Development of new lipophilic derivatives of tetragastrin: physicochemical characteristics and intestinal absorption of acyl-tetragastrin derivatives in rats.
In order to improve the intestinal absorption of tetragastrin (TG), we synthesized lipophilic derivatives of TG by acylation of its N-terminal amino group with acetic acid, caproic acid, and lauric acid. The purified TG derivatives, acetyl-tetragastrin (Ac-TG), caproyl-tetragastrin (Cap-TG), and lauroyl-tetragastrin (Lau-TG), were confirmed to be more lipophilic than the parent TG by high-performance liquid chromatography (HPLC). The pharmacological activities and the intestinal absorption of TG and its derivatives were examined by measuring gastric acid secretion. Stimulation of gastric acid secretion by these derivatives after intravenous administration was stronger than with native TG. When the acetyl- and caproyl-derivatives were administered into the large intestinal loops, a marked increase in gastric acid secretion was observed in comparison with TG, while no significant effect occurred following administration of the TG derivatives into the small intestines. These results indicated that chemical modification of TG with fatty acids improves the absorption of TG from the large intestines.


Lipopolysaccharide augments IgG and IgE responses of mice to the latex allergen Hev b 5.
LPS is a common contaminant in the health care environment and in latex examination gloves. We sought to investigate the role of LPS in enhancing the immune responses of mice to inhaled latex allergen. As our model allergen, we used a fusion protein containing the potent latex allergen Hev b 5. BALB/c mice were lightly anesthetized and given repeated intranasal doses of saline, LPS, and/or Hev b 5. The doses were given in 2 courses separated by a 6-week period, with the first course consisting of 6 doses and the second consisting of 3 doses. After the first set of immunizations, mice given Hev b 5 alone had no detectable IgG1 or IgE responses to Hev b 5, whereas mice given the antigen along with LPS had significant responses (IgG1, 0.73 U +/- 0.05; IgE, 0.88 U +/- 0.2). No enhancement of specific IgG2a was observed. A stimulatory effect of LPS on all 3 immunoglobulin types was apparent after the second course. Lymphocytes from mice immunized with LPS and Hev b 5 had increased proliferation to Hev b 5 and its fusion partner. LPS may be an important immunoadjuvant for the development of allergic reactions to latex protein allergens.


Intra-annual raw basal area increments (early-wood and late-wood) of Pinus nigra subsp. laricio Poiret trees from southern Italy at the pines׳ mesic to xeric distribution range.
This article contains tree rings data related to the research article entitled "An intra-stand approach to identify intra-annual growth responses to climate in Pinus nigra subsp. laricio Poiret trees from southern Italy" (Mazza et al., 2018). Most dendroclimatological studies on black pine have been conducted on the P. nigra subsp. nigra, while only few results on climate-growth relationships are available for other taxa such as P. nigra subsp. laricio, which has the narrowest distribution range of the collective species P. nigra. This data article provides tree rings data for the subsp. laricio at an intra-annual growth level, distinguishing early-wood (EW) and late-wood (LW), from an even aged forest stand from the Sila mountain area within the subspecies mesic to xeric distribution range.


Effect of adoptive T-cell immunotherapy on immunological parameters and prognosis in patients with advanced pancreatic cancer.
Immunotherapy is effective for many types of cancer, but its benefits in advanced pancreatic cancer, which has a poor prognosis, are not well established. In this study, the authors examined the effects of adoptive T-cell immunotherapy (ATI) on immune cell profiles and prognosis in patients with unresectable advanced pancreatic cancer. Seventy-seven patients with unresectable advanced pancreatic cancer were treated with six cycles of αβ T cells alone or in combination with chemotherapy or chemoradiation. Immune cell profiles in peripheral blood samples obtained before and after treatment were comprehensively evaluated by flow cytometry. Furthermore, associations between changes in immune cell frequencies and prognosis were determined. ATI prolonged survival to 18.7 months compared with previous estimates of 6.2-11.1 months for patients treated with chemotherapy alone. ATI decreased CD3+CD4+CD8- T cell frequency in peripheral blood and increased CD3+CD4-CD8+ T cell frequency. An increase in CD3+ T cells and CD3+TCRγδ- T cells in peripheral blood after treatment was associated with a good prognosis. ATI altered the immune profile in peripheral blood, including CD3+CD4-CD8+ T cells, and improved prognosis in pancreatic cancer.


Comparison of high-performance ion-exchange and ion-pair liquid chromatographic methods for the separation of tumour cell nucleotides.
Ion-exchange liquid chromatography (IELC) on a novel anion-exchanger, Polyanion SI HR 5/5, and the ion-pair technique (IPLC) using Hypersil ODS and/or MinoRPC reversed phases with tetrabutylammonium phosphate as pairing agent were compared for the separation of nucleotides. Modifications to the concentration gradient in IELC in the range 0.01-0.3 M ammonium phosphate resulted in the simultaneous separation of twelve to fourteen biologically important nucleotides. IPLC studies revealed that the capacity factors and resolution of nucleotides were more sensitive to the ionic strength than the methanol content. It was concluded that a well controlled ion concentration (0.08-0.09 M sodium chloride) should be maintained in the mobile phase and a linear methanol gradient ranging from 0 to 20% (v/v) was suitable for optimal resolution. Separations of four nucleotides and twelve nucleotides were further improved using a mixed-type reversed-phase column (C2/C18, MinoRPC). Using these complementary methods, it was possible to reveal the metabolic changes induced by different drug treatments (cyclophosphamide, DL-alpha-difluoromethylornithine) in the nucleotide pool of P388 leukaemia cells.


Novel potential inhibitors of complement system and their roles in complement regulation and beyond.
The complement system resembles a double-edged sword since its activation can either benefit or harm the host. Thus, regulation of this system is of utmost importance and performed by several circulating and membrane-bound complement inhibitors. The pool of well-established regulators has recently been enriched with proteins that either share structural homology to known complement inhibitors such as Sushi domain-containing (SUSD) protein family and Human CUB and Sushi multiple domains (CSMD) families or extracellular matrix (ECM) macromolecules that interact with and modulate complement activity. In this review, we summarize the current knowledge about newly discovered complement inhibitors and discuss their implications in complement regulation, as well as in processes beyond complement regulation such cancer development. Understanding the behavior of these proteins will introduce new mechanisms of complement regulation and may provide new avenues in the development of novel therapies.


Distribution of glycoconjugates in normal human skin using biotinyl lectins and avidin-horseradish peroxidase.
Lectin binding patterns in normal human skin were studied using five different biotinyl lectins and avidin-horseradish peroxidase. The staining pattern was specific for each lectin. In the epidermis, peanut agglutinin (PNA) and soybean agglutinin (SBA) preferentially stained the cell membranes of keratinocytes in the spinous and granular cell layers, indicating changes in the saccharide residues during keratinocyte differentiation. In the secretory segment of an eccrine sweat gland, the superficial cells gave a strong granular staining with Ricinus communis agglutinin (RCA). Dolichos biflorus agglutinin (DBA) and SBA, on the other hand, strongly stained the basal cells. With these lectins, two types of cells in the secretory segment were clearly distinguished. These results show that (1) PNA and SBA binding sites increase during the course of keratinocyte differentiation, and (2) RCA, DBA, and SBA are good markers to distinguish two types of cells in the secretory segment of an eccrine sweat gland.


Alcohol consumption and blood-cerebrospinal fluid barrier dysfunction in man.
The cerebrospinal fluid (CSF)/serum albumin ratio has been used a marker for blood CSF barrier permeability in 116 normal patients. We attempted to correlate the CSF/serum albumin ratio with a number of clinically measurable parameters including alcohol consumption. Alcohol consumption had a significant effect on the blood-CSF barrier. Our data indicate that alcohol increases blood CSF barrier permeability in a dose-dependent manner. The measured values of parameters indirectly indicative of alcohol consumption, such as gamma-glutamyltranspeptidase (gamma-GT) and erythrocyte mean corpuscular volume (MCV), were also correlated with enhanced blood-CSF barrier permeability. Although an apparent influence of age, body weight and sex on blood-CSF barrier permeability was observed, these correlations were not separable from the effect of alcohol consumption.


Localization of 99m Tc-pyrophosphate in an islet cell tumor of the pancreas.
A case of 99m Tc-pyrophosphate uptake in an islet cell tumor of the pancreas is presented. A possible relationship of pyrophosphate uptake in this tumor with uptake in other neuroectodermal tumors which are of neural crest origin is considered.


Could greenness modify the effects of physical activity and air pollutants on overweight and obesity among children and adolescents?
Greenness could theoretically increase the impact of physical activity (PA) and reduce the adverse effects of air pollution on overweight/obesity. However, no evidence systematically compares these two pathways, especially in longitudinal studies of children and adolescent's cohort. Greenness, PA, and air pollution were assessed by Normalized Difference Vegetation Index (NDVI), International Physical Activity Short Form, and 7 pollutants (PM1, PM2.5, PM10, SO2, NO2, CO, and O3). Each exposure was divided into low-/high-level groups based on the 50% quantile. Proportional hazards and logistic regression model were used to assess the associations of greenness, PA, pollutants with overweight/obesity. The incidence of overweight/obesity was 1.98% in the national survey, and the cumulative incidence and incidence density were 12.76% and 3.43 per 100 person-year in the dynamic cohort, separately. An increase of 0.1 units in NDVI was associated with a 12% lower risk of overweight/obesity, but no significant link between PA and incidence was observed. The HRs of the high-level of PM1, PM2.5, PM10, SO2, NO2, CO, and O3 on the risk of overweight/obesity were 2.21, 2.63, 1.88, 2.38, 1.33, 2.43, and 1.33 in the low-level of greenness, which was higher than those in the high-level of greenness. The AFs of PM1, PM2.5, PM10, SO2, NO2, CO, and O3 were 25.58%, 44.37%, 22.96%, 29.15%, 11.55%, 29.50%, and 10.92% in the low-level of greenness, which simultaneously was higher than those in the high-level of greenness. Moreover, the risk of overweight/obesity associated with high-level of greenness in the high-level of PM10, SO2, CO were 0.83, 0.81, and 0.83 respectively. Our findings confirmed that greenness has a moderating effect on the effects of air pollutants on childhood overweight/obesity especially in heavy-industry areas where PM10, SO2, and CO are the major pollutants, although it did not influence the association between PA and overweight/obesity risks.


