Allergen endotoxins induce T-cell-dependent and non-IgE-mediated nasal hypersensitivity in mice.
Allergen-mediated cross-linking of IgE on mast cells/basophils is a well-recognized trigger for type 1 allergic diseases such as allergic rhinitis (AR). However, allergens may not be the sole trigger for AR, and several allergic-like reactions are induced by non-IgE-mediated mechanisms. We sought to describe a novel non-IgE-mediated, endotoxin-triggered nasal type-1-hypersensitivity-like reaction in mice. To investigate whether endotoxin affects sneezing responses, mice were intraperitoneally immunized with ovalbumin (OVA), then nasally challenged with endotoxin-free or endotoxin-containing OVA. To investigate the role of T cells and mechanisms of the endotoxin-induced response, mice were adoptively transferred with in vitro-differentiated OVA-specific TH2 cells, then nasally challenged with endotoxin-free or endotoxin-containing OVA. Endotoxin-containing, but not endotoxin-free, OVA elicited sneezing responses in mice independent from IgE-mediated signaling. OVA-specific TH2 cell adoptive transfer to mice demonstrated that local activation of antigen-specific TH2 cells was required for the response. The Toll-like receptor 4-myeloid differentiation factor 88 signaling pathway was indispensable for endotoxin-containing OVA-elicited rhinitis. In addition, LPS directly triggered sneezing responses in OVA-specific TH2-transferred and nasally endotoxin-free OVA-primed mice. Although antihistamines suppressed sneezing responses, mast-cell/basophil-depleted mice had normal sneezing responses to endotoxin-containing OVA. Clodronate treatment abrogated endotoxin-containing OVA-elicited rhinitis, suggesting the involvement of monocytes/macrophages in this response. Antigen-specific nasal activation of CD4+ T cells followed by endotoxin exposure induces mast cell/basophil-independent histamine release in the nose that elicits sneezing responses. Thus, environmental or nasal residential bacteria may exacerbate AR symptoms. In addition, this novel phenomenon might explain currently unknown mechanisms in allergic(-like) disorders.


[Calcinosis of the meniscus. Morphologic and roentgenographic findings for zonal classification].
Primary and secondary meniscal chondrocalcinoses lead to typical changes in X-ray pictures of isolated menisci. Combined X-ray, light and electron microscopic examination of the four menisci in 70 autopsy cases showed calcifications in 13 cases (18.6%). Three types of calcification could be discriminated with the help of topographical and morphological criteria: Type 1 A: disseminated calcification. All four menisci were affected equally. Crystals of calcium pyrophosphate dihydrate (CPPD) were found on light and electron microscopy. Energy-dispersive X-ray analysis (EDX) showed the crystal deposits to consist of 46.5% calcium and 53.5% phosphorus. Type 1 B: Calcification occurring in limited areas. A calcification was found which did affected neither a whole meniscus nor all four menisci of any "quartet" observed. Crystals were found next to areas of stronger meniscal degeneration. EDX showed the same results described for type 1 A. Type 2: Confluent calcification. A cloud-like diffuse calcification was discerned on the X-ray pictures. Light and electron microscopically pseudocystic structures appeared which contained a fine granular amorphous material. No crystals were found. The structures appeared in the neighbourhood of necrotic fibres. EDX showed 44% calcium, 51.2% phosphorus, 2.8% sulphur, 0.74% magnesium and 0.6% potassium. The findings lead to the conclusion that calcification type 1 A represents primary chondrocalcinosis, whereas type 1 B corresponds to secondary chondrocalcinosis. Type 2 was identified as postnecrotic, dystrophic calcification. Careful analysis of X-ray pictures of isolated menisci can yield useful information concerning pathogenetic factors of meniscal calcification.


A renewal equation with a birth-death process as a model for parasitic infections.
A model is derived for the description of parasitic diseases on host populations with age structure. The parasite population develops according to a linear birth-death-process. The parasites influence mortality and fertility of the hosts and are acquired with a rate depending on the mean parasite load of the host population. The model consists of a system of partial differential equations with initial and boundary conditions. From the boundary condition a renewal equation for the host population is derived. The model is then generalized to describe a multitype process. Existence and uniqueness of solutions are proved. Results concerning persistent solutions are indicated.


Automation of the glycerolization of red blood cells with the high-separation bowl in the Haemonetics ACP 215 instrument.
The FDA has approved a closed-system red blood cell (RBC) glycerolization procedure with the ACP 215 (Haemonetics), which requires a centrifuge to prepare RBCs before and after glycerolization. In the study reported here, the Haemonetics high-separation bowl was evaluated in an attempt to automate these two concentration steps. Ten units of nonleukoreduced citrate phosphate dextrose (CPD)-anticoagulated whole blood were stored at 4 degrees C for 2 to 6 days before glycerolization and freezing as nonrejuvenated RBCs. Twenty-five units of nonleukoreduced CPD whole blood were stored at 4 degrees C for 2 to 8 days and then biochemically treated with a solution containing pyruvate, inosine, phosphate, and adenine (PIPA) before glycerolization and freezing as indated-rejuvenated RBC. Twenty units of leukoreduced CPD and AS-1 RBCs were stored at 4 degrees C for a mean of 48 days and treated with PIPA solution before glycerolization and freezing as outdated-rejuvenated RBCs. The glycerolized RBCs were frozen for at least 2 weeks at -80 degrees C, deglycerolized in the Haemonetics ACP 215 with the 325-mL bowl, and stored in AS-3 at 4 degrees C for 21 days. It took approximately 50 minutes to glycerolize the nonrejuvenated and rejuvenated RBCs. After freezing, deglycerolization, and postwash storage at 4 degrees C in AS-3 for 2 weeks, the quality was similar to that of RBCs processed by the current FDA-approved method. Processing time and need for technical expertise were significantly reduced with the completely automated functionally closed glycerolization procedure with the high-separation bowl in the Haemonetics ACP 215 instrument.


Primary health care reform in Slovenia: first results.
The paper explains the main features of the primary health care system and its reform in Slovenia. The reform that has started in 1992, was characterized by the following main changes: introducing the national health insurance scheme as opposed to budget financing, a new contrast between providers and the national health insurance and a possibility of independent contracting with the national health insurance. The data show that the number of consultations per person per year has increased, especially in general practice. A possible explanation to that would be the fact that people had to visit their physicians in order to register with a specific PHC physician. It remains to be seen whether the high level of new attendances will remain in the following year or whether this is just a temporary situation.


