The prognostic significance of carcinoembryonic antigen in the plasma and tumors of patients with endometrial adenocarcinoma.
Carcinoembryonic antigen (CEA) levels in plasma and the immunocytochemical detection of tumor CEA were studied in patients with endometrial adenocarcinoma treated at the University of Kentucky Medical Center from 1973 to 1976. The incidence of CEA elevation in a group of 60 patients varied directly with uterine size, histologic differentiation, and stage of disease. Immunoperoxidase staining for CEA was performed on 42 specimens, and four were positive, indicating a tissue concentration of CEA of at least 5 microng per gram. Following operation, CEA levels returned to normal within eight weeks in all but two patients, both of whom were later shown to have persistent or recurrent cancer. These data suggest that serial plasma CEA determinations may be useful in predicting occult recurrence of endometrial cancer in patients in whom the plasma or tumor initially contains elevated concentrations of this antigen.


Standardization and decay data of 237Np.
This paper reports contributions from participants in the EUROMET project (No. 416) which was entitled "237Np research into problems relating to purification, characterization and standardization". Primary standardizations were made by the defined low solid angle, coincidence, 4pi alpha, 2pi alpha and liquid scintillation counting methods. Secondary standardizations were made with calibrated gamma-ray spectrometers. Absolute X-ray, gamma-ray and alpha-particle emission probabilities were also determined. The results for the successful conclusion of both primary and secondary standardization are presented together with the values for alpha-particle and gamma-ray emission probabilities determined in this exercise. Several significant inconsistencies remain with the gamma-ray emission probabilities, and these are highlighted.


N-aryl pyrazoles, indazoles and azaindazoles as antagonists of CC chemokine receptor 1: patent cooperation treaty applications WO2010/036632, WO2009/134666 and WO2009/137338.
CC chemokine receptor 1 (CCR1) is a GPCR involved in the migration and activation of leukocytes. A number of studies have highlighted a role for CCR1 in preclinical animal models of inflammatory diseases, including MS and rheumatoid arthritis. This review examines three reports on a new series of CCR1 antagonists. The compounds of the title inventions are put in the context of earlier work in the area of CCR1 antagonism. The structure-activity relationships disclosed in the inventions are also discussed. Several of the compounds disclosed in patent cooperation treaty applications WO 2010/036632, WO 2009/134666 and WO 2009/137338 are sub-nanomolar antagonists of MIP-1α-induced calcium flux in CCR1-bearing cells. Further preclinical studies are required with these new CCR1 antagonists in order to understand their potential for ameliorating human inflammatory diseases.


A sensitive, nonradiometric assay for dihydroorotic acid dehydrogenase using anion-exchange high-performance liquid chromatography.
A new method to assay the mitochondrial pyrimidine de novo enzyme, dihydroorotate (DHO) dehydrogenase, which catalyzes the dehydrogenation of DHO, with orotic acid as the product was developed. The assay was optimized using a rat liver mitochondrial preparation. Orotic acid was quantified with high-performance liquid chromatography using an anion-exchange column (Partisil-SAX) with uv detection at 280 nm. Isocratic elution with low phosphate buffer at pH 4.0 was used. The detection limit was 20 pmol per injection, which is comparable to previously described radiometric assays. The HPLC assay was compared with a spectrophotometric assay measuring orotic acid formation in a deproteinized reaction mixture. Absorbance was measured at the optimal wavelength for orotic acid, 278.5 nm. This assay is less sensitive and less specific than the HPLC assay, which can also detect UMP which might be formed from orotic acid in whole homogenates. With both assays kinetic parameters of the enzyme were determined. In the high concentration range (80-1000 microM) both Km and Vmax values were comparable. With the HPLC assay the concentration range was extended down to 12 microM and initial rates could be determined. The apparent Km was about 12 microM. The HPLC assay is also suitable for use in the study of inhibition of DHO dehydrogenase.


Clinical applications of auditory event related potentials in neurology.
Auditory ERP (AERP) studies have been performed in 56 patients with central nervous system disturbances. Forty seven patients (90.5%), had AERP component abnormalities concerning mainly P300 topography alterations and secondarily P300 latency prolongation. It is concluded that P300 is a very useful tool in clinical neurology and that P300 topography or latency alterations are not specific of any cerebral disturbance but can be found in any disease whenever cognitive functions are impaired.


Lipid droplet of sebaceous carcinoma. Electron microscopic study utilizing glycol methacrylate-glutaraldehyde-urea procedure.
The ultrastructure of lipid droplets of sebaceous carcinoma (Meibomian gland carcinoma) was studied by conventional methods and a lipid-retention procedure. Two different structures were clearly differentiated by the latter technique. The peripheral part of the lipid droplet was composed of whirled lamellar structures (myelin-like structures) while the interior appeared to be continuously homogenous. The lamellar structures were presumed to have come from smooth-surfaced endoplasmic reticulum, and to transform to the amorphous material-triglyceride-during maturation of the lipid droplets. A true limiting membrane or membranous shell around the lipid droplet was not deceted.


[Studies on the estimation of the postmortem interval. 5. The turbidity of the cornea (author's transl)].
The authors have investigated the relationship between the postmortem interval and the turbidity of the cornea of 410 persons who had died at known times and had been subjected to medico-legal autopsies in our laboratory. The conclusions are as follows: 1) Differences due to the states of the eyelids of cadavers, either open or closed, gave rise to slight variations of the turbidity of the cornea only within 12 hours after death. Slight variations due to age and sex were seen only from 12 to 24 hours after death and only in the age group of 0 to 19 years. Seasonal variation was not seen on the cadavers which had remained indoors at the Hokkaido districts. 2) In death from exsanguination none became a state of the strong turbidity. In death from intracranial injuries and asphyxia the strong turbidity developed earlier than in the other types of death. 3) When the cornea is transparent, the time which has elapsed since death is less than 36 hours, with few exceptions, with eyelids either open or closed. On the cadavers with closed eyelids, the week turbidity of the cornea is seen between 6 hours and 3 days, the moderate turbidity between 12 hours and 2 weeks and the strong turbidity over 18 hours.


A receptor-based analysis of local ecosystems in the human brain.
As a complex system, the brain is a self-organizing entity that depends on local interactions among cells. Its regions (anatomically defined nuclei and areas) can be conceptualized as cellular ecosystems, but the similarity of their functional profiles is poorly understood. The study used the Allen Human Brain Atlas to classify 169 brain regions into hierarchically-organized environments based on their expression of 100 G protein-coupled neurotransmitter receptors, with no a priori reference to the regions' positions in the brain's anatomy or function. The analysis was based on hierarchical clustering, and multiscale bootstrap resampling was used to estimate the reliability of detected clusters. The study presents the first unbiased, hierarchical tree of functional environments in the human brain. The similarity of brain regions was strongly influenced by their anatomical proximity, even when they belonged to different functional systems. Generally, spatial vicinity trumped long-range projections or network connectivity. The main cluster of brain regions excluded the dentate gyrus of the hippocampus. The nuclei of the amygdala formed a cluster irrespective of their striatal or pallial origin. In its receptor profile, the hypothalamus was more closely associated with the midbrain than with the thalamus. The cerebellar cortical areas formed a tight and exclusive cluster. Most of the neocortical areas (with the exception of some occipital areas) clustered in a large, statistically well supported group that included no other brain regions. This study adds a new dimension to the established classifications of brain divisions. In a single framework, they are reconsidered at multiple scales-from individual nuclei and areas to their groups to the entire brain. The analysis provides support for predictive models of brain self-organization and adaptation.


The role of CD8+ T cells in immunoglobulin E regulation.
The link between immunoglobulin E (IgE) antibodies and environmental allergens, allergic sensitization and atopic diseases such as asthma, rhinitis and eczema is well established, yet treatment of these diseases is largely symptomatic and fails to correct the underlying immune disorder. B-cell production of IgE depends on interleukin 4 (IL-4) and is inhibited by interferon (IFN-gamma). These cytokines are produced by T-helper 2 (Th2) and T-helper 1 (Th1) CD4+ T cells respectively. In atopic dermatitis skin and asthmatic lung, Th2 cells predominate but antigen-specific CD4+ T-cell clones derived from peripheral blood are a mixture of Th1, Th2, and Th0. Circulating allergen-specific CD4+ T cells differentiate into Th1- and Th2-like clones in the presence of IL-12 and IL-4 respectively. In rats, CD8+ T cells are potent regulators of IgE responses in vivo, although the mechanism for this is still unclear. CD8+ T-cell depletion in immunized animals prolonged the IgE response but prior depletion did not. Indeed, prior depletion of CD8+ T cells actually inhibited IgE production, suggesting that there may be more than one type of IgE regulatory CD8+ T cell. This was supported by the observation that CD8+ T cells inhibited the differentiation of both Th1 and Th2 CD4+ T cells in vitro as well as IL-4- but not IL-2-induced Th2 CD4+ T-cell growth. The existence of distinct CD8+ T-cell subsets is supported by the observation that IL-4 and IFN-gamma regulate the growth and differentiation of CD8+ T cells.(ABSTRACT TRUNCATED AT 250 WORDS)


beta-Interferon alters the pattern of proteins secreted from quiescent and platelet-derived growth factor-treated BALB/c-3T3 cells.
Mouse beta-interferon (at a concentration of 100 units/ml or higher) inhibited the platelet-derived growth factor (PDGF)-induced replication of quiescent BALB/c-3T3 cells. The interferon treatment did not inhibit, but slightly enhanced, the accumulation of the following three PDGF-induced RNAs: myc RNA, JE RNA, and KC RNA. The treatment with interferon changed the pattern of secreted proteins from quiescent cells and from cells treated with partially purified PDGF; it inhibited the accumulation of the PDGF-induced proteins (including proteins of 63 and 32 kDa) and it induced the accumulation of several other proteins (including proteins of 89, 31.5, 30, and 10.5 kDa) in both quiescent and also in PDGF-treated cells.


Apolipoprotein E polymorphism in relation to plasma lipid levels and other risk factors of atherosclerosis in two ethnic groups from Slovakia.
The influence of apolipoprotein E (ApoE) genotypes on plasma lipid levels and interaction with other environmental factors was determined in two Slovakian population samples; 146 Romany and 351 Slovak individuals. The two samples differ significantly in the distribution of E3/3 genotypes (p<0.014) and E3/2 (p<0.035). Analysis of variance did not reveal any significant effect of the ApoE genotypes on any of the plasma lipid levels in the Romany individuals. In the Slovak sample the variation in plasma low-density lipoprotein cholesterol (LDL-C) levels was significantly associated with the ApoE genotypes (p=0.012). We detected decreased LDL-C concentrations in males with E2 genotype when compared with E3 and E4 carriers (p=0.008). Further, the E2 genotype was found to be associated with high triglycerides levels (p=0.009). The ethnic samples differ significantly in the prevalence of metabolic syndrome and in the case of males of diabetes. Both the Romany and the Slovak males can be considered as having a more atherogenic profile compared with the females.


