Berberine derivatives reduce atherosclerotic plaque size and vulnerability in apoE(-/-) mice.
Our previous in vitro and clinical work has demonstrated anti-inflammatory effects of berberine (BBR), but the clinical application of BBR is limited by its poor bioavailability. Derivatives of BBR have been suggested to have enhanced bioavailability compared to BBR. In this study, we tested whether BBR derivatives, compared with BBR, had superior beneficial effects on atherosclerotic plaques in apoE(-/-) mice, and defined possible molecular mechanisms underlying such effects. Macrophages were pretreated with BBR and its derivatives, dihydroberberine (dhBBR) and 8,8-dimethyldihydroberberine (Di-MeBBR), before incubation with oxLDL. Cell surface EMMPRIN expression was measured by flow cytometry and Western blotting, and phospho-(p)-p38, p-JNK, nuclear NFκB p65, and phospho-p65 were measured by Western blotting. ApoE-/- mice fed with the Western diet for 16 weeks were treated with BBR, dhBBR and Di-MeBBR 16 weeks. Aortic atherosclerotic lesion size, plaque matrix proteins, and EMMPRIN and other inflammatory factors were measured using Oil Red O Staining, Masson's trichromestaining and immunohistochemical staining and real-time PCR. Compared with BBR, dhBBR and Di-MeBBR significantly reduced EMMPRIN expression, which was associated with a greater inhibition of p-p38, p-JNK, nuclear NFκB p65 and phospho-p65 induced by oxLDL in macrophages. dhBBR and Di-MeBBR, but not BBR, reduced atherosclerotic plaque size and improved plaque stability indicated by increased α-smooth muscle actin and collagen content, and thicker fibrous caps. dhBBR and Di-MeBBR reduced expression of EMMPRIN, CD68, and NFκB p65, and Di-MeBBR also reduced expression of matrix metalloproteinase-9, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in aortic plaques. These results have demonstrated that BBR derivatives, dhBBR and Di-MeBBR, are superior to BBR in inhibiting inflammation and reducing plaque size and vulnerability.


T-cell-rich B-cell lymphoma and Epstein-Barr virus infection of the uterus in a postmenopausal patient with an intrauterine contraceptive device in place for over 20 years.
Although secondary involvement of the female genital tract occurs in up to 40% of cases of disseminated lymphomas, lymphomas presenting with primary female genital tract symptomatology are very unusual. We report a case of T-cell-rich B-cell lymphoma (TCRBCL) arising in the uterine corpus of a 57-year-old female who carried an intrauterine contraceptive device (IUD) for over 20 years. Malignant lymphoid cells expressed the Epstein-Barr virus (EBV) late membrane protein (LMP), a feature described in TCRBCL but not previously reported in primary uterine lymphomas. To our knowledge, this is the first reported case of a TCRBCL of the uterus.


A rare entity of an unusual site: adenomatoid tumour of the adrenal gland: a case report and review of the literature.
This is a case report of a 51 year old male who was found to have an incidental left sided non-functioning adrenal mass on routine medical examination and which was confirmed by CT and MRI scans. A laparoscopic left adrenalectomy was done. On gross examination the tumour was a solitary well circumscribed solid-cystic mass with a homogenous pinkish white cut surface. On microscopic examination, the tumour was composed of variably sized tubules and fenestrated channels lined by bland cuboidal cells to epithelioid cells. There was focal extension to capsule and peri-adrenal fat. Immunohistochemically the tumour cells stained with calretinin, Cam5.2, CK7, vimentin and focally with EMA. Ki-67 fraction was <1%. They were negative for ER, CD31, CD34, Factor 8, chromogranin, synaptophysin S100 and inhibin. A diagnosis of an adenomatoid tumour as made. Adenomatoid tumours are rare benign tumours of mesothelial derivation. The adrenal gland is devoid of a mesothelial lining and the most accepted hypothesis for an adenomatoid tumour originating in the adrenal gland is derivation from mesothelial rests. As the adrenal gland is an extremely rare site of occurrence for an adenomatoid tumour, it is frequently mistaken for adrenocortical tumours or a pheochromocytoma clinically and radiologically.


Privacy-Aware Collaborative Learning for Skin Cancer Prediction.
Cancer, including the highly dangerous melanoma, is marked by uncontrolled cell growth and the possibility of spreading to other parts of the body. However, the conventional approach to machine learning relies on centralized training data, posing challenges for data privacy in healthcare systems driven by artificial intelligence. The collection of data from diverse sensors leads to increased computing costs, while privacy restrictions make it challenging to employ traditional machine learning methods. Researchers are currently confronted with the formidable task of developing a skin cancer prediction technique that takes privacy concerns into account while simultaneously improving accuracy. In this work, we aimed to propose a decentralized privacy-aware learning mechanism to accurately predict melanoma skin cancer. In this research we analyzed federated learning from the skin cancer database. The results from the study showed that 92% accuracy was achieved by the proposed method, which was higher than baseline algorithms.


Hepatocyte apoptosis in hepatitis C/HIV co-infection.
Hepatocytes exposed in vitro to hepatitis C virus (HCV) and human immunodeficiency virus (HIV) envelope proteins and undergo apoptosis as a result of cell surface binding of the proteins. The studies indicate that HCV/HIV envelope proteins induce hepatocyte apoptosis by activating a novel downstream STAT1 signaling pathway.


Effect of n-3 and n-6 polyunsaturated fatty acids and their ethylesters on stimuli-dependent superoxide generation in neutrophils.
Polymorphonuclear leukocytes from healthy volunteers (HPMN) generated superoxide (O2*-) following treatment with various stimuli, such as phorbol myristate acetate (PMA), opsonized zymozan (OZ) and arachidonic acid (AA). Other types of n-3 polyunsaturated fatty acids (PUFAS), such as docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and eicosapentaenoic acid (EPA), also stimulated O2*- generation. The free form of DHA enhanced the generation of O2*- induced by PMA but inhibited that induced by OZ. In contrast, the ethylester of DHA (DHA-E) inhibited O2*- generation induced by PMA but stimulated that induced by OZ. Similar effects were also observed with ethylesters of EPA (EPA-E), DPA (DPA-E) and AA (AA-E). High concentrations of DHA-E reduced the PMA-induced formation of superoxide without affecting the cellular activity of protein kinase C (PKC). Similar phenomena were also observed with oral neutrophils from healthy volunteers (OPMN). These results indicate that PUFAS and their esters affect 02*- generation in human PMN via different pathways, thereby modulating inflammatory reactions.


Otodental syndrome. A case report.
A 12-year-old boy with characteristic findings of otodental syndrome is presented. Abnormalities of deciduous and permanent dentition included bulbous canines, globe-shaped posterior teeth and agenesis of maxillary premolars. High-frequency sensorineural hearing loss was demonstrated, and results of genetic studies indicated an autosomal dominant trait. This patient presented previously unreported findings, including generalized macrodontia, delayed mineralization of the mandibular premolars, and supplementary permanent maxillary canines.


Transplanted human umbilical cord blood mononuclear cells improve left ventricular function through angiogenesis in myocardial infarction.
Human umbilical cord blood contains an abundance of immature stem/progenitor cells, which may participate in the repair of hearts that have been damaged by myocardial infarction (MI). This study aimed to evaluate the effects of human umbilical cord blood mononuclear cells (hUCBC) transplantation on cardiac function and left ventricular remodeling in rat model of MI. Forty-five male Wistar rats were randomized into three groups: MI or control group (n = 15), MI plus cell transplantation (n = 15), and sham group (n = 15). Acute myocardial infarction (AMI) was established by ligating the left anterior descending artery, thereafter, hUCBC were implanted into the marginal area of infarcted myocardium. In MI/control group, DMEM was injected instead of hUCBC following the same protocol. Left ventricular function assessment was carried out by echocardiography and invasive hemodynamic measurements one month post MI. All rats were sacrificed for histological and immunochemical examinations. The transplanted hUCBC survived and engaged in the process of myocardial repair in the host heart. Echocardiography demonstrated that left ventricular function improved significantly in the rats that underwent cell transplantation. Hemodynamic studies found a significantly decreased left ventricular end-diastolic pressure (LVEDP) [(21.08 +/- 8.10) mmHg vs (30.82 +/- 9.59) mmHg, P < 0.05], increase in +dp/dt(max) [(4.29 +/- 1.27) mmHg/ms vs (3.24 +/- 0.75) mmHg/ms, P < 0.05), and increase in -dp/dt(max) [(3.71 +/- 0.79) mmHg/ms vs (3.00 +/- 0.49) mmHg/ms, P < 0.05] among MI group with hUCBC transplantation when compared with MI/control group. Masson's trichrome staining revealed that the collagen density in the left ventricle was significantly lower in rats of transplantation group than that in the MI control groups [(6.33 +/- 2.69)% vs (11.10 +/- 3.75)%, P < 0.01]. Based on immunostaining of alpha-actin, the numbers of microvessels were significantly (P < 0.01) increased at the boundary of infarction site. Similarly higher mRNA expression of vascular endothelial growth factor (VEGF) 164 and VEGF188 were found at 7- and 28-day post cell transplantation in MI group with hUCBC transplantation when compared with MI/control group. Transplanted hUCBC can survive in host myocardium without immunorejection, significantly improve left ventricular remodeling after AMI and promote a higher level of angiogenesis in the infarct zones. All these factors beneficially affect cardiac repair in the setting of MI. Therefore human umbilical cord blood may be potential source for cell-based therapy for AMI.


Autophagy in cardiac myocyte homeostasis, aging, and pathology.
Autophagy, an intralysosomal degradation of cells' own constituents that includes macro-, micro-, and chaperone-mediated autophagy, plays an important role in the renewal of cardiac myocytes. This cell type is represented by long-lived postmitotic cells with very poor (if any) replacement through differentiation of stem cells. Macroautophagy, the most universal form of autophagy, is responsible for the degradation of various macromolecules and organelles including mitochondria and is activated in response to stress, promoting cell survival. This process is also involved in programmed cell death when injury is irreversible. Even under normal conditions, autophagy is somewhat imperfect, underlying gradual accumulation of defective mitochondria and lipofuscin granules within aging cardiac myocytes. Autophagy is involved in the most important cardiac pathologies including myocardial hypertrophy, cardiomyopathies, and ischemic heart disease, a fact that has led to increasing attention to this process.