Heat-Shock Protein 90 Controls the Expression of Cell-Cycle Genes by Stabilizing Metazoan-Specific Host-Cell Factor HCFC1.
Molecular chaperones such as heat-shock proteins (HSPs) help in protein folding. Their function in the cytosol has been well studied. Notably, chaperones are also present in the nucleus, a compartment where proteins enter after completing de novo folding in the cytosol, and this raises an important question about chaperone function in the nucleus. We performed a systematic analysis of the nuclear pool of heat-shock protein 90. Three orthogonal and independent analyses led us to the core functional interactome of HSP90. Computational and biochemical analyses identify host cell factor C1 (HCFC1) as a transcriptional regulator that depends on HSP90 for its stability. HSP90 was required to maintain the expression of HCFC1-targeted cell-cycle genes. The regulatory nexus between HSP90 and the HCFC1 module identified in this study sheds light on the relevance of chaperones in the transcription of cell-cycle genes. Our study also suggests a therapeutic avenue of combining chaperone and transcription inhibitors for cancer treatment.


Helminth infections and allergic diseases: Systematic review and meta-analysis of the global literature.
There is considerable research interest in the role of helminth infections in the development of allergic diseases. However, findings from previous studies are mixed. Existing systematic reviews of these studies are outdated. We performed a systematic review of the global literature on the association between helminth infections and development and clinical outcomes of allergic diseases. We searched Cochrane Library, MEDLINE, EMBASE, ISI Web of Science, PubMed, Global Index Medicus, Scielo, KoreaMed, Google Scholar, and Lilacs for studies published up to January 2020. We included observational epidemiological studies (cohort, case-control, and cross-sectional studies) of children and adults reporting associations between helminth infections and asthma, allergic rhinitis, eczema, and atopy. We performed random-effects meta-analysis to summarize the effect estimates. We included 80 studies with 99,967 participants. In the meta-analyses, we did not observe an overall association between helminth infections and allergic diseases. There was, however, evidence that Ascaris lumbricoides infections were associated with an increased risk of bronchial hyperreactivity in children (risk ratio, 1.41; 95% CI, 1.17-1.70; I2 = 50; P for I2 = .09), and were associated with an increased risk of atopy among helminth-infected adults (risk ratio, 1.37; 95% CI, 1.18-1.61; I2 = 52; P for I2 = .02). We found no study that addressed the association between helminth infection and clinical outcomes of allergic diseases. The overall strength of the underlying evidence was low to moderate. Helminth infections may increase the risk of bronchial hyperreactivity in children and atopy in adults. Well-designed longitudinal cohorts may help clarify potential causal associations between chronic helminth infections and allergic diseases.


Tonic accommodation: a review. I. Basic aspects.
In the absence of an adequate visual stimulus, accommodation adopts an intermediate position of approximately 1 D. Since this position was believed to reflect the level of tonic innervation to the ciliary muscle, this response has been termed tonic accommodation (TA). Part I of this review will consider various aspects of this parameter, including its reference to closed-loop accommodative function and autonomic physiology. In addition, both the methods of measurement and appropriate terminology for this function will be discussed. It is concluded that the response, which becomes apparent under so-called 'stimulus-free' conditions, in fact probably represents an aggregate response resulting from multiple, non-optical stimuli. Thus the designation tonic accommodation may not be appropriate, since it fails to describe accurately the heterogeneous composition of the stimulus-free accommodative response. An associated paper (to be published as part II of this review) will examine accommodative adaptation and both clinical aspects of TA and adaptation of TA.


Analyzing Potential Intestinal Transporter Drug-Drug Interactions: Reevaluating Ticagrelor Interaction Studies.
Previous studies evaluating ticagrelor drug-drug interactions have not differentiated intestinal versus systemic mechanisms, which we do here. Using recently published methodologies from our laboratory to differentiate metabolic- from transporter-mediated drug-drug interactions, a critical evaluation of five published ticagrelor drug-drug interactions was carried out to investigate the purported clinical significance of enzymes and transporters in ticagrelor disposition. The suggested CYP3A4 inhibitors, ketoconazole and diltiazem, displayed unchanged mean absorption time (MAT) and time of maximum concentration (Tmax) values as was expected, i.e., the interactions were mainly mediated by metabolic enzymes. The potential CYP3A4/P-gp inhibitor cyclosporine also showed an unchanged MAT value. Further analysis assuming there was no P-gp effect suggested that the increased AUC and unchanged t1/2 for ticagrelor after cyclosporine administration were attributed to the inhibition of intestinal CYP3A4 rather than P-gp. Rifampin, an inducer of CYP3As after multiple dosing, unexpectedly showed decreased MAT and Tmax values, which cannot be completely explained. In contrast, grapefruit juice, an intestinal CYP3A/P-gp/OATP inhibitor, significantly increased MAT and Tmax values for ticagrelor, which may be due to activation of P-gp or inhibition of OATPs expressed in intestine. This study provides new insight into the role of transporter pathways in ticagrelor intestinal absorption by examining potential MAT and Tmax changes mediated by drug-drug interactions.


Expansion of the visual projection to the tectum of axolotls during metamorphosis.
During artificially induced metamorphosis in axolotls, the indirect visual projection from the ipsilateral eye develops followed by the expansion of the contralateral direct projection to occupy most of the tectal surface. During expansion the ipsilateral input is temporarily lost indicating the functional interdependence of the two projections. Final stabilization of the projections and congruence of the ipsilateral and contralateral inputs is achieved a month after arrival on land.


Ovarian follicular growth in humans: ovarian ageing and population of growing follicles.
By integrating morphometrical and endocrinological data, as well as biological effects of various peptides synthesized by the primate follicle, the current review proposes a morphofunctional view of the early follicle growth within the human ovary. From the time they enter the preantral stage (0.15 mm), during the early luteal phase, follicles need about 70 days to reach a size of 2 mm. These follicles are impervious to cyclic FSH and LH changes in terms of granulosa cell (GC) proliferation, and their steroidogenic activity is very low. From the time they enter the selectable stage (2-5 mm in diameter) during the late luteal phase, follicles become sensitive to cyclic changes of FSH in terms of quality and GC proliferation, but not in terms of GC aromatase activity. Thus, as the follicle develops, its responsiveness to gonadotropins progressively increases. In vitro studies suggest that this progressive acquisition of follicular cell responsiveness to gonadotropins might be under the control of peptides acting in an autocrine/paracrine fashion within the follicle. The numbers of growing follicles decrease with ageing, especially in women over the age of 40. During the follicular phase of the menstrual cycle, selectable follicles exhibit a mitotic activity of their GC higher in women older than 40 years than in younger women.


Clinical results of extracorporeal membrane oxygenation (ECMO) support for acute respiratory failure: a comparison of a centrifugal pump ECMO with a roller pump ECMO.
The purpose of this study was to compare the clinical results of extracorporeal membrane oxygenation (ECMO) using a centrifugal pump (CP group) and that using a roller pump (RP group) for the treatment of acute respiratory failure (ARF). From November 1990 to July 2001, the ECMO system was introduced for the treatment of 15 patients with ARF; 10 cases of pneumonia or adult respiratory distress syndrome (ARDS), 4 cases of pulmonary hemorrhage, and 1 case of hypoxemia following cardiac surgery. Five patients were included in the RP group, and 10 were included in the CP group. The mean PaO2/FIO2 ratio, PaCO2 prior to ECMO induction, and the mean duration of ECMO support were 59.8, 38.8 mmHg, and 125 h, respectively, in the RP group, and 65.6, 82.0 mmHg, and 107 h, respectively, in the CP group. The mean PaCO2 value was significantly (P < 0.05) higher in the CP group than in the RP group due to the ventilation with "permissive hypercapnia." In the RP group, all patients died of either complications or recurrence due to ARF. In the CP group, 3 patients including 2 with pulmonary hemorrhaging were discharged. Although the centrifugal pump ECMO improved the clinical results of ARF, the overall prognosis nevertheless depended on the original disease.