Safety and protective effects of an avirulent Salmonella Gallinarum isolate as a vaccine candidate against Salmonella Gallinarum infections in young chickens.
Fowl typhoid is an important disease of chickens and turkeys, which is caused by Salmonella Gallinarum (S. Gallinarum). Vaccines with high levels of protective effects against fowl typhoid need to be developed for the poultry industry. In this study, a S. Gallinarum strain, named SG01, was isolated from a poultry farm in Mashan region of Wuxi City, China, and identified through biochemical tests and specific PCR amplifications. Then, safety evaluations of the SG01 strain were performed in young chickens. No clinical symptom including depression and diarrhea and gross lesion involved in the cardiac nodule, hepatic necrotic lesion and splenic necrotic lesion, was determined on fifteen-day-old chickens after immunization with 1 × 1010 CFU of the SG01 strain through the oral route. However, diarrhea symptoms and hepatic lesions were identified from chickens immunized with the commercial vaccine strain SG9R by the same dose and route. At 14 days post inoculation, SG01 strain was eliminated in the liver and spleen from SG01-immunized chickens, while the SG9R strain still could be identified from SG9R-immunized chickens. After challenge with the virulent S. Gallinarum strain, significant reduction of the morbidity rate was found in the SG01 immunized group (20 %) compared to the challenge group (100 %) according to signs scoring systems for clinical symptoms and gross lesions. Additionally, immunization with the SG01 strain could provide more than 8 weeks of protection periods against fowl typhoid. These results demonstrate the SG01 strain is avirulent to young chickens and might be safer compared to the SG9R strain. In addition, SG01 strain is a potential vaccine candidate against fowl typhoid in young chickens.


Dropped Courses and Persistence in Online Undergraduate Nursing Programs.
Recent studies have linked dropped courses with an increased likelihood of persistence in nursing education. This study examined the association of dropped courses, demographic characteristics, and persistence among online undergraduate nursing students. A retrospective cohort study was conducted with 29,926 former undergraduate nursing students enrolled from 2015 to 2019. The study sample included 2,073 students formerly enrolled in an online baccalaureate nursing (BSN) program and 27,853 students formerly enrolled in an online RN-to-BSN program. RN-to-BSN students were more than twice as likely to drop a course than BSN students. For students in both programs, higher numbers of courses that were dropped before the course start date were associated with an increased likelihood of graduation. Understanding the extent to which course drops occur and their link to persistence in undergraduate nursing programs can assist academic program leaders in developing strategies to help students be successful. [J Nurs Educ. 2022;61(11):609-615.].


B-cell reconstitution for SCID: should a conditioning regimen be used in SCID treatment?
Bone marrow transplantation has resulted in life-saving sustained T-cell reconstitution in many infants with severe combined immunodeficiency (SCID), but correction of B-cell function has been more problematic. At the annual meeting of the Primary Immunodeficiency Treatment Consortium held in Boston, Massachusetts, on April 27, 2012, a debate was held regarding the use of pretransplantation conditioning versus no pretransplantation conditioning in an effort to address this problem. Reviews of the literature were made by both debaters, and there was agreement that there was a higher rate of B-cell chimerism and a lower number of patients who required ongoing immunoglobulin replacement therapy in centers that used pretransplantation conditioning. However, there were still patients who required immunoglobulin replacement in those centers, and therefore pretransplantation conditioning did not guarantee development of B-cell function. Dr Rebecca H. Buckley presented data on B-cell function according to the molecular defect of the patient, and showed that patients with IL-7 receptor α, ADA, and CD3 chain gene mutations can have normal B-cell function after transplantation with only host B cells. Dr Elie Haddad presented a statistical analysis of B-cell function in published reports and showed that only a conditioning regimen that contained busulfan was significantly associated with better B-cell function after transplantation. The question is whether the risk of immediate and long-term toxicity with use of busulfan is justified, particularly in patients with SCID with DNA repair defects and in very young newborns with SCID who will be detected by using newborn screening.


Milk chocolate as the fatty meal in oral cholecystography.
Four hundred and fifty cholecystograms were assessed regarding the effectiveness of various agents used as the fatty meal. 200 patients were given Arachis oil emulsion, 100 chocolate-Sorbitol preparation, 100 46 g of milk chocolate, and 50 26 g of milk chocolate. The films were assessed for degree of contraction, improvement in opacification, and visualisation of the biliary ducts. No statistically significant difference was found between any of the groups. It is concluded that milk chocolate is an effective palatable and cheap form of fatty meal.


Effect of cadmium on T4 outer ring monodeiodination by rat liver.
The effect of cadmium on thyroxine (T4) outer ring monodeiodination was studied in vivo and in vitro in the rat liver. One microgram of T4 was incubated with rat liver homogenates in 50 mM Tris--HCl buffer, pH 7.4, with or without 0.5, 5, and 50 mM dithiothreitol (DTT) for 60 min in the presence of 10(-8) to 10(-3) M CdCl2, and the amount of 3,5,3'-triiodothyronine (T3) produced was determined by a specific radioimmunoassay. Subcutaneous injection of CdCl2, 1 mg/kg BW/day, 5 days a week for 10 weeks, to the rats resulted in a significant reduction in serum T3 concentration (by 37%) and hepatic T3 production from T4 (by 78 to 92%). In vitro addition of 1 microM to 1 mM CdCl2 to liver homogenates caused a concentration-dependent reduction in T3 generation. Without DTT a 50% reduction in the T4 to T3 converting activity was caused by 4 X 10(-6) M CdCl2. DTT (0.5 to 50 mM) partially restored T3 generation roughly in a concentration-dependent manner. These results indicate that cadmium has some effects on the metabolism of thyroid hormone.


Causal factors of childhood pneumonia high mortalities and the impact of community case management on child survival in Sub-Saharan Africa: a systematic review.
This study aimed to (1) evaluate the effectiveness of community case management (CCM) and validity of its implementation in the context of Sub-Saharan Africa (SSA) region; (2) identify potential differences in pneumonia disease aetiology, geographic region and cultural factors that may impact the implementation and delivery of community-based interventions; and (3) identify strategies that public health practitioners, stakeholders and policymakers could use to implement CCM. This was a systematic review. Comprehensive searches were conducted in Cochrane Library, MEDLINE, CINAHL and Scopus databases from 2012 to 2023. Google Scholar, World Health Organization/United Nations Children's Fund websites, unpublished grey literature, PROSPERO (International Register of Systematic Reviews) and a manual search of references lists for relevant articles. A total of 441 articles were screened, and eight articles were included for the review. Studies were from seven countries in SSA located in three regions: East (Kenya, Tanzania, Ethiopia), West (Nigeria, Senegal, Sierra Leone) and South (South Africa). The study designs of articles included two cluster randomised control trials, four cohorts and two case-control studies. A cross-analysis of the papers identified themes under the subheadings CCM and causal factors and risk factors. Successful impact of implementation and adoption of CCM in the context of SSA culture and environment can be achieved when focused on creating high-demand, dependable and quality healthcare services. Continual monitoring and evaluation of emerging high trends of viral pathogens and co-infections are critical in reducing childhood pneumonia mortalities.


First report of drug-induced esophagitis by deferasirox.
Deferasirox is a new oral iron chelator used to treat transfusional iron overload. We describe a case of a 79-year-old man with myelodysplastic syndrome (MDS) who developed esophagitis induced by deferasirox. He repeatedly received multiple red blood cell transfusions after a diagnosis of MDS. Two years after starting red blood cell transfusions, he was diagnosed with iron overload, and was then started on deferasirox at 1 g/day with about 400 ml of water. He was admitted to our institution because he was unable to swallow his own saliva 1 month after starting deferasirox. Esophagogastroendoscopy revealed white-coated mucosa covering the entire esophagus. A component analysis of biopsy specimens using high-performance liquid chromatography identified deferasirox. Symptoms resolved within about 2 weeks after discontinuing deferasirox, and repeated endoscopy showed marked improvement of esophagitis after 1 month. Re-administration of deferasirox was not attempted. Unfortunately, the patient died due to pneumonia 6 months after administration of deferasirox was started. This is the first report of drug-induced esophagitis associated with deferasirox.


Synthesis and biological activity of 8a-phenyldecahydroquinolines as probes of PCP's binding conformation. A new PCP-like compound with increased in vivo potency.
The synthesis and chemical resolution of cis- and trans-fused 8a-phenyldecahydroquinolines 3 and 4 are described together with the affinity of the four optically pure compounds for the PCP recognition site of the NMDA receptor complex. These compounds were also evaluated for their antagonistic effects on cGMP levels in male Swiss Webster mice, and (-)-4 was found to exhibit in vivo potency comparable to that of MK-801. The results of the binding studies are interpreted in terms of a preferred orientation of PCP's N-H bond in binding to its NMDA receptor-associated recognition site.


[Effect of dehydration of heat-induced restructuring of the cytoplasm membrane of yeast cells].
The effect of dehydration on the cytoplasmic membrane of yeast cells was studied using the method of spin labels. In the course of dehydration, the thermoinduced transition of lipids from the solid to a liquid-crystalline state was found to occur at a higher temperature as compared with native membranes.


The binding of proteinase 3 antineutrophil cytoplasmic antibodies (PR3-ANCA) varies in different ELISAs.
The demonstration of proteinase 3 specific antineutrophil cytoplasmic antibodies (PR3-ANCA), and the estimation of antibody values are useful in the diagnosis and management of patients with Wegener's granulomatosis (WG). However, external quality assessment programmes suggest that PR3-ANCA binding varies in different assays. To demonstrate variations in PR3-ANCA binding in different commercial and in house enzyme linked immunosorbent assays (ELISAs). Binding of a PR3-ANCA standard and 19 sera from patients with WG was compared in eight commercial and in house assays. Binding was expressed in different units depending on the kit. One commercial assay performed unsatisfactorily. Three commercial kits produced PR3-ANCA binding (70, 102, and 84 U/ml) close to the expected value for the standard (100 U/ml). Serial dilutions of this standard were linear in only one commercial assay and the in house assay. Sera from patients with WG with borderline binding in the in house assay bound in the eight commercial kits at 0-148 kit units; low binding sera ranged from 0 to 273 units; moderately strong sera bound at 7-260 units; and strongly binding sera bound at 13-336 units. In four assays, at least one strongly positive serum bound at levels greater than the provided range. Levels of antibody binding and units of binding have not been standardised in commercially available PR3-ANCA ELISAs. This may affect the diagnosis and management of patients with WG, in addition to the implementation of international guidelines for treatment.