Non-obstructive, non-refluxing uretero-colonic anastomosis by colonic sero-muscular excision and extra mural peri-ureteric wrap - A new technique in 17 children.
Uretero-enteric anastomosis with concomitant neobladder/augmentation/conduit becomes necessary when the bladder is unavailable or unfit for reimplantation or the ureters are short after high diversion or resection of lower ureteric pathology. Aiming to prevent both obstruction and reflux, we report a novel technique of sero-muscle denuded extra mural uretero-colic anastomosis. (Fig 1) The ureter was brought through the colonic mesentery. An adjacent zone of colon "abcd" was chosen to receive the ureter and colonic sero-muscular layer was excised from this zone. The ureter was placed on the raw area and uretero-colic anastomosis was done (a-d).The edges of the sero-muscular layer (ab and cd) were sutured over the ureter to complete a submucosal tunnel. The augmentation/neo bladder was completed such that the implanted ureter lay within it between two regions of re-configured bowel, this adding to the anti-reflux mechanism created by the extra mural peri-ureteric wrap. Surgical audit of this technique. 17 children (exstrophy - 8, ectopic ureter with bladder agenesis/hypoplasia - 3, prune belly - 2, neurogenic bladder -2, eosinophilic cystitis -1 and posterior urethral valve -1) underwent colonic implantation of 23 ureters while 6 ureters were drained via a trans uretero-ureterostomy into the reimplanted ureter. Nine augmentation, seven neo bladders and one sigmoid conduit was performed. The colon was available for ureteric re-implant in all patients. Pre-operatively 21 had hydroureteronephrosis. The bladder was agenetic/hypoplastic, small and fibrosed or poorly compliant. Eleven ureters had been diverted. Post operatively (mean follow up - 3.4 years) 16 of 30 renal units were normal, 11 had mild and three had moderate residual hydronephrosis, with no new hydronephrosis. Cystogram showed no reflux in 14 children and unilateral reflux in three (one re-diverted). Of 29 renal units drained directly or via trans uretero-ureterostomy by the uretero-colic reimplantation, none are obstructed, 26 have no vesico-ureteric reflux while three (10%) have reflux. We report results comparable to other extra mural techniques into the bowel, mainly from adult literature. Pediatric refluxing ureters are often large megaureters with or without preliminary diversions. The technique described avoids obstruction although having a slightly higher incidence of recurrent VUR. The ureters with recurrent reflux were massively dilated preoperatively and showed decrease in ureteric diameter postoperatively. The wrap, made for a larger ureter could have become too roomy and allowed reflux. This technique of non refluxing non obstructive uretero-colonic anastomosis has proven useful in selected situations.


Mobile Application for Monitoring and Preventing Cognitive Decline Through Lifestyle Intervention.
Diagnosing and preventing Alzheimer's disease is a complex task, partly due to being characterized by a lengthy asymptomatic stage. In order to tackle this, most preclinical studies are multidimensional in nature and largely focus on prevention through lifestyle interventions, such as improving nutrition and introducing physical as well as cognitive exercise. With the widespread use of mobile smart devices today, mobile health applications can help inform high-risk individuals at a low cost, while also aiding in the prevention of cognitive decline through constant virtual coaching services that contribute to lifestyle interventions. Under this light, a mobile application is developed in the context of this paper that provides risk assessment of individuals, daily monitoring of factors that have been found to help prevent cognitive impairment, and individually tailored guidance based on the individual's progress. The developed application is also capable of reassessing users' risk to track their progress, while also providing these services in an intuitive and user-friendly manner, which could enable the future development of more accurate models through the collected data.


Re-evaluation of excision repair in the mus304, mus306 and mus308 mutants of Drosophila.
The excision repair capacity of the third chromosomal mus mutations of Drosophila has been re-evaluated. A partial deficiency in the excision repair of pyrimidine dimers originally observed in the mus304 mutants is now attributed to the presence of a secondary phr mutation in that stock. Since the mus306 and mus308 stocks also carry secondary phr mutations, their partial deficiency in repair of pyrimidine dimers may also be the result of that secondary mutation. Accordingly, the Drosophila mutations that are now definitively associated with defects in the incision step of pyrimidine dimers removal are mei-9, mus201 and phr. The genes mus302 and mus310 appear to play a role in later stages of excision repair.


Effect of yohimbine stress on reacquisition of oxycodone seeking in rats.
Stress, a powerful precipitant of drug seeking during abstinence, may also accelerate the return to pathological patterns of intake after initial instances of drug reuse. To explore the effect of stress on a learning process underlying relapse, this study assessed the effect of yohimbine on reacquisition of oxycodone seeking. One hundred thirty-two male Sprague-Dawley rats underwent place conditioning with oxycodone (2 mg/kg, SC; ×6 days), extinction (vehicle × 6 days), and reconditioning with 0, 0.25, 2, or 5 mg/kg oxycodone (2 days). Yohimbine (0, 2.5, or 5 mg/kg, IP) was administered 30 min prior to reconditioning. Pretreatment with 2.5 mg/kg yohimbine increased, while 5 mg/kg yohimbine decreased, reacquisition of oxycodone-induced place preference. A follow-up study (n = 30) further indicated that the effect of yohimbine was specific to reacquisition. The observation that yohimbine can enhance reacquisition of oxycodone seeking supports the hypothesis that stress can facilitate learning processes involved in the unfolding of relapse.


Viral interference phenomena induced by foot-and-mouth disease temperature-sensitive mutants in bovine kidney cells.
Cultures of bovine kidney (BK) cells infected with temperature-sensitive (ts) mutants of foot-and-mouth disease virus (FMDV) were incubated at 38.5 degrees C, a temperature nonpermissive for mutant virus growth and RNA synthesis. The cells were subsequently resistant to viral growth and RNA synthesis when superinfected with wild-type FMDV and with heterologous fowl plague virus. The extent of interference was proportional to the multiplicity of infection of the ts mutant. It increased with time elapsed between infection with mutant and challenge infection, becoming greater than 99 percent after 24 hours. Interference was not proportional to decreased levels of cellular protein synthesis. The interference could be produced in the presence of actinomycin D, and thus was apparently mostly caused by the ts mutant itself rather than by interferon. The interference could not be produced in other less susceptible cell lines. Supernatant fluids from the BK cells infected with ts mutant virus interfered with wild-type FMD viral growth and RNA synthesis in fresh BK cells, and also showed low levels of activity in a vesicular stomatitis virus-plaque reduction assay. The properties of the supernatant fluid-interfering agent resembled to some extent those of an interferon. The ts mutant-mediated interference factor was apparently not able to diffuse into the supernatant fluid.


Measurement of total-body 40potassium in patients with urate calculi.
Fifty-eight patients with urate calculi and 31 patients with other (non-urate) calculi were examined for total-body potassium by means of a total-body counter. The patients with urate calculosis were found to differ significantly in their total-body K from patients with other calculi as well as from normal subjects. The results indicate that total-body potassium deficiency is one of the factors causing urate calculosis.


Timing of palatal surgery and speech outcome.
To examine the impact of age and lexical status at the time of primary palatal surgery on speech outcome of preschoolers with cleft palate. Forty children (33 to 42 months) with nonsyndromic cleft palate participated in the study. Twenty children (Group 1) were less lexically advanced and younger (mean age = 11 months) and 20 children (Group 2) were more lexically advanced and older (mean age = 15 months) when palatal surgery was performed. Samples of the children's spontaneous speech were compared on 11 speech production measures (e.g., size of consonant inventory, total consonants correct, % correct for manner of articulation categories, compensatory articulation usage, etc.). Next, listeners rated a 30-second sample of each child's connected speech for articulation proficiency and hypernasality, separately, using direct magnitude estimation (DME). Group differences were noted for 4 of the 11 speech production measures. Children in Group 1 exhibited larger consonant inventories (and true consonant inventories) and more accurate production of nasals and liquids compared to children in Group 2. On the DME task, significant group differences were found for ratings of articulation proficiency and hypernasality. Children in Group 1 exhibited better articulation and less hypernasality than children in Group 2. The findings suggested that children who were less lexically advanced and younger at the time of palatal surgery exhibited better articulation and resonance outcomes at 3 years of age.


Additional bevacizumab in EGFR-mutant lung adenocarcinoma patients who had oligo-progression after the failure of EGFR-TKI: A single-institute retrospective study.
In EGFR-mutant NSCLC patients with oligo-progression disease (oligo-PD) after the EGFR-TKI failure, additional local ablative therapy (LAT) including stereotactic ablative radiotherapy reportedly extends the duration of the current EGFR-TKI and prolongs survival times. In clinical practice, however, all the patients cannot receive LAT for oligo-PD. We retrospectively evaluated the efficacy and tolerability of additional bevacizumab as an alternative to LAT for oligo-PD after the EGFR-TKI failure in previously treated lung adenocarcinoma patients (median number of previous therapies, 2 regimens). Oligo-PD was defined as a situation in which disease progression has occurred in less than 5 anatomical sites after EGFR-TKI that has achieved at least stable disease. During a median 29.6-month follow-up period from the initiation of EGFR-TKI, 9 patients developed oligo-PD. One patient underwent LAT, but other 8 patients did not because of a few micro-metastatic lesions (n = 2), meningitis (n = 1), no indication of pleurodesis (n = 1), patient refusal (n = 2) or oligo-PD in the LAT treated sites (n = 3). Additional bevacizumab with continuation of the current EGFR-TKI had a disease control rate of 100% and a median time of progression-free survival from additional bevacizumab until another PD was 8.8 months. The reason for the discontinuation was because of another PD (n = 6) or treatment-related adverse events (n = 3). Four patients received sequential therapy and overall survival from additional bevacizumab was 10.1 months. Additional bevacizumab could be useful for EGFR-mutant adenocarcinoma patients with oligo-PD after the EGFR-TKI failure.


Asymmetric Pentafulvene Carbometalation--Access to Enantiopure Titanocene Dichlorides of Biological Relevance.
Unprecedented asymmetric copper-catalyzed addition of ZnEt2 (ZnBu2) to the exocyclic C=C bond of pentafulvenes C5H4(=CHAr) (Ar=2-MeOPh and related species) results in enantiomerically enriched (up to 93:7 e.r.) cyclopentadienyl ligands (C5H4CHEtAr; abbreviated Cp(R)). Copper catalyst promotion with both chiral phosphoramidite ligands and a phosphate additive is vital in realizing both acceptable enantioselectivities and reaction rates. Enantiomeric Cp(R)2TiCl2 complexes have been prepared; the (S,S) isomer is twice as active towards pancreatic, breast, and colon cancer cell lines as its (R,R) enantiomer at 24 h.