Rouviere's sulcus - An anatomical landmark for safe laparoscopic cholecystectomy: A cross-sectional study.
Laparoscopic cholecystectomy (LC) has been established as the gold standard treatment for symptomatic gallstones, however surgeons face the risk of injuring bile ducts and vessels due to the inherent limitations of laparoscopy. This is a cross-sectional study done in the Department of Surgery, Shree Birendra Hospital (SBH) on patients who were posted for LC. The study period was through April 2021 to September 2021. During LC, the anatomy of RS was noted and classified into Group A (RS present) or Group B (RS absent). Data analyses were performed considering a p-value of <0.05 as statistically significant. RS was present in 169 (93.9%) out of 180 cases. The open sulcus type was found in 114 cases (67.5%), followed by closed type in 26 (15.4%), slit sulcus type in 22 (13.0%), and scar type in 7 (4.1%) cases. Injury to cystic artery occurred in one case (0.15%) of Group A while in two cases (18.18%) of Group B (p-value = 0.001). The adjusted operative time in Group A and Group B were 50.61 ± 10.33 min and 69.86 ± 15.28 min respectively (p-value = 0.005). There was significant difference between Group A and Group B in conversion to open surgery - 01 (0.59%) and 04 (36%) respectively (p-value < 0.001). Surgical Site Infection (SSI) was detected in nine (5.33%) cases among Group A and in three (27.2%) cases among Group B (p-value = 0.028). RS can be considered as an important anatomical landmark for safer LC with fewer injuries to cystic artery, SSI, conversion to open surgery and shorter operative time.


In Context: A Developmental Model of Reward Processing, With Implications for Autism and Sensitive Periods.
Differences in reward processing have been associated with numerous psychiatric disorders, including autism and attention-deficit/hyperactivity disorder (ADHD). Many attempts to understand reward processing characterize differences in clinical populations after disorder onset; however, divergence may begin much earlier. In fact, the typical developmental progression of reward processing in infancy and early childhood is poorly understood. We re-conceptualize classic infant developmental constructs such as preferential looking into a Six-Component Developmental Model of Reward Processing: an infant- and young child-focused framework to guide research and assessment of reward processing across development. The extant developmental literature including recent textbooks, systematic reviews, and meta-analyses was reviewed to build a conceptual framework. We describe experimental paradigms to assess each developmental component of reward processing longitudinally from infancy. A timeline of each component's emergence was estimated. Six components of reward processing were identified-association, discrimination, preference/valuation, effort, anticipation, and response. Selected evidence suggests emergence between birth and 6 months. Application of this model to autism led to a reinterpretation of existing disparate results, and illuminated a path to study the developmental processes underlying a popular hypothesis of autism, the motivation hypothesis. Current evidence further suggests that a sensitive period may exist for the emergence of reward processing. The proposed framework offers a useful reconceptualization of the extant literature. Future longitudinal work using the suggested experimental paradigms with high-risk populations could elucidate the developmental trajectory of the components and timing of potential sensitive period(s) for each component.


Complications and management of microwave coagulation therapy for primary and metastatic liver tumors.
Microwave coagulation therapy (MCT) has been widely used, both percutaneously and directly, as effective minimal invasive therapy for liver tumors. To facilitate the use of MCT, we describe the complications we have encountered, and their possible management and prophylaxis. MCT was performed for 42 patients with hepatocellular carcinoma (HCC) and for 29 with metastatic liver tumors, following which complications developed in 14.2% and 20.6% of the HCC and metastatic groups, respectively. The complications included abscess, biloma, bleeding, hepatic failure, and dissemination of cancer cells. In the HCC group, the mean value of tumor size and the clinical stage of patients with complications were significantly larger (P = 0.006) and higher (P = 0.032), respectively, than those of patients without complications. The incidence of complications increased significantly when the tumor size was more than 4cm (P = 0.008). Abscesses and bleeding were successfully treated using percutaneous drainage and interventional angiography, respectively, but as the other serious complications were not able to be treated effectively once induced, prophylaxis is important to facilitate MCT. Transcatheter cooling of the intrahepatic bile duct during MCT and the administration of an anticancer agent into the abdominal cavity are recommended to prevent biloma and dissemination, respectively. MCT is indicated for tumors less than 4 cm in diameter to reduce the risk of complications. The prophylaxis and treatment of these complications enhance the safety of MCT.


Parathyroid lesions localized by radionuclide subtraction and ultrasound.
Radionuclide subtraction technique and gray-scale echography were used to localize parathyroid lesions in 6 patients with primary hyperparathyroidism. In 3 cases, surgery verified the scintigraphic findings. All lesions weighed less than 1 g, with the smallest weighing 350 mg. These procedures provide complementary information in preoperative localization of hyperfunctioning parathyroid tissue.


Mucinous biliary cystadenocarcinoma containing gas bubbles secondary to duodenal invasion.
Biliary cystadenocarcinoma is a rare, usually intrahepatic neoplasm. A case is described in which an intrahepatic cystadenocarcinoma invaded the duodenum. This resulted in intratumoral gas.


Multimodality management of focal nodular hyperplasia
Focal nodular hyperplasia (FNH) is the second most common benign mass of the liver. According to the current recommendations, removal makes relative indication. Several different treatment methods are known. The purpose of the paper is to provide a summary of FNH care and to present alternative treatment options in two cases. A 40-year old woman was investigated for abdominal complaints; CT scan confirmed FNH of the liver. Given the localization of the lesion, we chose transarterial embolization (TAE) due to the high risk of surgical resection. After multiple treatments, regression was achieved, and the patient became asymptomatic. Painful FNH in a 25-year-old female was confirmed by MRI. The lesion was dominantly seen in segment 1, causing vena cava compression and collaptiform episodes. As a definitive solution, liver resection was performed, after which her complaints ceased. Long-term follow-up of patients may be sufficient when asymptomatic FNH is detected. In the case of symptoms or high risk of surgery, TAE can be used effectively by FNH either alone or in combination with surgical treatment. For lower-risk patients, primary laparoscopic resection is the most appropriate choice.