Columbin isolated from calumbae radix affects the sleeping time of anesthetized mice.
In a screening series of bioactive components in edible and medicinal plants, we found that Calumbae Radix (Colombo root, 1% powdered feed, for 5 d) and its component, columbin (20-40 mg/kg/d, for 5 d, orally), shortened the sleeping time induced by a urethane and alpha-chloralose mixture and prolonged the sleeping time induced by hexobarbital in mice.


Bilateral apical vertebral derotation technique by vertebral column manipulation compared with vertebral coplanar alignment technique in the correction of Lenke type 1 idiopathic scoliosis.
Widely used rod rotation and translation techniques for idiopathic scoliosis (IS) are effective in correcting spinal coronal deformity. Bilateral apical vertebral derotation technique by vertebral column manipulation (VCM) and vertebral coplanar alignment (VCA) technique are two strategies for three-dimensional (3D) correction for IS. The purpose of this study is to compare the post-surgical results and technical features of the bilateral apical vertebral derotation technique by VCM against the VCA technique in patients with Lenke type 1 IS. Forty-eight patients with Lenke type 1 IS were enrolled in the present prospective clinical assay. They were divided into groups A (bilateral apical vertebral derotation technique by VCM, n=24) and B (VCA technique, n=24). Radiographic parameters measured before and after surgery included the Cobb angle, thoracic kyphosis, and apical vertebral rotation. Scoliosis Research Society (SRS)-22 scores were evaluated during the final follow-up. The differences in the demographics, surgical details, and radiographic measurements between the two groups were determined using a T test. The Mann-Whitney U test was used to evaluate the differences in the SRS-22 scores. A value of P<0.05 was considered statistically significant. In the coronal plane, a significant difference was found in the correction rate of the major curve (group A: 84.8%, group B: 78.4%; P=0.045) and in the Cincinnati Correction Index between two groups (group A: 2.21, group B: 1.98; P=0.047). In the sagittal plane, no difference was found in the postoperative thoracic kyphosis between the two groups (P=0.328). In the transverse plane, no difference was found between the two groups in the correction rates of the rotation angle sagittal (P=0.298), rib hump (P=0.934), apical vertebral body-to-rib ratio (P=0.988), or apical rib spread difference (P=0.184). Patients underwent follow up for an average of 21.9 and 22.2 months in groups A and B, respectively. Results obtained at the final follow-up indicated no significant loss of correction. No differences were found in the SRS-22 scores between the two groups. No aortic or neurological complications were observed. The 3D deformity of the spine was effectively corrected using the bilateral apical vertebral derotation technique by VCM and the VCA technique, and encouraging post-surgical results were obtained for patients with Lenke type 1 IS. The two techniques were effective in allowing 3D correctional force that was applied in different ways.


Chronic Effects of Blast-Related TBI on Subcortical Functional Connectivity in Veterans.
Blast explosions are the most frequent mechanism of traumatic brain injury (TBI) in recent wars, but little is known about their long-term effects. Functional connectivity (FC) was measured in 17 veterans an average of 5.46 years after their most serious blast related TBI, and in 15 demographically similar veterans without TBI or blast exposure. Subcortical FC was measured in bilateral caudate, putamen, and globus pallidus. The default mode and fronto-parietal networks were also investigated. In subcortical regions, between-groups t tests revealed altered FC from the right putamen and right globus pallidus. However, following analysis of covariance (ANCOVA) with age, depression (Center for Epidemiologic Studies Depression Scale), and posttraumatic stress disorder symptom (PTSD Checklist - Civilian version) measures, significant findings remained only for the right globus pallidus with anticorrelation in bilateral temporal occipital fusiform cortex, occipital fusiform gyrus, lingual gyrus, and cerebellum, as well as the right occipital pole. No group differences were found for the default mode network. Although reduced FC was found in the fronto-parietal network in the TBI group, between-group differences were nonsignificant after the ANCOVA. FC of the globus pallidus is altered years after exposure to blast related TBI. Future studies are necessary to explore the trajectory of changes in FC in subcortical regions after blast TBI, the effects of isolated versus repetitive blast-related TBI, and the relation to long-term outcomes in veterans. (JINS, 2016, 22, 631-642).


Health care providers' perceived barriers to and need for the implementation of a national integrated health care standard on childhood obesity in the Netherlands - a mixed methods approach.
In 2010, a national integrated health care standard for (childhood) obesity was published and disseminated in the Netherlands. The aim of this study is to gain insight into the needs of health care providers and the barriers they face in terms of implementing this integrated health care standard. A mixed-methods approach was applied using focus groups, semi-structured, face-to-face interviews and an e-mail-based internet survey. The study's participants included: general practitioners (GPs) (focus groups); health care providers in different professions (face-to-face interviews) and health care providers, including GPs; youth health care workers; pediatricians; dieticians; psychologists and physiotherapists (survey). First, the transcripts from the focus groups were analyzed thematically. The themes identified in this process were then used to analyze the interviews. The results of the analysis of the qualitative data were used to construct the statements used in the e-mail-based internet survey. Responses to items were measured on a 5-point Likert scale and were categorized into three outcomes: 'agree' or 'important' (response categories 1 and 2), 'disagree' or 'not important'. Twenty-seven of the GPs that were invited (51 %) participated in four focus groups. Seven of the nine health care professionals that were invited (78 %) participated in the interviews and 222 questionnaires (17 %) were returned and included in the analysis. The following key barriers were identified with regard to the implementation of the integrated health care standard: reluctance to raise the subject; perceived lack of motivation and knowledge on the part of the parents; previous negative experiences with lifestyle programs; financial constraints and the lack of a structured multidisciplinary approach. The main needs identified were: increased knowledge and awareness on the part of both health care providers and parents/children; a social map of effective intervention; structural funding; task rearrangements; a central care coordinator and structural information feedback from the health care providers involved. The integrated health care standard stipulate that the care of overweight or obese children be provided using an integrated approach. The barriers and needs identified in this study can be used to define strategies to improve the implementation of the integrated health care standard pertaining to overweight and obese children in the Netherlands.


An experimental investigation of interactions in snail-macrophyte-epiphyte systems.
An experimental investigation under field conditions of enclosures containing freshwater pulmonate snails, the macrophyteCeratophyllum demersum and epiphytes, produced evidence of beneficial interactions.Ceratophyllum growth, measured in terms of stem length, numbers of leaf-nodes and growing tips and leaf survival was significantly enhanced in the presence of snails. This effect was attributed to the increased availability of plant nutrients of snail origin, such as phosphates and ammonia, as well as to the snails' action as "cleaning symbionts" in reducing the density of bacterial and algal epiphyton potentially deleterious to macrophytes. Principal component analysis revealed both seasonal and treatment effects of snail grazing on algal epiphyton. Small adnate algal species (e.g.Cocconeis placentula) survived grazing and benefited from the removal of larger, competitor, species. Snail densities increased in all treatments, despite high (86%) juvenile mortality. It is concluded that freshwater pulmonate snails are strong interactors in lentic habitats, enhancing the growth ofCeratophyllum and producing characterisic epiphyte communities. This benefits not only the snails, but also the plants and epiphytes that are associated with them. Thus the interactions between these component parts of the community can be considered as mutualistic.


Ultracytochemical study on eccrine acrosyringium of human embryos. Acid phosphatase activity during formation of lumen.
Ultracytochemical demonstration of acid phosphatase (ACPase) activity during the developing of intraepidermal eccrine sweat duct (eccrine acrosyringium) of human embryos was performed in order to elucidate the functional relationship between multivesicular dense bodies and intracellular cavities formed within the inner cells of eccrine sweat apparatus anlagen and to clarify the ultracytochemical characteristics of the multivesicular dense bodies. ACPase activity was characteristically detected in the unit membrane structures of small pinched-off vesicles within cavities and of immature microvilli lining these cavities as well as in those of multivesicular dense bodies. These findings give strong support to the theory that the multivesicular dense bodies are lysosomes and through their action the autolytic formation of intraepidermal eccrine sweat duct is carried out.


Vascular Malformations and Their Treatment in the Growing Patient.
Vascular anomalies consisting of 2 groups of lesions, vascular tumors and vascular malformations, frequently arise in the head and neck and often occur in the pediatric age group. This classification is based on the differences in natural history, histologic features, and cellular turnover of the 2 groups. The management of these anomalies can be challenging, and evidence-based decisions about treatment are complicated by an inconsistency in the nomenclature for these lesions found in the literature. This article covers the clinical presentation, etiology, and pathophysiology and treatment approaches of the vascular anomalies in the pediatric population.


How common are complications of Parkinson's disease?
Parkinson's disease (PD) can be associated with a wide range of complications of advancing disease and treatment. However, it is unclear how often these occur in the overall population of patients with PD. To assess the prevalence of disease and treatment complications and their clinical correlates in a community-based sample of 124 patients with PD. Average current age was 72 (SD 10.9) and mean disease duration 6 (SD 4.3) years. Falls with postural instability and other axial features were among the most common complications of advancing disease in this population (64 %). Motor fluctuations and dyskinesias affected approximately 30 and 20 % of the overall sample respectively, and changes in mental state such as dementia, depression and hallucinations each affected approximately one fifth of patients. Symptoms of autonomic nervous system dysfunction occurred in the great majority of patients, but were not associated with greater disease severity, disease duration or overall disability. In contrast to clinic-based samples, the most frequently occurring complications of PD in this community-based sample were axial features such as postural instability with falls. These factors should be more taken into account in the allocation of health care resources and the treatment of symptoms of patients with PD in the community.


Renal and hemodynamic effects of dopamine in infants following cardiac surgery.
The renal and hemodynamic effects of dopamine were measured during the immediate postoperative period in six infants following repair of congenital cardiac defects. Dopamine was infused at rates of 5, 10, and 15 micrograms/kg/min. Cardiac index (CI) increased significantly at a dopamine infusion rate of 15 micrograms/kg/min. The glomerular filtration rate (GFR) and urine output increased at dopamine infusion rates of 5 and 10 micrograms/kg/min and returned to baseline at 15 micrograms/kg/min. No significant changes occurred in right atrial pressure (RAP), left atrial pressure (LAP), systemic artery pressure, systemic vascular resistance (SVR), or pulmonary vascular resistance (PVR). Heart rate (HR) increased slightly at a dopamine infusion rate of 15 micrograms/kg/min. Pulmonary artery pressure (PAP) increased significantly in only one patient. These data demonstrate that infants require high doses of dopamine to produce the hemodynamic effects seen in adults and that these higher doses may be used without adverse renal effects.