Endotracheal intubation of pediatric patients by paramedics.
Although a number of studies have described endotracheal intubation of adult patients in the prehospital setting, there are few studies on prehospital endotracheal intubation of pediatric patients. The purposes of our study were to determine how frequently prehospital endotracheal intubation was used in pediatric cardiopulmonary arrests when a paramedic trained in endotracheal intubation was present, to determine the success rate and complications associated with the procedure in the field, and to compare resuscitation rates and outcome in patients with and without prehospital endotracheal intubation. Our retrospective study covered a 38-month period and included all prehospital victims of medical cardiopulmonary arrest under the age of 19 years. Data were collected from field assessment forms and validated by hospital charts, autopsy reports, coroner's reports, death certificates, and emergency medical services central dispatch logs. Of 63 victims of medical cardiorespiratory arrest, 42 had intubating paramedics present at the scene. Twenty-eight of 42 patients (66%) had endotracheal intubation attempted. Eighteen of 28 attempts (64%) were successful, associated with a major complication rate of 7% (two of 28) and a minor complication rate of 39% (11 of 28). In patients less than 1 year old, only six of 16 (38%) had endotracheal intubation attempted and only three of six (50%) attempts were successful. Of the 18 patients who were intubated successfully before arrival at the hospital, nine (50%) survived to hospital admission and one (6%) survived to discharge. The remainder died in the emergency department.(ABSTRACT TRUNCATED AT 250 WORDS)


Corrected formula for rectangular area ratio (RAR), a parameter used to quantify airflow limitation on expiratory flow-volume curves.
Quantification of expiratory flow limitation during exercise has been demonstrated using computerized breath-by-breath analysis of the flow-volume curve. One of the parameters used in quantitation of airflow limitation is the rectangular area ratio (RAR) described in this journal by Ma et al. (2010). Upon closer review of the formula utilized in this paper, it is noted that the formula does not accurately capture the RAR, and the formula may underestimate the true RAR due to errors in various terms contained within the numerator and the denominator. A correct version of the formula is presented in this report. The correct formula does not require re-measurement of new variables but uses the existing variables in the correct mathematical and geometric context. This study has implications for validity of the data contained in the original paper as well as several other studies utilizing the same formula that have been published since the original publication. All future research using the RAR should use the correct formula, as contained in this paper.


Rates, patterns, and correlates of fitness tracker use among older adults with multiple sclerosis.
Older adults with multiple sclerosis (MS) engage in alarmingly low levels of physical activity. Fitness trackers may be a promising approach for promoting and monitoring physical activity among older adults with MS. This study reports on the rates, patterns of fitness tracker use in adults with MS who are over 60 years of age. We hypothesized that older adults with MS who use fitness trackers "users" would report significantly more physical activity than those who don't "non-users." Participants across the United States completed an online survey that included self-reported demographic and clinical characteristics, fitness tracker use questionnaire, and Godin Leisure-Time Exercise Questionnaire (GLTEQ) for measuring total and health-promoting physical activity (GLTEQ-HCS). Of the 440 participants who completed the full survey, 112 (28%) identified as fitness tracker users. The most common activity monitors were Fitbit®, Smartphone app, Apple® watch, and Garmin®. Fitness tracker users mostly reported having relapsing-remitting MS, less disability (i.e., lower Patient Determined Disability Steps), higher income, and higher rates of employment. There was a statistically significant difference in GLTEQ Total (t(438) = -3.8, p = .001) and GLTEQ-HCS (t(438) = -2.8, p = .006) scores between fitness tracker users and non-users. Self-reported step counts were strongly correlated with both GLTEQ Total (ρ = .50) and GLTEQ-HCS (ρ = 0.54) scores in fitness tracker users. Further research is warranted investigating fitness tracker use and interests among older adults with MS and how technology may be applied as a behavioral tool to increase physical activity among this growing portion of the MS population.


Determinants of COVID-19 vaccine hesitancy among pregnant persons.
Vaccines reduce the risk of contracting and developing complications from coronavirus disease 2019 (COVID-19). Pregnant people are at increased risk of disease-related complications but have a higher prevalence of vaccine hesitancy (VH) than their nonpregnant counterparts. This study aimed to describe risk factors and COVID-19- and vaccine-related perspectives that lead to VH among pregnant people in Mexico to target strategies to increase vaccine acceptance in this population. A cross-sectional survey-based study to evaluate risk factors and COVID-19- and vaccine-related perspectives associated with VH among pregnant people was conducted. Respondents were pregnant people of all ages attending a regular follow-up visit or admitted to labor and delivery in a third-level maternity hospital in Mexico. VH was defined as not having received a COVID-19 vaccine and either declining or being undecided to accept a vaccine during their pregnancy. We used bivariate and multivariable logistic regression models to estimate assess the relationship among demographic factors, COVID-19- and vaccine-related perspectives, and VH. A total of 1475 respondents completed the questionnaire; 216 (18%) were under the age of 18 years, and 860 (58%) had received at least one dose of a COVID-19 vaccine. In this sample, 264 (18%) were classified as vaccine hesitant. Key factors associated with VH were adolescence, having family as a primary source of information, first pregnancy, and history of vaccines in previous pregnancies. COVID-19 perspectives were also strongly associated with VH. Among pregnant people in Mexico, VH is associated with demographic factors, vaccination history, sources of information, and perceived risks to the fetus. This information is relevant to policy makers and health care professionals to identify those more likely to be hesitant and to inform strategies to increase vaccine uptake among pregnant people.


Differences in the yoghurt gel microstructure and physicochemical properties of bovine milk containing A1A1 and A2A2 β-casein phenotypes.
β-casein (β-CN) comprises a major portion of milk caseins and are present as several genetic variants. In this study, we investigated the effects of the β-CN A2 variant versus the A1 variant on the calcium distribution, acid gelation and foaming properties of milk, and the microstructure of acid milk gels. The results showed that milk containing the β-CN phenotype A2A2 had a higher proportion of free ionic calcium, enhanced foam formation capability and required a longer time for gelation to occur. The storage modulus at the end of fermentation was significantly lower for β-CN A2A2 milk gel compared with that from β-CN A1A1 milk. The microstructures of the gels characterised by both confocal microscopy and Cryo-SEM demonstrated the differences in the gel porosity and protein strand thickness. The more porous microstructure and thinner protein strands in the β-CN A2A2 milk gel resulted in a lower gel strength compared to β-CN A1A1 milk gel. These findings provide new insights to the subtle differences in the physical properties of milk containing β-CN A2A2 and A1A1 phenotypes, which could support dairy producers in the development of new dairy products with different functional properties.


Management of anterior cruciate ligament revision in adults: the 2022 ESSKA consensus part I-diagnostics and preoperative planning.
The aim of this ESSKA consensus is to give recommendations based on evidence and expert opinion to improve diagnosis, preoperative planning, indication and surgical strategy in ACL revision. The European expert surgeons and scientists were divided into four groups to participate in this consensus. A "literature group" (four surgeons); "steering group" (14 surgeons and scientists); "rating group" (19 surgeons) and finally "peer review group" (51 representatives of the ESSKA-affiliated national societies from 27 countries). The steering group prepared eighteen question-answer sets. The quality of the answers received grades of recommendation ranging from A (high-level scientific support), to B (scientific presumption), C (low level scientific support) or D (expert opinion). These question-answer sets were then evaluated by the rating group. All answers were scored from 1 to 9. The comments of the rating group were incorporated by the steering group and the consensus was submitted to the rating group a second time. Once a general consensus was reached between the steering and rating groups, the question-answer sets were submitted to the peer review group. A final combined meeting of all the members of the consensus was held to ratify the document. The literature review for the diagnosis and preoperative planning of ACL revision revealed a rather low scientific quality. None of the 18 questions was graded A and six received a grade B. The mean rating of all the questions by the rating group was 8.4 ± 0.3. The questions and recommendations are listed below. ACL revision surgery is a widely debated subject with many different opinions and techniques. The literature reveals a poor level of standardisation. Therefore, this international consensus project is of great importance. II.


Platelets and autoimmunity.
Vascular injury is the initial manifestation of inflammation resulting in the recruitment and activation of various cell types. The integrity of the vascular wall is monitored by platelets that become activated in the presence of exposed subendothelium. Besides their well-established role in haemostasis, ample data are now emerging on the many immunoregulatory functions of platelets. Platelets store and release a large plethora of cytokines, chemokines and growth factors. They also represent the largest circulating pool of many inflammatory mediators like P-selectin, CD40L and non-neuronal serotonin. Furthermore, complement activation occurs on the platelet surface and deposition of complement results in platelet activation. Overall, platelets have multiple functions in both innate and adaptive immunity. Further insight into the multifaceted role of platelets could therefore provide important clues into how we could implement current platelet therapy to reduce both platelet-induced thrombosis and inflammation. In this review, we discuss the current perceptions of platelet involvement in various autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and multiple sclerosis.


Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications.
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. Countless CRC patients undergo disease progression. As a hallmark of cancer, Warburg effect promotes cancer metastasis and remodels the tumor microenvironment, including promoting angiogenesis, immune suppression, cancer-associated fibroblasts formation and drug resistance. Targeting Warburg metabolism would be a promising method for the treatment of CRC. In this review, we summarize information about the roles of Warburg effect in tumor microenvironment to elucidate the mechanisms governing Warburg effect in CRC and to identify novel targets for therapy.


The adverse cardiovascular risk factor profile of women with pre-eclampsia develops over time in the years before pregnancy.
Women with a history of pre-eclampsia have an elevated lifetime risk of cardiovascular disease that may be partly attributed to an adverse cardiovascular risk factor profile, the etiology of which is unclear. Hypothesising that this adverse risk profile may begin to arise over time in the years before pregnancy, we sought to evaluate the pregravid changes over time in cardiovascular risk factors in women who go on to develop pre-eclampsia and those who do not. Retrospective cohort study using population-based administrative databases. Ontario, Canada. All nulliparous women who had singleton pregnancies between January 2011 and December 2018. All results for the following analytes between January 2008 and the start of pregnancy were identified: A1c, glucose, lipids, and transaminases. Mean values were compared between those with and without preeclampsia. The annual change for each analyte in the years before pregnancy was estimated using generalized estimating equations. Preeclampsia. The 156 278 women (of whom 3827 developed preeclampsia) had mean 4.0 ± 3.3 pregravid tests overall. The two most recent pregravid tests were performed at median 0.6 and 1.9 years before pregnancy, respectively. Women who developed pre-eclampsia had higher pregravid A1c, fasting glucose, random glucose, LDL-cholesterol, triglycerides, and ALT, and lower HDL-cholesterol, than their peers (all P < 0.0001). In the years before pregnancy, women who went on to develop pre-eclampsia had higher annual increases than their peers in triglycerides (13.8-fold higher; P = 0.0004) and random glucose (1.55-fold higher; P = 0.001), coupled with a greater annual decrease in HDL-cholesterol (9.7-fold higher; P = 0.002). During this time, fasting glucose increased in women who developed pre-eclampsia but decreased in their peers (P = 0.01). In women who develop pre-eclampsia, an adverse cardiovascular risk factor profile evolves over time in the years before pregnancy. In women who develop pre-eclampsia, an adverse CV risk factor profile evolves in the years before pregnancy.