Amyloidosis and the Kidney: An Update.
Various types of systemic amyloidosis can wreak havoc on the architecture and functioning of the kidneys. Amyloidosis should be suspected in patients with worsening kidney function, proteinuria, and multisystem involvement, but isolated kidney involvement also is possible. Confirming the amyloidosis type and specific organ dysfunction is of paramount importance to select the appropriately tailored treatment and aim for better survival while avoiding treatment-associated toxicities. Amyloid renal staging in light chain amyloidosis amyloidosis helps inform prognosis and risk for end-stage kidney disease. Biomarker-based staging systems and response assessment guide the therapeutic strategy and allow the timely identification of refractory or relapsing disease so that patients can be switched to salvage therapy. Kidney transplantation is a viable option for selected patients with amyloidosis. Because of the complex nature of the pathophysiology and treatment of amyloidosis, a multidisciplinary team-based approach should be used in the care of these patients.


Ethanol-induced hypothermia and hyperglycemia in genetically obese mice.
Blood glucose and rectal temperatures were monitored in two strains of genetically obese mice (C57 BL/6J ob/ob) prior to and following intragastric ethanol administration in an attempt to relate the hypothermic response to ethanol to extracellular glucose concentration. In contrast to expectation, ethanol administration was typically associated with a hyperglycemia and a hypothermic response. In the ob/ob genotype, the hypothermic response was associated with pronounced hyperglycemia which was more emphatic in older animals. The data support the conclusion that ethanol-induced hypothermia is independent of blood glucose levels. In light of the known sensitivity of ob/ob mice to insulin, it is suggested further that the observed hypothermic response was not a function of the animals' ability to transport glucose into peripheral cells. The observed hyperglycemia of the obese animals was most likely stress-related.


Role of pre-revision tissue biopsy in evaluation of painful shoulder arthroplasty: a systematic review and meta-analysis.
Pre-revision tissue biopsy (PTB) for culture has been used as a diagnostic tool in the evaluation for periprosthetic joint infection among patients with a painful shoulder arthroplasty. The purpose of this study was to (1) determine the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of PTB culture results compared with results of "gold-standard" tissue biopsy for culture taken at the time of subsequent revision surgery (TBR), and (2) report the current indications and protocols described for use of PTB. The hypothesis was that PTB culture results would correlate highly with results of TBR and that protocols for PTB would vary by institution. By use of Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, a systematic review and meta-analysis of English-language literature were performed using the Embase, MEDLINE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and Cochrane databases from inception through March 2020. Methodological Index for Non-randomized Studies (MINORS) validated grading criteria were used to summarize the quality and bias of included studies. Studies were included if an arthroscopic or open tissue biopsy was performed in patients who had previously undergone anatomic total shoulder arthroplasty, shoulder hemiarthroplasty, or reverse total shoulder arthroplasty as a separate procedure prior to revision of components, if applicable. Meta-analysis to identify the sensitivity, specificity, NPV, and PPV of PTB was performed. Analysis was performed by first defining 1 positive PTB culture result as infection and then defining 2 positive culture results as infection. A total of 1751 titles were screened, and 66 full-text articles were reviewed for inclusion. Four total studies encompassing 72 cases met the inclusion criteria. All studies were small (N = 13 to N = 23), retrospective series, with all but 12 biopsies performed arthroscopically. Sixty-five patients (90.2%) underwent subsequent revision surgery and TBR. Of these patients, 23 (35.4%) had ≥1 positive culture result with PTB and TBR. By this definition, the sensitivity of PTB was 92.0% (95% confidence interval [CI], 72.5%-98.6%); specificity, 70.0% (95% CI, 53.3%-82.9%); PPV, 65.7% (95% CI, 47.7%-80.3%); and NPV, 93.3% (95% CI, 76.5%-98.8%). For 2 positive PTB results, the sensitivity of PTB was 100% (95% CI, 51.7%-100%); specificity, 50.0% (95% CI, 31.4%-68.6%); PPV, 33.3% (95% CI, 14.4%-58.8%); and NPV, 100% (95% CI, 69.9%-100%). No complications of PTB were reported. The mean Methodological Index for Non-randomized Studies (MINORS) grade was 11.4 (range, 8.5-14). PTB is a sensitive diagnostic modality with a high NPV that may aid in the diagnosis of shoulder periprosthetic joint infection in patients with a painful shoulder arthroplasty. Given the disparate biopsy protocols, greater standardization of clinical best practices and broader prospective studies are necessary to define the future role of PTB in dictating treatment.


Allerton III. Beyond livestock genomics.
Throughout the Allerton III Conference, several consistent research needs were identified across scientific disciplines. First, additional basic research is needed to identify genomic mechanisms and novel genes/proteins in a variety of tissues under different conditions. Second, expansion of the infrastructure of the scientific community is needed. This can best be accomplished by additional competitive grants programs for training grants, program project grants, and multidisciplinary research projects. Third, the need for improved tools for animal bioinformatics was emphasized. Fourth, competitive grants programs for extension/outreach efforts and application of genomic technologies to production systems are needed. Finally, efforts to publicize and document the benefits of animal genomics for improved human health and animal production systems to members of Congress and the general public should be enhanced.


Inhibition of the classical pathway of the complement system by saliva of Amblyomma cajennense (Acari: Ixodidae).
Inhibition of the complement system during and after haematophagy is of utmost importance for tick success in feeding and tick development. The role of such inhibition is to minimise damage to the intestinal epithelium as well as avoiding inflammation and opsonisation of salivary molecules at the bite site. Despite its importance, the salivary anti-complement activity has been characterised only in species belonging to the Ixodes ricinus complex which saliva is able to inhibit the alternative and lectin pathways. Little is known about this activity in other species of the Ixodidae family. Thus, the aim of this study was to describe the inhibition of the classical pathway of the complement system by the saliva of Amblyomma cajennense at different stages of the haematophagy. The A. cajennense saliva and salivary gland extract (SGE) were able to inhibit the complement classical pathway through haemolytic assays with higher activity observed when saliva was used. The anti-complement activity is present in the salivary glands of starving females and also in females throughout the whole feeding process, with significant higher activity soon after tick detachment. The SGE activity from both females fed on mice or horses had no significant correlation (p > 0.05) with tick body weight. The pH found in the intestinal lumen of A. cajennense was 8.04 ± 0.08 and haemolytic assays performed at pH 8.0 showed activation of the classical pathway similarly to what occurs at pH 7.4. Consequently, inhibition could be necessary to protect the tick enterocytes. Indeed, the inhibition observed by SGE was higher in pH 8.0 in comparison to pH 7.4 reinforcing the role of saliva in protecting the intestinal cells. Further studies should be carried out in order to identify the inhibitor molecule and characterise its inhibition mechanism.