24,25(OH)2D3 enhances the calcemic effect of 1,25(OH)2D3.
The effect of 24,25(OH)2D3 on 1,25(OH)2D3-induced hypercalcemia was studied in normal rats. Serum (S) levels and urinary excretion of Ca2+ (UCaV) were measured in (a) control rats, (b) rats receiving a daily sc injection of 54 ng 1,25(OH)2D3, (c) rats receiving 24,25(OH)2D3 in the same dose and same manner, and (d) rats receiving 1,25(OH)2D3 + 24,25(OH)2D3. The animals were housed in metabolic cages and 24-hr urine specimens were collected. After 24 hr SCa2+ increased similarly with 1,25(OH)2D3 and with 1,25(OH)2D3 + 24,25(OH)2D3, while 24,25(OH)2D3 alone did not change SCa2+. UCaV after 24 hr increased significantly less (P less than 0.025) with 1,25(OH)2D3 + 24,25(OH)2D3 than with 1,25(OH)2D3 alone. After 5 days of 1,25(OH)2D3, SCa2+ rose from 5.1 +/- 0.15 to 6.29 +/- 0.08 whereas 1,25(OH)2D3 + 24,25(OH)2D3 effected a greater increase in SCa2+ up to 6.63 +/- 0.09 (P less than 0.01). 24,25(OH)2D3 alone did not change SCa2+. UCaV after 5 days of treatment rose similarly with 1,25(OH)2D3 and with 1,25(OH)2D3 + 24,25(OH)2D3. After 10 days of 1,25(OH)2D3 SCa2+ was 6.17 +/- 0.15 meq/liter while with the combination SCa2+ rose to 6.74 +/- 0.2 (P less than 0.025). 24,25(OH)2D3 alone did not change SCa2+. These results show that (a) 24,25(OH)2D3 alone does not alter SCa2+ in normal rats, (b) combined administration of 1,25(OH)2D3 + 24,25(OH)2D3 enhances the hypercalcemic response to 1,25(OH)2D3 without a parallel increase in UCaV, and (c) it is suggested that the effect of 24,25(OH)2D3 on serum Ca2+ level, at least partly, may result from its hypocalciuric effect.


Adoptive transfer of type 1 regulatory T cells suppressed the development of airway hyperresponsiveness in ovalbumin-induced airway inflammation model mice.
Type 1 regulatory T (Tr1) cells are CD4+ T cells that produce a large amount of IL-10, an anti-inflammatory cytokine. However, it has not been fully elucidated whether Tr1 cells suppress allergic asthma. In this study, the effects of adoptive transfer of in vitro-induced Tr1 cells on allergic asthma were evaluated. Splenocytes from ovalbumin (OVA)-sensitized BALB/c mice were cultured with OVA, IL-21, IL-27, and TGF-β. After culture, IL-10-producing CD4+ T cells were isolated by Dynabeads mouse CD4 and IL-10 secretion assay, and analyzed by flow cytometry. Purified Tr1 cells (IL-10+ CD4+ T cells) were intravenously injected into OVA-sensitized BALB/c mice. The recipient mice were intratracheally challenged with OVA. Airway hyperresponsiveness to methacholine was assessed by the forced oscillation technique, followed by bronchoalveolar lavage (BAL). Almost all of the induced IL-10-producing CD4+ T cells were negative for interferon-γ, IL-4, IL-17A, and forkhead box P3, suggesting that the cells were Tr1 cells. The adoptive transfer of Tr1 cells significantly suppressed the development of airway hyperresponsiveness, and increases in IL-5, eosinophils, and neutrophils in BAL fluid. In conclusion, we demonstrated that Tr1 cells suppressed allergic asthma in mice.


Stratified medicine in inflammatory disorders: From theory to practice.
Chronic inflammatory disorders are complex and characterized by significant heterogeneity in molecular, pathological, and clinical features. This heterogeneity poses challenges for the development of targeted molecular interventions for these disorders, as not all patients with a given clinical diagnosis have disease driven by a single dominant molecular pathway, hence not all patients will benefit equally from a given intervention. Biomarkers related to molecular manifestations of disease are increasingly being applied to enable stratified approaches to drug development. Biomarkers may be used to identify which patients are most likely to benefit from an intervention (predictive), identify patients at increased risk of disease progression (prognostic), and monitor biological responsiveness to an intervention (pharmacodynamic). Here we consider how biomarker-guided stratification of patients may increase benefit from targeted therapies for asthma, rheumatoid arthritis and inflammatory bowel diseases.


Ecological organization of a Chihuahuan desert lizard community.
Niche relationships among 11 diurnal lizard species were studied for 3 years. The community appeared to be subdivided spatially into different subsets of only four to six species. Coexisting species of each subgroup were separated further by differential utilization of microhabitats. In late spring and early summer, when food shortage is likely, dietary overlaps between syntopic species were generally low but increased broadly after the rains, when food became plentiful. Because of the high similarity in prey-size utilization among large and medium species, effects of prey selection according to size were generally slight except for very different-sized species. Overlap in the three-dimensional resource space was high between Cnemidophorus scalaris and C. tigris, but close observation of the ecology of the two populations showed many small differences between them. We suggest that the very diversified ecological opportunism of C. scalaris allows it to coexist with C. tigris in a very heterogeneous ecosystem. Several hypotheses are discussed to explain the ecological determinism of resource partitioning within such a community.


Prevalence and distribution of human papillomavirus genotypes in cervical intraepithelial neoplasia in China: a meta-analysis.
Data on type-specific human papillomavirus (HPV) are needed to investigate HPV-based screening tests and HPV vaccines. However, Chinese relevant data are insufficient. Therefore, this meta-analysis aimed to summarize and demonstrate the prevalence and distribution of HPV genotypes in cervical intraepithelial neoplasia (CIN) and compensate for the shortage of HPV vaccines in China. The Medline, Embase, and the Cochrane Library databases, as well as references cited in the selected studies, were systematically searched for studies investigating the prevalence and distribution of HPV genotypes between January 2000 and April 2019 in China. A total of 8 studies were identified, which comprised 2950 patients with CIN1 and 5393 with CIN2/3. The overall HPV infection rate was 84.37%. The HPV infection rate was significantly higher in the CIN2/3 group (87.00%) than in the CIN1 group (79.56%) (χ2 = 80.095, P < 0.001). The most common HPV types in CIN1 in order of decreasing prevalence were as follows: HPV52 (20.31%), HPV16 (16.81%), HPV58 (14.44%), HPV18 (6.44%), and HPV53 (5.76%). However, in the CIN2/3 group, HPV16 (45.69%) was the predominant type, followed by HPV58 (15.50%), HPV52 (11.74%), HPV33 (9.35%), and HPV31 (4.34%). This study suggested that HPV16, HPV52, and HPV58 were the top three types of CIN in China. The findings might provide a reference for future HPV-based cervical cancer screening tests, treatment of HPV infection, and application of HPV vaccines in China.


Pervasive irregular migration and the vulnerabilities of irregular female migrants at Plumtree border post in Zimbabwe.
Migration is a common and visible feature of global mobility where the driving factors would be the search for better livelihood opportunities. Due to economic hardships in Zimbabwe, women have also been noted to migrate to neighbouring countries in search of opportunities to look after their left-behind families. However, the COVID-19 restrictions and other state regulations have become facilitators of illicit migration as irregular migrants (including women) devise more complex means to traverse borders and gain access. This paper assesses the vulnerabilities and the lived realities of female irregular migrants between Zimbabwe and Botswana during the clandestine migration journeys. A qualitative descriptive survey that targeted nineteen (19) participants was conducted using semi-structured and unstructured interviews. The participants included fifteen (15) Female irregular migrants and four (4) Key Informants who worked at Plumtree Border Post. The interviews were recorded, transcribed verbatim, coded and thematically analysed. Four vulnerabilities were reported/experienced by the participants: violence and robbery, Rape and sexual harassment, Psycho-emotional harassment, and health vulnerabilities in detention. The participants reported that these vulnerabilities are experienced at different levels of the migration process and deportation. Female migrants are generally at risk as they are bound to be taken advantage of at different levels during migration and deportation. Therefore, there is a need to relook at the policies implemented at the ports and ensure women are subjected to humane treatment even during the deportation process.


Gene expression levels of S100 protein family in blood cells are associated with insulin resistance and inflammation (Peripheral blood S100 mRNAs and metabolic syndrome).
Visceral fat obesity is located upstream of metabolic syndrome and atherosclerotic diseases. Accumulating evidences indicate that several immunocytes including macrophages infiltrate into adipose tissue and induce chronic low-grade inflammation. We recently analyzed the association between visceral fat adiposity and the gene expression profile in peripheral blood cells in human subjects and demonstrated the close relationship of visceral fat adiposity and disturbance of circadian rhythm in peripheral blood cells. In a series of studies, we herein investigated the association of visceral fat adiposity and mRNA levels relating to inflammatory genes in peripheral blood cells. Microarray analysis was performed in peripheral blood cells from 28 obese subjects. Reverse transcription-polymerase chain reaction (RT-PCR) was conducted by using blood cells from 57 obese subjects. Obesity was defined as body mass index (BMI) greater than 25 kg/m2 according to the Japanese criteria. Gene expression profile analysis was carried out with Agilent whole human genome 4×44K oligo-DNA microarray. Gene ontology (GO) analysis showed that 14 genes were significantly associated with visceral fat adiposity among 239 genes relating to inflammation. Among 14 genes, RT-PCR demonstrated that S100A8, S100A9, and S100A12 positively correlated with visceral fat adiposity in 57 subjects. Stepwise multiple regression analysis showed that S100A8 and S100A12 mRNA levels were closely associated with HOMA-IR and S100A9 mRNA was significantly related to adiponectin and CRP. Peripheral blood mRNA levels of S100 family were closely associated with insulin resistance and inflammation.


The reorienting system of the human brain: from environment to theory of mind.
Survival can depend on the ability to change a current course of action to respond to potentially advantageous or threatening stimuli. This "reorienting" response involves the coordinated action of a right hemisphere dominant ventral frontoparietal network that interrupts and resets ongoing activity and a dorsal frontoparietal network specialized for selecting and linking stimuli and responses. At rest, each network is distinct and internally correlated, but when attention is focused, the ventral network is suppressed to prevent reorienting to distracting events. These different patterns of recruitment may reflect inputs to the ventral attention network from the locus coeruleus/norepinephrine system. While originally conceptualized as a system for redirecting attention from one object to another, recent evidence suggests a more general role in switching between networks, which may explain recent evidence of its involvement in functions such as social cognition.