Premenopausal osteoporosis associated with vitamin D-responsive calcium malabsorption. A case report.
A premenopausal woman with severe osteoporosis was found to have impaired calcium absorption, without other evidence of intestinal malabsorption. Although circulating levels of 25-OH-vitamin D and 1,25-(OH)2-vitamin D were normal, calcium absorption improved markedly following two weeks of treatment with synthetic 1,25-(OH)2-vitamin D. This suggests that a partial intestinal resistance to the actions of 1,25-(OH)2-vitamin D contributed to the development of her osteoporosis. This case report demonstrates the feasibility of using the calciuric response to a standard oral calcium load to screen for impaired calcium absorption in osteoporotic patients.


Histological preservation and ultrastructure of alveolar surfactant.
We have discussed the three-dimensional structure of lamellar bodies as visible intracellular storage sites of surfactant. Among the intraalveolar structures, tubular myelin, a liquid crystal, represents a large aggregate of surfactant lipids and proteins of still-unclear significance. Elaborate fixation methods permit visualization in situ of localized pools of fluid that sometimes extend laterally, covering small areas of the alveolar surface.


Treatment of Pain in Birds.
This article provides an overview of the current understanding of evidence-based clinical analgesic use in birds. The field of avian analgesia has dramatically expanded during the last 20 years, affording more options for alleviating both acute and chronic pain. These options include opioids, nonsteroidal anti-inflammatory drugs, local anesthetics, and/or other drugs like gabapentin, amantadine, and cannabinoids, acting at different points in the nociceptive system thereby helping to provide greater pain relief while reducing the risk of adverse effects when combined.


High-throughput synthesis and direct screening for the discovery of novel hydrolytic metal complexes.
A 'combinatorial catalysis' strategy was utilized to both rapidly synthesized organometallic complexes and to screen them for catalytic activity in chemical reactions. The application of this strategy has yielded several metal-complexes that catalyze the hydrolysis of carboxylic acid esters efficiently.


Measurement of the vaginal wall thickness by transabdominal and transvaginal ultrasound of women with vaginal laxity: a cross-sectional study.
An objective diagnostic method to understand vaginal laxity (VL) is still missing. The aim of our study is to determine whether vaginal wall thickness (VWT) measured by ultrasound may differ according to the abdominal or vaginal techniques and to assess whether clinical variables are associated with vaginal measurements of women with VL. A cross-sectional study conducted at a tertiary hospital included 82 women aged ≥ 18 years with VL complaints assessed by the Vaginal Laxity Questionnaire. Women who reported severe comorbidities or vulvovaginal disorders, previous treatment for VL, and use of vaginal estrogen in the last 6 months were excluded. Participants reporting VL underwent transabdominal (TAUS) and transvaginal ultrasound (TVUS) and physical examination and answered validated questionnaires. Descriptive data were given as mean and standard deviation, median (range), and absolute and relative frequency. The significance level adopted for this study was 5%. Sample size calculation was not performed for the present study. Mean age was 41.20 ± 8.64 years, and most participants were multiparous, with previous vaginal delivery and having vaginal intercourse. A statistically significant difference (up to 3 mm) between TAUS and TVUS measurements of the VWT was found in the proximal, middle-third, and distal compartments. A significant correlation was found between VWT and TAUS or TVUS in the mid-third and distal compartments. A significant correlation was found between the VWT measurements in TVUS and TAUS. Our findings might give the health professional more possibilities for investigating VWT according to patient characteristics.


Endoscopic injection of adrenalin in bleeding peptic ulcers.
Endoscopic injection of actively bleeding peptic ulcers with adrenalin was performed in 37 patients. Initial hemostasis was achieved in all. Five patients rebled and three required emergency surgery. Definitive hemostasis was achieved in 34 (92%). No significant local or systemic complication was observed. The technique in our patients was safe and deserves further comparative study with other methods of endoscopic hemostasis.


Simultaneous determination of iloperidone and its two active metabolites in human plasma by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study.
A selective, sensitive and accurate high-performance liquid chromatographic- tandem mass spectrometry (HPLC-MS/MS) method for simultaneous determination of iloperidone and its two active metabolites, P88 and P95, in human plasma has been first developed and validated. The analytes and internal standard (IS), pioglitazone hydrochloride, were extracted from human plasma via liquid-liquid extraction with ethyl acetate and separated on a CAPCELL PAK C18 MG IIIcolumn (150mm×2.0mm, 5μm) set at 40°C. The mobile phase was acetonitrile: 5mM ammonium formate containing 0.3% formic acid (pH 4.8) (25:75, v/v), with a flow rate of 0.35mL/min. The mass spectrometer was operated in multiple reaction monitoring (MRM) mode using the transitions m/z 427.2→261.2 for iloperidone, m/z 429.1→261.1 for P88 and P95, and m/z 357.1→133.7 for the I.S. (pioglitazone hydrochloride). The method was validated to be linear over the concentration range of 10-10,000pg/mL for iloperidone and P88, 50-15,000pg/mL for P95. The mean recoveries were more than 78.88%, and the intra- and inter-day precisions were less than 10.24% and accuracy was -5.78 to 5.40%, which indicated that the quantitative method was reliable and accurate. The validated method has been successfully applied to a human pharmacokinetic study of iloperidone and two active metabolites, P88 and P95, after oral administration of 4mg iloperidone tablets in 12 healthy Chinese volunteers.


A prediction rule for food challenge outcome in children.
In children with food-related symptoms, a food challenge is considered as the gold standard to diagnose allergy. If food allergy could be predicted by patient history and/or diagnostic tests, the number of time-consuming and sometimes risky food challenges could be decreased. We aimed to determine questionnaire and test-based characteristics, to predict the food challenge outcome (FCO) in children referred to a tertiary centre for the evaluation of food-related symptoms. Pre-challenge standardized questionnaires, skin prick tests (SPT), and specific IgE levels (sIgE) were obtained in patients that underwent a food challenge in our hospital in 2009. Characteristics of patients with positive and negative FCO were compared, and uni- and multivariate associations between predictors and FCO were calculated. Based on the multivariate model, a risk score was developed to predict the FCO. One hundred and twenty-nine challenges were analyzed, 41.9% had a positive outcome. Median age of both groups was 4.9 yrs (range 2.8-8.3). Patients with a positive FCO reacted faster with symptoms after allergen ingestion and had higher sIgE levels compared to children with negative FCO. A clinical risk score was developed based on the index food, 'time between allergen ingestion and complaints' and sIgE levels (range 0-10). The prognostic capacity of this model (AUC) was excellent (0.90). The very high- and low-risk groups (24% of patients) are both predicted excellent without misclassification. Positive FCO can be predicted by the index food, time between allergen ingestion and development of symptoms, and the sIgE level.


Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1.
In this study, we used small interfering RNA (siRNA) directed against vascular endothelial growth factor receptor 1 (vegfr1) mRNA to investigate the role of VEGFR1 in ocular neovascularization (NV). After evaluating many siRNAs, Sirna-027 was identified; it cleaved vegfr1 mRNA at the predicted site and reduced its levels in cultured endothelial cells and in mouse models of retinal and choroidal neovascularization (CNV). Compared to injection of an inverted control sequence, quantitative reverse transcriptase-PCR demonstrated statistically significant reductions of 57 and 40% in vegfr1 mRNA after intravitreous or periocular injection of Sirna-027, respectively. Staining showed uptake of 5-bromodeoxyuridine-labeled Sirna-027 in retinal cells that lasted between 3 and 5 days after intravitreous injection and was still present 5 days after periocular injection. In a CNV model, intravitreous or periocular injections of Sirna-027 resulted in significant reductions in the area of NV ranging from 45 to 66%. In mice with ischemic retinopathy, intravitreous injection of 1.0 mug of Sirna-027 reduced retinal NV by 32% compared to fellow eyes treated with 1.0 mug of inverted control siRNA. These data suggest that VEGFR1 plays an important role in the development of retinal and CNV and that targeting vegfr1 mRNA with siRNA has therapeutic potential.


Correlation of nitrites in breath condensates and lung function in asthmatic children.
We aimed to evaluate the value of exhaled breath condensates in monitoring airway inflammation in childhood asthma before and after high altitude climate therapy. Forty-eight asthmatic children on regular anti-asthma treatment with a normal FEV1 and positive skin prick test for house dust mites were recruited. All children had been referred to an alpine clinic for high altitude climate therapy, because of persistent asthmatic symptoms despite use of daily anti-inflammatory treatment. Subjects were assessed on their arrival and before departure from the alpine clinic. Spirometry, bronchial provocation tests and measurements of nitrites in breath condensates were performed. Median levels of nitrites were significantly higher before than after high altitude climate therapy (1.27 vs. 0.93 microm; p = 0.008). In addition, MEF50 improved significantly (p < 0.0005). There was a significant correlation between nitrites in breath condensates and MEF50 (r = -0.63, p < 0.0001), symptoms (r = 0.47, p = 0.0007) and airway hyper-reactivity (AHR) (r = -0.41, p = 0.004). In summary, we found a reduction in nitrites in breath condensates after a high altitude climate therapy. Significant correlations were found between nitrites and MEF50, AHR and symptoms. We conclude that the measurement of nitrites may be feasible to objectively assess airway inflammation in asthmatic children in order to detect ongoing inflammation in children with normal FEV1 but persistent symptoms.