Brain microstructural abnormalities in patients with Wilson's disease: A systematic review of diffusion tenor imaging studies.
Wilson's disease (WD) is an autosomal recessive that can lead to high copper concentrations and copper accumulation in bodily organs, specifically the liver, nervous system, and cornea of the eye. Previous meta-analysis studies have evaluated literature reports of diffusion tensor imaging (DTI) to characterize brain microstructural abnormalities in specific neurological diseases, but there have been no systematic reviews of DTI findings in Wilson's disease (WD). Therefore, this study aimed to systematically review studies reporting DTI findings in patients with WD. This systematic review was conducted according to the PRISMA 2020 guidelines. PubMed, Scopus, and Embase databases were searched on May 6th, 2021. We then performed a two-step screening process comprising title/abstract and full-text screening phases. Data from the included studies were then extracted. We found 10 eligible studies. Most of the included studies identified altered DTI metrics. Affected brain regions included the basal ganglia, thalamus, brainstem, cerebellum, corpus callosum, projection and association fibers. DTI alterations were also observed in patients clinically presenting with hepatic-only WD without neurological symptoms. DTI alterations preceded structural magnetic resonance imaging findings in studies of the thalamus and frontal and occipital lobe white matter changes. The extent of DTI alterations correlated with disease severity and clinical disability, cognitive memory declines, and asymmetry in motor symptoms in several studies. DTI allows early detection of brain abnormalities associated with WD, prior to the occurrence of morphological brain changes by MRI. Correlations with treatment outcomes and clinical severity may provide objective and quantitative assessment of early and ongoing treatment response. Future studies are required to elucidate the role of DTI in WD clinical practice and find the most consistent DTI markers that may improve clinical outcome.


Mannich bases of 7-piperazinylquinolones and kojic acid derivatives: synthesis, in vitro antibacterial activity and in silico study.
Novel Mannich bases of 7-piperazinylquinolones with kojic acid and chlorokojic acid were designed as new quinolone antibacterials. All compounds showed significant in vitro antibacterial activity against both Gram-positive and Gram-negative bacteria. Particularly, chlorokojic derivative 2b was the most potent compound against Staphylococcus aureus and Pseudomonas aeruginosa (MIC values≤0.19 μg/mL). Its activity was 4-8 times more than that of standard drug norfloxacin. The molecular docking study of compound 2b further supported the molecular basis of the designed compounds.


Removal efficiency for emerging contaminants in a WWTP from Madrid (Spain) after secondary and tertiary treatment and environmental impact on the Manzanares River.
The effluents from wastewater treatment plants (WWTPs) can be an important contamination source for receiving waters. In this work, a comprehensive study on the impact of a WWTP from Madrid on the aquatic environment has been performed, including a wide number of pharmaceuticals and pesticides, among them those included in the European Watch List. 24-h composite samples of influent (IWW) and effluent wastewater after secondary (EWW2) and after secondary + tertiary treatment (EWW3) were monitored along two campaigns. Average weekly concentrations in IWW and EWW2 and EWW3 allowed estimating the removal efficiency of the WWTP for pharmaceutical active substances (PhACs). In addition, the impact of EWW3 on the water quality of the Manzanares River was assessed, in terms of PhAC and pesticide concentrations, through analysis of the river water collected upstream and downstream of the discharge point. After a preliminary risk assessment, a detailed evaluation of the impact on the aquatic environment, including a toxicological study and screening of pharmaceutical metabolites, was made for the seven most relevant PhACs: sulfamethoxazole, azithromycin and clarithromycin (antibiotics), metoprolol (antihypertensive), diclofenac (anti-inflammatory/analgesic), irbesartan (antihypertensive), and the antidepressant venlafaxine. Among selected PhACs, irbesartan, clarithromycin and venlafaxine presented moderate or high risk in the river water downstream of the discharge. Albeit no acute toxicity was detected, more detailed studies should be carried out for these substances, including additional toxicological studies, to set up potential sublethal and chronic effects on aquatic organisms.


Distinguishing Features Common to Dual Fatal Herpes Simplex Virus Infections That Occur in Both a Pregnant Woman and Her Newborn Infant.
Deaths from herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are rare. A major exception is perinatally acquired HSV-1 or HSV-2 infection where the neonatal death rate is substantial. Fatal HSV infection also occurs occasionally in pregnant women. The goal of this review is to enumerate the reports that describe dual deaths of both a pregnant woman and her newborn from a herpesvirus infection. A total of 15 reports were found in the medical literature, of which five described pregnant women with HSV encephalitis and 10 described women with disseminated HSV infection. When the virus was typed, most cases of dual mother/newborn deaths were caused by HSV-2. Of interest, in two situations caused by HSV-1, the pregnant woman probably acquired her primary HSV-1 infection from one of her children and not by sexual transmission. Complete genomic sequencing was performed on one set of HSV-1 isolates collected from mother (blood) and newborn (blood and skin). The mother's strain and the newborn's skin strain were 98.9% identical. When the newborn's two strains were compared, they were 97.4% identical. Only one mother was tested by the HerpeSelect IgG antibody kit. During the nine days of her undiagnosed disseminated infection preceding her death, her serology was negative. In summary, although dual mother/newborn deaths from HSV infection are rare, they continue to be reported as recently as 2017.


The correlation between testosterone and stroke and the mediating role of blood pressure: The Henan rural cohort study.
We aimed to investigate the association of serum testosterone with stroke and calculate the proportion explained by blood pressure on this association. A total of 6175 subjects were included in this study. Serum testosterone was quantified by liquid chromatography-tandem mass spectrometry. The logistic regression model was used to evaluate the association between serum testosterone and stroke. Linear regression analysis was used to assess the associations of serum testosterone with blood pressure. In addition, mediation analysis was performed to identify the mediation effects of blood pressure on the association of serum testosterone with stroke. Sex-stratified analysis was employed throughout the research. After adjusting for multiple variables, serum testosterone levels were negatively associated with stroke in males (per 1 unit natural log-transformed, odds ratio (OR) = 0.81, 95% confidence interval (CI): 0.69-0.94; Tertile 3 vs Tertile 1, OR = 0.65, 95% CI:0.44-0.96). Furthermore, blood pressure played a partial mediating role in the relationship between testosterone and stroke in males. The indirect effect/total effect of systolic blood pressure, diastolic blood pressure and mean arterial pressure were 7.37%, 9.54% and 9.22%, respectively. Notably, the relationship between testosterone and stroke and the role of blood pressure in regulating them was not observed in females. This study describes that in rural Chinese males, testosterone can reduce the risk of stroke by affecting blood pressure. To some extent, we provide a new epidemiological evidence for the relationship between testosterone and stroke.