Crying out in pain-A systematic review into the validity of vocalization as an indicator for pain.
Vocalization is often used to assess pain, sometimes combined with other behaviours such as facial expressions. Contrary to facial expressions, however, for vocalization, there is little evidence available on the association with pain. The aim of this systematic review was to critically analyse the association between vocalization and pain, to explore if vocalizations can be used as a "stand-alone" indicator for pain. The search was performed according to the Prisma Guidelines for systematic reviews and meta-analysis. The following terms were used: "Pain Measurement," "Vocalization" and "Verbalization." The study population included verbal and non-verbal individuals, including older people and children. The search was performed in three different databases: PubMed, Embase and CINAHL. A total of 35 studies were selected for detailed investigation. Quality assessments were made using two grading systems: Grading of Recommendations Assessment Development and Evaluation system and the Newcastle-Ottawa scale. An association between vocalization and pain was found in most studies, particularly when different types of vocalizations were included in the investigation. Different types of vocalization, but also different types of pain, shape this association. The association is observed within all groups of individuals, although age, amongst others, may have an influence on preferred type of vocalization. There is an association between vocalization and pain. However, vocalization as a "stand-alone" indicator for pain indicates only a limited aspect of this multifactorial phenomenon. Using vocalization as an indicator for pain may be more reliable if other pain indicators are also taken into account. Vocalizations are frequently used in pain scales, although not yet thoroughly investigated as a "single indicator" for pain, like, e.g. facial expression. This review confirms the role of vocalizations in pain scales, and stresses that vocalizations might be more reliable if used in combination with other pain indicators.


Children's surgery verification and value-based care in pediatric surgery.
With the prevailing focus on increasing value in healthcare, understanding the different components of the value equation is of primary importance. Michael E. Porter's writings on the value agenda and the use of integrated practice units (IPUs) have provided easy correlation to adult disease entities with large populations sharing common pathways and providers in the diagnosis and care of these patients. In pediatric surgery, with smaller populations and larger numbers of rare or unique conditions and anatomic challenges, utilizing the concept of an IPU is more challenging. The literature has generally shown the improvements in quality of care through participation in various programs through the American College of Surgeons (ACS) such as trauma verification, or the National Surgical Quality Improvement Project (NSQIP), but that participation alone does not guarantee better outcomes. Use of these programs in conjunction with participation in quality collaboratives have tended to show favorable returns on investment for these programs. We seek to demonstrate how the Children's Surgery Verification (CSV) program provides pediatric surgeons an effective vehicle with which to engage the value agenda, evaluating and improving care over the care continuum in order to improve the function of children's hospitals as larger integrated units.


Helicobacter pylori growth stimulation by adrenaline detected by two methods.
Our aim was to assess growth effects of adrenaline on 32 Helicobacter pylori strains on 2.5% blood agar. By agar-well diffusion and disk diffusion methods, concentration-dependent growth stimulation occurred in ≤50.0% and 36.8% of the strains, respectively. Growth inhibition was less frequent. Most strains were adrenaline-responsive and growth stimulation prevailed.


An investigation into the enhancement of sea-spray exposed fingerprints on glass.
Fingerprints are considered one of the best forms of personal identification. While numerous enhancement techniques exist to develop fingerprints under various conditions, the enhancement of fingerprints exposed to sea spray aerosol (SSA) still remains problematic. 1056 fingerprints from four donors, using a depletion series and triplicate repeats, were deposited onto glass panels and exposed to SSA for 1 week and 1 month. Control prints were deposited in the same manner and left under laboratory conditions. All prints were enhanced using fingerprint enhancement techniques available to Forensic Police Officers and subsequently examined for identifiability by a Fingerprint Expert. Significantly fewer identifiable prints (p<0.01) were developed after exposure to SSA for 1 month (11%) compared to exposure for 1 week (69%) (compared to the control prints 99%) for all enhancement techniques. After 1 week's exposure, all techniques enhanced over 50% of prints, except SPR white (12%), with iron (III) oxide and Wetwop™ white producing over 90% identifiable prints. Only iron (III) oxide, Wetwop™ white and SPR black returned any identifiable prints following 1 month's SSA exposure. Iron (III) oxide being significantly better (p<0.01, 67%) than the other techniques. Iron (III) oxide suspension and Wetwop™ white were found to be superior at enhancing prints at both SSA exposure times.


Identification of conserved amino acids in the human granulocyte-macrophage colony-stimulating factor receptor alpha subunit critical for function. Evidence for formation of a heterodimeric receptor complex prior to ligand binding.
A superfamily of growth factor and cytokine receptors has recently been identified, which is characterized by four spatially conserved cysteine residues, a tryptophan-serine motif (WSXWS) in the extracellular domain, and a proline-rich cytoplasmic domain. The high affinity human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (hGM-CSFR) consists of two subunits, alpha (hGM-CSFR alpha) and beta (hGM-CSFR beta), both of which are members of the receptor superfamily. In this study, we prepared mutations in conserved amino acids of the receptor subunit necessary for GM-CSF binding (hGM-CSFR alpha) and analyzed mutant receptors for low affinity binding, internalization, and high affinity binding when complexed with the beta subunit. Mutations in the cytoplasmic domain did not affect GM-CSF binding or receptor internalization. Mutation of a single conserved serine residue within the WSXWS motif diminishes cell surface receptor expression but not ligand binding. Mutation of either the second or third conserved cysteine residue of hGM-CSFR alpha resulted in complete loss of low affinity binding; however, co-expression of the cysteine 2 mutant with hGM-CSFR beta yielded a high affinity receptor complex. Since neither the cysteine 2 mutant nor the beta subunit can bind ligand alone, this result suggests that hGM-CSFR alpha and hGM-CSFR beta exist in a preformed heterodimeric protein complex on the plasma membrane.


Recovery of Active Pharmaceutical Ingredients from Unused Solid Dosage-Form Drugs.
The concept of drug recycle by recovering active pharmaceutical ingredients (APIs) from unused tablets and capsules was demonstrated using acetaminophen, tetracycline HCl, and (R,S)-(±)-ibuprofen as case examples. The recovery process comprised three core unit operations: solid-liquid extraction, filtration, and crystallization. Recovery yields of 58.7 wt %, 73.1 wt %, and 67.6 wt % for acetaminophen, tetracycline HCl, and (R,S)-(±)-ibuprofen were achieved, respectively. More importantly, all of the APIs were of high purity based on high-performance liquid chromatography assay. The crystal forms of the recovered APIs were in conformity with the standards.


Rods in the terminal cisternae of skeletal muscle.
The purpose of the study was to investigate rod-like structures (rods) in the terminal cisternae membrane of freeze fracture replicas of fast- and slow-twitch mammalian muscle. The 9 X 50 nm rods crossed the junctional gap perpendicular to the T-tubule membrane and terminated near indentations. Rods are likely to have a structural basis because (1) grooves were seen in the complimentary membrane leaflet, (2) rods were seen in tissue fixed in 0.5, 5, or 6% glutaraldehyde or 5% acrolein, (3) rods were seen in tissue fractured over a range of temperatures from -40 to -196 degrees C, (4) the number of rods was correlated with the contractile properties of fibers, and (5) the density of rods increased when fibers were depolarized before fixation. The rods are in a unique location that would allow them to participate in excitation-contraction coupling, perhaps by transmitting an electrical signal from the T-tubule membrane to calcium release sites in the terminal cisternae.


Clinical and genetic findings in two siblings with X-Linked agammaglobulinemia and bronchiolitis obliterans: a case report.
X-linked agammaglobulinemia (XLA) is an Inborn Errors of Immunity (IEI) characterized by pan-hypogammaglobulinemia and low numbers of B lymphocytes due to mutations in BTK gene. Usually, XLA patients are not susceptible to respiratory tract infections by viruses and do not present interstitial lung disease (ILD) such as bronchiolitis obliterans (BO) as a consequence of acute or chronic bacterial infections of the respiratory tract. Although many pathogenic variants have already been described in XLA, the heterogeneous clinical presentations in affected patients suggest a more complex genetic landscape underlying this disorder. We report two pediatric cases from male siblings with X-Linked Agammaglobulinemia and bronchiolitis obliterans, a phenotype not often observed in XLA phenotype. The whole-exome sequencing (WES) analysis showed a rare hemizygous missense variant NM_000061.2(BTK):c.1751G>A(p.Gly584Glu) in BTK gene of both patients. We also identified a gain-of-function mutation in TGFβ1 (rs1800471) previously associated with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. TGFβ1 plays a key role in the regulation of immune processes and inflammatory response associated with pulmonary impairment. Our report illustrates a possible role for WES in patients with known inborn errors of immunity, but uncommon clinical presentations, providing a personalized understanding of genetic basis, with possible implications in the identification of potential treatments, and prognosis for patients and their families.


Co-infected C57BL/6 mice mount appropriately polarized and compartmentalized cytokine responses to Litomosoides sigmodontis and Leishmania major but disease progression is altered.
This study examines the capacity of the mammalian host to fully compartmentalize the response to infection with type 1 vs. type 2 inducing organisms that infect different sites in the body. For this purpose, C57BL/6 mice were infected with the rodent filarial nematode Litomosoides sigmodontis followed by footpad infection with the protozoan parasite Leishmania major. In this host, nematode infection is established in the thoracic cavity but no microfilariae circulate in the bloodstream. We utilized quantitative ELISPOT analysis of IL-4 and IFN-gamma producing cells to assess cytokine bias and response magnitude in the lymph nodes draining the sites of infection as well as more systemic responses in the spleen and serum. Contrary to other systems where co-infection has a major impact on bias, cytokine ratios were unaltered in either local lymph node. The most notable effect of co-infection was an unexpected increase in the magnitude of the IFN-gamma response to L. major in mice previously infected with L. sigmodontis. Further, lesion development was significantly delayed in these mice. Thus, despite the ability of the immune system to appropriately compartmentalize the immune response, interactions between responses at distinct infection sites can alter disease progression.


Roles of neonatal and prepubertal testicular androgens on androgen-induced proliferative response of seminal vesicle cells in adult mice.
Male mice were castrated at 0, 10, 20, 30, 40 and 60 days of age; daily injections of testosterone propionate (TP, 4 micrograms/g b. wt) were started from day 90. On various days after starting the TP injections, the incorporation of 5-[125I]iodo-2'-deoxyuridine into the whole seminal vesicles was determined as an index for proliferation. The seminal vesicle cells in mice castrated on days 0 and 20 were characterized by low weight (0.5-1 mg) before TP injection, long duration of androgen-induced proliferation (greater than 20 days) with a low peak, and involvement of both epithelial and fibromuscular cells (neonatal castration type). The seminal vesicle cells in mice castrated on days 60 and 40 were characterized by relatively high weight (5-10 mg) before TP injection, short duration of androgen-induced proliferation (10 days) with a high peak, and involvement of only the epithelial cells (adult castration type). In mice castrated on days 0 and 20, the neonatal castration type of androgen-induced proliferation was completely changed to the adult castration type when TP pretreatment (2 micrograms/g b. wt per 12 h) had been given from day 20 to day 40. However, the TP pretreatment given from day 90 to day 110 instead of days 20-40 had no such effect in 140-day old mice castrated on day 0. The present findings suggest that testicular androgens secreted from day 20 to day 40 play an indispensable role in the induction of irreversible proliferative response of the mouse seminal vesicle. The activity of the prepubertal androgens may not be completely compensated by androgen activity at adulthood.


