: clinical experience in 28 patients and literature review.
Our clinical experience in 28 patients receiving chlorambucil for rheumatoid arthritis (RA) and the reports on chlorambucil therapy are reviewed. Our study population and other reports generally represent patients with severe RA who had either failed to improve or developed significant toxicity during previous treatment with conventional slow acting anti-rheumatic drugs (SAARDs). Seventy-two percent of patients had a significant clinical improvement during chlorambucil therapy and reports of complete remission are given, although the incidence of remission is unknown. Hematologic complications are often reported, but appeared more frequently in our experience than previously reported. Hematologic toxicity required that chlorambucil be discontinued in the majority of our cases. Two deaths from suspected drug induced malignancies are reported. Although chlorambucil appears to be effective in the control of active RA, the potential for drug induced toxicity and malignancies may outweigh the benefit of continued use of this experimental therapy in RA.


Recovery of the autonomic nervous system following football training among division I collegiate football athletes: The influence of intensity and time.
The autonomic nervous system (ANS) is profoundly affected by high intensity exercise. However, evidence is less clear on ANS recovery and function following prolonged bouts of high intensity exercise, especially in non-endurance athletes. Therefore, this study aimed to investigate the relationships between duration and intensity of acute exercise training sessions and ANS recovery and function in Division I football athletes. Fifty, male football athletes were included in this study. Subjects participated in 135 days of exercise training sessions throughout the 25-week season and wore armband monitors (Warfighter Monitor, Tiger Tech Solutions) equipped with electrocardiography capabilities. Intensity was measured via heart rate (HR) during an 'active state', defined as HR ≥ 85 bpm. Further, data-driven intensity thresholds were used and included HR < 140 bpm, HR < 150 bpm, HR < 160 bpm, HR ≥ 140 bpm, HR ≥ 150 bpm and HR ≥ 160 bpm. Baseline HR and HR recovery were measured and represented ANS recovery and function 24h post-exercise. Linear regression models assessed the relationships between time spent at the identified intensity thresholds and ANS recovery and function 24h post-exercise. Statistical significance set at α < 0.05. Athletes participated in 128 training sessions, totaling 2735 data points analyzed. Subjects were predominantly non-Hispanic black (66.0%), aged 21.2 (±1.5) years and average body mass index of 29.2 (4.7) kg⋅(m2)-1. For baseline HR, statistically significant associations between duration and next-day ANS recovery were observed at HR < 140 bpm (β = -0.08 ± 0.02, R2 = 0.31, p < 0.001), HR above 150 and 160 bpm intensity thresholds (β = 0.25 ± 0.02, R2 = 0.69, p < 0.0000 and β = 0.59 ± 0.06, R2 = 0.71, p < 0.0000). Similar associations were observed for HR recovery: HR < 140 bpm (β = 0.15 ± 0.03, R2 = 0.43, p < 0.0000) and HR above 150 and 160 bpm (β = -0.33 ± 0.03, R2 = 0.73, p < 0.0000 and β = -0.80 ± 0.06, R2 = 0.71, p < 0.0000). The strengths of these associations increased with increasing intensity, HR ≥ 150 and 160 bpm (baseline HR: β range = 0.25 vs 0.59, R2: 0.69 vs 0.71 and HR recovery: β range = -0.33 vs -0.80, R2 = 0.73 vs 0.77). Time spent in lower intensity thresholds, elicited weaker associations with ANS recovery and function 24h post-exercise, with statistical significance observed only at HR < 140 bpm (β = -0.08 ± 0.02, R2 = 0.31, p < 0.001). The findings of this study showed that ANS recovery and function following prolonged high intensity exercise remains impaired for more than 24h. Strength and conditioning coaches should consider shorter bouts of strenuous exercise and extending recovery periods within and between exercise training sessions.


Progress towards development of immunoassays for detection of Mycobacterium leprae infection, employing 35kDa antigen: an update.
The 35 kDa antigen of Mycobacterium leprae is a membrane component that contains both B and T-cell stimulating epitopes. Monoclonal antibodies, primarily specific to M. leprae, have been developed against this antigen. Moreover, this antigen has been genetically engineered. Using recombinant 35 kDa antigen and/or a monoclonal antibody against an epitope on 35 kDa, a variety of antibody/antigen detecting tests have been described for detection of M. leprae infection. 35 kDa protein also stimulates peripheral blood mononuclear cells (PBMCs) from the majority of paucibacillary (PB) patients. Approaches using combined antibody and T cell are discussed.


Kinetic characteristics and binding process of substrate analogs to the adenosine deaminase in the marine mussel, Mytilus edulis.
1. The purified mussel enzyme deaminated several adenosine analogs with different Km and relative Vmax values. Affinity for adenine was similar to that for adenosine but the deamination rate was extremely slow. 2. Purine riboside was competitive, coformycin was a tight, slow binding inhibitor, and inhibition by both these compounds was pH-dependent. 3. Inosine, hypoxanthine, guanosine and 6-mercapto-purine riboside were slightly inhibitory. 4. The results suggested that initial binding of the substrate was guided by the adenine moiety followed by a stereospecific steering due to a ribose-dependent distortion in the complex to facilitate nucleophilic attack at C-6.


Dosimetric comparison of 3-dimensional conformal radiation therapy and intensity modulated radiation therapy and impact of setup errors in lower limb sarcoma radiation therapy.
This study compared dosimetric data between 3-dimensional conformal radiation therapy (3DCRT) and intensity modulated radiation therapy (IMRT) plans in a population of patients with lower limb sarcoma immobilized with an in-house device and quantified the impact of systematic and random errors on these techniques. The dosimetric effects of displacements on target coverage and organs at risk (OARs) were considered. Plans were created for 11 postoperative patients using both 3DCRT and IMRT. The techniques were compared dosimetrically. Population-based systematic and random errors were applied and the results compared with the initial plans. Higher target D95, D2, D98, and D50 and the best homogeneity index resulted with IMRT compared with 3DCRT. Systematic errors increased target D2 in IMRT. Random errors decreased target homogeneity in IMRT. Maximum bone dose was higher in IMRT than in 3DCRT. Neither error type increased OAR dose for either technique. IMRT could become the favored lower limb sarcoma radiation therapy technique because of superior target coverage and homogeneity. Offline imaging can adequately correct for systematic errors in these patients when an in-house immobilization device is used.


Peripheral Blood As a Source of Stem Cells for Regenerative Medicine: Emphasis Towards Corneal Epithelial Reconstruction-An In Vitro Study.
Mesenchymal stem cell-based treatments are now emerging as a therapy for corneal epithelial damage. Although bone marrow, adipose tissue and umbilical cord blood are the main sources of mesenchymal stem cells (MSCs), other tissues like the peripheral blood also harbor mesenchymal-like stem cells called peripheral blood-derived mononuclear cells (PBMNCs). These blood derived stem cells gained a lot of attention due to its minimally invasive collection and ease of isolation. In this study, the feasibility of using PBMNCs as an alternative cell source to corneal limbal stem cells envisaging corneal epithelial regeneration was evaluated. Rabbit PBMNCs were isolated using density gradient centrifugation and was evaluated for mesenchymal cell properties including stemness. PBMNCs were differentiated to corneal epithelial lineage using rabbit limbal explant conditioned media and was evaluated by immuno-cytochemistry and gene expression analysis. Further, the differentiated PBMNCs were engineered into a cell sheet using an in-house developed thermo-responsive polymer. These blood derived cells were demonstrated to have similar properties to mesenchymal stem cells. Corneal epithelial lineage commitment of PBMNCs was confirmed by the positive expression of CK3/12 marker thereby demonstrating the aptness as an alternative to limbal stem cells. These differentiated cells effectively generated an in vitro cell sheet that was then demonstrated for cell sheet transfer on an ex vivo excised rabbit eye. PBMNCs as an alternative autologous cell source for limbal stem cells is envisaged as an effective therapeutic strategy for corneal surface reconstruction especially for patients with bilateral limbal stem cell deficiency.