Continuous assessment of neuro-ventilatory drive during 12 h of pressure support ventilation in critically ill patients.
Pressure support ventilation (PSV) should allow spontaneous breathing with a "normal" neuro-ventilatory drive. Low neuro-ventilatory drive puts the patient at risk of diaphragmatic atrophy while high neuro-ventilatory drive may causes dyspnea and patient self-inflicted lung injury. We continuously assessed for 12 h the electrical activity of the diaphragm (EAdi), a close surrogate of neuro-ventilatory drive, during PSV. Our aim was to document the EAdi trend and the occurrence of periods of "Low" and/or "High" neuro-ventilatory drive during clinical application of PSV. In 16 critically ill patients ventilated in the PSV mode for clinical reasons, inspiratory peak EAdi peak (EAdiPEAK), pressure time product of the trans-diaphragmatic pressure per breath and per minute (PTPDI/b and PTPDI/min, respectively), breathing pattern and major asynchronies were continuously monitored for 12 h (from 8 a.m. to 8 p.m.). We identified breaths with "Normal" (EAdiPEAK 5-15 μV), "Low" (EAdiPEAK < 5 μV) and "High" (EAdiPEAK > 15 μV) neuro-ventilatory drive. Within all the analyzed breaths (177.117), the neuro-ventilatory drive, as expressed by the EAdiPEAK, was "Low" in 50.116 breath (28%), "Normal" in 88.419 breaths (50%) and "High" in 38.582 breaths (22%). The average times spent in "Low", "Normal" and "High" class were 1.37, 3.67 and 0.55 h, respectively (p < 0.0001), with wide variations among patients. Eleven patients remained in the "Low" neuro-ventilatory drive class for more than 1 h, median 6.1 [3.9-8.5] h and 6 in the "High" neuro-ventilatory drive class, median 3.4 [2.2-7.8] h. The asynchrony index was significantly higher in the "Low" neuro-ventilatory class, mainly because of a higher number of missed efforts. We observed wide variations in EAdi amplitude and unevenly distributed "Low" and "High" neuro ventilatory drive periods during 12 h of PSV in critically ill patients. Further studies are needed to assess the possible clinical implications of our physiological findings.


Cancer of the skin in blacks. V. A review of 175 black patients with squamous cell carcinoma of the penis.
Histologically diagnosed squamous cell carcinoma of the penis in black patients was reviewed through the Tumor Registry of Charity Hospital covering the years 1948 to 1985. There were 175 cases, including 15 cases of squamous cell carcinoma in situ. The overall mortality was 15.4%. Associated second primary malignancies, almost all of which were found after the diagnosis of squamous cell carcinoma of the penis, occurred in 17.7% of the patients.


Microbial changes and aroma profile of nitrate reduced dry sausages during vacuum storage.
Slow fermented sausages with reduced ingoing amounts of sodium nitrate (control, 15% and 25% reduction) were stored under vacuum up to three months. Changes in microbiology, chemical parameters and volatile compounds were studied. Residual nitrate was not affected by vacuum storage and its reduction resulted in a reduction of sausage redness. General microbial counts decreased during vacuum storage, though nitrate reduction increased the growth of total mesophilic bacteria and Gram positive cocci. Long storage time and 25% nitrate reduction affected microbial activity and sausage aroma profile. Short vacuum storage times and moderate nitrate reduction (15%) were related to compounds producing pleasant odours (3-hydroxy-2-butanone, ethyl octanoate, ethyl-3-methylbutanoate and 2,3-pentanedione) and cheesy/buttery odour (2,3-butanedione and ethyl-2-hydroxypropanoate). In contrast, 25% nitrate reduction increased compounds like heptanal (green, unpleasant odour) and those related to unpleasant odours, methanethiol (rotten odour) and methional (cooked potato).


Patterns of failure for rhabdomyosarcoma of the perineal and perianal region.
To analyze prognostic factors and patterns of failure for rhabdomyosarcoma of the perineal and perianal region (PRMS), with an emphasis on radiation therapy for locoregional control. Detailed records of all 14 patients treated for PRMS at Memorial Sloan-Kettering Cancer Center between 1998 and 2012 were reviewed. The Kaplan-Meier method was used to assess the event-free survival (EFS) and overall survival (OS), and a competing-risks analysis was used to assess the cumulative incidence of local, regional, and distant failures. Median age was 15.8 years (range, 1.1-31.9 years). High-risk features were identified: 9 of 14 patients (64%) had group 3 disease and 3 of 14 (21%) had group 4; 11 of 14 tumors (78%) were alveolar; 12 of 14 tumors (86%) were ≥5 cm; and 9 of 14 patients (64%) had involved lymph nodes (N1). Of those aged ≥10 years at diagnosis, 9 of 10 (90%) had alveolar histology, all had tumors ≥5 cm, and 8 of 10 (80%) presented with N1 disease. The rates of local, regional, and distant failure at 5 years were 17%, 31%, and 52%, respectively. Although 3 of the 4 patients with regional failure received nodal irradiation, only one of the nodal failures occurred in the radiation therapy field. The 5-year EFS was 33%, and OS was 39%. Age ≥10 years was associated with poor outcomes: EFS was 13% in patients aged ≥10 years, compared with 75% in those aged <10 years (P=.04); the OS was 13% in patients aged ≥10 years, compared with 100% in those aged <10 years (P=.04). Patients with PRMS, especially those aged ≥10 years, present with poor prognostic features and continue to have poor outcomes. Given the high incidence of regional node recurrence, we recommend prophylactic ilioinguinal lymph node irradiation for all patients aged ≥10 years. For children aged <10 years, nodal evaluation is essential to determine the role for lymph node irradiation.


Abnormal 3,4-dihydroxyphenylalanine (dopa) concentrations in plasma and urine of patients with cystic fibrosis.
Plasma and urine concentrations of the free amino acid 3,4-dihydroxyphenylalanine (dopa) were determined in a blind study in 16 children and adolescents with cystic fibrosis (CF), eight heterozygote parents of these children and in 11 healthy subjects who served as controls. To exclude any drug interference with catecholamine metabolism and to evaluate a tentative basic metabolic alteration in cystic fibrosis, the same determinations were done in 11 newly diagnosed infants (age 1-84 months). Free plasma dopa was significantly (P less than 0.01) elevated in CF (27.0 +/- 6.1 nmol l-1 vs. 19.1 +/- 5.0 nmol l-1 in the controls); heterozygotes had the lowest concentration: 11.5 +/- 5.8 nmol l (P less than 0.01 compared with normals). Increased plasma dopa concentrations were measured in the newly diagnosed infants (35.4 +/- 16.9 nmol l-1). Renal dopa clearance was the same in cystic fibrosis (9.26 +/- 5.71 ml min-1 1.73 m-2) and controls (10.87 +/- 2.46 ml min-1 1.73 m-2). A concomitant elevation of metabolic products as dopamine and noradrenaline in plasma and urine was noticed. These data are consistent with a dopa abnormality in this genetic disease.


Glyco-Decipher enables glycan database-independent peptide matching and in-depth characterization of site-specific N-glycosylation.
Glycopeptides with unusual glycans or poor peptide backbone fragmentation in tandem mass spectrometry are unaccounted for in typical site-specific glycoproteomics analysis and thus remain unidentified. Here, we develop a glycoproteomics tool, Glyco-Decipher, to address these issues. Glyco-Decipher conducts glycan database-independent peptide matching and exploits the fragmentation pattern of shared peptide backbones in glycopeptides to improve the spectrum interpretation. We benchmark Glyco-Decipher on several large-scale datasets, demonstrating that it identifies more peptide-spectrum matches than Byonic, MSFragger-Glyco, StrucGP and pGlyco 3.0, with a 33.5%-178.5% increase in the number of identified glycopeptide spectra. The database-independent and unbiased profiling of attached glycans enables the discovery of 164 modified glycans in mouse tissues, including glycans with chemical or biological modifications. By enabling in-depth characterization of site-specific protein glycosylation, Glyco-Decipher is a promising tool for advancing glycoproteomics analysis in biological research.