Fasudil promotes polyploidization of megakaryoblasts in an acute megakaryocyte leukemia model.
Acute megakaryocytic leukemia (AMKL) is a rare neoplasm caused by abnormal megakaryoblasts. Megakaryoblasts keep dividing and avoid undergoing polyploidization to escape maturation. Small-molecule probes inducing polyploidization of megakaryocytic leukemia cells accelerate the differentiation of megakaryocytes. This study aims to determine that Rho kinase (ROCK) inhibition on megakaryoblasts enhances polyploidization and the inhibition of ROCK1 by fasudil benefits AMKL mice. The study investigated fasudil on the megakaryoblast cells in vitro and in vivo. With the differentiation and apoptosis induction, fasudil was used to treat 6133/MPLW515L mice, and the differentiation level was evaluated. Fasudil could reduce proliferation and promote the polyploidization of megakaryoblasts. Meanwhile, fasudil reduced the disease burden of 6133/MPLW515L AMKL mice at a dose that is safe for healthy mice. Combination therapy of ROCK1 inhibitor fasudil and reported clinical AURKA inhibitor MLN8237 achieved a better antileukemia effect in vivo, which alleviated hepatosplenomegaly and promoted the differentiation of megakaryoblast cells. ROCK1 inhibitor fasudil is a good proliferation inhibitor and polyploidization inducer of megakaryoblast cells and might be a novel rationale for clinical AMKL treatment.


CXCR4/CXCL12 Activities in the Tumor Microenvironment and Implications for Tumor Immunotherapy.
CXCR4 is a G-Protein coupled receptor that is expressed nearly ubiquitously and is known to control cell migration via its interaction with CXCL12, the most ancient chemokine. The functions of CXCR4/CXCL12 extend beyond cell migration and involve the recognition and disposal of unhealthy or tumor cells. The CXCR4/CXCL12 axis plays a relevant role in shaping the tumor microenvironment (TME), mainly towards dampening immune responses. Notably, CXCR4/CXCL12 cross-signal via the T and B cell receptors (TCR and BCR) and co-internalize with CD47, promoting tumor cell phagocytosis by macrophages in an anti-tumor immune process called ImmunoGenic Surrender (IGS). These specific activities in shaping the immune response might be exploited to improve current immunotherapies.


Candida albicans meningitis and brain abscesses in a neonate: a case report.
Invasive Candida infection is an increasingly important cause of morbidity and mortality in the neonatal intensive care unit. Neonatal candidemia occurs in 4-15% of extremely low birth weight infants. Meningitis occurs in 5-9% of patients with candidemia. A few infants with Candida meningitis (4%) present ventriculitis or brain abscess. We report a neonate born at 34 weeks gestational age, who at 12 days old presented apnea and seizures. Cerebrospinal fluid (CSF) grew Candida Albicans, and blood cultures were negative. A head sonogram and head computed tomography scan were negative. Brain magnetic resonance imaging (MRI) detected multiple brain parenchyma micro abscesses. This case confirms the need of obtaining adequate cultures including blood, urine, and CSF when sepsis is suspected. Neuroimaging studies should be included in diagnostic workup of patients with systemic fungal infection. Improved neuroimaging techniques such as MRI may lead to earlier diagnosis of cerebral abscesses.


Regional and temporal variability of Indian summer monsoon rainfall in relation to El Niño southern oscillation.
The Indian summer monsoon rainfall (ISMR) exhibits significant variability, affecting the food and water security of the densely populated Indian subcontinent. The two dominant spatial modes of ISMR variability are associated with the El Niño Southern Oscillation (ENSO) and the strength of the semi-permanent monsoon trough along with related variability in monsoon depressions, respectively. Although the robust teleconnection between ENSO and ISMR has been well established for several decades, the major drivers leading to the time-varying relationship between ENSO and ISMR patterns across different regions of the country are not well understood. Our analysis shows a consistent increase from a moderate to substantially strong teleconnection strength between ENSO and ISMR from 1901 to 1940. This strengthened relationship remained stable and strong between 1941 and 1980. However, in the recent period from 1981 to 2018 the teleconnection decreased consistently again to a moderate strength. We find that the ENSO-ISMR relationship exhibits distinct regional variability with time-varying relationship over the north, central, and south India. Specifically, the teleconnection displays an increasing relationship for north India, a decreasing relationship for central India and a consistent relationship for south India. Warm SST anomalies over the eastern Pacific Ocean correspond to an overall decrease in the ISMR, while warm SST anomalies over the Indian Ocean corresponds to a decrease in rainfall over the north and increase over the south of India. The central Indian region experienced the most substantial variation in the ENSO-ISMR relationship. This variation corresponds to the variability of the monsoon trough and depressions, strongly influenced by the Pacific Decadal Oscillation and North Atlantic Oscillation, which regulate the relative dominance of the two spatial modes of ISMR. By applying the PCA-Biplot technique, our study highlights the significant impacts of various climate drivers on the two dominant spatial modes of ISMR which account for the evolving nature of the ENSO-ISMR relationship.


Human immunodeficiency virus type 1 Vif-derived peptides inhibit the viral protease and arrest virus production.
Human immunodeficiency virus type 1 (HIV-1) Vif protein is required for productive HIV-1 infection of peripheral blood lymphocytes and macrophages in cell culture and for pathogenesis in the SCID-hu mouse model of HIV-1 infection. Vif inhibits the viral protease (PR)-dependent autoprocessing of truncated HIV-1 Gag-Pol precursors expressed in bacterial cells and efficiently inhibits the PR-mediated hydrolysis of peptides in cell-free systems. The obstructive activity of Vif has been assigned to the 92 amino acids residing at its N'-terminus (N-Vif). To determine the minimal Vif sequence required to inhibit PR, we synthesized overlapping peptides derived from N-Vif. These peptides were then assessed, using two in vitro and two in vivo systems: (i) inhibition of purified PR, (ii) binding of PR, (iii) inhibition of the autoprocessing of the Gag-Pol polyprotein expressed by a vaccinia virus vector, and (iv) inhibition of mature virus production in human cells. The peptides derived from two regions of N-Vif encompassing residues Tyr-30-Val-65 and Asp-78-Val-98, inhibited PR activity in both the in vitro and the in vivo assays. Thus, these peptides can be used as lead compounds to design new PR inhibitors.


Isolation and characterization of an orthoreovirus from Indonesian fruit bats.
Nelson Bay orthoreovirus (NBV) is an emerging bat-borne virus and causes respiratory tract infections in humans sporadically. Over the last two decades, several strains genetically related to NBV were isolated from humans and various bat species, predominantly in Southeast Asia (SEA), suggesting a high prevalence of the NBV species in this region. In this study, an orthoreovirus (ORV) belonging to the NBV species was isolated from Indonesian fruit bats' feces, tentatively named Paguyaman orthoreovirus (PgORV). Serological studies revealed that 81.2% (108/133) of Indonesian fruit bats sera had neutralizing antibodies against PgORV. Whole-genome sequencing and phylogenetic analysis of PgORV suggested the occurrence of past reassortments with other NBV strains isolated in SEA, indicating the dispersal and circulation of NBV species among bats in this region. Intranasal PgORV inoculation of laboratory mice caused severe pneumonia. Our study characterized PgORV's unique genetic background and highlighted the potential risk of PgORV-related diseases in Indonesia.


Flumazenil induces localised increases in glucose utilization during diazepam withdrawal in rats.
The quantitative [14C]2-deoxyglucose autoradiographic technique has been employed to identify the neural circuits involved in diazepam withdrawal. Local cerebral glucose utilization (LCGU) was assessed in parallel groups of rats chronically treated with diazepam (5 mg/kg i.p., daily for 28 days), in rats that were withdrawn from chronic diazepam 24 h previously and in those that received flumazenil (5 mg/kg i.v.) immediately or 24 h after the last dose of diazepam. Two further groups received chronic vehicle or acute flumazenil (5 mg/kg i.v.). Rats withdrawn from diazepam 24 h previously did not produce changes in LCGU in the 51 structures examined compared with both control and chronic diazepam treated groups, suggesting that spontaneous withdrawal from small doses of diazepam does not evoke marked alterations in functional activity. In contrast, flumazenil-precipitated diazepam withdrawal produced a marked increase in glucose use in structures of the Papez circuit of emotion (mammillary body, anterior thalamus, cingulate cortex), together with increases in the septal nucleus, basolateral amygdala and nucleus accumbens. Less widespread increases in glucose use occurred in primary auditory and visual areas and in extrapyramidal areas. This pattern resembles that produced after acute FG-7142 administration (Brain Res., 475 (1988) 218-231). In rats receiving flumazenil 24 h after the last dose of diazepam there was a similar, but more restricted, pattern of change in LCGU. Flumazenil had no effect on LCGU in drug naive rats. Thus, flumazenil could only exert an effect upon LCGU in rats chronically treated with diazepam. These data provide functional neuroanatomical evidence for a withdrawal shift in the inverse agonist direction after chronic diazepam and suggest that flumazenil-precipitated withdrawal changes may merely be a reflection of this phenomenon.


Annual stability in the levels of lymphocyte subpopulations identified by monoclonal antibodies in blood of healthy individuals.
The absolute numbers and percentages of lymphocytes, monocytes, and lymphocyte subpopulations in the blood mononuclear cells were examined monthly in two healthy individuals over a 22-month period. The object of this study was to determine whether the levels of lymphocyte subpopulations identified by monoclonal antibodies, Leu4+ (T), Leu3+ (helper T), Leu2+ (suppressor/cytotoxic T), and Leu7+ (natural killer) cells, were stable during the year for healthy donors. The results were analyzed by the cosiner method to estimate the rhythmicity of these subpopulations. The number of lymphocytes varied, showing a moderate circannual rhythm with a peak in early summer, whereas the number of monocytes also varied but its variation did not show a specific rhythm. The absolute numbers of T-lymphocyte subpopulations and Leu3+ and Leu2+ cells showed a covariation, with a peak in early summer in parallel with the circannual rhythm of total lymphocyte counts. A subpopulation of granular lymphocytes with natural killer function, Leu7+ cells, also showed a significant variation during the year. Of particular interest is that Leu3/Leu2 ratios were considerably stable during the year. The two-time point examination of these lymphocyte markers including HB-2+ B cells in August and January in 15 normal donors did not show any significant differences, although the mean values were slightly higher in summer. The stability and variability of these lymphocyte markers are displayed graphically and the details of these variations are listed.