Effectiveness and Safety of Iguratimod Monotherapy or Combined With Methotrexate in Treating Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.
Objectives: We aimed to estimate the effectiveness and safety of iguratimod (IGU) monotherapy or in combination with methotrexate (MTX) in treating rheumatoid arthritis (RA) to provide an evidence-primarily-based foundation for clinical application. Methods: We conducted a systematic review of the meta-analysis using eight databases and two clinical trial websites searching for randomized controlled trials (RCTs) from conception to 15 March 2022, based on outcomes of patients with RA treated with IGU. The evidence quality assessment of primary outcomes was evaluated by the GRADE tool, and RevMan 5.3 and StataMP 14.0 were used to perform this research. Results: A total of 4302 patients with RA from 38 RCTs was included in this research. Pooled results demonstrated as follows: 1) Compared with methotrexate (MTX) alone, IGU alone was superior in improving ACR20 and DAS28-ESR, while having no significant difference in ACR50 and ACR70 [ACR20: (RR 1.15, 95% CI 1.05-1.27, p = 0.004); ACR50: (RR 0.97, 95% CI 0.66-1.44, p = 0.88); ACR70: (RR 0.92, 95% CI 0.45-1.90, p = 0.83); DAS28-ESR: mean difference (MD) -0.15, 95% CI -0.27 to -0.03, p = 0.01]. 2) Compared with MTX alone, IGU + MTX was more effective in improving ACR20, ACR50, ACR70, and DAS28-ESR. [ACR20: (RR 1.24, 95% CI 1.14-1.35, p < 0.00001); ACR50: (RR 1.96, 95% CI 1.62-2.39, p <0.00001); ACR70: (RR 1.91, 95% CI 1.41-2.57, p < 0.0001)]; [DAS28-ESR: (MD) -1.43, 95% CI -1.73 to -1.12, p < 0.00001]. 3) Compared with MTX + leflunomide (LEF), ACR20, ACR50, ACR70, and DAS28-ESR of IGU + MTX had no significant difference [ACR20: (RR 1.06, 95% CI 0.94-1.19, p = 0.38); ACR50: (RR 1.10, 95% CI 0.66-1.84, p = 0.72); ACR70: (RR 1.20, 95% CI 0.45-3.20, p = 0.71); DAS28-ESR: (MD -0.02, 95% CI -0.13 to -0.10, p = 0.77)]. 4) Compared with MTX + hydroxychloroquine (HCQ), IGU + MTX was superior in improving DAS28-ESR (MD -2.16, 95% CI -2.53 to -1.79, p < 0.00001). 5) Compared with MTX + tripterygium glycosides (TGs), IGU + MTX was more effective in improving DAS28-ESR (MD -0.94, 95% CI -2.36 to 0.48, p = 0.19). 6) There were no significant differences in adverse events (AEs) between the groups of IGU vs. MTX (RR 0.96, 95% CI 0.71-1.31, p = 0.80), IGU + MTX vs. MTX (RR 1.10, 95% CI 0.90-1.35, p = 0.34), IGU + MTX vs. MTX + HCQ (RR 0.64, 95% CI 0.29-1.42, p = 0.27), and IGU + MTX vs. MTX + TGs (RR 0.75, 95% CI 0.28-2.02, p = 0.57). The incidence of AEs in the IGU + MTX group was lower than the MTX + LEF group (RR 0.83, 95% CI 0.71-0.98, p = 0.03). Conclusion: Compared to the MTX alone subgroup, IGU alone offers clear advantages in improving ACR20 and DAS28-ESR, despite the insufficient evidence for DAS28-ESR findings. IGU + MTX shows clear benefits in improving ACR20, ACR50, ACR70, and DAS28-ESR scores compared to standard therapies. When the intervention (IGU alone or IGU + MTX) lasted for 52 weeks, it demonstrated superior efficacy in improving ACR20 of patients without prominent adverse events. Notably, IGU or IGU + MTX has apparent advantages in improving ACR20 of first-visit RA, and IGU + MTX has obvious advantages in improving DAS28-ESR of refractory RA. Furthermore, IGU + MTX does not increase the risk of leukopenia, but it can decrease the risk of liver function tests (LFTs), regardless of the age or the stage of RA. Clinical Trial Registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier CRD42022295217.


Dynamics and internal links of dissolved carbon in a karst river system: Implications for composition, origin and fate.
Dissolved carbon (DC) deciphers biotic and abiotic processes in aquatic ecosystems, representing a critical component of global carbon cycling. However, underlying drivers of riverine DC dynamics and internal links have yet to be studied. Here, we investigated fluvial physicochemical characteristics, dissolved inorganic carbon (DIC) species, carbon dioxide (CO2) exchange, dissolved organic carbon (DOC) compositions and properties in a karst river system Qijiang, Southwest China. Carbonate dissolution combined with photosynthetic uptake could explain dynamics of DIC species. Carbon sequestration caused low-magnitude of partial pressure of aqueous CO2 (pCO2, 620.3 ± 1028.7 μatm) and water-air CO2 flux (F, 154.3 ± 772.6 mmol/m2/d), yielding an annual CO2 emission of 0.079 Tg CO2/y. Relatively high biological index (BIX, 0.77-0.96 on average) but low humification index (HIX, 0.67-0.78 on average) indicated notable autochthonous processes. Humic-like component was the predominant DOC, accounting for 39.0%-75.2% with a mean of 57.2% ± 6.17%. Meanwhile, tryptophan-like component (5.84% ± 2.31%) was also identified as collective DOC by parallel factor analysis (PARAFAC) across samples. Biological metabolism established internal linkages between DIC and DOC in the karst river system. Our findings highlighted biological process as a determinant for DC cycling in karst aquatic ecosystems.


Lifestyle factors and health-related quality of life in adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort Study.
Survivors of childhood cancer report poor health-related quality of life (HRQOL). Modifiable lifestyle factors such as nutrition and physical activity represent opportunities for interventions to improve HRQOL. The authors examined the association between modifiable lifestyle factors and HRQOL among 2480 adult survivors of childhood cancer in the St. Jude Lifetime Cohort Study. Dietary intake, physical activity, cigarette smoking, and alcohol consumption were assessed through questionnaires. Weight and height were measured in the clinic. HRQOL was evaluated using the Medical Outcome Study 36-Item Short Form Survey. The physical component summary (PCS), mental component summary (MCS), and 8 domain scores of HRQOL were calculated. Multivariable linear regression models were used to estimate regression coefficients (β) associated with HRQOL differences. Being physically active (PCS β = 3.10; and MCS β = 1.48) was associated with higher HRQOL whereas current cigarette smoking (PCS β = -2.30; and MCS β = -6.49) and obesity (body mass index ≥30 kg/m2 ) (PCS β = -3.29; and MCS β = -1.61) were associated with lower HRQOL in both the physical and mental domains. Better diet (Healthy Eating Index-2015) was associated with higher physical HRQOL (PCS β = 1.79). Moderate alcohol consumption was associated with higher physical (PCS β = 1.14) but lower mental (MCS β = -1.13) HRQOL (all P <.05). Adherence to multiple healthy lifestyle factors demonstrated a linear trend with high scores in both physical and mental HRQOL (highest vs lowest adherence: PCS β = 7.60; and MCS β = 5.76 [P for trend, <.0001]). The association between healthy lifestyle factors and HRQOL is cumulative, underscoring the importance of promoting multiple healthy lifestyles to enhance HRQOL in long-term survivors of childhood cancer.