Derivation of human embryonic stem cells in xeno-free conditions.
Human embryonic stem cells (hESC) have the potential to treat a wide range of diseases. Currently, the use of existing hESC lines in human clinical applications is limited, as they are derived from blastocysts subjected to immunosurgery with animal derived antibodies, and are maintained on mouse embryonic feeder (MEF) cells, in the presence of either fetal calf serum (FCS) or on Matrigel or with conditioned media from MEFs. Successful derivation of hESCs in xeno-free conditions is crucial in advancing stem cell therapy applications. Two hESC lines, one from chromosomally abnormal embryos and another cell line from normal embryos from the inner cell mass of human blastocysts are derived using a culture media that had 20% serum replacement (SR) and human FGF2 on human foreskin fibroblasts as feeder cells. Derivation and characterization of such xenofree hESCs suitable for clinical studies is described in this chapter.


[Psychiatric and postsurographic approach in the study of post-concussion syndromes following head or whiplash injuries. Correlation and additional aspects].
Purpose of this paper is to point out the interest in case of post-concussional syndroma following an head or whiplash injury to practice both: a posturographic examination objectiving the functioning of the different sensori-motor systems who maintain the body equilibrium giving an approach of the possibility of an organic etiology, psychiatric one giving the psychogenic aspect. Different therapeutics are proposed in regard of this double approach. Four cases illustrate this purpose.


Medicinal plants used for ophthalmological problems in Navarra (Spain).
Several plants have been found to have effective against number of ophthalmological problems in Navarra. Information was collected using semi-structured ethnobotanical interviews with 686 informants in 267 locations. In order to confirm the pharmacological application of the uses more cited by the informants, a literature review was conducted. A total of 57 pharmaceutical uses were reported, for 19 plants and 13 families, mainly represented by Asteraceae. The most frequently used parts were inflorescences, flowers, aerial parts, leaves and flowered aerial parts. The related affections fell into eleven categories: bloodshot eyes, watery eyes and wounds, improve vision, irrited eyelids, rheums and styes, tired eyes, conjunctivitis, eyewash, ocular problems in general. The most cited plants were: Chamaemelum nobile (L.) All., Santolina chamaecyparissus L. ssp. squarrosa (DC.) Nyman, Sambucus nigra L. ssp. nigra, Rosa agrestis Savi and Calendula officinalis L. None of them have been pharmacologically validated by Official International Organisms. From the therapeutic point of view, Allium sativum L., Foeniculum vulgare Mill., C. officinalis, and S. chamaecyparissus ssp. squarrosa deserve special attention, because ethnobotanical and pharmacological studies suggest that these medicinal plants are effective for ophthalmological problems. The present study constitutes a good basis for further phytochemical and pharmacological research of these four plants, which could be of interest in the design of new inexpensive, effective and safe drugs. The remaining plants are needed to be screened through standard pharmacological and clinical procedures for their activities.


Progressive oxidative membrane damage in erythrocytes after pulse treatment with t-butylhydroperoxide.
Development of membrane damage in erythrocytes in the presence of the radical-forming oxidant t-butylhydroperoxide is a well established fact (see, for example, Deuticke et al. (1986) Biochim. Biophys. Acta 854, 169-183). We have now demonstrated that a mere pulse treatment of erythrocytes (5-15 min) with this agent leads to subsequent development of progressive oxidative membrane damage in spite of the absence of exogenous oxidant. Damage comprises the occurrence of ion leakiness and subsequent colloid-osmotic lysis, enhancement of the transbilayer mobility of phospholipid analogues, and lipid peroxidation. There is, however, only very little concomitant oxidation and precipitation of hemoglobin. Defect formation is not due to oxidation of SH-groups nor is it directly related to lipid peroxidation, since it can be suppressed by thiourea without concommitant inhibition of lipid peroxidation. This 'spontaneous' development of membrane damage can be antagonized by metabolic substrates and by desferrioxamine, indicating that lack of protective metabolic resources as well as the presence of catalytic metal (iron) complexes are required for the development of membrane damage. This progressive development of injury in cells only temporarily exposed to an exogenous oxidant may be regarded as a more appropriate model for oxidative membrane damage under pathophysiological conditions in vivo than cells exposed to continuous damage by exogenous oxidants.


Calreticulin overexpression correlates with integrin-α5 and transforming growth factor-β1 expression in the atria of patients with rheumatic valvular disease and atrial fibrillation.
The aim of this study was to determine whether altered calreticulin expression and distribution contribute to the pathogenesis of atrial fibrillation (AF) associated with valvular heart disease (VHD). AF affects electrophysiological and structural changes that exacerbate AF. Atrial remodeling reportedly underlies AF generation, but the precise mechanism of atrial remodeling in AF remains unclear. Right and left atrial specimens were obtained from 68 patients undergoing valve replacement surgery. The patients were divided into sinus rhythm (SR; n=25), paroxysmal AF (PaAF; n=11), and persistent AF (PeAF; AF lasting >6 months; n=32) groups. Calreticulin, integrin-α5, and transforming growth factor-β1 (TGF-β1) mRNA and protein expression were measured. We also performed immunoprecipitation for calreticulin with either calcineurin B or integrin-α5. Calreticulin, integrin-α5, and TGF-β1 mRNA and protein expression were increased in the AF groups, especially in the left atrium in patients with mitral valve disease. Calreticulin interacted with both calcineurin B and integrin-α5. Integrin-α5 expression correlated with TGF-β1 expression, while calreticulin expression correlated with integrin-α5 and TGF-β1 expression. Despite similar cardiac function classifications, calreticulin expression was greater in the PeAF group than in the SR group. Calreticulin, integrin-α5, and TGF-β1 expression was increased in atrial tissue in patients with AF and was related to AF type, suggesting that calreticulin is involved in the pathogenesis of AF in VHD patients.


An observation-based adjustment method of regional contribution estimation from upwind emissions to downwind PM2.5 concentrations.
We propose a method to adjust contributions from upwind emissions to downwind PM2.5 concentrations to account for the differences between observed and simulated PM2.5 concentrations in an upwind area. Emissions inventories (EI) typically have a time lag between the inventory year and the release year. In addition, traditional emission control policies and social issues such as the COVID-19 pandemic cause steady or unexpected changes in anthropogenic emissions. These uncertainties could result in overestimation of the emission impacts of upwind areas on downwind areas if emissions used in modeling for the upwind areas were larger than the reality. In this study, South Korea was defined as the downwind area while other regions in Northeast Asia including China were defined as the upwind areas to evaluate applicability of the proposed adjustment method. We estimated the contribution of emissions released from the upwind areas to PM2.5 concentrations in South Korea from 2015 to 2020 using a three-dimensional photochemical model with two EIs. In these two simulations for 2015-2020, the annual mean foreign contributions differed by 4.1-5.5 µg/m3. However, after adjustment, the differences decreased to 0.4-1.1 µg/m3. The adjusted annual mean foreign contributions were 12.7 and 8.8 µg/m3 during 2015-2017 and 2018-2020, respectively. Finally, we applied the adjustment method to the COVID-19 pandemic period to evaluate the applicability for short-term episodes. The foreign contribution of PM2.5 during the lockdown period in China decreased by 30% after adjustment and the PM2.5 normalized mean bias in South Korea improved from 15% to -4%. This result suggests that the upwind contribution adjustment can be used to alleviate the uncertainty of the emissions inventory used in air quality simulations. We believe that the proposed upwind contribution adjustment method can help to correctly understand the contributions of local and upwind emissions to PM2.5 concentrations in downwind areas.


[Features of thrombophilia in nephrotic syndrome in children].
A comprehensive study was made of the hemostatic system in 25 children with the nephrotic syndrome and combined forms of glomerulonephritis. Hypercoagulation and a number of factors preventing thrombosis formation were revealed, namely the presence of so-called thrombin-resistant blocked fibrinogen, a rise of the total antithrombin potential at the expense of proteins differing from antithrombin III, sufficient reserves of plasminogen, and a moderate increase of fibrin degradation products.


Role of monocarboxylic acid transport in intracellular pH regulation of isolated proximal cells.
Isolated proximal cells were prepared from rabbit kidney cortex by mechanical dissociation. The intracytoplasmic pH (pHi) was measured in HCO3(-)-free media (external pH (pHe), 7.3) using the fluorescent dye 2,7-biscarboxyethyl-5,6-carboxyfluorescein (BCECF). Cells were acid-loaded by the nigericin technique. Addition of 70 mM Na+ to the cells caused a rapid pHi recovery, which was blocked by 0.5 mM amiloride. When the cells were exposed to 5 mM sodium butyrate in the presence of 1 mM amiloride, the H+ efflux was significantly increased and followed Michaelis-Menten kinetics. Increasing pHe from 6.4 to 7.6 at a constant pHi of 6.4 enhanced the butyrate activation of the H+ efflux. Increasing pHi from 6.5 to 7.2 at a constant pHe of 7.2 reduced the butyrate effect. 22Na uptake experiments in the presence of 1 mM amiloride showed that 1.5 mM butyrate increased the Na+ flux in the proximal cells (pHi 7.10). The efficiency of monocarboxylic anions in promoting a pHi recovery increased with the length of their straight chain (acetate less than propionate less than butyrate less than valerate). The data show that when the Na+/H+ antiporter is blocked, the proximal cells can regulate their pHi by a Na+-coupled absorption of butyrate followed by non-ionic diffusion of butyric acid out of the cell and probably also by OH- influx by means of the OH-/anion exchanger.


Synthesis and structure-function study about tenecin 1, an antibacterial protein from larvae of Tenebrio molitor.
Tenecin 1, an inducible antibacterial protein secreted in the larvae of Tenebrio molitor, has a long N-terminal loop and common structural feature of insect defensin family corresponding to cysteine stabilized alpha/beta motif. To study the function of the N-terminal loop and disulfide bridges, N-terminal loop deleted tenecin 1, reduced tenecin 1 and tenecin 1 were chemically synthesized and their activities were measured. N-terminal loop deleted tenecin and reduced tenecin 1 did not show antibacterial activity. Circular dichroism (CD) spectroscopy data revealed that the alpha-helical content of tenecin 1 and the other proteins increased in the presence of 50% (v/v) trifluoroethanol (TFE) and the alpha-helical content of tenecin 1 was much higher than that of the other proteins in buffer with or without 50% (v/v) TFE. These results suggest that disulfide bridges are necessary for the activity structure and the N-terminal loop plays an important role in the increase of alpha-helix in the membrane mimetic environment and the activity.