William Boven's 1915 thesis "Similarity and Mendelism in the heredity of dementia praecox and manic-depressive insanity".
Boven published, in 1915, his MD thesis at the University of Lausanne in which he examined 60 3- to 4-generation pedigrees ascertained from admitted patients with dementia praecox (DP) and manic-depressive insanity (MDI). He asked three questions: (i) were DP and MDI hereditary? (ii) were they the same or distinct conditions? and (iii) were they Mendelian disorders? Based on the rarity of environmental precipitants severe enough to cause disorder onset and the pattern of disorders in relatives, Boven concluded that both disorders were inherited. He found that MDI largely ran in families through direct transmission across generations while DP was only common in collateral relatives. Both pedigrees contained a substantial number of "psychopathic" (personality disordered) relatives in which DP and MDI pedigrees typically had, respectively, paranoid, and dysthymic/cyclothymic features. Boven concludes that their inheritance is largely distinct but not exclusive, as some pedigrees contained cases of both disorders. With assistance from Wilhelm Weinberg, Boven applied algebraic models with proband correction to rates of DP and MDI in sibships and found the results inconsistent with Mendelian transmission. His study represents among the first examinations, using "modern" methods, of the familial relationship between DP and MDI and the first published in French.


Design, Synthesis, and Preclinical Evaluation of Fused Pyrimidine-Based Hydroxamates for the Treatment of Hepatocellular Carcinoma.
Class I histone deacetylases (HDACs) are highly expressed and/or upregulated in hepatocellular carcinoma (HCC) and are associated with aggressiveness, spread, and increased mortality of HCC. Activation of phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway was involved in the development of HCC and acquired resistance to sorafenib. A series of purine or 5H-pyrrolo[3,2-d]pyrimidine based hydroxamates were designed and developed as multitarget drugs to modulate both HDACs and the PI3K/Akt/mTOR pathway. Among 39 cell lines screened, the molecules (e.g., 20e, 20f, and 20q) were the most selective against leukemia, lymphoma, and HCC cells; they also demonstrated target modulation in cancer cell lines and in mice bearing MV4-11 and HepG2 tumors. Compound 20f in particular showed significant single agent oral efficacy in hypervascular liver cancer models (e.g., HepG2, HuH-7, and Hep3B) and was well-tolerated. These encouraging results, along with its favorable target profile and tissue distribution, warrant further development of 20f.


Effects of training on suicide risk assessment.
This study evaluated the impact of structured training in evidence-based risk assessment for suicide. Forty-five psychiatry and psychology trainees participated in a workshop on evidence-based risk assessment. A comparison group of ten psychiatry trainees participated in a different workshop on the application of evidence-based medicine to psychiatry that was not focused specifically on risk assessment. Before and after each workshop, participants rated their skills in assessing patients' risk of suicide and wrote progress notes regarding clinical vignettes that included the assessment of and plan regarding suicide risk. Researchers systematically rated the progress notes. Participation in risk assessment training predicted improvement on specific indicators of documentation quality, ratings of the overall quality of documentation of suicide risk, and self-rated competence in suicide risk assessment. Structured clinical training in evidence-based risk assessment can improve documentation of assessment and management of patients' risk of suicide.


Sub-micron picoplankton shape, orientation, and internal structure combined to preferentially amplify the forward scatter.
Compelling evidence is presented that sub-micron picoplankton shape, internal structure and orientation in combination leads to a disproportionate enhancement of differential forward scatter compared with differential side scatter when analyzed with a flow cytometer. Theoretical evidence is provided which results in an order of magnitude amplification in the forward scatter direction, with little or no change in the side scatter: this discounts the possibility of "doublets" caused by multiple particles simultaneously present in the laser beam. Observational evidence from progressively finer filtered seawater samples shows up to three orders of magnitude enhancement in the forward scatter direction and sizes of Prochlorococcus close to that reported in the literature (0.61 ± 0.17 µm). It therefore seems likely that flow cytometrically observed "bi-modal size distributions" of Prochlorococcus are instead the manifestation of intra-population differences in shape (spherical - prolate with preferential alignment) and internal structure (homogenous - heterogenous).


[Insomnia due to hypnotic abuse].
Insomnia due to hypnotic abuse and dependence is a common and serious problem of somnology irrespectively of which one comes first: sleep disturbances or drug use. Modern hypnotics demonstrate selective affinity to some types of benzodiazepine receptors. This explains its higher safety profile compared to first-generation hypnotics. Nevertheless, there are reports of dependence and withdrawal syndrome associated with its administration as well. This literature review shows that seizures, hemodynamic and respiratory disturbances are the most dangerous symptoms of withdrawal. Treatment of hypnotic dependence includes detoxication and gradual withdrawal of medicines.


[Differential diagnosis of incarcerated inguinal hernia in an infant: appendicitis in the hernial sac].
The article reports on the case of a 10-week-old male infant with a perforated appendix localised in the hernial sac of a right-sided inguinal hernia. The simultaneous occurrence of an acute appendicitis in infancy with the atypical localisation in the hernial sac presenting as an incarcerated hernia is a rare combination.


Cloning and sequence analysis of truncated T-DNA inserts from Nicotiana tabacum.
Transgenic plants produced by Agrobacterium-mediated transformation usually have one or a few stable and intact T-DNA insertions. However, in a significant number of the transformants Southern blot analysis has revealed the occurrence of aberrant T-DNA insertions missing one or both ends. During the study of this phenomenon, we obtained KmR Nicotiana tabacum clones after cocultivation with an Agrobacterium strain containing a promoterless nptII gene located internally in the T-DNA. Expression of this nptII gene requires a break in the T-DNA region upstream from the nptII-coding sequence and insertion of the truncated T-DNA in a transcriptionally active plant DNA region. The most conspicuous result from Southern analyses on four such KmR plant clones is that they contain several T-DNAs truncated at other positions besides the upstream region of the nptII sequence. Four truncated T-DNA insertions have been cloned. Two insertions contain the nptII gene fused to plant expression signals and are missing the right part of the T-DNA. Another is missing the left T-DNA part and the last T-DNA is lacking both ends. Sequence analysis of the T-DNA::plant junctions has shown that the T-DNA breakpoints are randomly distributed and do not show obvious homologies to one another or to the border consensus sequence. S1-type mapping of the most strongly expressed plant genome::nptII fusion revealed a specific transcription start point and putative TATA and CAAT boxes in the upstream plant DNA region; the steady-state nptII mRNA in these plants is about 20 times more abundant than in transgenic Pnos-nptII plants.


Patient safety attitude in primary health care settings in Giza, Egypt: Cross-sectional study.
Although there is increasing interest in patient safety, yet there is a general lack of awareness of the problem. This study aims to investigate patient safety attitudes among health care providers in primary health care (PHC) facilities in Egypt through employing the Safety Attitudes Questionnaire in order to explore the areas of deficiency and opportunities for improvement concerning patients' safety. A cross-sectional study was conducted in an urban PHC and one rural unit where 130 working team at the time of the study was interviewed with response rate of 63.7%, SPSS 18 was used for data analysis. Descriptive analyses, independent samples t tests, and/or analysis of variance (ANOVA) were performed to examine the relationship between patient's safety culture and independent variables, namely, profession, gender, or age groups. Highest positivity percentage was found for job satisfaction dimension (23%), while it was the least for the ambulatory care (2.3%). Participants belonging to age group older than or equal to 50 scored statistically significant mean values in both job satisfaction and working conditions dimensions (P = 0.03 and 0.02, respectively). Health care managers scored statistically significant mean in the ambulatory care dimension 68.1 ± 15.3, (P = 0.03). Managers had more positive attitudes regarding patient safety issues in the practices they are responsible for, compared with the employees. This could be an opportunity to enhance safety attitudes within PHC centers and gain their commitment to guarantee safer and higher quality patient care.


Validation of the Retinopathy of Prematurity Activity Scale (ROP-ActS) using retrospective clinical data.
The International Neonatal Consortium recently published a proposed retinopathy of prematurity (ROP) activity scale intended for use in clinical trials after validation. The aim of this study was to validate the ROP activity scale (ROP-ActS) in a ROP screened cohort with protocol based collected data by evaluating the ability of the ROP-Act scores to predict ROP treatment. In addition, we aimed to evaluate the scale's sensitivity characteristic of disease severity by studying association with gestational age (GA) in comparison with conventionally used ROP stage and zone. A cohort of 535 preterm infants with 3324 ROP examinations with an end-point of ROP treatment or end of screening in Gothenburg, Sweden, was included. Median GA was 28.1 weeks, 47.5% were girls, and 74 (13.8%) infants were treated for ROP. The validation was performed by estimating probabilities for ROP treatment, and by applying logistic and linear regression. The original ROP-ActS was overall well-ordered with respect to ability to predict ROP treatment but could be improved by re-ordering score 3 (zone II stage 1) and 5 (zone III stage 3) based on our clinical cohort data. The modified ROP-ActS was superior to ROP stage and zone in the prediction analysis of ROP treatment. Modified ROP-ActS was more strongly related to GA than currently used ROP stage, but not zone. In the studied cohort, the modified ROP-ActS could better predict ROP treatment compared to ROP stage and zone. Retinopathy of Prematurity Activity Scale (ROP-ActS) had a superior sensitivity characteristic studied through association to GA than conventionally used ROP stage.


Risk factors and outcomes for hyperbilirubinaemia after heart surgery in children.
Liver dysfunction, associated with morbidity and mortality, is common in patients with CHD. We investigate risk factors for and outcomes of hyperbilirubinaemia in neonates and infants after cardiac surgery. In a retrospective analysis of neonates and infants undergoing cardiac surgery at our institution between January 2013 and December 2017, we identified those with post-operative conjugated hyperbilirubinaemia. We tested various demographic and surgical risk factors, and use of post-operative interventions, for an association with conjugated hyperbilirubinaemia. We also tested hyperbilirubinaemia for association with post-operative mortality and prolonged length of stay. We identified 242 post-operative admissions, of which 45 (19%) had conjugated hyperbilirubinaemia. The average conjugated bilirubin level in this group was 2.0 mg/dl versus 0.3 mg/dl for peers without hyperbilirubinaemia. The post-operative use of both extracorporeal membrane oxygenation (OR 4.97, 95% CI 1.89-13.5, p = 0.001) and total parenteral nutrition (OR 2.98, 95% CI 1.34-7.17, p = 0.010) was associated with conjugated hyperbilirubinaemia. No demographic variable analysed was found to be a risk factor. Hyperbilirubinaemia was associated with higher odds of mortality (OR 3.74, 95% CI 2.69-13.8, p = 0.005) and prolonged length of stay (OR 2.87, 95% CI 2.02-7.97, p = 0.005), which were independent of other risk factors. We identified the post-operative use of total parenteral nutrition and extracorporeal membrane oxygenation as risk factors for hyperbilirubinaemia. These patients were more likely to experience morbidity and mortality than control peers. As such, bilirubin may be marker for elevated risk of poor post-operative outcomes and should be more frequently measured after cardiac surgery.