Optimization of extracellular glucan production from Pleurotus eryngii and its impact on angiogenesis.
Pleurotus eryngii, an edible mushroom with therapeutic potential was optimized using response surface methodology of four-factor Box-Behnken design for maximum mycelial biomass and extracellular glucan (EPS) production. The model predicts to gain a maximal mycelial biomass and extracellular polysaccharide at 39.4 g/l; 36.04 g/l of glucose, 8.27 g/l; 7.51 g/l of yeast extract, pH 6.99; 7.07 and temperature 26.2°C; 25.84°C, respectively. The validation experiments showed that the model was significant and in close agreement with the model prediction. The evaluation of extracellular polysaccharide on angiogenesis by ex vivo CAM assay showed that there was significant inhibition in neo-vascularization.


Anabolic-androgenic steroids: use and abuse in pediatric patients.
The "win at all costs" mentality fuels athletes to seek performance-enhancing substances, such as anabolic-androgenic steroids, to gain an advantage over their opponents. Nonathletes espouse this same attitude to "win" the battle of attractiveness. An enhanced understanding of anabolic-androgenic steroids and the motivations behind their abuse will arm pediatricians with the ability to engage their patients in a balanced discussion of the benefits and costly risks of anabolic-androgenic steroids and successfully deter further use.


Effect of theanine and polyphenols enriched fractions from decaffeinated tea dust on the formation of Maillard reaction products and sensory attributes of breads.
The antiglycoxidative properties of theanine (TEF) and polyphenols enriched fractions (PEF) prepared from tea dust were tested in a model system composed of bovine serum albumin (BSA) and methylglyoxal (MGO). PEF caused a decrease in available free amino groups of BSA in presence and absence of MGO, suggesting the simultaneous occurrence of glycoxidation reaction and phenols-protein interaction. The presence of PEF and TEF inhibited formation of fluorescent advanced glycation end-products (AGEs). Moreover, theanine (TB) and polyphenol-enriched bread (PB) were formulated. A significant increase in free amino groups was observed in TBs with a dose-response effect, while addition of PEF in bread produced a significant decrease (p<0.05). PEF efficiently reduced fluorescent AGE formation in breads compared with TEF. The results are in line with the simplified model systems. PEF used as food ingredient allows obtaining a tasty food possessing health promoting properties and lower content of potential harmful compounds (AGEs).


COVID-19 omicron variant outbreak in a hematopoietic stem cell transplant unit.
Recommendations and guidelines for management of SARS-COV-2 infection in hematologic patients were developed in the very difficult context of dealing with novel viral variants from one pandemic wave to another, with different susceptibility to available drugs and vaccines. Moreover, the largest SARS-COV-2 case series in patients treated for hematologic malignancies, including stem cell transplant recipients, was published before the Omicron surge, and refers mainly to Alpha and Delta viral variants. These infections had very high mortality, in a period when antivirals and monoclonal antibodies were mostly unavailable. Here, we report for the first time a SARS-COV-2 Omicron variant outbreak inside a Bone Marrow Transplant (BMT) Unit, describing the characteristics, clinical course, and infection outcomes shortly before and shortly after myeloablative transplantation. We detail how infections were treated off-label and managed inside the BMT ward, to guarantee the best possible outcomes while avoiding risks for non-infected inpatients. The positive outcomes observed suggest that it may not be absolutely necessary to obtain SARS-CoV-2 PCR negativity before BMT in hematologic patients after treated infection, in cases with long-term PCR positivity and high-risk hematologic disease.


Quantitative Pathologic Analysis of Digitized Images of Colorectal Carcinoma Improves Prediction of Recurrence-Free Survival.
To examine whether quantitative pathologic analysis of digitized hematoxylin and eosin slides of colorectal carcinoma (CRC) correlates with clinicopathologic features, molecular alterations, and prognosis. A quantitative segmentation algorithm (QuantCRC) was applied to 6468 digitized hematoxylin and eosin slides of CRCs. Fifteen parameters were recorded from each image and tested for associations with clinicopathologic features and molecular alterations. A prognostic model was developed to predict recurrence-free survival using data from the internal cohort (n = 1928) and validated on an internal test (n = 483) and external cohort (n = 938). There were significant differences in QuantCRC according to stage, histologic subtype, grade, venous/lymphatic/perineural invasion, tumor budding, CD8 immunohistochemistry, mismatch repair status, KRAS mutation, BRAF mutation, and CpG methylation. A prognostic model incorporating stage, mismatch repair, and QuantCRC resulted in a Harrell's concordance (c)-index of 0.714 (95% confidence interval [CI], 0.702-0.724) in the internal test and 0.744 (95% CI, 0.741-0.754) in the external cohort. Removing QuantCRC from the model reduced the c-index to 0.679 (95% CI, 0.673-0.694) in the external cohort. Prognostic risk groups were identified, which provided a hazard ratio of 2.24 (95% CI, 1.33-3.87, P = .004) for low vs high-risk stage III CRCs and 2.36 (95% CI, 1.07-5.20, P = .03) for low vs high-risk stage II CRCs, in the external cohort after adjusting for established risk factors. The predicted median 36-month recurrence rate for high-risk stage III CRCs was 32.7% vs 13.4% for low-risk stage III and 15.8% for high-risk stage II vs 5.4% for low-risk stage II CRCs. QuantCRC provides a powerful adjunct to routine pathologic reporting of CRC. A prognostic model using QuantCRC improves prediction of recurrence-free survival.


Minimal clinical benefit of single agent Orathecin (Rubitecan) in heavily pretreated metastatic breast cancer.
The purpose of this phase II study was to evaluate the efficacy and tolerability of Orathecin, an oral camptothecin analog that has exhibited antitumor activity in breast cancer patients during preclinical studies. Sixteen patients with metastatic breast cancer previously treated with anthracycline and taxane were utilized in the study. Orathecin was administered orally at 1.5 mg/m2 /day for the first five consecutive days of the cycle followed by 2 days of rest on a 7-day schedule. The end points of the study were efficacy and toxicity. The median age of the patients was 51 years (range, 35-73). Eight patients (50%) had multiple disease sites, and nine patients (56%) received more than three chemotherapy regimens. All patients were evaluated for toxicity, three patients were removed from the study for toxicity or disease progression prior to 8 weeks and were thus not evaluated for efficacy. The median follow-up was 110 days (range, 15-554). There were no responses to treatment. Five of the 13 evaluable patients (38%) had stable disease, eight (61%) had progressive disease. Most adverse events were mild to moderate in intensity. The median time to progression (TTP) for evaluable patients was 109 days (range, 56-374 days) (lower 95% C.I., 57 days). The median survival time was 272 days (lower 95% C.I., 209 days). Orathecin at the dose and regimen used in this study resulted in no objective tumor responses for this heavily pretreated population. Accurate risk stratification strategies can improve patients' selection and contribute to determine the appropriate benefit of therapies in MBC.


[Preparation of suspension of gastric mucous membrane single cell and expression of cyclins in cells].
To explore a method which can remove the gastric mucus in order to prepare mucous membrane single cell suspension for the research of cytomics. Enzymology was used to remove the mucus gel and to separate mucous layer from the normal fresh gastric tissue. The mucous layer was broken to prepare single cell suspension with machine method. Expression of major cyclins in mucous layer cells was examined by cytoimmunochemistry, flow cytometry(FCM) and confocal microscopy. The 0.1% pepsin could dissolve the mucus gel and 1.2-2.4 U/L dispase could separate the mucous layer completely. The single mucous cell suspension was prepared successfully. FCM results from mucous single cell suspension revealed that expression of cyclin D(3), B(1) was obvious, that of cyclin D(2) was weak and that of cyclin D(1), A, E was the least. Similar results were found with confocal microscopy. Single cell suspension from mucous layer can be easily prepared by pepsin and dispase. Cyclins schedule expression in vivo is different from cyclins schedule expression in vitro.


Induction of atherosclerosis by low-fat, semisynthetic diets in LDL receptor-deficient C57BL/6J and FVB/NJ mice: comparison of lesions of the aortic root, brachiocephalic artery, and whole aorta (en face measurement).
A semisynthetic diet with varying amounts of cholesterol was used to achieve hypercholesterolemia and atherosclerosis in LDL receptor-deficient (LDLR-/-) mice. Atherosclerotic lesions were measured as cross-sectional area at the aortic root and brachiocephalic artery and by en face analysis of aortic lesion area in 209 male and female animals on the C57BL/6J (B6.LDLR-/-) and FVB/NJ (FVB.LDLR-/-) backgrounds. The semisynthetic diet containing 4.3% fat and 0.00% or 0.02% cholesterol was sufficient to induce hypercholesterolemia (12.6+/-2.4 mmol/L) and atherosclerosis in B6.LDLR-/- mice at the aortic root (98,980+/-37 727 microm2) and brachiocephalic artery (12,039+/-12,750 microm2) but did not produce significant lesions in the aorta measurable by the en face method. Raising dietary cholesterol to 0.15%, 0.30%, or 0.50% more than doubled plasma cholesterol levels (35.9+/-8.5 mmol/L) and resulted in significant en face lesions. It also led to a significant increase in atherosclerotic lesion area at the aortic root (547,753+/-182,151 microm2) and brachiocephalic arteries (125,666+/-59,339 microm2). Although FVB.LDLR-/- mice developed comparable cholesterol levels, they were relatively atherosclerosis resistant and had many-fold smaller lesions. These results should aid investigations of atherosclerosis in LDLR-/- mice by informing the selection of diet to be used and the location of lesions to be scored.


Historical smelting activities in Eastern Canada revealed by Pb concentrations and isotope ratios in tree rings of long-lived white cedars (Thuja occidentalis L.).
Mining activities at Duparquet in Western Quebec (Canada) have significantly affected the local environment and left behind significant amounts of metals. Monitoring this contamination is essential to infer its past and present impacts on environmental quality and to evaluate the resulting human exposure. In that context, we measured long time series of Pb concentrations and their corresponding stable isotope ratios in long-lived white cedars (Thuja occidentalis L.) growing at Duparquet Lake in order to evaluate potential time variations of the Pb environmental contamination as well as to identify the responsible source(s). Results show that before 1950, Pb at Duparquet is mostly terrigenous. Lead concentrations rapidly increase afterwards. A simultaneous shift to lower 206Pb/207Pb ratios identifies the smelting of Abitibi ores as the source of contamination. An isotope mass balance model evaluates at roughly 7.5-20%, 5-40%, 5-9% and <3% the Pb contributions from local smelters at distances of 3.6, 3.9, 7 and 9 km, respectively. The dispersion of the Pb contamination plume is possibly driven by the distance from the Beattie smelter. We finally estimated a delay of at least 13 years between atmospheric emissions from the Beattie smelting activities and the time they are recorded by tree rings. Ultimately, this study demonstrates that white cedar tree rings series provide reliable archives of past and present Pb atmospheric contamination.