Cognitive load causes kinematic changes in both elite and non-elite rowers.
The current motor literature suggests that extraneous cognitive load may affect performance and kinematics in a primary motor task. A common response to increased cognitive demand, as observed in past studies, might be to reduce movement complexity and revert to previously learned movement patterns, in line with the progression-regression hypothesis. However, according to several accounts of automaticity, motor experts should be able to cope with dual task demands without detriment to their performance and kinematics. To test this, we conducted an experiment asking elite and non-elite rowers to use a rowing ergometer under conditions of varying task load. We employed single-task conditions with low cognitive load (i.e., rowing only) and dual-task conditions with high cognitive load (i.e., rowing and solving arithmetic problems). The results of the cognitive load manipulations were mostly in line with our hypotheses. Overall, participants reduced movement complexity, for example by reverting towards tighter coupling of kinematic events, in their dual-task performance as compared to single-task performance. The between-group kinematic differences were less clear. In contradiction to our hypotheses, we found no significant interaction between skill level and cognitive load, suggesting that the rowers' kinematics were affected by cognitive load irrespective of skill level. Overall, our findings contradict several past findings and automaticity theories, and suggest that attentional resources are required for optimal sports performance.


Photodynamic efficiency of a chlorophyll-a derivative in vitro and in vivo.
This paper reports the antitumor activity of a chlorophyll-a derivative, 2-[1-hydroxyethyl]-2-devinylpyropheophorbide-a (HEPa). Photophysical characteristics of HEPa were measured. And its cytotoxicity, intracellular localization, biodistribution, efficiency of photodynamic therapy (PDT), histological analysis were investigated using human bile duct carcinoma cells (QBC-939) and QBC-939 tumor bearing BABL/c nude mice as animal model. The results showed that HEPa was localized mainly within the cytoplasmic region and partially in lysosome. Biodistribution of HEPa in QBC-939 tumor bearing BABL/c nude mice showed its fast rate of clearance and high tumor selectivity. In vitro, HEPa had low dark toxicity and high photoxicity against QBC-939 cells. The inhibition rate of QBC-939 tumor could increase up to 92.3%, and H&E staining confirmed that HEPa could cause serious damage to the tumor with light dose of 100J/cm(2), implying that HEPa has potential to be a new antitumor candidate for photodynamic therapy (PDT).


Predictive factors of PNE success in a contemporary series: A single institution experience.
Peripheral nerve evaluation (PNE) permits a trial of sacral neuromodulation to determine candidates for single stage implant. Before routine fluoroscopy, PNE success rates were 40%-50% compared to approximately 77% with staged procedures. There are limited data on PNE success rates with the use of fluoroscopy and improved techniques. We evaluated a contemporary series of PNE patients to determine predictors of PNE success and persistent functional response following permanent implantation. A retrospective review of PNE patients at a large academic center from 2015 to 2019 was performed. Patients with urgency-frequency, urge incontinence, and/or fecal incontinence (FI) were included. Rates of permanent implant after successful PNE trial and continued improvement at ≥1 month were reviewed. Multivariable logistic regression determined predictors of PNE success and continued response at follow-up. A total of 102 PNE patients were included. A total of 78 patients (76.5%) were PNE responders. Predictors of PNE success included younger age (p = .014), urgency incontinence (p = .021), FI (p = .017), absence of a neurologic diagnosis (p = .04), presence of bellows and toe responses (p = .038), and perineal sensation (p = .027). A total of 68 of 78 PNE responders (87.2%) maintained optimal responses at ≥1 month. Absence of a neurologic diagnosis was predictive of persistent success at follow-up (p = .013). This contemporary PNE series revealed screening success equivalent to a two-staged approach. A small proportion of patients demonstrate suboptimal responses following permanent implant. Conversion from testing to permanent implant may not be the ideal outcome as it may overestimate success, and evaluation for persistent improvement should be investigated further as a more reliable indicator of successful screening.


[A comparative study of craniofacial morphologic differences between groups with shallow and deep antegonial notch depth].
To evaluate the correlation between craniofacial morphology and antegonial notch depth of the mandible. 42 patients of ear ly permanent dentition from Nanchang city, 21 with shallow and 21 with deep antegonial notch were selected. Lateral cephalometric film before treatment were taken. Hard tissue angular and linear measurement were performed. The correlation between antegonial notch depth and craniofacial morphology were analysed statistically. The angular measurements of SN-GoGn, S-ArGo, FH-GoMe,and ANS-Xi-Pm were significantly greater in the deep antegonial notch group. Other angles as SNB, SNP-BaN-CCGn, FH-NPg and MD-AA were significantly greater in the shallow antegonial notch group. For the linear measurements, those items as N-Me, ANS-Me,Convexity and LM-GoGn were significantly greater in the deep antegonial notch group. The deep antegonial notch group showed steeper mandibular plane, smaller chin, greater anterior facial height and gonial angle, and has a mandible with more backward and downward growth.


Conservation of the Bird Cherry (Padus Mill.) Germplasm by Cold Storage and Cryopreservation of Winter Cuttings.
Conservation at cryogenic temperatures, usually in liquid nitrogen (LN) or in its vapor, is the only reliable method for the long-term ex situ conservation of fruit and berry crops with vegetative reproduction. In this study, five bird cherry (Padus Mill.) varieties of different genetic origin from the bird cherry genebank at the N.I. Vavilov All-Russian Institute of Plant Genetic Resources (VIR, Russia) were tested for their response to cryopreservation in LN vapor (-183--185 °C). The response included viability under laboratory and field conditions, morphological assessment of the developed plants and biochemical analysis of fruits produced during three consecutive years by plants developed from cryopreserved cuttings. All parameters were compared to those recorded after cold storage of cuttings (-5 °C), a routine mid-term conservation method currently used at the VIR genebank. The initial viability of winter cuttings varied from 86.7% to 93.3%. Six-month cold storage and cryopreservation reduced viability to 53.3-86.7% and 43.3-60.0%, respectively, which was above the 40% viability threshold in all varieties tested. Cuttings after cold storage showed better viability when recovered in the laboratory (80% mean viability) than in the field (58% mean viability); viability of cryopreserved cuttings was not affected by recovery conditions. The results of a two-way analysis of covariance suggested that storage and recovery conditions had the most significant effect on viability (p < 0.0001), while the effects of genotype (p = 0.062) and factor interactions (p = 0.921) were minor. Cryopreservation had little or no influence on morphological parameters of the plants recovered in the field, including plant height, number of shoots, internodes and roots, and root length. Similarly, no effect of cryopreservation was recorded on dry matter content, total sugar content and ascorbic acid concentration in fruits produced by plants developed from the cryopreserved cuttings. These results suggest that cryopreservation in LN vapor is a reliable method for conservation of the bird cherry genetic collection and is worth testing with a broader variety of genotypes.


[Base excision repair of DNA: glycosylases].
The review considers the role of base excision repair in maintaining the constancy of genetic information in the cell. The genetic control and biochemical mechanism are described for the first stage of base excision repair, which is catalyzed by specific enzymes, DNA glycosylases.


Cholesterol-nitrone conjugates as protective agents against lipid oxidation: A model membrane study.
Free radical scavengers such as α-phenyl-N-tert-butylnitrone (PBN) have been widely used as protective agents in several biological models. We recently designed two PBN derivatives by adding a cholesterol moiety to the parent nitrone to increase its lipophilicity. In addition to the cholesterol, a sugar group was also grafted to enhance the hydrophilic properties at the same time. In the present work we report on the synthesis of a third derivative bearing only a cholesterol moiety and the physical chemical and antioxidant characterization of these three derivatives. We demonstrated they were able to form stable monolayers at the air/water interface and with the two derivatives bearing a sugar group, repulsive interactions with 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) were observed. We next investigated the interaction with DLPC on a liposome model. Fluorescence spectroscopy experiments showed the addition of a cholesterol moiety causes an ordering effect whereas the presence of the sugar group led to a disordering effect. The protective effect against lipid oxidation was then investigated using dynamic light scattering and the formation of conjugated dienes was quantified spectrophotometrically. Two oxidizing systems were tested, i.e. the AAPH-thermolysis which generates peroxyl radicals and the Fenton reagent which is responsible of the formation of hydroxyl radicals. Due to their membrane localization, the three cholesteryl-PBN derivatives are able to prevent lipid oxidation with the two types of radical inducers but with a different mode of action.


Comparing early withdrawal or avoidance of steroids with standard steroid therapy in kidney transplant recipients.
This Practice Point commentary discusses the findings and limitations of an open-label, multicenter, prospective trial conducted by Vincenti et al., in which kidney transplant recipients receiving basiliximab, ciclosporin microemulsion, and enteric-coated mycophenolate sodium were randomized to standard corticosteroid therapy, steroid withdrawal 7 days after transplantation, or complete steroid avoidance. The trial failed to show noninferiority of the steroid-sparing arms in terms of calculated glomerular filtration rate at 12 months. In addition, the steroid-sparing groups had an increased cumulative incidence of biopsy-proven acute rejection at 12 months. This commentary highlights the issues to consider when interpreting and generalizing these results, including the under-representation of African Americans in the study population, the short duration of follow-up, and the switching of some patients between steroid-containing and steroid-sparing immunosuppressive regimens. The benefits of steroid-free immunosuppression versus low maintenance doses of steroids in kidney transplant recipients remain unclear.


Quantifying semantic similarity of clinical evidence in the biomedical literature to facilitate related evidence synthesis.
Published clinical trials and high quality peer reviewed medical publications are considered as the main sources of evidence used for synthesizing systematic reviews or practicing Evidence Based Medicine (EBM). Finding all relevant published evidence for a particular medical case is a time and labour intensive task, given the breadth of the biomedical literature. Automatic quantification of conceptual relationships between key clinical evidence within and across publications, despite variations in the expression of clinically-relevant concepts, can help to facilitate synthesis of evidence. In this study, we aim to provide an approach towards expediting evidence synthesis by quantifying semantic similarity of key evidence as expressed in the form of individual sentences. Such semantic textual similarity can be applied as a key approach for supporting selection of related studies. We propose a generalisable approach for quantifying semantic similarity of clinical evidence in the biomedical literature, specifically considering the similarity of sentences corresponding to a given type of evidence, such as clinical interventions, population information, clinical findings, etc. We develop three sets of generic, ontology-based, and vector-space models of similarity measures that make use of a variety of lexical, conceptual, and contextual information to quantify the similarity of full sentences containing clinical evidence. To understand the impact of different similarity measures on the overall evidence semantic similarity quantification, we provide a comparative analysis of these measures when used as input to an unsupervised linear interpolation and a supervised regression ensemble. In order to provide a reliable test-bed for this experiment, we generate a dataset of 1000 pairs of sentences from biomedical publications that are annotated by ten human experts. We also extend the experiments on an external dataset for further generalisability testing. The combination of all diverse similarity measures showed stronger correlations with the gold standard similarity scores in the dataset than any individual kind of measure. Our approach reached near 0.80 average Pearson correlation across different clinical evidence types using the devised similarity measures. Although they were more effective when combined together, individual generic and vector-space measures also resulted in strong similarity quantification when used in both unsupervised and supervised models. On the external dataset, our similarity measures were highly competitive with the state-of-the-art approaches developed and trained specifically on that dataset for predicting semantic similarity. Experimental results showed that the proposed semantic similarity quantification approach can effectively identify related clinical evidence that is reported in the literature. The comparison with a state-of-the-art method demonstrated the effectiveness of the approach, and experiments with an external dataset support its generalisability.