Towards an improved methodology for modelling climate change impacts on cropping systems in cool climates.
Assessment of the impact of climate change on agricultural sustainability requires a robust full system estimation of the interdependent soil-plant-atmospheric processes coupled with dynamic farm management. The simplification or exclusion of major feedback mechanisms in modelling approaches can significantly affect model outcomes. Using a biogeochemical model, DNDCv.CAN, at three case-study locations in Canada, we quantified the impact of using commonly employed simplified modelling approaches on model estimates of crop yields, soil organic carbon (SOC) change and nitrogen (N) losses across 4 time periods (1981-2010, 2011-2040, 2041-2070, and 2071-2100). These approaches included using climate with only temperature and precipitation data, annual re-initialization of soil status, fixed fertilizer application rates, and fixed planting dates. These simplified approaches were compared to a more comprehensive reference approach that used detailed climate drivers, dynamic planting dates, dynamic fertilizer rates, and had a continuous estimation of SOC, N and water budgets. Alternative cultivars and rotational impacts were also investigated. At the semi-arid location, the fixed fertilizer, fixed planting date, and soil re-initialization approaches reduced spring wheat (Triticum aestivum L.) yield estimates by 40%, 25%, and 29%, respectively, in the 2071-2100 period relative to the comprehensive reference approach. At both sub-humid locations, the re-initialization of soil status significantly altered SOC levels, N leaching and N runoff in all three time periods from 2011 to 2100. At all locations, SOC levels were impacted when using simplified approaches relative to the reference approach, except for the fixed fertilizer approach at the sub-humid locations. Results indicate that simplified approaches often lack the necessary characterization of the feedbacks between climate, soil, crop and management that are critical for accurately assessing crop system behavior under future climate. We recommend that modellers improve their capabilities of simulating expected changes in agronomy over time and employ tools that consider robust soil-plant-atmospheric processes.


[Changes in the catecholamine level and energy metabolism of the myocardium in rats during cold and emotional stress].
The catecholamine content in adrenergic plexuses and the oxidative enzyme activity (succinate dehydrogenase, lactate dehydrogenase) during cold and emotional stress were studied histochemically in the rat myocardium. An acute short-term cooling led to an increase in the catecholamine fluorescence intensity and succinate dehydrogenase activity, whereas a short-term emotional stress resulted in a decrease in both these parameters.


Binding of zinc to bovine and human milk proteins.
Zn binding by whole bovine and human casein and by purified bovine caseins and whey proteins was investigated by equilibrium dialysis. Bovine alpha s1-casein had the greatest Zn-binding capacity (approximately 11 atoms Zn/mol). Protein aggregation was observed as Zn concentration was increased and the protein precipitated at a free Zn concentration of 1.7 mM. Zn binding increased with increasing pH in the range 5.4-7.0 and decreased with increasing ionic strength. Competition between Zn and Ca was observed for binding to alpha s1-casein indicating common binding sites for these two metals. Bovine beta-casein bound up to 8 atoms Zn/mol and precipitated at a free Zn concentration of approximately 2.5 mM, while kappa-casein bound 1-2 atoms Zn/mol. Whole bovine and human casein bound 5-8 atoms Zn/mol and precipitated at a free Zn concentration of approximately 2.0 mM. Scatchard plots for Zn binding to caseins showed upward convexity, possibly due to Zn-induced association of caseins. Apparent average association constants (Kapp) for all caseins were similar (log Kapp 3.0-3.2). Enzymic dephosphorylation of alpha s1- or whole bovine casein markedly reduced, but did not eliminate, Zn binding. Thus, phosphoserine residues appeared to be the primary Zn-binding sites in caseins. With the exception of bovine serum albumin, which bound over 8 atoms Zn/mol, the bovine whey proteins, beta-lactoglobulin, alpha-lactalbumin and lactotransferrin, had little capacity for Zn binding.


HCV-associated exosomes promote myeloid-derived suppressor cell expansion via inhibiting miR-124 to regulate T follicular cell differentiation and function.
Virus-infected cells can regulate non-permissive bystander cells, but the precise mechanisms remain incompletely understood. Here we report that this process can be mediated by transfer of viral RNA-loaded exosomes shed from infected cells to myeloid-derived suppressor cells (MDSCs), which in turn regulate the differentiation and function of T cells during viral infection. Specifically, we demonstrated that patients with chronic hepatitis C virus (HCV) infection exhibited significant increases in T follicular regulatory (TFR) cells and decreases in T follicular helper (TFH) cells. These MDSC-mediated T-cell dysregulations resulted in an increased ratio of TFR/TFH and IL-10 production in peripheral blood. Specifically, co-culture of MDSCs derived from HCV patients with healthy peripheral blood mononuclear cells (PBMCs) induced expansion of TFR, whereas depletion of MDSCs from PBMCs of HCV patients reduced the increases in TFR frequency and IL-10 production, and promoted the differentiation of IFN-γ-producing TFH cells. Importantly, we found that exosomes isolated from the plasma of HCV patients and supernatant of HCV-infected hepatocytes could drive monocytic myeloid cell differentiation into MDSCs. These exosomes were enriched in tetraspanins, such as CD63 and CD81, and contained HCV RNA, but exosomes isolated from patients with antiviral treatment contained no HCV RNA and could not induce MDSC differentiation. Notably, these HCV RNA-containing exosomes (HCV-Exo) were sufficient to induce MDSCs. Furthermore, incubation of healthy myeloid cells with these HCV-Exo inhibited the expression of miR-124, whereas reconstitution of PBMCs with miR-124 abolished the effects of HCV-Exo on MDSC induction. Taken together, these results indicate that HCV-associated exosomes can transfer immunomodulatory viral RNA from infected cells to neighboring immune cells and trigger MDSC expansion, which subsequently promotes TFR differentiation and inhibits TFH function. This study reveals a previously unrecognized path that represents a novel mechanism of immune dysregulation during chronic viral infection.


Deregulation by zinc of the sodium efflux in barnacle muscle fibers.
Single muscle fibers from the barnacle Balanus nubilus were employed to study the behavior of the resting Na+ efflux toward external and internal application of zinc (Zn2+). This involved both unpoisoned and ouabain-poisoned fibers. The results obtained are as follows: (i) External application of Zn2+, e.g., 2 mM (a maximal dosage) in 10 mM Hepes-ASW (pH 7.3) causes a fall in the resting Na+ efflux which exceeds that caused by 10(-4) M ouabain in companion controls. (ii) The buffer of choice is found to be Hepes, rather than HCO3- or imidazole. (iii) The observed fall in the resting Na+ efflux caused by external application of Zn2+ is concentration-dependent, the IC50 being 10 microM. (iv) The inhibitory effect of Zn2+ is partially reversible; occasionally, however, reversibility is not seen. (v) The Zn(2+)-insensitive component of the Na+ efflux is reduced by 10(-4) M ouabain. (vi) The ouabain-insensitive component of the Na+ efflux is reduced by external application of Zn2+. This response is concentration-dependent. (vii) Preinjection of EGTA reduces the sensitivity of the Na+ efflux to external application of Zn2+. This is true of both unpoisoned and ouabain-poisoned fibers. (viii) (a) The resting Na+ efflux is reduced by injecting Zn2+. Ouabain application reduces the remaining Na+ efflux. (b) Injection of Zn2+ reduces the ouabain-insensitive component of the Na+ efflux. (c) External application of Zn2+ following the injection of Zn2+ reduces the remaining Na+ efflux. Ouabain is ineffective when applied after both maneuvers. (d) Injection of Zn2+ after its external application is without effect. Subsequent application of ouabain is also without effect. (e) Injection or external application of Zn2+ reduces the ouabain-insensitive Na+ efflux. Whereas in the former case subsequent external application of Zn2+ reduces the remaining Na+ efflux, in the latter case Zn2+ injection after external application of Zn2+ is ineffective. Collectively, these results provide evidence in support of the hypothesis that Zn2+ is a potent inhibitor of the ouabain-sensitive and ouabain-insensitive components of the Na+ efflux, and that the inhibitory effect is partly due to the entry of Zn2+ into the myoplasm. They also raise the possibility that the inhibitory effect caused by Zn2+ injection may be the result of Zn2+ leakage from the fiber interior.