Electroporation ablation of bronchial smooth muscle cells: A novel non-thermal asthma therapy.
Asthma is a common disease which places significant burden on the US healthcare system and which can be associated with significant patient morbidity and mortality. Current medical therapies are costly and not curative. A new approach for a more permanent asthma treatment is the use of radiofrequency ablation. However, this radiofrequency approach is thermal-based and can result in deleterious effects to the airways, such as stenosis or ulceration. We describe a novel, improved therapeutic approach for smooth muscle ablation using non-thermal DC electroporation ablation. We developed and tested prototype electroporation ablation devices that access the airways both endoscopically and via a bronchoscope. We tested the feasibility of this approach and demonstrated proof-of-concept in 2 mongrel dogs. In order to assess for smooth muscle function, we performed functional studies pre and post ablation with methacholine challenge to assess for airway reversibility. We also evaluated bronchial lesions via direct vision with bronchoscopy. We developed novel electroporation catheters to delivery energy to the bronchial smooth muscle through an endoscopic approach. We tested these catheters in 2 acute canine studies and successfully demonstrated the ability to destroy smooth muscle tissue via novel prototypes and saline irrigation for widespread non-thermal electroporation ablation. Our functional studies demonstrate the efficacy of this approach. We report a novel method for non-thermal bronchial smooth muscle ablation using novel prototypes and electroporation with normal saline. These early findings require further evaluation in larger, chronic canine studies to assess for use as a potential curative therapy.


Antigen Specificity of Type I NKT Cells Is Governed by TCR β-Chain Diversity.
NKT cells recognize lipid-based Ags presented by CD1d. Type I NKT cells are often referred to as invariant owing to their mostly invariant TCR α-chain usage (Vα14-Jα18 in mice, Vα24-Jα18 in humans). However, these cells have diverse TCR β-chains, including Vβ8, Vβ7, and Vβ2 in mice and Vβ11 in humans, joined to a range of TCR Dβ and Jβ genes. In this study, we demonstrate that TCR β-chain composition can dramatically influence lipid Ag recognition in an Ag-dependent manner. Namely, the glycolipids α-glucosylceramide and isoglobotrihexosylceramide were preferentially recognized by Vβ7(+) NKT cells from mice, whereas the α-galactosylceramide analog OCH, with a truncated sphingosine chain, was preferentially recognized by Vβ8(+) NKT cells from mice. We show that the influence of the TCR β-chain is due to a combination of Vβ-, Jβ-, and CDR3β-encoded residues and that these TCRs can recapitulate the selective Ag reactivity in TCR-transduced cell lines. Similar observations were made with human NKT cells where different CDR3β-encoded residues determined Ag preference. These findings indicate that NKT TCR β-chain diversity results in differential and nonhierarchical Ag recognition by these cells, which implies that some Ags can preferentially activate type I NKT cell subsets.


Adipose tissue-derived mesenchymal stem cells induce expansion of interleukin-10-producing regulatory B cells and ameliorate autoimmunity in a murine model of systemic lupus erythematosus.
Mesenchymal stem cells (MSCs) are multipotent cells characterized by immunomodulatory properties and are therefore considered a promising tool for the treatment of autoimmune diseases. One functional B-cell subset, regulatory B cells (Bregs), has recently been shown to restrain excessive inflammatory responses in autoimmune diseases. In the present study, we investigated the impact of human adipose-derived MSCs on Bregs and their therapeutic effect in an animal model of systemic lupus erythematosus (SLE). Coculture of human adipose-derived MSCs with splenocytes from C57BL/6 mice expanded the population of interleukin-10-producing B cells (B10 B cells). In vivo treatment with human adipose-derived MSCs reduced serum anti-double-stranded antibody levels and improved renal pathology of lupus mice (Roquin(san/san) mice). MSCs decreased ICOS(+)CD44(+) follicular helper T cells, Th1 cells and Th17 cells, in spleens of Roquin(san/san) mice. In contrast, MSCs increased Foxp3-expressing regulatory T cells. MSCs also decreased the size and number of germinal centers and effector B cells. As expected, in vivo treatment with MSCs expanded the population of Bregs in spleens of Roquin(san/san) mice. Our results indicate that human adipose-derived MSCs induce the expansion of Bregs and ameliorate autoimmunity in a murine model of SLE. These findings suggest that human adipose-derived MSCs may be a promising therapeutic strategy targeting B-cell-mediated autoimmune diseases such as SLE.


Effect of supplemental dietary leucine and immune system stimulation on whole-body nitrogen utilization in starter pigs.
The increase in circulating pro-inflammatory cytokines following an immune challenge (e.g., with bacterial lipopolysaccharide [LPS]) causes a disruption in normal AA metabolism and increases visceral protein synthesis at the expense of muscle protein synthesis. The objective of this study was to determine the effect of supplemental dietary Leu on the dynamics of whole body nitrogen (N) retention in starter pigs before and after immune system stimulation (ISS) induced by LPS. A total of 28 starter pigs (14.46 ± 0.73 kg BW) were assigned to isoenergetic and isonitrogenous diets formulated to supply essential AA 10% above estimated requirements for maximum whole-body protein deposition (PD) and to contain increasing amounts of Leu: CON (1.36% SID Leu); LEU-M (2.04% SID Leu); and LEU-H (2.72% SID Leu). Pigs were housed in metabolic crates, scale-fed every 4 h based on BW, and adjusted to dietary treatments for 5 d. The 108-h N-balance experiment was divided into two periods: prechallenge (before LPS challenge; six 12-h collections) and challenge (after LPS challenge; three 12-h collections) periods. In both periods, blood was collected to determine plasma AA and urea N concentrations. At the start of the challenge period, one-half of the pigs fed CON and all pigs fed LEU-M and LEU-H were challenged with LPS (ISS+; 30 µg/kg injected intramuscularly); the remaining pigs fed CON were injected with saline (ISS-). Whole-body N retention was determined during subsequent 12-h collections. Plasma free Leu concentration increased linearly with increasing Leu content in the diet before LPS was administered (CON, 124 µmol/L; LEU-M, 185 µmol/L; LEU-H, 227 µmol/L; < 0.01). During the prechallenge period, N retention was lower in pigs fed LEU-M ( < 0.01) and there was no difference between pigs fed CON and LEU-H (7.91, 7.18, and 7.71 g/12 h for CON, LEU-M, and LEU-H, respectively). During the challenge period, N retention in pigs fed CON was higher in ISS- than ISS+ (5.37 vs. 3.83 g/12 h; < 0.01) but was not affected by diet in ISS+ pigs (3.83, 3.21, and 3.45 g/12 h for CON, LEU-M, and LEU-H, respectively; > 0.10). In healthy pigs, feeding a high excess of dietary Leu induced an anabolic response to compensate for reduced N retention that occurred in pigs fed an intermediate excess of dietary Leu. There was no effect of supplemental Leu on N retention in pigs after an LPS challenge.


A new species of Derobrachus Audinet-Serville, 1832 (Coleoptera, Cerambycidae, Prioninae) from a cloud forest in Honduras.
A yearly biodiversity monitoring of longhorned beetles (Cerambycidae) in a Honduran cloud forest revealed a new species of prionine. Derobrachus cusucoensis sp. nov. is a locally relatively common species described from Cusuco National Park in Honduras, becoming the ninth species of this genus recorded for the country. Similar both in morphology and a montane habitat to D. dohrni, there is a possibility that this new species represents a disconnected population from the latter that evolved separately. An adapted insert for an existing identification key to all Derobrachus species is included.


Computer modeling of antibiotic fermentation with on-line product removal.
The fermentation of Streptomyces griseus for the production of cycloheximide is similar to other antibiotic fermentations in that product synthesis is subject to feedback regulation and the desired product is degraded in the fermentation broth. The productivity of this fermentation can thus be dramatically increased by removing the antibiotic from the whole broth as it is produced. One means for effecting this on-line product removal is to contact the whole fermentation broth with neutral polymeric resin immobilized in hydrogel beads. The antibiotic adsorbs to the immobilized resin via hydrophobic interactions. In this work, the adsorption of the antibiotic onto the immobilized resin was characterized. A biochemical model of the fermentation was then used to describe the time profiles of biomass, substrate, and antibiotic in a fermentation system in which whole broth is circulated from the fermentor through a continuously stirred extractor containing the adsorbent beads. Various operating conditions were examined to optimize the productivity of the fermentation.


Cognitive deficits of pure subcortical vascular dementia vs. Alzheimer disease: PiB-PET-based study.
Despite many neuropsychological studies to differentiate subcortical vascular dementia (SVaD) from Alzheimer disease (AD), previous studies did not eliminate confounding effects of mixed Alzheimer and vascular pathology. We aimed to investigate neuropsychological differences between patients with Pittsburgh compound B (PiB)-negative SVaD and those with PiB-positive AD. We recruited patients who were clinically diagnosed with SVaD or AD and underwent an 11C-PiB-PET scan. All patients with SVaD fulfilled DSM-IV criteria for vascular dementia and had severe white matter hyperintensities. The diagnosis of AD was made on the basis of criteria for probable AD proposed by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association. The final patient sample consisted of 44/67 (65.7%) patients with SVaD who tested negative for PiB retention [PiB- SVaD] and 61/68 (89.7%) patients with AD who tested positive for PiB retention [PiB(+) AD]. Patients with PiB- SVaD performed better than patients with PiB(+) AD on both verbal and visual memory tests including delayed recalls of the Seoul verbal learning test and Rey complex figure test. Patients with PiB- SVaD were worse than patients with PiB(+) AD on phonemic fluency of the Controlled Oral Word Association Test and Stroop color test. Patients with PiB- SVaD were better at memory but worse at frontal function than patients with PiB(+) AD. The differences in memory/frontal functions observed between the 2 groups, however, could not differentiate all individual data due to some overlap in the cutoff threshold.


Ophthalmomyiasis in Kuwait: first report of infections due to the larvae of Oestrus ovis before and after the Gulf conflict.
We report for the first time four cases of ophthalmomyiasis due to the larvae of Oestrus ovis in Kuwait, before and after Operations Desert Shield and Desert Storm. The larvae were easily removed under local anaesthetic. The symptom complex of acute foreign body sensation, irritation, redness, lacrimation and photophobia resolved rapidly. Ophthalmic antibiotic and corticosteroid drops were also instilled and recovery was uneventful. The ophthalmomyiasis may not always be associated with contact with sheep-rearing per se. Medical personnel should therefore be aware that in cases of what might appear initially as acute, non-specific catarrhal conjunctivitis, patients with the persistent symptom complex should be re-examined to exclude ophthalmomyiasis due to the larvae of O. ovis in endemic areas.