Smoking and obesity associated BDNF gene variance predicts total and cardiovascular mortality in smokers.
The brain derived neurotrophic factor (BDNF) locus has been implicated in psychiatric and substance related disorders. Recent genome-wide association studies (GWAS) have shown strong associations between single nucleotide polymorphisms in BDNF, smoking behaviour and high body mass index (BMI). Our aim was to test whether genetic BDNF variation alters the risk of smoking related morbidity and mortality. Cox proportional hazards models were used to relate the BDNF rs4923461(A/G) polymorphisms to all-cause, cancer and cardiovascular mortality and cardiovascular disease (CVD) incidence adjusted for age, sex, BMI, and smoking quantity. The Malmö Diet and Cancer Study (MDCS), a population based prospective cohort study (n=30 447). We obtained complete data on 25 071 subjects, of whom 6507 were current smokers and 18 564 were non-smokers who underwent a baseline examination from 1991-1996. During a mean follow-up time of 12 years, 1049 deaths (346 cardiovascular deaths and 492 cancer deaths) and 802 incident CVD events occurred among current smokers. The major allele (A) of rs4923461 was significantly associated with ever having smoked (p=0.03) and high BMI (p=0.001). The A-allele was associated with risk of all-cause (HR=1.12, 95% CI 1.00 to 1.25; p<0.05) and CVD (HR=1.23, 95% CI 1.01 to 1.49; p=0.04) mortality. There was no significant association between the rs4923461 and cancer mortality or CVD incidence. Our data suggest that smoking- and obesity-associated variation of the BDNF gene affects the risk of death, especially due to cardiovascular causes, in smokers. Determination of the BDNF genotype in smokers may guide the need for smoking cessation interventions.


Influence of solar radiation and leaf angle on leaf xanthophyll concentrations in mangroves.
Mangroves have similar xanthophyll cycle components/chlorophyll ratios [i.e. (V+A+Z)/chl] to other plant species. (V+A+Z)/chl ratios were sensitive to the light environment in which leaves grew, decreasing as light levels decreased over a vertical transect through a forest canopy. The (V+A+Z)/chl ratio also varied among species. However, in sun leaves over all species, the (V+A+Z)/chl ratios correlate with the proportion of leaf area displayed on a horizontal plane, which is determined by leaf angle. Thus, leaf angle and the xanthophyll cycle may both be important in providing protection from high light levels in mangrove species. A canopy survey assessed whether (V+A+Z)/chl ratios could be correlated with species dominance of exposed positions in forest canopies.Rhizophora mangroves, with near-vertical leaf angles, andBruguiera parviflora, with small, horizontal, xanthophyllrich leaves, dominated the canopy, whileB. gymnorrhiza, a species with large, horizontally arranged leaves, was less abundant at the top of the canopy. Thus, two different strategies for adapting to high solar radiation levels may exist in these species. The first strategy is avoidance through near vertical leaf angles, and the second is a large capacity to dissipate energy through zeaxanthin. The (V+A+Z)/chl ratio was also negatively correlated with the epoxidation state of the xanthophyll cycle pool (the proportion present as violaxanthin and half that present as antheraxanthin) at midday. This suggested that the requirement for dissipation of excess light (represented by the midday epoxidation state) may influence the (V+A+Z)/chl ratio.


Lateral subluxation of the atlas in rheumatoid arthritis.
Two patients with lateral subluxation of the atlas resulting from rheumatoid disease involving the upper cervical spine have been described. The deformity can be suspected on clinical grounds and in one of our two patients spinal cord damage was a sequel. Erosion of the opposing surfaces of the odontoid and lateral masses of the atlas with detachment of the transverse ligament and deeper fibres of the posterior longitudinal ligament appear to underlie this deformity. Radiological confirmation may require AP views with the head tilted to one or other side.


Spatial configuration of mRNA 5'-terminus.
Nuclear magnetic resonance investigation has revealed that the 5'-terminus m7G5'ppp5'Am of mRNA displays a spatial configuration in which the bases form stacked arrays. Details of the conformation as derived from coupling constants, shift trends and ring current considerations are discussed.


Ventral tegmental area lesions differentially affect responses controlled by CS-US contiguity and response-reinforcer contingency in the rat.
Rats with electrolytic lesions of the ventral tegmental area (VTA, n = 32), or sham lesions (n = 32), were tested in four behavioral paradigms in a shuttlebox. The paradigms were designed to assess the motivational influence of CS-US contiguity and response-reinforcer contingency. The VTA lesion increased the number of shuttle responses in the paradigms involving contiguity between a warning signal and a shock, without affecting responses controlled by the contingency between shuttling and shock avoidance. Escape latency was reduced by the lesion, but the general locomotor activity of the rats was not increased.The data suggest that the VTA normally acts to inhibit behavior motivated by classically conditioned fear. The results are discussed in terms of the hypothesis that the dopaminergic projection from the VTA to the nucleus accumbens plays a role in the inhibition of emotionally motivated motor responses.


Atheromatosis of the brain-supplying arteries: Circle of Willis, basilar, vertebral and their branches.
Atherosclerotic plaques in the brain-supplying arteries are slowly-developing alterations of vascular structures that can lead to neurological impairment due to stenosis and insufficient oxygenation of eloquent brain areas. The aim of this study is to provide detailed demographic information related to the incidence of atherosclerotic plaques in the cerebral arteries. Forty-eight circles of Willis (21 men, 21 women, mean age: 70.26, six samples unknown) were macroscopically analyzed for length, diameter, and presence of atherosclerotic plaques. Statistical analysis was used to identify potential differences in the locations and frequencies of atherosclerotic plaques in relation to age and sex. The study sample revealed 261 atherosclerotic plaques. The key findings were significant correlations between plaque development and age and between plaque location and age; however, there was no significant sex difference. The upper and lower branches of the middle cerebral artery (MCA) were novel locations predisposing to plaque development. A cut-off value at 60 years revealed a significant difference in plaque development and distribution. There were no significant sex differences in the occurrence of atherosclerotic plaques.


Correction: Cazzoletti et al. Risk Factors Associated with Nursing Home COVID-19 Outbreaks: A Retrospective Cohort Study. Int. J. Environ. Res. Public Health 2021, 18, 8434.
The authors would like to make the following corrections to this paper [...].


A neural network model of a quasiperiodic elliptically polarizing undulator in universal mode.
Machine learning has recently been applied and deployed at several light source facilities in the domain of accelerator physics. Here, an approach based on machine learning to produce a fast-executing model is introduced that predicts the polarization and energy of the radiated light produced at an insertion device. This paper demonstrates how a machine learning model can be trained on simulated data and later calibrated to a smaller, limited measured data set, a technique referred to as transfer learning. This result will enable users to efficiently determine the insertion device settings for achieving arbitrary beam characteristics.


Oxidation-reduction potential studies: a new method in pharmacology principles, materials, and methods.
Oxidation-reduction (redox) potential measurement is not used in pharmacology at the present time. However, it represents a physicochemical parameter that may be as important as the other currently used physicochemical parameters, such as pH and pKa. Redox potential variations include conformational modifications that may influence bioavailability of drugs. We report here an original and convenient equilibrium method to determine this potential in biological fluids, especially in blood.


Prediction of long-term hospitalisation and all-cause mortality in patients with chronic heart failure on Dutch claims data: a machine learning approach.
Accurately predicting which patients with chronic heart failure (CHF) are particularly vulnerable for adverse outcomes is of crucial importance to support clinical decision making. The goal of the current study was to examine the predictive value on long term heart failure (HF) hospitalisation and all-cause mortality in CHF patients, by exploring and exploiting machine learning (ML) and traditional statistical techniques on a Dutch health insurance claims database. Our study population consisted of 25,776 patients with a CHF diagnosis code between 2012 and 2014 and one year and three years follow-up HF hospitalisation (1446 and 3220 patients respectively) and all-cause mortality (2434 and 7882 patients respectively) were measured from 2015 to 2018. The area under the receiver operating characteristic (ROC) curve (AUC) was calculated after modelling the data using Logistic Regression, Random Forest, Elastic Net regression and Neural Networks. AUC rates ranged from 0.710 to 0.732 for 1-year HF hospitalisation, 0.705-0.733 for 3-years HF hospitalisation, 0.765-0.787 for 1-year mortality and 0.764-0.791 for 3-years mortality. Elastic Net performed best for all endpoints. Differences between techniques were small and only statistically significant between Elastic Net and Logistic Regression compared with Random Forest for 3-years HF hospitalisation. In this study based on a health insurance claims database we found clear predictive value for predicting long-term HF hospitalisation and mortality of CHF patients by using ML techniques compared to traditional statistics.


The influence of mouse strain and housing on the immune response.
Five strains of mice housed individually (one per cage) or in a group (five per cage) were immunized with sheep erythrocytes (SRBC) to determine if the major histocompatibility complex (MHC) was associated with altered immune reactivity based on housing. Individually housed mice from two strains which shared neither the H2D and H2K loci, produced more antibody forming spleen lymphocytes to SRBC than group-housed mice. Corticosterone levels were not related to the level of the immune response. Thus, genetic factors related to the MHC do not influence alteration of the immune response which occurs with differential housing conditions.


Survey of abortion providers in Seoul, Korea.
A survey of abortion providers in Seoul in late 1977 reveals a threefold increase in the rate of abortion and a greater than threefold rise in the ratio of abortions to live births since 1970. The survey findings also show that the overwhelming proportion of these abortions are performed in private clinics, by obstetrician-gynecologists, during the first trimester. The Seoul figures, which are similar to those of Romania and are higher than those of Japan in the early 1960s, indicate that abortion has contributed substantially to Korea's reduced fertility.