Parents' experiences of children with a rare disease attending a mainstream school: Australia.
To explore the perceptions of parents who had a child or adolescent (6-18 years) diagnosed with a rare disease who attended a mainstream school in Western Australia. A cross-sectional online survey was conducted with 41 parents of children with a rare disease. Here we report the findings of 14 open-ended questions on their experience of illness-related factors and impact on school-related social activities, such as sports, school camps and leadership roles whilst their child with a rare disease attended a mainstream school in Australia. Responses were analysed using an inductive thematic content approach. We identified three themes (resources, experiences and needs), seven categories (illness, support, knowledge, acceptance, isolation, activities of daily living and adjunctive therapy) and 24 codes from the parents' responses describing the experiences of their child at school. Parents want the government and educational systems to provide the necessary funding and resources to reflect an inclusive curricula and supportive environment that can meet the learning needs of children with a rare disease at a mainstream school. Further research, policy development and interventions are needed to explore how schools can meet the diverse psychosocial physical and emotional needs of children diagnosed with a rare disease who attend a mainstream school in Australia. A child needs to be viewed from a holistic ecological viewpoint; future research with larger representative samples to explore rare disease experiences and a critical review of existing legislation, interventions and initiatives is required.


A brief review concerning the latest advances in the influence of nanoparticle reinforcement into polymeric-matrix biomaterials.
Nanoparticles (NPs) have been studied for a wide variety of applications, due to the elevated surface area and outstanding properties. Several types of NPs are available nowadays, each one with particular characteristics and challenges. Bionanocomposites, especially composed by polymer matrices, are gaining attention in the biomedical field. Although, several studies have shown the potential of adding NPs into these materials, some investigation is still needed until their clinical use for in vivo application is consummated. Besides that, is essential to evaluate whether the addition of nanoparticles changes the matrix property. In this review, we summarize the latest advances concerning polymeric bionanocomposites incorporated with organic (polymeric, cellulosic, carbon-based), and inorganic (metallic, magnetics, and metal oxide) NPs.


HUBO and QUBO models for prime factorization.
The security of the RSA cryptosystem is based on the difficulty of factoring a large number N into prime numbers [Formula: see text] and [Formula: see text] satisfying [Formula: see text]. This paper presents a prime factorization method using a D-Wave quantum computer that could threaten the RSA cryptosystem in the future. The starting point for this method is very simple, representing two prime numbers as qubits. Then, we set the difference between the product of the two prime numbers expressed in qubits and N as a cost function, and we find the solution when the cost function is minimized. D-Wave's quantum annealer can find the minimum value of any quadratic problem. However, the cost function must be a higher-order unconstrained optimization (HUBO) model because it contains second- or higher-order terms. We used a hybrid solver accessible via Leap, D-Wave's real-time quantum cloud service, and the dimod package provided by the D-Wave Ocean software development kit (SDK) to solve the HUBO problem. We also successfully factorized 102,454,763 with 26 logical qubits. In addition, we factorized 1,000,070,001,221 using the range-dependent Hamiltonian algorithm.


Aortic diameter and pressure-flow sequence identify mechanism of blood flow during external chest compression in dogs.
Aortic flow and pressure relations and aortic diameter were examined during sinus rhythm, internal cardiac massage, vest cardiopulmonary resuscitation, conventional manual cardiopulmonary resuscitation and high impulse manual cardiopulmonary resuscitation in 14 anesthetized large dogs. During sinus rhythm and during internal cardiac massage, ascending aortic flow and pressure increased simultaneously and the rise in ascending aorta pressure preceded the rise in descending aortic pressure by (mean +/- SEM) 28 +/- 4 and 30 +/- 1 ms, respectively. In contrast, during vest, conventional and high impulse cardiopulmonary resuscitation, ascending aortic flow lagged behind the initial rise in aortic pressure by 40 +/- 4 to 46 +/- 4 ms and ascending and descending aortic pressure increased simultaneously (p less than 0.001 for each external compression mode versus sinus rhythm and internal massage). The ratio of pulse pressure to stroke volume increased by an order of magnitude during all modes of external chest compression (p less than 0.001 versus sinus rhythm and internal massage) and aortic diameter decreased during vest and high impulse cardiopulmonary resuscitation (p less than 0.05 versus sinus rhythm and internal massage). The hemodynamics of external chest compression depart from the normal physiologic sequence of stroke volume-induced increase in aortic pressure and diameter. The rise in aortic pressure precedes flow into the aorta, stroke volume does not fully account for pulse pressure, and aortic diameter decreases during chest compression. These data support the hypothesis that blood flow is due to fluctuations in intrathoracic pressure for high impulse as well as vest and conventional cardiopulmonary resuscitation.


Identifying and modulating disulfide formation in the biopharmaceutical production of a recombinant protein vaccine candidate.
Structural conversion of the serotype A recombinant botulinum neurotoxin heavy chain fragment (rBoNTA(Hc)) produced intracellularly in Pichia pastoris yeast was observed and characterized during purification development efforts. A pH screening study captured the transformation stages of the original recovered species into its derived counterpart and a number of analytical tools such as peptide mapping by LC/MS confirmed the formation of a disulfide bond, especially in samples of neutral to basic pH. A cation exchange chromatographic method proved useful in following the incidence of the reaction in various rBoNTA(Hc) samples. The disulfide formation kinetics were characterized using a one-quarter quadratic factorial design, following the investigation and development of controlled oxidation conditions using cysteine and cystamine as the redox pair. Temperature, pH and concentration of the redox pair had a significant effect on the yield and rate of the disulfide formation. This controlled reaction was eventually introduced as a functional unit operation in the purification process. The summation of preliminary scale-up and potency data showed scalability and robustness in the production of an active disulfide-bonded form of a recombinant botulism vaccine candidate. The presence of the disulfide bond did not effect the vaccine potency and it enhanced the molecule's thermal stability.


Breast cancer in a man 30 years after radiation for metastatic osteogenic sarcoma.
A man developed breast cancer 30 years after chest radiation for metastatic osteogenic sarcoma. At least eight previous cases of radiation-associated breast cancers have been reported in males, but this man represents the first to develop breast cancer following a childhood malignancy.


Early Palliative Care in Acute Myeloid Leukemia.
Several novel targeted therapies seem to improve the outcome of acute myeloid leukemia (AML) patients. Nonetheless, the 5-year survival rate remains below 40%, and the trajectory of the disease remains physically and emotionally challenging, with little time to make relevant decisions. For patients with advanced solid tumors, the integration of early palliative care (EPC) with standard oncologic care a few weeks after diagnosis has demonstrated several benefits. However, this model is underutilized in patients with hematologic malignancies. In this article, we analyze the palliative care (PC) needs of AML patients, examine the operational aspects of an integrated model, and review the evidence in favor of EPC integration in the AML course. AML patients have a high burden of physical and psychological symptoms and high use of avoidant coping strategies. Emerging studies, including a phase III randomized controlled trial, have reported that EPC is feasible for inpatients and outpatients, improves quality of life (QoL), promotes adaptive coping, reduces psychological symptoms, and enhances the quality of end-of-life care. EPC should become the new standard of care for AML patients. However, this raises issues about the urgent development of adequate programs of education to increase timely access to PC.