Cerebral toxoplasmosis associated with treatment with rituximab, azathioprine and prednisone for dermatomyositis.
We observed a severe case of cerebral toxoplasmosis in a 22-year-old woman diagnosed with dermatomyositis in 2016 in Venezuela, and treated with rituximab and azathioprine. The patient met clinical and microbiological criteria. Treatment with pyrimethamine and sulfadiazine was initiated, and the patient was discharged. She was rehospitalized with signs and symptoms of a manic episode. During hospitalization, the patient developed acute kidney injury related to sulfadiazine crystalluria. Finally, acute kidney injury was resolved and the patient was successfully discharged.


Solid-phase synthesis of multiantennary oligonucleotide glycoconjugates utilizing on-support oximation.
A novel method for preparation of multivalent oligonucleotide glycoconjugates on a solid support has been described. A pentaerythritol-based phosphoramidite (1) bearing two masked aminooxy groups has been used as the key building block. After conventional chain assembly, the aminooxy functions have been deblocked by a hydrazinium acetate treatment and subsequently oximated with fully acetylated 4-oxobutyl alpha-D-mannopyranoside. The conjugates obtained have been shown to withstand standard ammonolytic deprotection and cleavage from the support. Four different oligonucleotide glycoconjugates containing two, four, or six alpha-D-mannopyranosyl units (12-15) have been prepared to demonstrate the applicability of the procedure. The glycosyl residues only moderately retards hybridization of the oligonucleotide moiety.


Expression of Gastrin-Releasing Peptide Receptor in Breast Cancer and Its Association with Pathologic, Biologic, and Clinical Parameters: A Study of 1,432 Primary Tumors.
A growing body of evidence suggests that gastrin-releasing peptide receptor (GRPR) might be a valuable target in breast cancer. To understand which patients can be potential candidates for GRPR-based imaging or targeted therapy, we screened invasive breast cancers by immunohistochemistry for the presence and intensity of GRPR expression. Methods: We explored a tissue microarray of 1,432 primary breast tumors from patients who underwent surgery between 2000 and 2005 at Institut Bergonié, without prior neoadjuvant treatment. We studied associations between GRPR expression and clinical, pathologic, and biologic parameters. The association between GRPR expression and distant metastasis-free interval was also examined. Results: GRPR overexpression was found in 75.8% of the 1,432 tumors and was most strongly associated with estrogen receptor (ER) positivity (GRPR was high in 83.2% of ER-positive and 12% of ER-negative tumors; P < 0.00001). When molecular subtypes of breast cancer were considered, GRPR was overexpressed in 86.2% of luminal A-like tumors, 70.5% of luminal B-like human epidermal growth factor receptor 2 (HER2)-negative tumors, 82.8% of luminal B-like HER2-positive tumors, 21.3% of HER2-enriched tumors, and 7.8% of triple-negative tumors. Importantly, when breast tumors overexpressed GRPR, high GRPR expression was also found in metastatic lymph nodes in 94.6% of cases. Primary tumors with high GRPR expression were associated with lower risk of distant metastases at follow-up in univariate analysis (Log-rank P = 0.0084) but not in multivariate analysis. Hence, the prognostic impact of GRPR was lost when examined within specific molecular subtypes. Conclusion: Because GRPR is overexpressed in a high percentage of ER-positive tumors, GRPR targeting offers wide perspectives for imaging and treatment in patients with ER-positive breast cancer, using recently developed radiolabeled GRPR ligands.


Impact and appreciation of two methods aiming at reducing hazardous drug environmental contamination: The centralization of the priming of IV tubing in the pharmacy and use of a closed-system transfer device.
The main objective was to evaluate the impact of two methods aiming at reducing hazardous drug environmental contamination: the centralization of the priming of IV tubing in the pharmacy and the use of a closed-system transfer device. The secondary objective was to evaluate the satisfaction of pharmacy technicians using a survey. Sites in the hematology-oncology satellite pharmacy and care unit were analyzed for the presence of cyclophosphamide, ifosfamide and methotrexate before and after the centralization of the priming of IV tubing in the pharmacy and before and after using a closed-system transfer device. The limits of detection for cyclophosphamide, ifosfamide and methotrexate were, respectively, of 0.0015 ng/cm(2), 0.0012 ng/cm(2) and 0.0060 ng/cm(2). The pharmacy technician satisfaction was evaluated using a questionnaire. A total of 225 samples was quantified. After the centralization of priming in the pharmacy, no significant difference was found in the proportion of positive samples for cyclophosphamide, ifosfamide and methotrexate. Traces of cyclophosphamide found on the floor in patient care areas was significantly reduced (median[min-max] 0.08[0.06-0.09]ng/cm(2) vs. 0.03[0.02-0.05], p < 0.0001). After using a closed-system transfer device, a significant difference was found for the proportion of cyclophosphamide positive samples (15/45(33%) vs. 0/45(0%), p < 0.0001), but no significant difference was found for ifosfamide (12/45(27%) vs. 5/45(11%), p = 0.059) and methotrexate (1/45(2%) vs. 2/45(4%), p = 0.557). Pharmacy technicians raised issues following the centralization of priming (e.g. workload) and the use of closed-system transfer devices (e.g. spills, particles, workload and handling difficulties). The centralization of the priming of IV tubing in the pharmacy reduced floor contamination in patient care areas without increasing surface contamination in the pharmacy. Closed-system transfer devices reduced contamination in pharmacy, but handling issues were raised by pharmacy technicians.


Targeting intrinsic apoptosis and other forms of cell death by BH3-mimetics in glioblastoma.
Novel approaches to treat malignant brain tumors are necessary since these neoplasms still display an unfavorable prognosis. Areas covered: In this review, the authors summarize and analyze recent preclinical data that suggest that targeting intrinsic apoptosis may be a suitable strategy for the treatment of malignant gliomas. They focus on the anti-apoptotic Bcl-2 family members of proteins and the recent drug developments in that field with a special focus on BH3-mimetics. With the discovery of BH3-mimetics that interfere with anti-apoptotic Bcl-2 family members in the low nanomolar range significant excitement has been generated towards these class of inhibitors, such as ABT-737, ABT-263 and the most recent successor, ABT-199 which is most advanced with respect to clinical application. The authors discuss the more recent selective inhibitors of Bcl-xL and Mcl-1. Concerning Mcl-1, these novel classes of inhibitors have the potential to impact malignant gliomas since these tumors reveal increased levels of Mcl-1. Expert opinion: The recent development of certain small molecules raises significant hope that intrinsic apoptosis might soon be efficiently targetable for malignancies of the central nervous system. That being said, additional studies are necessary to determine which of the BH3-mimetics might be most suitable.


Characterization of regions in hsMAD1 needed for binding hsMAD2. A polymorphic change in an hsMAD1 leucine zipper affects MAD1-MAD2 interaction and spindle checkpoint function.
In eukaryotes, the mitotic spindle assembly checkpoint provides a monitor for the fidelity of chromosomal segregation. In this context, the mitotic arrest deficiency protein 2 (MAD2) censors chromosomal mis-segregation by monitoring microtubule attachment/tension, a role that requires its attachment to kinetochores. Studies in yeast have shown that binding of MAD1 to MAD2 is important for the checkpoint function of the latter. The interactions between human MAD1 (hsMAD1) and human MAD2 (hsMAD2) have, however, remained poorly characterized. Here we report that two leucine zipper domains (amino acids 501-522 and 557-571) in hsMAD1 are required for its contact with hsMAD2. Interestingly, in several cancer cell lines, we noted the frequent presence of a coding single nucleotide Arg to His polymorphism at codon 558 located within the second leucine zipper of hsMAD1. We found that hsMAD1H558 is less proficient than hsMAD1R558 in binding hsMAD2 and in enforcing mitotic arrest. We also document a first example of loss-of-heterozygosity for a spindle checkpoint gene (at the hsMAD1 558 locus) in a human breast cancer. Based on our findings, it is possible that hsMAD1H558 could be an at-risk polymorphism that contributes to attenuated spindle checkpoint function in human cells.


Cabozantinib in the treatment of hepatocellular carcinoma.
Despite clinical studies with different mechanisms of action, no new systemic therapies were approved for hepatocellular carcinoma (HCC) between sorafenib in 2007 and regorafenib in 2017. This is an area of interest to improve outcomes and quality of life. Cabozantinib is oral, small-molecule tyrosine kinase inhibitor that primarily targets MET, VEGFR2, AXL and RET, with additional effect on KIT and FLT3. Cabozantinib is approved for progressive metastatic medullary thyroid cancer and previously treated renal cell carcinoma, and is in development for multiple solid tumors. Given positive results from a Phase II study, cabozantinib is under evaluation in a Phase III randomized controlled trial for patients with advanced HCC previously treated with sorafenib. It has been granted orphan drug status in the USA for this indication. This review summarizes the development of cabozantinib in HCC.


Lymphomagenesis in SCID-X1 mice following lentivirus-mediated phenotype correction independent of insertional mutagenesis and gammac overexpression.
The development of leukemia as a consequence of vector-mediated genotoxicity in gene therapy trials for X-linked severe combined immunodeficiency (SCID-X1) has prompted substantial research effort into the design and safety testing of integrating vectors. An important element of vector design is the selection and evaluation of promoter-enhancer elements with sufficient strength to drive reliable immune reconstitution, but minimal propensity for enhancer-mediated insertional mutagenesis. In this study, we set out to explore the effect of promoter-enhancer selection on the efficacy and safety of human immunodeficiency virus-1-derived lentiviral vectors in gammac-deficient mice. We observed incomplete or absent T- and B-cell development in mice transplanted with progenitors expressing gammac from the phosphoglycerate kinase (PGK) and Wiscott-Aldrich syndrome (WAS) promoters, respectively. In contrast, functional T- and B-cell compartments were restored in mice receiving an equivalent vector containing the elongation factor-1-alpha (EF1alpha) promoter; however, 4 of 14 mice reconstituted with this vector subsequently developed lymphoma. Extensive analyses failed to implicate insertional mutagenesis or gammac overexpression as the underlying mechanism. These findings highlight the need for detailed mechanistic analysis of tumor readouts in preclinical animal models assessing vector safety, and suggest the existence of other ill-defined risk factors for oncogenesis, including replicative stress, in gene therapy protocols targeting the hematopoietic compartment.