Sterile products: advances and challenges in formulation, manufacturing and regulatory aspects--a regulatory review perspective.
For several decades, the FDA has undertaken many initiatives to improve the quality and safety of sterile drug products. In recent years, efforts have also been undertaken to accelerate the rate for application approval by adding earlier involvement of microbiology reviewers in drug development. Product and manufacturing process development, as well as safe use and product design, are among the elements of enhanced technical involvement. An overview of the product quality microbiology aspects for sterile drugs is provided.


Efficacy of selamectin against adult flea infestations (Ctenocephalides felis felis and Ctenocephalides canis) on dogs and cats.
Selamectin was evaluated in eight controlled studies (4 in dogs, 4 in cats) to determine the efficacy of a single topical unit dose providing the recommended minimum dosage of 6mgkg(-1) against Ctenocephalides felis felis and Ctenocephalides canis fleas on dogs and against C. felis on cats. In addition, the effect of bathing on the efficacy of selamectin against C. felis was evaluated. Identical studies were performed in Beagles and domestic shorthaired cats. For each study, animals were allocated randomly to treatments of 8-12 animals each. All studies (dog studies A, B, C, and D and cat studies A, B, C, and D) evaluated the efficacy of selamectin without bathing. In addition, study C in both dogs and cats evaluated efficacy with a shampoo bath at 24h after dosing, and study D evaluated the efficacy of selamectin with water soaking at 2h after dosing or with a shampoo bath at 2-6h after dosing. Dog study B evaluated efficacy against C. canis, whereas all other studies used C. felis. In each study, selamectin was administered on day 0 as a topical dose that was applied directly to the skin in a single spot at the base of the neck in front of the scapulae. Dogs and cats were infested with approximately 100 viable unfed C. felis or C. canis on days 4, 11, 18, and 27. On days 7, 14, 21, and 30, approximately 72h after infestation, a comb count of the number of viable fleas present on each animal was made. For C. felis and C. canis for dogs and cats, compared with controls, selamectin achieved significant reductions in geometric mean adult flea comb counts of > or =98.9% on days 7, 14, and 21 in all eight studies. On day 30, the reduction for C. felis remained at or above 98.0%. This included the dogs and cats that were soaked with water or bathed with shampoo at 2, 6, or 24h after treatment. There were no significant (P>0.05) differences between the flea counts from selamectin-treated animals in these studies, regardless of bathing status. On day 30, a significant reduction of 91.8% was achieved against C. canis on dogs. Thus, these studies demonstrated that a single topical unit dose of selamectin was highly effective against adult fleas on dogs and cats for at least 27 days.


Dissociation of beta-adrenergic receptors from hormone responsiveness during maturation of the rat reticulocyte.
Intact rat erythrocytes and reticulocytes have been studied in relation to their concentration of beta-adrenergic receptors and their responsiveness to beta-adrenergic catecholamines. Characteristics of the beta-receptor, as determined by binding of 125I-labelled hydroxybenzylpindolol, were compared among control erythrocytes and reticulocytes. The dissociation constant (Kd = 0.1--0.2 nM), association and dissociation kinetics, and stereospecificity for (--)-isomers of agonists and antagonists were similar in both cell types. The reticulocyte population contained four times more receptors per cell than the control erythrocytes. However, reticulocytes were 25 times more responsive than control cells to isoproterenol, as measured by the formation of cyclic AMP. After peak reticulocytosis, cells rapidly lost 95% of their maximum hormone responsiveness, but beta-receptors declined much more slowly. The 4-fold decrease in beta-receptors was associated with a 4-fold decrease in cell volume as the reticulocytes matured. The density of beta-receptors was unchanged. However, responsiveness to isoproterenol in the reticulocytes when expressed on the basis of cell volume was still nine times greater than the control cells. Thus, maturation of reticulocytes is associated with an uncoupling of persistent beta-receptors from catecholamine responsiveness.


Platelet and extracellular vesicles in COVID-19 infection and its vaccines.
Platelets are at the crossroads between thrombosis and inflammation. When activated, platelets can shed bioactive extracellular vesicles [pEVs] that share the hemostatic potential of their parent cells and act as bioactive shuttles of their granular contents. In a viral infection, platelets are activated, and pEVs are generated with occasional virion integration. Both platelets and pEVs are engaged in a bidirectional interaction with neutrophils and other cells of the immune system and the hemostatic pathways. Severe COVID-19 infection is characterized by a stormy thromboinflammatory response with platelets and their EVs at the center stage of this reaction. This review sheds light on the interactions of platelets, pEVS and SARS-CoV-2 infection and prognostic and potential therapeutic role of pEVs. The review also describes the role of pEVs in the rare adenovirus-based COVID-19 vaccine-induced thrombosis thrombocytopenia.


Clinical predictors and microbiology of ventilator-associated pneumonia in the intensive care unit: a retrospective analysis in six Italian hospitals.
The purpose of this study was to assess the main clinical predictors and microbiological features of ventilator-associated pneumonia (VAP) in the Intensive Care Unit (ICU) environment. This work is a retrospective analysis over one year from September 2010 to September 2011. Patients' risk factors, causes of admission, comorbidities and respiratory specimens collected in six Italian ICUs were reviewed. Incidence and case fatality rate of VAP were evaluated. After stratification for VAP development, univariate and multivariate analyses were performed to assess the impact of patients' conditions on the onset of this infection. A total of 1,647 ICU patients (pts) were considered. Overall, 115 patients (6.9 %) experienced at least one episode of VAP. The incidence rate for VAP was 5.82/1,000 pts-days, with a case fatality rate of 44.3 %. Multivariate analysis showed that admission for neurological disorders (aIRR 4.12, CI 1.24-13.68, p = 0.02) and emergency referral to ICU from other hospitals (aIRR 2.11, CI 1.03-4.31, p = 0.04) were associated with higher risk of VAP, whereas a tendency to a higher risk of infection was detected for admission due to respiratory disease, cardiac disease, trauma and for having obesity or renal failure. A total of 372 microbiological isolates from respiratory specimens were collected in VAP patients. The most common species were Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa, showing high resistance rates to carbapenems. Neurological disorders and emergency referral at the admission into the ICU are significantly associated with the onset of VAP. A high incidence of multi-drug resistant Gram- species was detected in the respiratory specimens.


Lectin mediated adhesion of Streptococcus pneumoniae and its specific inhibition in vitro and in vivo.
According to our hypothesis, bacterial lectins play an important role in the organotropy of infectious diseases which is analogous to the metastasis of tumor cells. As a model for proving this, we investigated the specific lectin of Streptococcus pneumoniae, which has N-acetyl-D-glucosamine/D-galactose (GlcNAc-Gal) specificity. In vitro, after incubation with Streptococcus pneumoniae, cryotome sections of various organs from Balb/c-mice showed remarkable quantitative differences of bacterial adhesion to the organ cells. Whereas lungs and meninges were closely settled with bacteria, attachment to other organs (e.g. liver, spleen, brain) was lacking. In vitro lectin-blocking by GlcNAc completely prevented the adherence of Streptococcus pneumoniae to lungs and meninges. Other non-related carbohydrates (e.g. D-mannose, D-xylose) showed no effect. During in vivo experiments with Balb/c-mice, intratracheal application of Streptococcus pneumoniae led to a diffuse settlement of the lung. However, bacterial lectin-blocking with intratracheal GlcNAc administration completely inhibited adhesion to the organ cells of the lung. Therefore blocking of bacterial adhesins with competitive specific monosaccharides can completely prevent bacterial adhesion processes, a fact, which opens therapeutical aspects.


[National and regional social observatories of tuberculosis in eight countries in Latin America and the CaribbeanObservatórios sociais nacionais e regional de tuberculose em oito países da América Latina e do Caribe].
Ending tuberculosis (TB) requires a multisectoral approach, including participation from organized civil society. With the support of a regional project (OBSERVA TB) financed by the Global Fund, TB social observatories have been created since 2019 in eight countries in Latin America and the Caribbean (Bolivia, Colombia, the Dominican Republic, El Salvador, Guatemala, Haiti, Mexico, and Peru), as well as a regional TB social observatory, as part of implementation of the ENGAGE-TB approach promoted by the World Health Organization. This article presents the implementation model, advances, and challenges of TB social observatories. As of December 2021, 135 civil society organizations in Latin America and the Caribbean were included in the eight observatories. These are spaces that serve as platforms for social surveillance, policy advocacy, and social monitoring of national TB responses, in addition to contributing to ENGAGE-TB indicators related to TB case detection and support during treatment. It is recommended to consolidate and expand the existing observatories, with the participation of other countries in the LAC region.


Human brain imaging studies of DISC1 in schizophrenia, bipolar disorder and depression: a systematic review.
Disrupted-in-Schizophrenia 1 (DISC1) is a well researched candidate gene for schizophrenia and affective disorders with a range of functions relating to neurodevelopment. Several human brain imaging studies investigating correlations between common and rare variants in DISC1 and brain structure and function have shown conflicting results. A meta-analysis of case/control data showed no association between schizophrenia and any common SNP in DISC1. Therefore it is timely to review the literature to plan the direction of future studies. Twenty-two human brain imaging studies have examined the influence of DISC1 variants in health, schizophrenia, bipolar disorder or depression. The most studied common SNPs are Ser704Cys (rs821616) and Leu607Phe (rs6675281). Some imaging-genomic studies report effects on frontal, temporal and hippocampal structural indices in health and illness and a volumetric longitudinal study supports a putative role for these common SNPs in neurodevelopment. Callosal agenesis is described in association with rare deletions at 1q42 which include DISC1 and rare sequence variants at DISC1 itself. DISC1 interactions with translin-associated factor X (TRAX) and neuregulin have been shown to influence several regional volumes. In the first study involving neonates, a role for Ser704Cys (rs821616) has been highlighted in prenatal brain development with large clusters of reduced grey matter reported in the frontal lobes. Functional MRI studies examining associations between Ser704Cys (rs821616) and Leu607Phe (rs6675281) with prefrontal and hippocampal activation have also given inconsistent results. Prefrontal function was reported to be associated with interaction between DISC1 and CITRON (CIT) in health. Preliminary magnetic resonance spectroscopy and diffusion tensor data support the influence of Ser704Cys (rs821616) status on grey and white matter integrity. The glutamate system remains uninvestigated. Associations between rare sequence variants and structural changes in brain regions including the corpus callosum and effects of gene-gene interactions on brain structure and function are promising areas for future study.