Endovascular treatment for large and giant fusiform aneurysms of the vertebrobasilar arteries.
Fusiform aneurysms of vertebrobasilar arteries pose great challenge to surgical and endovascular treatment, especially large and giant aneurysms. We retrospectively reviewed our experiences and results of endovascular treatments for a series of 10 consecutive patients with large and giant fusiform aneurysms. Eight patients underwent stents placement (5 patients) or stent-assisted coiling (3 patients), and 2 patients underwent proximal occlusion of the parent arteries. Retreatment was needed in 2 patients. With the exception of 1 patient who died of rebleeding after sole stenting, the remaining 9 patients had good outcome. Reconstructive strategies using stents is a useful alternative for large and giant fusiform aneurysms of the vertebrobasilar arteries.


Response of kynurenine pathway enzymes to pregnancy and dietary level of vitamin B-6.
The kynurenine pathway of tryptophan metabolism produces several neuroactive metabolites including 3-hydroxykynurenine, kynurenic acid, and quinolinic acid. This pathway is sensitive to reductions in vitamin B-6 availability because two key enzymes, kynurenine aminotransferase (KAT) and kynureninase (KYNase), require pyridoxal 5'-phosphate. During pregnancy abnormal concentrations of kynurenine metabolites are also found. We measured the effects of pregnancy and vitamin B-6 availability on KAT and KYNase in liver. DBA/2Ibg and A/Ibg mice were fed diets containing 0.25, 0.5, 2.0, 3.6, or 7.0 mg/kg pyridoxine-HCl (PN-HCl) for 4 weeks. Mitochondrial KAT and cytosolic KYNase were measured in control mice and pregnant mice on gestational days 16-18. The response of the two inbred strains was similar throughout. There were no marked alterations in KAT activity as a function of diet or pregnancy. In contrast, KYNase activities were significantly reduced by dietary restriction of vitamin B-6, and pregnant mice had significantly lower activity than nonpregnant controls for all but the highest dietary level of PN-HCl. These data show that pregnancy has a more pronounced effect on KYNase activity than vitamin B-6 restriction, and that the effects of pregnancy and diet are additive. The alteration in the kynurenine pathway in pregnancy is due to a reduction in KYNase activity, which is resistant to alleviation by vitamin B-6 supplementation.


Time-course transcriptome analysis reveals regulation of Arabidopsis seed dormancy by the transcription factors WOX11/12.
The induction of seed dormancy and its release involve a finely regulated genetic program controlled by various environmental and developmental cues that are critical for plant survival and population expansion. Light plays a key role in seed dormancy and germination, but the molecular mechanisms underlying the control of dormancy are unclear. In the present study, high-resolution temporal RNA-seq in Arabidopsis identified WOX11 as encoding a hub transcription factor during the seed dormancy induction and release stages. This gene might have evolved from gymnosperms and expanded in angiosperms with highly conserved expression patterns in seeds. WOX11 and its homolog WOX12 were highly expressed from 2 d after pollination, and mRNA abundance was greatly increased during the seed dormancy induction and release stages. Further, we found that WOX11 plays a role in the regulation of seed dormancy downstream of phytochrome B (PHYB)-mediated red-light signaling during the induction stage, indicating that WOX11/12 are newly identified components of red-light signaling transduction. Taken together, our results suggest that WOX11/12-mediated PHYB signaling regulates seed dormancy in Arabidopsis, and provide insights into the developmental regulation and evolutionary adaptation of plants to changes in the light environment.


The effect of chronic nausea on gastric slow wave spatiotemporal dynamics in children.
Chronic nausea in adolescents with functional gastrointestinal disorders is an increasingly reported but poorly understood symptom that negatively affects quality of life. Functional gastrointestinal disorders are known to correlate closely with slow wave rhythm disturbances. The ability to characterize gastric electrophysiologic perturbations in functional nausea patients could provide potential diagnostic and therapeutic tools for nausea patients. We used high-resolution electrogastrograms (HR-EGG) to measure gastric slow wave parameters in pediatric chronic nausea patients and healthy subjects both pre- and postprandial. We computed the dominant frequency, percentage power distribution, gastric slow wave propagation direction, and speed from HR-EGG. We observed significant differences in the dominant frequency and power distributed in normal and bradyarrhythmia frequency ranges when comparing patients and healthy subjects. Propagation patterns in healthy subjects were predominantly anterograde, while patients exhibited a variety of abnormalities including retrograde, anterograde, and disrupted patterns. There was a significant difference in the preprandial mean slow wave direction between healthy subjects (222° ± 22°) and patients (103° ± 66°; p ˂ 0.01), although the postprandial mean direction between healthy subjects and patients was similar (p = 0.73). No significant difference in slow wave propagation speed was found between patients and healthy subjects in either pre- (p = 0.21) or postprandial periods (p = 0.75). The spatiotemporal characterization of gastric slow wave activity using HR-EGG distinguishes symptomatic chronic nausea patients from healthy subjects. This characterization may in turn inform and direct clinical decision-making and lead to further insight into its pathophysiology.


Recent advancements on biochars enrichment with ammonium and nitrates from wastewaters: A critical review on benefits for environment and agriculture.
During the last decade, biochars have been considered as attractive and eco-friendly materials with various applications including wastewater treatment, energy production and soil amendments. However, the important nitrogen losses during biochars production using the pyrolysis process have limited their potential use in agriculture as biofertilizer. Therefore, it seems necessary to enrich these biochars with nitrogen sources before their use in agricultural soils. This paper is the first comprehensive review on the assessment of biomass type and the biochars' properties effects on N recovery efficiency from aqueous solutions as well as its release and availability for plants when applying the N-enriched chars in soils. In particular, the N recovery efficiency by raw biochars versus the type of the raw feedstock is summarized. Then, correlations between the adsorption performance and the main physico-chemical properties are established. The main mechanisms involved during ammonium (NH4-N) and nitrates (NO3-N) recovery process are thoroughly discussed. A special attention is given to the assessment of the biochars physico-chemical modification impact on their N recovery capacities improvement. After that, the application of these N-enriched biochars in agriculture and their impacts on plants growth as well as methane and nitrous oxide greenhouse gas emissions reduction are also discussed. Finally, the main future development and challenges of biochars enrichment with N from wastewaters and their valorization as biofertilizers for plants growth and greenhouse gas (GHG) emissions reduction are provided. This systematic review is intended to promote the real application of biochars for nutrients recovery from wastewaters and their reuse as eco-friendly fertilizers.


Idiopathic left ventricular tachycardia: new insights into electrophysiological characteristics and radiofrequency catheter ablation.
This study was performed to investigate the electrophysiological characteristics of idiopathic left ventricular tachycardia and to determine the feasibility of radiofrequency catheter ablation for nonpharmacological cure. The underlying electrophysiological mechanism of idiopathic left ventricular tachycardia with right bundle branch block morphology and left-axis deviation is presently not known. Additionally, only limited data describing the results of radiofrequency catheter ablation for treatment of idiopathic left ventricular tachycardia so far exist. Electrophysiological studies and radiofrequency catheter ablation were performed in 5 patients (3 male and 2 female, mean age 31 +/- 10 years) with idiopathic left ventricular tachycardia (cycle length 376 +/- 72 msec). The patients had a history of recurrent palpitations of 4 +/- 1 years and had been treated unsuccessfully with 2 +/- 1 antiarrhythmic drugs. Sustained ventricular tachycardia with right bundle branch block morphology and left- or right-axis deviation was documented in all patients. Inducibility with critically timed ventricular extrastimuli, inverse relationships of the coupling interval of the initiating extrastimulus and the interval to the first beat of the tachycardia, continuous diastolic or mid-diastolic electrical activity during ventricular tachycardia, and fragmented late potentials during sinus rhythm suggested reentrant activation as the underlying mechanism in three patients. On the other hand, induction dependent on isoproterenol infusion and rapid ventricular pacing and exercise inducibility indicated different electrophysiological characteristics in the remaining two patients. During electrophysiological study, intravenous verapamil terminated ventricular tachycardia in all patients, whereas ventricular tachycardia did not respond to intravenous adenosine, autonomic maneuvers, or intravenous beta-blocking agent esmolol. Catheter mapping revealed earliest endocardial activation during ventricular tachycardia in different areas of the left ventricular septum being distributed from the base to the mid-apical portion of the septum in all patients. In 4 of 5 patients, radiofrequency catheter ablation (median number of pulses 4, range 1-9) resulted in complete abolition of idiopathic left ventricular tachycardia during a follow-up of 4-43 months (median 10) without antiarrhythmic drugs. Successful target sites for catheter ablation included continuous diastolic or mid-diastolic electrical activity during ventricular tachycardia and late potentials during sinus rhythm (2 patients), polyphasic fragmented presystolic potentials during ventricular tachycardia (1 patient), and pace mapping with identical QRS morphology compared to the ventricular tachycardia and "earliest" detectable activity during tachycardia (1 patient). No procedure related complications occurred. Two different patterns of electrophysiological properties of idiopathic left ventricular tachycardia were observed, indicating that this arrhythmia entity does not represent a homogeneous group. The "origin" of the tachycardias as identified by successful radiofrequency catheter ablation was located in different areas of the left ventricular septum and was distributed from the base to the mid-apical region. Radiofrequency catheter ablation was an effective and safe treatment modality in most of these patients. Distinct target site characteristics for successful catheter ablation including polyphasic diastolic activity during tachycardia and fragmented late potentials during sinus rhythm could be identified.