Vapour pressure deficit control in relation to water transport and water productivity in greenhouse tomato production during summer.
Although atmospheric vapour pressure deficit (VPD) has been widely recognized as the evaporative driving force for water transport, the potential to reduce plant water consumption and improve water productivity by regulating VPD is highly uncertain. To bridge this gap, water transport in combination with plant productivity was examined in tomato (Solanum lycopersicum L.) plants grown under contrasting VPD gradients. The driving force for water transport was substantially reduced in low-VPD treatment, which consequently decreased water loss rate and moderated plant water stress: leaf desiccation, hydraulic limitation and excessive negative water potential were prevented by maintaining water balance. Alleviation in water stress by reducing VPD sustained stomatal function and photosynthesis, with concomitant improvements in biomass and fruit production. From physiological perspectives, suppression of the driving force and water flow rate substantially reduced cumulative transpiration by 19.9%. In accordance with physiological principles, irrigation water use efficiency as criterions of biomass and fruit yield in low-VPD treatment was significantly increased by 36.8% and 39.1%, respectively. The reduction in irrigation was counterbalanced by input of fogging water to some extent. Net water saving can be increased by enabling greater planting densities and improving the evaporative efficiency of the mechanical system.


Can intramuscular glucose levels diagnose compartment syndrome?
Compartment syndrome is difficult to diagnose, particularly in patients who are not able to undergo adequate clinical examination. Current methods rely on pressure measurements within the compartment, have high false-positive rates, and do not reliably indicate presence of muscle ischemia. We hypothesized that measurement of intramuscular glucose and oxygen can identify compartment syndrome with high sensitivity and specificity. Compartment syndrome was created in 12 anesthetized adult mixed-sex beagles, in the craniolateral compartment of a lower leg, by infusion of lactated Ringer's solution with normal serum concentration of glucose. The contralateral leg served as a control. Hydrostatic pressure, oxygen tension, and glucose concentration were recorded with commercially available probes. Compartment syndrome was maintained for 8 hours, and the animals were recovered. Two weeks later, compartment and control legs underwent muscle biopsy. Specimens were reviewed by a blinded pathologist. Within 15 minutes of creating compartment syndrome, glucose concentration and oxygen tension in the experimental limb were significantly lower than in the control limb (glucose, p = 0.02; oxygen, p = 0.007; two-tailed t test). Intramuscular glucose concentration of less than 97 mg/dL was 100% sensitive (95% confidence interval [CI], 73-100%) and 75% specific (95% CI, 40-94%) for the presence of compartment syndrome. Partial pressure of oxygen less than 30 mm Hg was 100% sensitive (95% CI, 72-100%) and 100% specific (95% CI, 69-100%) for the presence of compartment syndrome. Pathology confirmed compartment syndrome in all experimental limbs. Our results show that intramuscular glucose concentration and partial pressure of oxygen rapidly identify muscle ischemia with high sensitivity and specificity after experimentally created compartment syndrome in this animal model.


Acute trichinellosis in children compared with adults.
Trichinellosis is a cosmopolitan parasite infection caused by Trichinella nematodes that is acquired from consumption of raw meat from several animal species. Knowledge of the clinical pattern and laboratory features of the disease in childhood is limited. The purpose is to study the clinical pattern of trichinellosis caused by Trichinella britovi in children and to compare it in household adults. We evaluated all children up to 17 years of age and their adult householders exposed to the consumption of infected meat during an outbreak of trichinellosis. A questionnaire was developed to record clinical data. The blood sample was collected for blood count, muscle enzymes, serum electrolytes, albumin and serology. All exposed children were treated with mebendazole, and severe symptomatic patients received prednisolone. Clinical and laboratory presentations and outcome were recorded. To evaluate the clinical picture of trichinellosis in childhood, clinical and laboratory findings were compared between children and household adults with a confirmed diagnosis who consumed the same amount of infected meat. In 47 (62%) of 76 children with suspected trichinellosis, the diagnosis was serologically confirmed. The main clinical and laboratory findings in children were fever, abdominal pain, myalgia, facial and/or eyelid edema, rash, eosinophilia and increased muscular enzymes. The incubation period was similar in children and adults, but myalgia (66% versus 96%, P < 0.01), facial and/or eyelid edema (57% versus 86%, P < 0.05), eosinophilia (52% versus 96%, P < 0.01) and increased serum creatine kinase (38% versus 79%, P < 0.01) were less common in children than in adults. Seroconversion occurred in fewer children than adults, but the difference was not statistically significant. T. britovi infection shows a benign course and a milder clinical picture in children than in adults who consumed the same amount of infected meat.


Odor-Active Compounds in the Special Flavor Hops Huell Melon and Polaris.
The volatiles isolated from samples of the special flavor hop varieties, Huell Melon and Polaris, and from the aroma hop variety, Hallertau Tradition, by solvent extraction and solvent-assisted flavor evaporation (SAFE) were subjected to a comparative aroma extract dilution analysis (cAEDA), which resulted in 46 odor-active compounds in the flavor dilution (FD) factor range of 16 to 2048. On the basis of high FD factors, myrcene, (3R)-linalool, and 2- and 3-methylbutanoic acid were confirmed as important variety-independent hop odorants. (1R,4S)-Calamenene was identified for the first time as an odor-active compound in hops. Clear differences in the FD factors and their subsequent objectification by stable isotope dilution quantitation suggested that high concentrations of the esters ethyl 2-methylbutanoate, ethyl 2-methylpropanoate, and propyl 2-methylbutanoate cause the characteristic fruity, cantaloupe-like odor note in Huell Melon hops, whereas the fruity and minty odor notes in Polaris are associated with high amounts of 3-methylbutyl acetate and 1,8-cineole.


Applying Vernix Caseosa for Accidental Foetal Lacerations during Caesarean Delivery: A Case Series.
The caesarean section is a frequently performed method of delivery. Although the caesarean section is a low-risk and safe surgery, there is an increase in maternal and infant morbidity and mortality due to caesarean delivery. One of the most common infant morbidities is foetal laceration. Caesarean delivery has a 1-2% risk of laceration to the foetus. Various methods have been proposed to deal with laceration wounds. Studies have been conducted on vernix caseosa, which can heal wounds on the skin. This case series report aims to demonstrate that vernix caseosa application is a wound healing method that is highly effective, costless, and of immediate availability.


Patient and provider perspectives on barriers and facilitators to reproductive healthcare access for women experiencing homelessness with substance use disorders in San Francisco.
Women experiencing homelessness with substance use disorders face unique and intersecting barriers to realizing their reproductive goals. This study explored the reproductive aspirations of this population, as well as the barriers to accessing reproductive services from the perspectives of affected individuals, and the healthcare providers who serve them. This mixed-methods study included surveys and interviews with women experiencing homelessness with substance use disorders and healthcare providers. We conducted surveys and semi-structured interviews with women recruited from opiate treatment programs and homeless encampments in San Francisco, California in 2018. We also conducted interviews and focus groups with healthcare providers in reproductive health and substance use treatment settings. Interviews were recorded, transcribed, and coded. Descriptive statistics of survey results were performed. Twenty-eight women completed surveys, 96% of whom reported current substance use. Ten women participated in interviews. One-third (9/28) reported desiring pregnancy in the next year; over half (16/28) reported they would be somewhat or very happy to learn they were pregnant. A majority used no contraception at last intercourse (14/28). Twenty-six healthcare providers participated in interviews (n = 15) and focus groups (n = 2). Patients and providers identified similar barriers to care access, including discrimination, logistical and financial challenges, and delayed pregnancy awareness. While providers proposed solutions focused on overcoming logistical challenges, patients emphasized the importance of transforming the healthcare environment to treat patients affected by substance use and homelessness with dignity and respect. Women experiencing homelessness with substance use disorders face intersecting and compounding barriers to accessing reproductive health services. For patients, the impact of stigma and bias on treatment experiences are particularly salient, in contrast to logistical barriers emphasized by providers. Improving access will require structural and individual-level solutions to address stigma and create person-centered, trauma-informed, and respectful care environments.


Dependence on treatment time of melphalan resistance and DNA cross-linking in human melanoma cell lines.
In the human melanoma cell line MM127 , the melphalan survival curve was linear and exhibited reciprocity with respect to concentration and treatment time. The survival curve of an allogeneic line, MM253c1 , exhibited a shoulder and, on a concentration X time basis, was resistant to 1-hr compared with 4-hr treatment. This type of resistance, which was not found using chlorambucil, nitrogen mustard, or methyl methanesulfonate, could be overcome by simultaneous hyperthermia (42 degrees) but not by treatment with thymidine or caffeine. Both lines had similar levels of DNA interstrand cross-linking (perchlorate renaturation method) after 1-hr treatment, but MM253c1 cells were able to repair most of this damage during the next 23 hr. The cross-links formed in MM253c1 cells after 1 hr were predominantly heat sensitive and photoresistant , whereas those formed in MM127 cells were heat resistant and photosensitive. These results suggest that melphalan formed repairable (possibly diadeninyl or adeninyl - guaninyl ) cross-links in MM253c1 cells during the first hr of treatment and nonrepairable , possibly diguaninyl cross-links in MM127 cells at all stages of treatment. It appears therefore that the mode of action of melphalan and the effect of synergistic agents may not be identical in all cells.


Respiratory system, lung, and chest wall mechanics in guinea pigs.
1. Volume, airflow, tracheal, esophageal and transpulmonary pressures were measured in 6 mechanically ventilated, anesthetized and paralyzed guinea pigs. 2. The elastic and resistive properties of the respiratory system were partitioned into their lung and chest wall components a) following end-inflation occlusion of the airways subsequent to constant flow inspirations, and b) during relaxed expirations following release of occlusion. The values obtained by both methods were similar. 3. Mean respiratory system, lung and chest wall elastances were 3.518, 2.671, and 0.847 cm H2O/ml, respectively. 4. Mean respiratory system, pulmonary and chest wall resistances (at flows of 4.3 ml/s) were 0.302, 0.184, and 0.118 cm H2O ml-1 s, respectively. 5. Respiratory system, lung and chest wall resistances were partitioned into two components: 1) a homogeneous one whose values corresponded to 0.171, 0.095, and 0.076 cm H2O ml-1 s, for respiratory system, lung and chest wall, respectively, and 2) a component due to Pendelluft and stress relaxation and corresponding to 0.131, 0.089, and 0.042 cm H2O ml-1 s, respectively. 6. Resistive pressure vs flow relationships for the respiratory system, lung and chest wall were also determined during the entire tidal expiration. 7. We conclude that the chest wall participates significantly in respiratory system unevenness.