Pneumocystis: immune recognition and evasion.
Pulmonary infection caused by the opportunistic fungal organism Pneumocystis continues to be a leading AIDS defining illness. The initiation of highly active antiretroviral therapy (HAART) in the HIV-infected population has led to a significant reduction in the incidence of Pneumocystis pneumonia (PCP), although recent trends suggest the incidence has plateaued rather than decreased. Host defense against Pneumocystis involves a delicate, concerted balance between the inflammatory response and immune-mediated clearance. Innate cellular immunity is a cornerstone in this response as it provides the initial recognition event that precipitates an immune response, ultimately leading to clearance of the organism from the host. This review will focus on carbohydrate moieties found in the Pneumocystis cell wall and the immune events that occur following their recognition.


Subacute static magnetic field exposure in rat induces a pseudoanemia status with increase in MCT4 and Glut4 proteins in glycolytic muscle.
The purpose of this study was to investigate the effect of subacute exposure to static magnetic fields (SMF) on hematological and muscle biochemical parameters in rats. Male Wistar rats, daily exposed to SMF, were exposed to SMF (128 mT, 1 h/day) during 15 consecutive days. SMF-exposed rats showed a significant decrease in red blood cell (RBC) count, hemoglobin (Hb), and hematocrit (Ht) values compared to sham-exposed rats (p < 0.05). Concomitant decreases of plasma iron level against increase in transferrin amount were also observed after SMF exposure (p < 0.0.05). In postprandial condition, SMF-exposed rats presented higher plasma lactate (p < 0.01). Additionally, SMF exposure increased monocarboxylate transporters (MCT4) and glucose transporter 4 (Glut4)'s contents only in glycolytic muscle (p < 0.05). SMF exposure induced alteration of hematological parameters; importantly, we noticed a pseudoanemia status, which seems to affect tissue oxygen delivery. Additionally, SMF exposure seems to favor the extrusion of lactate from the cell to the blood compartment. Given that, these arguments advocate for an adaptive response to a hypoxia status following SMF exposure.


Redox-Triggered α-C-H Functionalization of Pyrrolidines: Synthesis of Unsymmetrically 2,5-Disubstituted Pyrrolidines.
By using o-benzoquinone as an internal oxidant, the regio- and diastereoselective functionalization of the secondary over the tertiary α-C-H bond of 2-substituted pyrrolidines is first realized. Subsequent intermolecular addition of a nucleophile to the generated N,O-acetal and cleavage of the aromatic substituent leads to 2,5-disubstituted pyrrolidines.


Expansion in the latitudinal distribution of Rhipicephalus sanguineus sensu stricto (Acari: Ixodidae) to southern Chile.
Rhipicephalus sanguineus is a species complex with a challenging diagnosis. There are two main lineages: a temperate lineage-now recognized as R. sanguineus sensu stricto (s.s.)-and a tropical lineage. In the Americas, several studies examined the distribution of both lineages. Meanwhile, in Chile, the distribution of the tropical lineage was reported from 18° to 22° S and R. sanguineus s.s. from 20° to 33° S; the morphological diagnosis located R. sanguineus in south-central Chile. In this study, we assessed the morphological and genetic identity of ticks collected from 47 dogs in southern Chile. Six dogs (12.8%) were parasitized by ticks that were morphologically and genetically assigned to R. sanguineus s.s. This finding would represent the southernmost record of this species in the country, located at over 308 km further south than the previous record, suggesting a latitudinal expansion of its distribution. Experimental studies are further required to understand how this tick survives extreme weather conditions when compared to other R. sanguineus s.s. from lesser latitudes.


Single-walled carbon nanotube: One specific inhibitor of cancer stem cells in osteosarcoma upon downregulation of the TGFβ1 signaling.
Cancer stem cells (CSCs) are believed to have a critical role in tumorigenesis, metastasis, therapeutic resistance or recurrence. Therefore, strategies designed to specifically target and eliminate CSCs have become one of the most promising and desirable ways for tumor treatment. Osteosarcoma stem cells (OSCs), the CSCs in osteosarcoma (OS), are critically associated with OS progression. Here, we show that single-walled carbon nanotubes (SWCNTs), including unmodified SWCNT (SWCNT-Raw) and SWCNT-COOH, have the ability to specifically inhibit the process of TGFβ1-induced OS cells dedifferentiation, prevent the stem cell phenotypes acquisition in OS cells and reduce the OSC viability under conditions which mimic the OS microenvironment. Concurrently, SWCNT treatment significantly down-regulates the expression of OSC markers in OS, and markedly reduces the tumor microvessel density and tumor growth. Furthermore, we found that SWCNT could suppress the TGFβ1-induced activation of TGFβ type I receptor and downstream signaling, which are key for the OSC formation and maintenance. Our results reveal an unexpected function of SWCNT in negative modulation of OSCs, and provide significant implications for the potential CSCs-targeted therapeutic applications of SWCNT.


Epstein-barr virus-induced cap formation in human lymphoblastoid cells.
Redistribution and consequent cap formation of Epstein-Barr virus adsorbed to human lymphoblastoid cells were studied by indirect membrane immunofluorescence carried out at 0 degrees C. When EBV was adsorbed on cells at 0 degrees C, the cell surface fluorescence had a mostly r-ng-like pattern. However, the ring cells could be transformed into cap cells when warmed at 37 degrees C. This cap formation could be induced by EBV alone without participation of antibodies involved in the immunofluorescence procedure. The cap formation was temperature- and pH-dependent, and was reversibly inhibited by sodium azide or some sugars. Thus the EBV-induced cap formation was analogous to that induced by antibodies or ligands on other lymphoid cells.


Economic impact of ovarian stimulation with corifollitropin alfa versus conventional daily gonadotropins in oocyte donors: a randomized study.
Assisted reproductive technologies are well-established treatments for many types of subfertility representing substantial economic and healthcare implications for patients, healthcare providers and society as a whole. In order to optimize outcomes according to the type of gonadotrophins within an oocyte donor programme, we performed an economic evaluation based on data collected in a multicentre, prospective, randomized study within three private clinics belonging to the IVI Group. Results showed no relevant between-group differences in the clinical variables. According to the economic analysis, ovarian stimulation with corifollitropin alfa increased the overall cost of the treatment as well as the cost per retrieved and effective oocyte, although the differences were not statistically significant. In conclusion, cost savings can be achieved using cheaper gonadotrophins during ovarian stimulation. The cost of corifollitropin alfa compared with recombinant FSH and highly purified human menopausal gonadotrophin should be considered when making treatment decisions.