Assessment of phylogenetic inter-relationships in the genus Cymbidium (Orchidaceae) based on internal transcribed spacer region of rDNA.
Sequence data obtained from nrITS region were used to assess phylogenetic inter-relationships and infrageneric classification of ten Cymbidium species collected from north-east India. The final aligned data matrix of combined ITS 1, 5.8S and ITS 2 yielded 684 characters. The ITS 1 and ITS 2 regions showed variable sequence lengths and G+C content (%). The 5.8S region was found to be more conserved (98.71%) followed by ITS 1 (86.12%) and ITS 2 (69.40%). ITS 2 recorded highest percentage of parsimony informative sites (7.46%), high sequence divergence with indels (24.63%), high number of transitions and transversions. ITS sequence data determined the phylogeny of Asiatic Cymbidiums with high bootstrap values. All three proposed subgenera could be distinguished clearly by all four (MP, ML, NJ, and BI) phylogenetic methods. This study validates the utility of ITS rDNA region as a reliable indicator of phylogenetic relationships, especially ITS 2 as probable DNA barcode at higher levels and can serve as an additional approach for identification of broader range of plant taxa especially orchids.


Avidity mechanism of dendrimer-folic acid conjugates.
Multivalent conjugation of folic acid has been employed to target cells overexpressing folate receptors. Such polymer conjugates have been previously demonstrated to have high avidity to folate binding protein. However, the lack of a monovalent folic acid-polymer material has prevented a full binding analysis of these conjugates, as multivalent binding mechanisms and polymer-mass mechanisms are convoluted in samples with broad distributions of folic acid-to-dendrimer ratios. In this work, the synthesis of a monovalent folic acid-dendrimer conjugate allowed the elucidation of the mechanism for increased binding between the folic acid-polymer conjugate and a folate binding protein surface. The increased avidity is due to a folate-keyed interaction between the dendrimer and protein surfaces that fits into the general framework of slow-onset, tight-binding mechanisms of ligand/protein interactions.


Developing instruments for measurement of criteria: a clinical nursing practice perspective.
Development of an instrument for measuring care given to a specific patient population in an extended care facility is described.


Transfection of SSTR-1 and SSTR-2 inhibits Panc-1 cell proliferation and renders Panc-1 cells responsive to somatostatin analogue.
Somatostatin inhibits cell proliferation through interaction with its cellular receptor, somatostatin receptors (SSTRs). We have previously demonstrated that overexpression of individual SSTR-1 or SSTR-2 genes in receptor-negative pancreatic cancer cells inhibited cell proliferation. We hypothesize that reintroduction of SSTR genes back into pancreatic cancer cells might be an effective gene therapy strategy for pancreatic cancer. We transfected human pancreatic cancer cell line (Panc-1) with human SSTR-1 and SSTR-2 genes and examined the expression by real-time reverse transcriptase-polymerase chain reaction and immunofluorescence. Panc-1 cell proliferation was determined by [(3)H]-thymidine incorporation assay. Activation of phosphorylated c-Jun N-terminal protein kinase (JNK) and cytokine secretion after SSTR-1 and SSTR-2 transfection were detected by Bio-Plex 4-plex phosphoprotein assay and cytokine assay. Panc-1 cells did not express SSTR-1 or SSTR-2, although Panc-1 cells transfected with SSTR-1 and SSTR-2 genes showed a significant amount of SSTR expression. Cell growth rate in Panc-1 cells transfected with SSTR-1 and SSTR-2 was inhibited about 41%, and the cell proliferation of Panc-1 expressing SSTR-1 and SSTR-2 was further reduced about 12% on treatment with somatostatin analogue as compared with the control group. SSTR-1 and SSTR-2 cotransfected Panc-1 cells activated phosphorylation of JNK and increased secretion of interferon-gamma and interleukin-5. These findings suggest, for the first time, a synergistic inhibitory effect of multiple SSTRs in response to a somatostatin analogue in Panc-1 cells. These studies may improve our understanding of the mechanism by which SSTR inhibits cell growth and lead to novel gene therapies for pancreatic cancer.


Parsing the role of sleep in memory processing.
It would be nice if we could talk about sleep and memory as if there were only one type of memory and one type of sleep. But this is far from the case. Sleep and memory each comes in many forms, and furthermore, memories can go through multiple forms of post-encoding processing that must be individually addressed. Finally, sleep stages per se do not affect memories. Rather, the neuromodulatory and electrophysiological events that characterize these sleep stages must mediate sleep-dependent memory processing. In this review, we attempt to parse out the relative contributions and interactions of these often frustratingly complex systems.


Green tea and cancer and cardiometabolic diseases: a review of the current epidemiological evidence.
Green tea is commonly consumed in China, Japan, and Korea and certain parts of North Africa and is gaining popularity in other parts of the world. The aim of this review was to objectively evaluate the existing evidence related to green tea consumption and various health outcomes, especially cancer, cardiovascular disease and diabetes. This review captured evidence from meta-analyses as well as expert reports and recent individual studies. For certain individual cancer sites: endometrial, lung, oral and ovarian cancer, and non-Hodgkins lymphoma the majority of meta-analyses observed an inverse association with green tea. Mixed findings were observed for breast, esophageal, gastric, liver and a mostly null association for colorectal, pancreatic, and prostate cancer. No studies reported adverse effects from green tea related to cancer although consuming hot tea has been found to possibly increase the risk of esophageal cancer and concerns of hepatotoxity were raised as a result of high doses of green tea. The literature overall supports an inverse association between green tea and cardiovascular disease-related health outcomes. The evidence for diabetes-related health outcomes is less convincing, while the included meta-analyses generally suggested an inverse association between green tea and BMI-related and blood pressure outcomes. Fewer studies investigated the association between green tea and other health outcomes such as cognitive outcomes, dental health, injuries and respiratory disease. This review concludes that green tea consumption overall may be considered beneficial for human health.