Red wine polyphenols prevent cardiovascular alterations in L-NAME-induced hypertension.
Red wine polyphenols have been reported to possess beneficial properties for preventing cardiovascular diseases but their effects on hemodynamic and functional cardiovascular changes during inhibition of nitric oxide (NO) synthesis have not been elucidated. The effects of the red wine polyphenols, Provinols, on arterial hypertension as well as left ventricular (LV) hypertrophy, myocardial fibrosis and vascular remodeling were investigated in rats during chronic inhibition of nitric oxide synthase (NOS) activity. Rats were divided into four groups: a control group, a group treated with N-nitro-L-arginine methyl ester (L-NAME) (40 mg/kg per day), a group receiving Provinols (40 mg/kg per day) alone or Provinols plus L-NAME. Provinols markedly reduced the increase in both blood pressure and protein synthesis in the heart and aorta caused by chronic inhibition of NO synthesis. Provinols reduced myocardial fibrosis even though it did not affect LV hypertrophy. In addition, Provinols prevented aortic thickening and corrected the augmented reactivity of the aorta to norepinephrine and the attenuated endothelium-dependent relaxation to acetylcholine in NO-deficient rats. These alterations were associated with an increase of NOS activity, a moderate enhancement of endothelial NOS expression and a reduction of oxidative stress in the LV and aorta. Our results provide evidence that Provinols partially prevents L-NAME-induced hypertension, cardiovascular remodeling and vascular dysfunction via the increase of NO-synthase activity and prevention of oxidative stress. Thus, the beneficial effects of plant polyphenols in prevention of hypertension may result from their complex influence on the NO balance in the cardiovascular system.


Interventions for primary vesicoureteric reflux.
Vesicoureteric reflux (VUR) results in urine passing, in a retrograde manner, up the ureter. Urinary tract infections (UTIs) have been considered to be the main cause of permanent renal parenchymal damage in children with reflux. Therefore management of these children has been directed at preventing infection by antibiotic prophylaxis and/or surgical correction of reflux. However controversy remains as to the optimum strategies for management of children with primary VUR. To evaluate the benefits and harms of the different treatment options for primary VUR. Published and unpublished randomised controlled trials (RCTs) were identified from the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, reference lists of articles and abstracts from conference proceedings. RCTs were included if they compared any treatments of VUR including surgery (open and closed techniques), antibiotic prophylaxis of any duration, non-invasive techniques such as bladder training and any combination of therapies. Two reviewers independently searched the literature, determined trial eligibility, assessed quality, extracted and entered data. For dichotomous outcomes, results were expressed as relative risk (RR) and 95% confidence intervals (CI). Data were pooled using the random effects model. Ten trials involving 964 evaluable children comparing long-term antibiotics and surgical correction of VUR with antibiotics (seven trials), antibiotics with no treatment (one trial) and different materials for endoscopic correction of VUR (two trials) were identified. Risk of UTI by 1-2 and 5 years was not significantly different between surgical and medical groups (by 2 years RR 1.07, 95% CI 0.55 to 2.09; by 5 years RR 0.99; 95% CI 0.79 to 1.26). Combined treatment resulted in a 60% reduction in febrile UTI by 5 years (RR 0.43, 95% CI 0.27 to 0.70) but no concomitant significant reduction in risk of new or progressive renal damage at 5 years (RR 1.05, 95% CI 0.85 to 1.29). In one small study no significant differences in risk for UTI or renal damage were found between antibiotic prophylaxis and no treatment. It is uncertain whether the identification and treatment of children with VUR confers clinically important benefit. The additional benefit of surgery over antibiotics alone is small at best. Assuming a UTI rate of 20% for children with VUR on antibiotics for five years, nine reimplantations would be required to prevent one febrile UTI, with no reduction in the number of children developing any UTI or renal damage.


Rothmund-Thomson syndrome associated with annular pancreas and duodenal stenosis: a case report.
The Rothmund-Thomson syndrome is a rare autosomal recessive condition. It is primarily a clinical diagnosis with manifestations that include poikiloderma, short stature, sparse hair, juvenile cataracts, small hands and feet, bone defects, photosensitivity, hypogonadism, defective dentition, onychodystrophy, and hyperkeratosis. There is only one published case of associated gastrointestinal abnormalities. We report a patient with Rothmund-Thomson syndrome with annular pancreas and duodenal stenosis.


Craniomaxillofacial fibrous dysplasia.
Fibrous dysplasia is a nonneoplastic developmental disease of osseous tissue. It is a lesion of unknown etiology, uncertain pathogenesis, and diverse histopathology. In this series of 16 patients with fibrous dysplasia of the craniomaxillofacial bones, the disease was generally monostotic and most commonly maxillary in location. Two patients demonstrated typical symptoms of the McCune Albright syndrome. Marked deformity or functional disturbances were the major indications for treatment. Total excision of the involved bone was the most successful form of treatment but produced the greatest functional and cosmetic deficits and long-term postoperative complications. A conservative therapeutic approach with a modest reduction in the bulk of these lesions may be sufficient to relieve signs and symptoms effectively. Periodic follow-up is indicated to detect recurrences or malignant changes in the early stages.


A Weighted Error Distance Metrics (WEDM) for Performance Evaluation on Multiple Change-Point (MCP) Detection in Synthetic Time Series.
Change-point detection (CPD) is to find abrupt changes in time-series data. Various computational algorithms have been developed for CPD applications. To compare the different CPD models, many performance metrics have been introduced to evaluate the algorithms. Each of the previous evaluation methods measures the different aspects of the methods. Based on the existing weighted error distance (WED) method on single change-point (CP) detection, a novel WED metrics (WEDM) was proposed to evaluate the overall performance of a CPD model across not only repetitive tests on single CP detection, but also successive tests on multiple change-point (MCP) detection on synthetic time series under the random slide window (RSW) and fixed slide window (FSW) frameworks. In the proposed WEDM method, a concept of normalized error distance was introduced that allows comparisons of the distance between the estimated change-point (eCP) position and the target change point (tCP) in the synthetic time series. In the successive MCPs detection, the proposed WEDM method first divides the original time-series sample into a series of data segments in terms of the assigned tCPs set and then calculates a normalized error distance (NED) value for each segment. Next, our WEDM presents the frequency and WED distribution of the resultant eCPs from all data segments in the normalized positive-error distance (NPED) and the normalized negative-error distance (NNED) intervals in the same coordinates. Last, the mean WED (MWED) and MWTD (1-MWED) were obtained and then dealt with as important performance evaluation indexes. Based on the synthetic datasets in the Matlab platform, repetitive tests on single CP detection were executed by using different CPD models, including ternary search tree (TST), binary search tree (BST), Kolmogorov-Smirnov (KS) tests, t-tests (T), and singular spectrum analysis (SSA) algorithms. Meanwhile, successive tests on MCPs detection were implemented under the fixed slide window (FSW) and random slide window (RSW) frameworks. These CPD models mentioned above were evaluated in terms of our WED metrics, together with supplementary indexes for evaluating the convergence of different CPD models, including rates of hit, miss, error, and computing time, respectively. The experimental results showed the value of this WEDM method.


Dietary chloride and urinary calcium in stone disease.
We studied six patients with renal stone disease, hypercalciuria, cystinuria and/or hyperuricosuria, during variations in dietary Na and Cl intake. Switching between equimolar NaCl and NaHCO3 intakes reduced urinary Ca (UCa) during the NaHCO3 phase, despite steady-state urinary Na. Switching between equimolar NaCl and KCl did not change UCa, despite a sharp fall in UNa. The results suggest a predominant role for Cl rather than Na ions during sodium-chloride-induced changes in UCa. In stone disease of mixed aetiology, where alkalinization of the urine as well as reduction in UCa may be desirable, treatment with NaHCO3 loading is not accompanied by a rise in UCa, provided that dietary Cl is maintained moderately low at 80-100 mmol/day. The mechanism whereby Cl intake influences UCa remains undefined. Plasma PTH and calcitriol levels showed no significant alteration, and atrial natriuretic peptide levels in one patient remained unchanged.


[Hypnotic drugs in a population. Prescriptions by the specialist and the general practitioner].
The aims of our survey were to estimate the prevalence of hypnotic drug prescription in a representative sample of population in 5 cities of Northern Italy and to analyse the pattern of prescription of these drugs by general practitioners (GPs) and psychiatrists. The data were collected with the collaboration of pharmacists working in 145 pharmacies. All consecutive patients presenting a prescription for a hypnotic drug were interviewed by the pharmacists during a two-week period. The pharmacists interviewed 7744 consecutive patients. The highest prevalence of prescriptions for hypnotic drugs was found in the elderly and in women. The majority of prescriptions were for benzodiazepines (BDZ), with lorazepam and triazolam accounting for about 50% of the total prescriptions. Short-acting and ultra-short-acting BDZ were more frequently prescribed for sleep induction by GPs than by psychiatrists. Approximately 73% of subjects reported that they had been taking the prescribed drug for one year or more. The high proportion of long-term BDZ users may be a consequence of the short period surveyed, which produced data weighted toward long-term consumption. Our data, however, do not permit to establish whether long-term use is appropriate from a clinical point of view or is the consequence of a physical dependence. We must be aware that this practice needs to be studied more accurately, with the aim to assess the risk/benefit ratio of long-term BDZ use.


Scatchard plots with a positive slope: dependence upon ligand concentration.
The inverse dependence of binding constants (nK) upon albumin concentration for 2-(4'-hydroxybenzeneazo) benzoic acid (HABA) has been investigated with bovine and human albumin by equilibrium dialysis. Data obtained by the use of a range of concentrations of either bovine or human albumin, together with a single ligand concentration, gave positive Scatchard plots indicative of binding constants inversely dependent upon protein concentration. The slope of each plot was influenced by the particular ligand concentration used and an increase in the ligand concentration in the case of both bovine and human albumin resulted in a decrease in the slope of the positive Scatchard plot. Higher concentrations of ligand produced a transformation from a positive to a negative plot with both bovine and human albumin.