Radiographic changes associated with giant cell hyaline angiopathy.
A case report of a rare oral lesion termed giant cell hyaline angiopathy is presented. The clinical, radiographic, and histopathologic appearances are discussed, together with a successful mode of antibiotic treatment. The absence of vasculitis and foreign bodies and the therapeutic efficacy of antibiotics suggest that angiopathy may not be the appropriate term.


Role of hyaluronic acid in maturation and further early embryo development of bovine oocytes.
Hyaluronic acid (HA), an important component of the extracellular matrix, plays a crucial role for cumulus cell expansion. Genes and proteins involved in HA synthesis and its receptor CD44 are expressed in cumulus oocyte complexes (COCs) in different animal species and increase during maturation. Hyaluronidase enzymes (Hyal) degrade HA into smaller biologically active HA fragments. To investigate the effects of the molecular size and concentration of HA on oocyte maturation and further embryo development, bovine oocytes were matured in vitro in the presence or absence of HA, Hyal-2 or 4-methylumbelliferone (4-MU); an HA synthesis inhibitor. The rates of oocyte nuclear maturation to metaphase II stage and development of embryos to blastocyst stage and blastocyst quality were recorded. Hyal-2 inhibited cumulus cell expansion without affecting oocyte maturation and further embryo development. Whereas, 4-MU at 1 mm reduced cumulus cell expansion, oocyte maturation rate and further embryo development; an effect which was partially abrogated by exogenous HA supplementation. These data suggest that HA production by cumulus cells during maturation is essential not only for cumulus cell expansion, but also for oocyte maturation and further embryo development. This effect is not affected by HA-degradation by Hyal-2.


Operative treatment of congenital aortic stenosis.
The operative treatment of 131 patients with congenital aortic stenosis is reviewed. Of the 131 patients, 77% had left ventricular outflow tract (LVOT) obstruction at a single level and 23%, major obstruction at more than one level. There were 3 operative deaths (2.3%) and 10 late deaths (7.8%). Twenty of the 128 discharged patients have undergone a second procedure and 6 a third procedure for recurrent or residual LVOT obstruction. The 26 reoperations included 7 aortic valve replacements, 4 left ventricular apical-abdominal aortic (LV-AA) valved conduits, and 15 extensive aortic valvotomies with or without supravalvular aortoplasty. Five of the 20 patients undergoing reoperation died; 4 of these deaths occurred in patients who had valve replacement at reoperation. The 4 who received LV-AA conduits have sustained excellent hemodynamic and clinical results with no complications. Highly satisfactory clinical results can be obtained with minimal operative risk, regardless of the level of LVOT obstruction. Reoperation for recurrent or residual LVOT obstruction, however, is comparatively more hazardous, and alternative surgical approaches (LV-AA conduits) should be considered.


Immunological studies in children with type I diabetes mellitus and their healthy relatives: in vitro antigen stimulated IgM production, T-cell subsets and islet-cell antibodies.
Several defects in immunoregulation have been described in patients with insulin dependent diabetes mellitus (IDDM). We have looked at immunoregulatory T-cell subsets autoantibodies and in vitro IgM production in IDDM patients and their healthy first degree relatives. The proportions of total T-cells (OKT11+), helper/inducer (OKT4+), suppressor/cytotoxic T-cells (OKT8+) and OKT4/OKT8 ratio were normal in 8 patients as well as in their 26 family members and in 40 age-matched controls. Anti islet-cell antibodies (ICA) were found in sera of 6 out of 17 patients (35%) in 1 out of 62 (1.6%) family members and in none of the age-matched healthy controls. A significant increase of in vitro IgM production was found in 8 patients (130 +/- 10 PFC/10(6) cultured cells, mean +/- S.E.) as compared to 21 healthy controls (57 +/- 5.0) (p less than 0.01). In vitro IgM production by B-cells of 22 family members was also increased compared to controls (83 +/- 8.0) (p greater than 0.05). This increased antibody production is characteristic for clinical states associated with impaired immunoregulation, and reflects perturbation of immunoregulatory mechanisms in IDDM.


Structural, optical, and luminescence properties of Dy3+ -activated potassium calcium silicate phosphor for white light-emitting diodes.
A dysprosium (Dy3+ )-activated potassium calcium silicate (K4 CaSi3 O9 ) phosphor was prepared using a solid-state synthesis route. The phosphor had a cubic structure with the space group Pa 3 ¯ as confirmed using X-ray diffraction (XRD) measurements. Details of surface morphology and elemental composition of the as-synthesized undoped KCS phosphor was obtained using scanning electron microscopy (SEM) and energy-dispersive X-ray (EDX) spectroscopy. The chemical structure as well as the vibrational modes present in the as-prepared KCS phosphor was analyzed using Fourier transform infrared (FT-IR) spectroscopy. Diffuse reflectance spectra (DRS) were used to determine the optical bandgap of the phosphors and were found to be in the optical range 3.52-3.71 eV. Photoluminescence (PL) spectra showed intense yellow emission corresponding to the 4 F9/2 →6 H13/2 transition under 350 nm excitation. Commission International de l'Eclairage colour chromaticity coordinates were evaluated using the PL spectral data lie within the white region. Dexter theory and the Inokuti-Hirayama (I-H) model were applied to study the nature of the energy transfer mechanism in the as-prepared phosphors. The relatively high activation energy of the phosphors was evaluated using temperature-dependent PL (TDPL) data and confirmed the high thermal stability of the titled phosphor. The abovementioned results indicated that the as-prepared KCS:Dy3+ phosphor was a promising candidate for n-UV-based white light-emitting diodes.


Agglutination of chicken lymphocytes by infectious bursal disease virus.
Four serotype 1 field strains of infectious bursal disease virus (IBDV) and one reference standard serotype 1 strain were tested for their ability to agglutinate peripheral blood lymphocytes of chickens. All the five strains agglutinated chicken lymphocytes. The agglutination was not inhibited by serotype 1 reference anti-IBDV serum. These results suggest the need for detailed analysis of IBDV ligand(s) and cell surface receptor(s) relationships.


Etoposide (VP-16) in the treatment of advanced adenocarcinoma of the pancreas.
Twenty-six patients with advanced adenocarcinoma of the pancreas were treated with etoposide (VP-16), 100-180 mg/m2 i.v., days 1, 2, and 3, monthly. Twenty-five had bidimensionally measurable disease and one had evaluable disease only. This regimen and dosage schedule were well tolerated, with minimal toxicity including myelosuppression; a median WBC count nadir of 3,600 cells/mm3 (range 200-2,400); and a median platelet nadir of 215,000 cells/mm3 (range 15,000-405,000). However, no patients responded and only two had stable disease for 3.5 and 4 months, respectively. At this dosage and schedule, there is no role for VP-16 in the treatment of advanced pancreatic adenocarcinoma.


Evaluation of indirect sequence-specific magneto-extraction-aided LAMP for fluorescence and electrochemical SARS-CoV-2 nucleic acid detection.
Nucleic acid amplification tests (NAATs) such as quantitative real-time reverse transcriptase PCR (qRT-PCR) or isothermal NAATs (iNAATs) such as loop-mediated isothermal amplification (LAMP) require pure nucleic acid free of any polymerase inhibitors as its substrate. This in turn, warrants the use of spin-column mediated extraction with centralized high-speed centrifuges. Additionally, the utilization of centralized real-time fluorescence readout and TaqMan-like molecular probes in qRT-PCR and real-time LAMP add cost and restrict their deployment. To circumvent these disadvantages, we report a novel sample-to-answer workflow comprising an indirect sequence-specific magneto-extraction (also referred to as magnetocapture, magneto-preconcentration, or magneto-enrichment) for detecting SARS-CoV-2 nucleic acid. It was followed by in situ fluorescence or electrochemical LAMP. After in silico validation of the approach's sequence selectivity against SARS-CoV-2 variants of concern, the comparative performance of indirect and direct magnetocapture in detecting SARS-CoV-2 nucleic acid in the presence of excess host nucleic acid or serum was probed. After proven superior, the sensitivity of the indirect sequence-specific magnetocapture in conjunction with electrochemical LAMP was investigated. In each case, its sensitivity was assessed through the detection of clinically relevant 102 and 103 copies of target nucleic acid. Overall, a highly specific nucleic acid detection method was established that can be accommodated for either centralized real-time SYBR-based fluorescence LAMP or portable electrochemical LAMP.


Three new species of the millipede genus Hyleoglomeris Verhoeff, 1910 from the Aegean region of Greece (Diplopoda, Glomerida, Glomeridae).
Three new cavernicolous species of Hyleoglomeris are described from Greece: Hyleoglomerissubreducta sp.n., from Chios Island, Hyleoglomeristranslucida sp.n., from Rhodes Island, and Hyleoglomerisinsularis sp.n., from Kalymnos Island, all in the Aegean Sea.


Impact of the COVID-19 pandemic on HIV testing rates across four geographically diverse urban centres in the United States: An observational study.
Non-emergent clinical services were limited or suspended during the early stages of the coronavirus disease 2019 (COVID-19) pandemic in the United States (U.S.). This could adversely impact epidemics of public health importance, such as HIV, and access to testing, which is a cornerstone of prevention efforts. In this observational study, we collected HIV testing and positivity rate clinical data from four geographically diverse U.S. healthcare systems in New Orleans, Louisiana; Minneapolis, Minnesota; Providence, Rhode Island; and, Seattle, Washington. Data from 2019 to 2020 were examined to assess changes in HIV testing in community-based, emergency department, and outpatient settings. Poisson regression was used to explore trends in HIV testing through phases of the COVID-19 pandemic. In outpatient settings, there was a 68-97% reduction in the number of HIV tests per week during each state's stay-at-home order period, compared to during the pre-stay-at-home order period in early 2020. HIV testing remained reduced 11-54% after states transitioned to advisory phases. The HIV positivity rate increased slightly at outpatient settings, except in New Orleans where it fell. We found a concerning trend of substantially decreased HIV testing across four geographically diverse sites. These findings suggest that new HIV infections within the U.S. may be undiagnosed and not yet linked to clinical care and services, as a consequence of the COVID-19 pandemic. Thus, augmented efforts to identify patients and link them to HIV services will be needed as healthcare settings return to full operation. U.S. National Institute of Mental Health.