Evaluation of the acute phase response in cloned pigs following a lipopolysaccharide challenge.
The objective of this study was to evaluate the acute phase response (APR) in cloned pigs derived from two different cell lines [C1 (n = 2) and C2 (n = 7)] as compared to genetically similar non-cloned pigs (CONT; n = 11) following a lipopolysaccharide (LPS; 25 microg/kg BW) challenge. Pigs were weaned at 21 days of age and maintained in individual pens in the same room until sample collection approximately 1 week later. Blood samples were collected every 30 min for 2 h prior to and 4h after the LPS challenge. Serum samples were analyzed for cortisol, tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6). Average gestational length for cloned pigs, 118.8 +/- 0.97 days, was longer (P < 0.005) than that of CONT pigs, 114+/-0.41 days. For serum cortisol, there was a time by group interaction (P < 0.0001) such that the cortisol response was greater in CONT pigs as compared to C2 pigs (P < 0.0001), but not different from C1 pigs (P > 0.74). A time by group interaction (P < 0.0001) was observed for serum TNF-alpha such that the TNF-alpha response was greater in CONT pigs as compared to C2 pigs (P = 0.0002) and tended to be greater (P < 0.06) than C1 pigs. A time by group interaction (P < 0.0001) was also observed for serum IL-6 such that the serum IL-6 response was greater (P < 0.003) in CONT pigs as compared to C2 pigs and there was a trend (P = 0.10) for serum IL-6 to be greater in CONT pigs compared to the C1 pigs. These are the first results to demonstrate that cortisol and proinflammatory cytokine profiles associated with the APR of cloned pigs are altered compared to genetically similar non-cloned pigs. Our results also indicate that the cell line from which clones are derived may dictate the APR. The hormone and cytokine profiles reported herein are a significant contribution towards our understanding, and perhaps our ability to prevent or reduce the incidence of premature deaths in cloned animals and warrants further investigation of the immune system of cloned animals.


The role of telemedicine in joint replacement surgery? An updated review.
The usage of telemedicine and telehealth services has grown tremendously and has become increasingly relevant and essential. Technological advancements in current telehealth services have supported its use as a viable alternative tool to conduct visits for consultations, follow-up, and rehabilitation in total joint arthroplasty. Such technology has been widely implemented, particularly during the coronavirus 2019 (COVID-19) pandemic, to deliver postoperative rehabilitation among patients receiving total joint arthroplasty (TJA), further demonstrating its feasibility with a lower cost yet comparable clinical outcomes when compared with traditional care. There remains ample potential to utilize telemedicine for prehabilitation to optimize the preoperative status and postoperative outcomes of patients with osteoarthritis. In this review, various implementations of telemedicine within total joint arthroplasty and future application of telemedicine to deliver tele-prehabilitation in TJA are discussed.


Erectile failure in the aged: evaluation and treatment.
With aging, there are changes in both libido and erectile function. Although the majority of aged men remain interested in sex, less than 15% report continued sexual intercourse. The cause of this "libido-potency gap" is due primarily to erectile failure. Penile erection is dependent upon a complex interaction of the autonomic nervous system, cardiovascular system, and local neurotransmitters such as acetylcholine and vasoactive intestinal polypeptide. Sexual stimulation causes augmented blood flow into the corpora cavernosa, and restricted outflow, resulting in penile rigidity. With aging, there is a decline in gonadal steroids, nerve conduction velocity, and vascular compliance, any of which could interfere with normal erections. When disease is superimposed on the normal changes of aging, erectile function is further impaired. Evaluation of an elderly male with impotence may consist of a detailed drug history and trial of alternate therapy, as in the case of adverse drug reactions. More often, evaluation entails hormonal assays, penile vascular assessment, neurologic assessment, and an evaluation of nocturnal erectile function. Based on the results of these assessments, appropriate treatment alternatives can be chosen. With the availability of multiple treatment options, patients and physicians can now choose from a range of noninvasive or invasive alternatives depending upon the etiology, associated disorders, and preference of the patient.


Activation and nuclear translocation of ERK1/2 by the formyl peptide receptor is regulated by G protein and is not dependent on beta-arrestin translocation or receptor endocytosis.
G protein-coupled receptors (GPCRs) transmit diverse cellular signals in response to a large number of stimuli such as chemoattractants, lipids, neurotransmitters, odorants and light. The classical signaling pathway is through heterotrimeric G proteins, but GPCRs can also transmit signals through mechanisms that are not dependent on G proteins. In mammalian cells, the key component for this type of signaling is the family of scaffolding molecules called beta-arrestins. They can function as scaffolds for activation of mitogen-activated protein kinases, including extracellular signal-regulated kinases 1 and 2 (ERK1/2). In this study we examined the role of G protein and beta-arrestin in formyl peptide receptor (FPR)-mediated activation of chemotaxis, receptor endocytosis and ERK1/2 activation using wild type and mutant receptors. Our findings suggest that, unlike certain other GPCRs that can activate ERK1/2 without the involvement of G protein, FPR requires signaling through a G protein-mediated pathway. Previous observations have shown that ERK1/2, activated through G protein, translocates to the nucleus where it stimulates transcription factors. In contrast, the scaffolding protein beta-arrestin retains the activated ERK1/2 in the cytoplasm to allow phosphorylation of cytoplasmic targets. Our experimental data show that both wild-type FPR and a mutant FPR, defective in beta-arrestin binding, induce nuclear translocation of activated ERK1/2 with similar ligand concentration dependence as seen for activation of cytosolic ERK1/2. We propose that FPR-mediated activation of ERK1/2 takes place primarily through G protein and is physiologically important to ensure transcriptional activation of myeloid immunomodulators, such as cytokines.


Roles of activated microglia in hypoxia induced neuroinflammation in the developing brain and the retina.
Amoeboid microglial cells (AMCs) in the developing brain display surface receptors and antigens shared by the monocyte-derived tissue macrophages. Activation of AMCs in the perinatal brain has been associated with periventricular white matter damage in hypoxic-ischemic conditions. The periventricular white matter, where the AMCs preponderate, is selectively vulnerable to hypoxia as manifested by death of premyelinating oligodendrocytes and degeneration of axons leading to neonatal mortality and long-term neurodevelopmental deficits. AMCs respond vigorously to hypoxia by producing excess amounts of inflammatory cytokines e.g. the tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) along with glutamate, nitric oxide (NO) and reactive oxygen species which collectively cause oligodendrocyte death, axonal degeneration as well as disruption of the immature blood brain barrier. A similar phenomenon is observed in the hypoxic developing cerebellum in which activated AMCs induced Purkinje neuronal death through production of TNF-α and IL-1β via their respective receptors. Hypoxia is also implicated in retinopathy of prematurity in which activation of AMCs has been shown to cause retinal ganglion cell death through production of TNF-α and IL-1β and NO. Because AMCs play a pivotal role in hypoxic injuries in the developing brain affecting both neurons and oligodendrocytes, a fuller understanding of the underlying molecular mechanisms of microglial activation under such conditions would be desirable for designing of a novel therapeutic strategy for management of hypoxic damage.


Size-selective microplastic uptake by freshwater organisms: Fish, mussel, and zooplankton.
Microplastics, as an emergent pollutant, have garnered substantial attention within aquatic environments, yet a significant knowledge gap persists regarding the interplay of organism size and pollution impacts on microplastic uptake in freshwater ecosystems. The main aim of the current study is to assess the microplastic ingestion by aquatic organisms across diverse trophic levels. To achieve this objective, zooplankton, mussels (Anodonta anatina), and fish (Carassius gibelio) were collected from the highly polluted Susurluk River Basin in Türkiye. The size distribution encompassed 160.8 ± 56.9 μm for the prevailing zooplankton, 6.9 ± 2.2 cm for mussel, and 20.4 ± 3.1 cm for fish, respectively. While no microplastic ingestion was observed among zooplankton, the finding highlights the influence of body-size and pollution on microplastic ingestion. In contrast, A. anatina and C. gibelio contained 617 and 792 microplastic particles, respectively. Predominantly, fibers emerged as the most prevalent microplastic type across trophic levels (except zooplankton) followed by films. Notably, only fish exhibited fragments within their gastrointestinal tract. A substantial correlation emerged between microplastic abundance and mussel size and weight, but no such correlation manifested for fish. The study also revealed a positive link between microplastic count and turbidity (phosphate and high Chl a level), impacting mussel ingestion capacity due to the variability in the food availability and potential shifts in feeding preferences. Conversely, no distinct pattern emerged for fish concerning water quality parameters and ingested microplastics. Consequently, our study underscores diverse microplastic uptake patterns in freshwater ecosystems, with a predominant frequency of microplastics falling with the 0.3 mm-3.0 mm range, emphasizing the significance of size-selective uptake by organisms.