[Role of nitric oxide in apoptosis of retinal neurons in human fetuses].
The localization of NADPH-diaphorase (NADPH-d), inducible NO-synthase (iNOS) and TUNEL-immunoreactive neurons was studied in the retina of human fetuses in the I-III trimesters of pregnancy. High NADPH-d activity was found in internal segments of photosensory cells, amacrine and ganglion cells. The population of NADPH-d-positive amacrine cells included three types of neurons. Neurons of the 1st type had large size and scarce dendritic field, occupying the inner nuclear and outer plexiform layers. Small neurons of the 2nd type were located in the inner plexiform layer. Ectopic amacrine cells of 3rd type could be found in the outer part of the ganglion cell layer. High density of the NADPH-d-positive neurons was detected in the central portion of retina surrounding fovea centralis and the optic disk area. The activity of NADPH-d was found to grow progressively in ontogenesis and to correlate with the appearance of immunoreactive iNOS in neurons. Immunoreactive iNOS marked a subpopulation of amacrine and ganglion cells which appeared in weeks 20-21 of gestation and attained maximal immunoreactivity by the end of the III trimester. TUNEL-immunoreactive nuclei of the neurons with the signs of the apoptotic destruction were found in weeks 30-31 of gestation. The highest apoptotic index was found in the population of ganglion cells. The data obtained strongly suggest that NO is a factor, mediating the neuronal apoptosis during the critical period of a differentiation of interneuronal connections in the human retina.


A computational study on the usability of amino acid-functionalised nitrogen-doped graphene oxides as temperature-responsive drug delivery systems.
The usability of amino acid-functionalised nitrogen-doped graphene oxide (GO) structures (AA-NGO) in drug delivery (DD) systems was studied using the computational approaches. Docking, molecular dynamic (MD) and molecular mechanics generalised born surface area studies were carried out. The calculations were done at 37 and 42 °C to study the usability of the mentioned structures in thermally induced DD systems. In this method, the drug is released by increasing the temperature. For the representative cases, studies at 32, 37, 42 and 47 °C were carried out, as well. Both one-to-one and two-to-one ratio between the AA-NGO and Taxol were studied. In the one-to-one system the Lys-NGO is the best structure to be used in the thermo-sensitive DD systems, based on the binding energy differences calculated at mentioned four temperatures. In the two-to-one systems, the Glu-NGO is leading to the most promising results. In this case, the longer distance between the two layers at higher temperature was regarded as the reason for the better release of the drug at a higher temperature. In this case, at a lower temperature, the Taxol is trapped between two layers of Glu-NGO and has interactions with both of them. At higher temperature, the interaction with just one of the layers is observable, which means lesser interactions and better release of the Taxol.


affron® a novel saffron extract (Crocus sativus L.) improves mood in healthy adults over 4 weeks in a double-blind, parallel, randomized, placebo-controlled clinical trial.
In recent years phytotherapy has been explored as a source for alternative treatments for mood disorders. One potential candidate is saffron (Crocus sativus L.), whose main bioactive components are crocins and safranal. The aim of this study was to investigate the efficacy of affron®, a standardised stigmas extract from Crocus sativus L. for improving mood, stress, anxiety and sleep quality in healthy adults. In this 3 arm study, 128 participants self-reporting low mood but not diagnosed with depression, were given affron® at 28mg/day, 22mg/day, or a placebo treatment in a randomized, double-blind, placebo-controlled trial for 4 weeks. Mood was measured at baseline and at the end of the study, using the POMS (primary outcome measure) and PANAS questionnaires, and the DASS-21 scale. Sleep was monitored using Sleep Quality Index (PSQI). Analysis indicated a significant decrease in negative mood and symptoms related to stress and anxiety at a 28mg/day dose (with a significant difference between 28mg/day and placebo on the POMS Total Mood Disturbance scale, p<0.001, d=-1.10), but no treatment effect at the 22mg/day dose. The main weaknesses of this investigation were found in the self-reporting nature of both the screening and the testing. affron® increased mood, reduced anxiety and managed stress without side effects, offering a natural alternative to standard treatments.


Structural model of the open-closed-inactivated cycle of prokaryotic voltage-gated sodium channels.
In excitable cells, the initiation of the action potential results from the opening of voltage-gated sodium channels. These channels undergo a series of conformational changes between open, closed, and inactivated states. Many models have been proposed for the structural transitions that result in these different functional states. Here, we compare the crystal structures of prokaryotic sodium channels captured in the different conformational forms and use them as the basis for examining molecular models for the activation, slow inactivation, and recovery processes. We compare structural similarities and differences in the pore domains, specifically in the transmembrane helices, the constrictions within the pore cavity, the activation gate at the cytoplasmic end of the last transmembrane helix, the C-terminal domain, and the selectivity filter. We discuss the observed differences in the context of previous models for opening, closing, and inactivation, and present a new structure-based model for the functional transitions. Our proposed prokaryotic channel activation mechanism is then compared with the activation transition in eukaryotic sodium channels.


Bronchobiliary fistula evaluated with magnetic resonance imaging.
Bronchobiliary fistula (BBF) is a rare disorder consisting of a passageway between the biliary ducts and the bronchial tree. Many conditions may give rise to this development. Management of these fistulas is often difficult and can be associated with high morbidity and mortality rates. We present a case of BBF developing after hemihepatectomy in a 74-year-old man treated with endoscopic biliary drainage and illustrate MRCP findings.


Wavelength conversion using fiber cross-phase modulation driven by two pump waves.
Wavelength conversion using all-optical phase modulation in a fiber driven by two pump waves is investigated. The operation features are analyzed using an all-optical phase modulation model with two parallel-/cross-polarized pump waves to generate a phase-preserving copy of the optical signal at an exact frequency up-/down-shifted by the two-pump detuning. The conversion efficiency is experimentally verified using a 300-m highly-nonlinear fiber. The results agree well with a theoretical prediction. The conversion bandwidth over 4 THz is achieved and error-free wavelength conversion for a 32-GBd polarization-division multiplexed 16QAM signal is demonstrated. The technique's applicability to a large-capacity wavelength-division multiplexed signals is also discussed.


Circulating adiponectin levels increase in rats on caloric restriction: the potential for insulin sensitization.
Caloric restriction (CR) has a well-known insulin sensitizing effect in vivo. Although this effect has been confirmed in rodents and primates for many years, its precise molecular mechanisms remain unknown. Here we show a significant increase in plasma adiponectin and a decrease in blood glucose, plasma triglyceride and insulin levels in rats maintained on CR diet for 2, 10, 15, and 20 months. Long-term CR rats exhibited significantly higher insulin-stimulated insulin receptor tyrosine phosphorylation and lower PTP-1B activity both in liver and skeletal muscle than those observed in rats fed ad libitum (AL). In addition, the triglyceride levels in these tissues were significantly lower in long-term CR animals. Interestingly, concentrations of plasma adiponectin in long-term CR rats were associated with increased expression of the transcription factor mRNAs for the peroxisome proliferator-activated receptor (PPAR)alpha, gamma and delta, but decreased expression for SREBP-1c, resulting in a concerted modulation in the expression of key transcription target genes involved in fatty acid oxidation and energy combustion in liver. Taken together, our findings suggest an important role for adiponectin in the beneficial effects of long-term CR.


Endothelial Progenitor Cells of the Human Placenta and Fetoplacental Circulation: A Potential Link to Fetal, Neonatal, and Long-term Health.
The fetoplacental circulation plays a key role in both short- and long-term outcomes, and aberrant flow indices as manifested by abnormal fetal Doppler velocimetry within this compartment have been associated with significant adverse consequences. These include fetal growth restriction, which often coexists with preeclampsia, and long-lasting medical issues as a result of both the underlying pathology and prematurity such as bronchopulmonary dysplasia, chronic lung disease, and neurodevelopmental delay. Furthermore, it is also clear that exposure to an abnormal in utero environment increases risk for long-term, adulthood issues such as cardiovascular disease. Endothelial progenitor cells (EPCs) have been implicated in vasculogenesis and angiogenesis, and they have been isolated from both human placenta and umbilical cord blood. This review outlines the extensive nomenclature of EPCs, summarizes existing literature surrounding human placental and umbilical cord blood EPCs, explores their potential role in pregnancy complications and adverse perinatal outcome, and highlights key areas where future investigations are needed.


A phantom study to determine the theoretical accuracy and precision of radial MRI to measure cross-sectional area differences for the application of coronary endothelial function assessment.
MRI has been used to noninvasively assess coronary endothelial function by measuring the vasoreactivity in response to handgrip exercise. However, the spatial resolution of MRI is limited relative to the expected vasodilation response of healthy coronary arteries (10%-20%), and the sensitivity of MRI to detect such small cross-sectional area differences has yet to be quantitatively examined. Holes of different diameters were drilled in a phantom to simulate a range of physiological responses of coronary arteries to stress. Radial cine MR images with different spatial resolutions were acquired under moving conditions, and different noise levels were simulated. Cross-sectional areas were automatically measured and statistically analyzed to quantify the smallest detectable area difference. Statistical analyses suggest that radial MRI is capable of distinguishing area differences of 0.2 to 0.3 mm2 for high signal-to-noise ratio images, which correspond to a percentage coronary area difference of 3% to 4% for a 3-mm baseline diameter. Furthermore, the smallest detectable area difference was largely independent of the pixel size for the sequence and range of diameters investigated in this study. Radial MRI is capable of reliably detecting small differences in cross-sectional areas that are well within the expected physiological range of stress-induced area changes in of healthy coronary arteries. Magn Reson Med 79:108-120, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


SH3BGRL2 exerts a dual function in breast cancer growth and metastasis and is regulated by TGF-β1.
SH3 domain-binding glutamic acid-rich-like protein 2 (SH3BGRL2) is a poorly defined member of the SH3BGR gene family with potential roles in cell differentiation and tissue development. Here, we report for the first time that SH3BGRL2 exerts a dual function in breast tumor growth and metastasis. SH3BGRL2 was downregulated in a subset of primary breast tumors, and suppressed breast cancer cell proliferation and colony formation in vitro and xenograft tumor growth in vivo. Strikingly, SH3BGRL2 enhanced breast cancer cell migratory, invasive, and lung metastatic capacity. Mechanistic investigations revealed that SH3BGRL2 interacted with and transcriptionally repressed spectrin alpha, non-erythrocytic 1 (SPTAN1) and spectrin beta, non-erythrocytic 1 (SPTBN1), two important cytoskeletal proteins. Functional rescue assays further demonstrated that depletion of SH3BGRL2 reduced breast cancer cell invasive potential, which was partially rescued by knockdown of SPTAN1 and SPTBN1 using specific small interfering RNA. Moreover, transforming growth factor-β1 (TGF-β1) transcriptionally activated SH3BGRL2 expression in breast cancer cells through the canonical TGF-β receptor-Smad pathway. Collectively, these results establish a dual function of SH3BGRL2 in breast cancer growth and metastasis and uncover SH3BGRL2 as a downstream target of the TGF-β1 signaling pathway in breast cancer cells.