Wandering spleen presenting as an adnexal mass.
Wandering spleen is an uncommon entity. The authors report the fifth case of wandering spleen presenting as a left adnexal mass.


2-Aza-1,3-butadiene derivatives featuring an anthracene or pyrene unit: highly selective colorimetric and fluorescent signaling of Cu2+ cation.
[Structure: see text] A new probe based on an anthryl derivative bearing an azadiene side chain selectively senses Cu2+ in acetonitrile through two different channels: the yellow-to-orange color change and a remarkable enhancement of the fluorescence, whereas the pyrenyl analogous behaves as a fluorescent sensor for Cu2+ and Hg2+ in aqueous environment.


Application of high-content screening for the study of hepatotoxicity: Focus on food toxicology.
Safety evaluation of thousands of chemicals that are directly added to or come in contact with food is needed. Due to the central role of the liver in intermediary and energy metabolism and in the biotransformation of foreign compounds, the hepatotoxicity assessment is essential. New approach methodologies have been proposed for the safety evaluation of compounds with the idea of rapidly gaining insight into effects on biochemical mechanisms and cellular processes and screening large number of compounds. In this sense, high-content screening (HCS) is the application of automated microscopy and image analysis for better understanding of complex biological functions and mechanisms of toxicity. HCS multiparametric measurements have been shown to be a useful tool in early toxicity testing during drug development, but also in assessing the impact from food chemicals and environmental toxicants. Reviewing the use of cellular imaging technology in the safety evaluation of food-relevant chemicals offers evidence about the impact of this technology in safety assessment.


Proton pump inhibitors and the risk of colorectal cancer: a systematic review and meta-analysis of observational studies.
The increased risk of colorectal cancer (CRC) associated with long-term use of proton pump inhibitors (PPIs) has attracted considerable attention; however, the conclusions of studies evaluating this correlation are inconsistent or even controversial. Therefore, we conducted a systematic review and meta-analysis to determine the association of PPI use with the risk of CRC. A systematic literature search was conducted in PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials to identify relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) for the associations between PPI use and the risk of CRC were estimated with a fixed-effects or random-effects model. We identified and included 9 observational studies (3 cohort studies and 6 case-control studies) comprising 1,036,438 participants. Overall, there was no statistically significant association between PPI use and the risk of CRC (pooled OR 1.26, 95% CI: 0.90-1.73; p = 0.166) when PPI exposure was assessed as a binary variable. However, a weak association between long-term use of PPIs and CRC was demonstrated (pooled OR 1.19, 95% CI: 1.09-1.31; p < 0.001) when the cumulative duration of PPI exposure was confined to > 5 years. Although the present meta-analysis suggests a weak association between long-term use (> 5 years) of PPIs and CRC, there is not enough statistical power to refute or confirm an association between the use of PPIs and CRC. More high-quality prospective cohort studies are needed to assess this correlation.


Survival Outcomes of Early-Stage Hormone Receptor-Positive Breast Cancer in Elderly Women.
Elderly women (≥ 70 years old) form a significant proportion of patients affected by breast cancer (BC); however, the treatment decisions for this patient population are complicated, owing to the presence of comorbidities, limited life expectancy, reduced tolerability of therapy, and limited enrollment in clinical trials. A growing body of evidence suggests equivalent outcomes in elderly patients with hormone receptor-positive early-stage breast cancer receiving primary endocrine therapy only or surgery with subsequent endocrine therapy. Whether these results are reproduced in the larger BC population outside of a clinical trial currently remains unclear. Women ≥ 70 years old diagnosed with early-stage invasive breast cancer between January 2008 and December 2013 with tumor size T1 or T2, minimal nodal involvement (N0 and N1), and estrogen and/or progesterone receptor positivity who started endocrine therapy within a year of diagnosis were identified using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked datasets. Endocrine therapy was identified using outpatient prescription fills for anastrozole, exemestane, fulvestrant, letrozole, raloxifene, tamoxifen, and toremifene; the first fill date was used as the treatment initiation date. Surgical intervention included either breast-conserving surgery or mastectomy. Women who received chemotherapy were excluded. Trends in the use of primary endocrine therapy only were assessed using Poisson regression. Multivariable Cox proportional hazard regression was used to estimate the association between undergoing surgery within a year of diagnosis and 5-year all-cause mortality, after adjusting for patient demographics, comorbidities, and clinical cancer characteristics. Similar methods were used to assess 5-year cancer-specific mortality, where noncancer mortality was treated as a competing risk. Overall, 8784 women were included in the analysis: 8006 (91%) received surgery with endocrine therapy and 778 (9%) received primary endocrine therapy alone. The proportion of women not receiving surgery remained consistent between 2008 and 2013 (p = 0.10). The 5-year mortality was 11% (n = 619), and 19% of all deaths were due to cancer causes (n = 117). After adjustment, 5-year mortality was lower among women undergoing surgery (HR 0.59, 95% CI 0.47-0.74, p < 0.0001). Similar results were found when looking at 5-year cancer-specific mortality (HR 0.52, 95% CI 0.30-0.90, p < 0.0001). Elderly breast cancer patients with early-stage hormone-receptor-positive disease receiving primary surgical intervention plus endocrine therapy may have significantly improved survival than those receiving primary endocrine therapy alone. This study suggests the importance of surgical intervention for elderly breast cancer patients and warrants further investigation and comprehensive geriatric assessment to identify subsets of elderly breast cancer patients who may benefit significantly from surgical intervention.


Retinofugal projections in the eel, Anguilla anguilla L. (Teleostei), visualized by the cobalt-filling technique.
The retinofugal projections in the eel were studied by use of the cobalt-filling technique. The optic tract projects contralaterally to the hypothalamic optic nucleus, the anterior periventricular nucleus, the lateral geniculate nucleus, the dorsomedial optic nucleus, four pretectal recipient areas, the optic tectum, and the tegmentum. Small ipsilateral projections were demonstrated in the hypothalamic optic nucleus, the dorsomedial optic nucleus, and the optic tectum.


Tyrosine dephosphorylated cortactin downregulates contractility at the epithelial zonula adherens through SRGAP1.
Contractile adherens junctions support cell-cell adhesion, epithelial integrity, and morphogenesis. Much effort has been devoted to understanding how contractility is established; however, less is known about whether contractility can be actively downregulated at junctions nor what function this might serve. We now identify such an inhibitory pathway that is mediated by the cytoskeletal scaffold, cortactin. Mutations of cortactin that prevent its tyrosine phosphorylation downregulate RhoA signaling and compromise the ability of epithelial cells to generate a contractile zonula adherens. This is mediated by the RhoA antagonist, SRGAP1. We further demonstrate that this mechanism is co-opted by hepatocyte growth factor to promote junctional relaxation and motility in epithelial collectives. Together, our findings identify a novel function of cortactin as a regulator of RhoA signaling that can be utilized by morphogenetic regulators for the active downregulation of junctional contractility.Epithelial cell-cell adhesions are contractile junctions, but whether contractility can be down-regulated is not known. Here the authors report how tyrosine dephosphorylation of the cytoskeletal scaffold, cortactin, recruits the RhoA antagonist SRGAP1 to relax adherens junctions in response to HGF.