[Selective effectiveness of galactose-containing liposome IL-2 on liver lymphocytes].
We have performed immunochemical intraarterial infusion immunochemotherapy containing IL-2, mitomycin C and 5-FU as the main active ingredient for metastatic liver tumor and obtained favorable results. However, we are obliged to perform intra-hepatic arterial infusion once or twice a week, because of the short half-life of IL-2. Thus, we are using a drug delivery system to activate lymphocytes of the liver. We noticed many galactose-receptors in the liver and prepared galactose-containing liposome preparations using various carriers/bases. As a result, galactose-containing liposome preparations showed the highest accumulation and the highest localized enhancing effect on the antitumor activity of lymphocytes in the liver sites.


COVID-19 disruption to cervical cancer screening in England.
In England, routine invitations for cervical screening were reduced between April 2020 and June 2020 due to the COVID-19 pandemic. We quantify the impact of COVID-19 disruptions on attendance and excess diagnoses of cervical cancer (CC). Using Public Health England CC screening data on laboratory samples received in 2018 as a baseline we quantify the reduction in screening attendances due to the COVID-19 pandemic between April 2020 and March 2021 for women aged 25-64. We model the impact on excess CC diagnoses assuming once invitations resume 87.5% of women attend within 12 months and 12.5% delay screening for 3 or 5 years (depending on age). The number of samples received at laboratories was 91% lower than expected during April, 85% during May and 43% during June 2020 compared to the same period in 2018. Although on average laboratories received 12.6% more samples between August 2020 and April 2021 than over the same months in 2018, by April 2021 there was a short fall of 200,949 samples (6.4% fewer than in 2018). An excess of 41 CC (4.0 per 100,000 women with a maximum screening delay of 12 months) are predicted to occur among the estimated 1,024,794 women attending this screening round with a delay. An excess of 60 CC (41.0 per 100,000 women) are predicted to occur among the estimated 146,391 women who do not attend this screening round. Prompt restoration of cervical screening services limited the impact on excess CC diagnoses. However, in 2020 a 6.4% shortfall of screening samples was observed. Every effort should be made to reassure these women that services are open and safe to attend.


Identification of high-performing antibodies for Superoxide dismutase [Cu-Zn] 1 (SOD1) for use in Western blot, immunoprecipitation, and immunofluorescence.
Superoxide dismutase [Cu-Zn] 1 (SOD1), is an antioxidant enzyme encoded by the gene SOD1, responsible for regulating oxidative stress levels by sequestering free radicals. Identified as the first gene with mutations in Amyotrophic lateral sclerosis (ALS), SOD1 is a determinant for studying diseases of aging and neurodegeneration. With guidance on well-characterized anti-SOD1 antibodies, the reproducibility of SOD1 research would be enhanced. In this study, we characterized eleven SOD1 commercial antibodies for Western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.


Sequelae of chorioamnionitis.
Chorioamnionitis correlates to preterm delivery prior to 30 weeks of gestation. In most studies, proxies of intrauterine infection (clinical chorioamnionitis, histological chorioamnionitis, intra-amniotic increase in cytokines) are associated with acute neonatal morbidity and mortality and, at least to some degree, with neurological impairments (periventricular leukomalacia, intraventricular hemorrhage, cerebral palsy, polymicrogyria), chronic lung disease, and involution of the thymus in the preterm infant. The connection to visual impairment and cognitive deficits is uncertain or unknown. Full-term babies exposed to intrauterine infection often present with depressed Apgar scores and neonatal encephalopathy, and are at markedly increased risk of developing cerebral palsy. The infectious/inflammatory mechanisms involved are incompletely understood, and the types of microbes, as well as the genetic characteristics of the host adaptive and innate immune response, need to be better characterized.


Neurons in the medullary gigantocellular reticular nucleus mediate cardioinhibition in cats.
The cardioinhibitory mechanisms (bradycardia) of the gigantocellular reticular nucleus (GRN) of medulla was studied in chloralose-urethane anesthetized cats by means of microinjection of sodium glutamate (0.5 M, 100 nl) and single neuron recording. Microinjection of glutamate excited the GRN neurons and produced the bradycardiac responses. The rostral GRN (rostral to the caudal superior olivary nucleus) had higher proportion of bradycardiac loci than the caudal GRN. This suggests that the density of cardioinhibitory neurons in GRN is higher in the rostral than the caudal level. Seventy-eight GRN neurons were recorded extracellularly. Activities of 60 neurons were tested if they were correlated with cardiac rhythm or systemic arterial blood pressure (SAP) changes following intravenous norepinephrine or nitroglycerin. Among these neurons 45% (27/60) exhibited changes related to SAP and 25% (15/60) related to cardiac rhythm. Sixty-one GRN neurons were tested by antidromic activation to determine whether they have axonal projection to the dorsal motor nucleus of vagus and nucleus tractus solitarius (DMN/NTS). Eighteen percent (11/61) of them had axonal projections to the DMN/NTS. These findings suggest that: (i) In GRN there are neurons which mediate cardioinhibition. (ii) These neurons may receive baroreceptor inputs. (iii) They may decrease heart rate through the DMN/NTX.


Effects of subtherapeutic concentrations of antimicrobials on gene acquisition events in Yersinia, Proteus, Shigella, and Salmonella recipient organisms in isolated ligated intestinal loops of swine.
To assess antimicrobial resistance and transfer of virulence genes facilitated by subtherapeutic concentrations of antimicrobials in swine intestines. 20 anesthetized pigs experimentally inoculated with donor and recipient bacteria. 4 recipient pathogenic bacteria (Salmonella enterica serotype Typhimurium, Yersinia enterocolitica, Shigella flexneri, or Proteus mirabilis) were incubated with donor bacteria in the presence of subinhibitory concentrations of 1 of 16 antimicrobials in isolated ligated intestinal loops in swine. Donor Escherichia coli contained transferrable antimicrobial resistance or virulence genes. After coincubations, intestinal contents were removed and assessed for pathogens that acquired new antimicrobial resistance or virulence genes following exposure to the subtherapeutic concentrations of antimicrobials. 3 antimicrobials (apramycin, lincomycin, and neomycin) enhanced transfer of an antimicrobial resistance plasmid from commensal E coli organisms to Yersinia and Proteus organisms, whereas 7 antimicrobials (florfenicol, hygromycin, penicillin G, roxarsone, sulfamethazine, tetracycline, and tylosin) exacerbated transfer of an integron (Salmonella genomic island 1) from Salmonella organisms to Yersinia organisms. Sulfamethazine induced the transfer of Salmonella pathogenicity island 1 from pathogenic to nonpathogenic Salmonella organisms. Six antimicrobials (bacitracin, carbadox, erythromycin, sulfathiazole, tiamulin, and virginiamycin) did not mediate any transfer events. Sulfamethazine was the only antimicrobial implicated in 2 types of transfer events. 10 of 16 antimicrobials at subinhibitory or subtherapeutic concentrations augmented specific antimicrobial resistance or transfer of virulence genes into pathogenic bacteria in isolated intestinal loops in swine. Use of subtherapeutic antimicrobials in animal feed may be associated with unwanted collateral effects.


Safety and Tolerability of Overdosed Artificial Tears by Abraded Rabbit Corneas.
Purpose: Preservative-free cationic emulsion-based artificial tear (AT) is an innovative eye drop based on the Novasorb® technology with cetalkonium chloride (CKC) as the cationic agent. The cationic emulsion Cationorm is designed for the management of mild-to-moderate dry eye disease (DED) patients that present cornea epithelium alterations. The aim of the present study was to evaluate the safety and tolerability of overdosed ATs by altered corneal epithelium in vivo and assess the usefulness of the ex vivo eye irritation test (EVEIT) as a predictive alternate toxicity test method. Methods: The experimental procedure, treatment duration, and instillation frequency closely mimic in vivo the ex vivo protocol described by Pinheiro et al. and discussed in the Discussion and Conclusion section of this article. Two to 3-month-old female New Zealand white rabbits, n = 6 per group, were treated with ATs (21 instillations/day over 3 days) following corneal abrasion. Corneal fluorescein staining, in vivo confocal microscopy (IVCM), and slit lamp examinations were performed to assess corneal epithelium recovery and the ocular tolerability of the overdosed ATs. Results: All abraded eyes experienced almost complete epithelium recovery within 3 days following treatments with Cationorm, Optive, Vismed, and Saline. Benzalkonium chloride (BAK, 0.02%) treatment resulted in 82.4% reepithelialization. IVCM data illustrated corneal epithelium normal recovery. Acute local tolerability of the overdosed ATs was confirmed using Draize and McDonald-Shadduck's test scales. Conclusions: The different ATs were demonstrated to be well tolerated by abraded corneas in vivo, and the extreme overdosing regimen did not hamper the wound healing process of the rabbit eye in comparison to saline. These data did not confirm the ones obtained with the nonvalidated ex vivo eye irritation test.


A review of frailty instruments in human medicine and proposal of a frailty instrument for dogs.
Over the last few decades, frailty has become a pillar of research and clinical assessment in human gerontology. This complex syndrome, characterized by loss of physiologic reserves leading to decreased resilience to stressors, is of critical importance because it predicts higher risks of poor health outcomes, including mortality. Thus, identifying frailty among the elderly human population has become a key focus of gerontology. This narrative review presents current scientific literature on frailty in both humans and animals. The authors discuss the need for an accessible frailty instrument for companion dogs suitable for general use in veterinary medicine and the advances that would be facilitated by this instrument. A phenotypic frailty instrument for companion dogs, utilizing components that are easily collected by owners, or in the general practice setting, is proposed. The authors elaborate on the domains (physical condition, physical activity, mobility, strength, cognitive task performance, and social behavior), factors that will be included, and the data from the Dog Aging Project that inform each domain.


[Short intertrial interval as a phrasing cue in the reinforcement-pattern learning in rats].
The effect of short intertrial interval as a phrasing cue on the reinforcement-pattern learning was investigated in a rat experiment using a runway. In the acquisition session, 20 rats were trained for NNR sequence in which two nonreinforced trials were followed by a reinforced one with equal ITI of 30 min. In the sequence-addition session, a new sequence with consisting of three nonreinforced trials with 30-min ITI was added 30 min and 30 s after the original sequence of trials for Group L-ITI and for Group S-INT, respectively. Rats of Group S-INT responded on trials 4-6 with the similar pattern of running speed as they showed on Trials 1-3 from the second day. In Group L-ITI, the running speed on Trial 4 did not decrease. This suggests that Group S-INT rats learn to use the ITI of 30 s as a phrasing cue not on the first day but from the second day on. The phrasing effect of short ITI (30 s) was discussed in comparison with that of longer ITI (30 min).