Evaluation of pharmaceutical pictograms by older "turkers": A cross-sectional crowdsourced study.
Well-designed pharmaceutical pictograms may improve patients' understanding of medication instructions. However, the iterative participatory design process required to produce effective pictograms can be costly in terms of money, time, and effort. Crowdsourcing has been applied to bring down the costs of the participatory design process, but the feasibility of using this approach with older adults remains largely unknown. To evaluate the feasibility of using Amazon Mechanical Turk (MTurk), a leading crowdsourcing platform, for participatory pictogram evaluation with older adults (55+) and to evaluate the comprehensibility of USP pictogram, identify common misinterpretations, and explore the relationship between selected participant characteristics and their pictogram comprehension performance. 108 older adults (56.5% female; 57-80 years of age) were recruited via MTurk to complete a cross-sectional online survey that asked them to interpret 15 USP pictograms and answer questions about their health and health literacy. It was feasible to perform pictogram evaluation with older adults on MTurk, as shown by ease of recruitment and high data quality. Of the 15 pictograms tested, seven (46.7%) resulted in a comprehensibility score below the threshold established by the American National Standards Institute (ANSI), eight (53.3%) elicited common misinterpretations, and two (13.3%) resulted in ANSI-defined "critical confusion." Age (P = 0.04) was associated with pictogram comprehension performance. Certain issues with the pictogram subtitles emerged during the evaluation. MTurk is a feasible platform for participatory pictogram evaluation, even for a sole target of older adults. The USP should develop a pictogram user manual, redesign pictograms confusing to older adults, and establish policies and procedures to ensure that pictogram subtitles conform to evidence-based best practices and standards for patient-centered written drug information.


HSF1 inhibition attenuates HIV-1 latency reversal mediated by several candidate LRAs In Vitro and Ex Vivo.
HIV-1 latency is a major barrier to cure. Identification of small molecules that destabilize latency and allow immune clearance of infected cells could lead to treatment-free remission. In vitro models of HIV-1 latency involving cell lines or primary cells have been developed for characterization of HIV-1 latency and high-throughput screening for latency-reversing agents (LRAs). We have shown that the majority of LRAs identified to date are relatively ineffective in cells from infected individuals despite activity in model systems. We show here that, for diverse LRAs, latency reversal observed in model systems involves a heat shock factor 1 (HSF1)-mediated stress pathway. Small-molecule inhibition of HSF1 attenuated HIV-1 latency reversal by histone deactylase inhibitors, protein kinase C agonists, and proteasome inhibitors without interfering with the known mechanism of action of these LRAs. However, latency reversal by second mitochondria-derived activator of caspase (SMAC) mimetics was not affected by inhibition of HSF1. In cells from infected individuals, inhibition of HSF1 attenuated latency reversal by phorbol ester+ionomycin but not by anti-CD3+anti-CD28. HSF1 promotes elongation of HIV-1 RNA by recruiting P-TEFb to the HIV-1 long terminal repeat (LTR), and we show that inhibition of HSF1 attenuates the formation of elongated HIV-1 transcripts. We demonstrate that in vitro models of latency have higher levels of the P-TEFb subunit cyclin T1 than primary cells, which may explain why many LRAs are functional in model systems but relatively ineffective in primary cells. Together, these studies provide insights into why particular LRA combinations are effective in reversing latency in cells from infected individuals.


Expansion of SAR studies on triaryl bis sulfone cannabinoid CB2 receptor ligands.
We report further expansion of the structure activity relationship (SAR) on the triaryl bis sulfone class of compounds (I), which are potent CB(2) receptor ligands with excellent selectivity over the CB(1) receptor. This study was extended to B ring changes, followed by simultaneous optimization of the A-, B-, and C-rings. Compound 42 has excellent CB(2) potency, selectivity and rat exposure.


Hydrogen-plasma-induced magnetocrystalline anisotropy ordering in self-assembled magnetic nanoparticle monolayers.
Self-assembled two-dimensional arrays of either 14 nm hcp-Co or 6 nm ε-Co particle components were treated by hydrogen plasma for various exposure times. A change of hysteretic sample behavior depending on the treatment duration is reported, which can be divided in two time scales: oxygen reduction increases the particle magnetization during the first 20 min, which is followed by an alteration of the magnetic response shape. The latter depends on the respective particle species. Based on the Landau-Lifshitz equations for a discrete set of magnetic moments, we propose a model that relates the change of the hysteresis loops to a dipole-driven ordering of the magnetocrystalline easy axes within the particle plane due to the high spatial aspect ratio of the system.


Cooperating, congenital neutropenia-associated Csf3r and Runx1 mutations activate pro-inflammatory signaling and inhibit myeloid differentiation of mouse HSPCs.
Patients with the pre-leukemia bone marrow failure syndrome called severe congenital neutropenia (CN) have an approximately 15% risk of developing acute myeloid leukemia (AML; called here CN/AML). Most CN/AML patients co-acquire CSF3R and RUNX1 mutations, which play cooperative roles in the development of AML. To establish an in vitro model of leukemogenesis, we utilized bone marrow lin- cells from transgenic C57BL/6-d715 Csf3r mice expressing a CN patient-mimicking truncated CSF3R mutation. We transduced these cells with vectors encoding RUNX1 wild type (WT) or RUNX1 mutant proteins carrying the R139G or R174L mutations. Cells transduced with these RUNX1 mutants showed diminished in vitro myeloid differentiation and elevated replating capacity, compared with those expressing WT RUNX1. mRNA expression analysis showed that cells transduced with the RUNX1 mutants exhibited hyperactivation of inflammatory signaling and innate immunity pathways, including IL-6, TLR, NF-kappaB, IFN, and TREM1 signaling. These data suggest that the expression of mutated RUNX1 in a CSF3R-mutated background may activate the pro-inflammatory cell state and inhibit myeloid differentiation.


5-iodo-2-pyrimidinone-2'-deoxyribose-mediated cytotoxicity and radiosensitization in U87 human glioblastoma xenografts.
5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is a novel orally administered (p.o.) prodrug of 5-iododeoxyuridine. Because p.o. IPdR is being considered for clinical testing as a radiosensitizer in patients with high-grade gliomas, we performed this in vivo study of IPdR-mediated cytotoxicity and radiosensitization in a human glioblastoma xenograft model, U87. Groups of 8 or 9 athymic male nude mice (6-8 weeks old) were implanted with s.c. U87 xenograft tumors (4 x 10(6) cells) and then randomized to 10 treatment groups receiving increasing doses of p.o. IPdR (0, 100, 250, 500, and 1000 mg/kg/d) administered once daily (q.d.) x 14 days with or without radiotherapy (RT) (0 or 2 Gy/d x 4 days) on days 11-14 of IPdR treatment. Systemic toxicity was determined by body weight measurements during and after IPdR treatment. Tumor response was assessed by changes in tumor volumes. IPdR alone at doses of > or =500 mg/kg/d resulted in moderate inhibition of tumor growth. The combination of IPdR plus RT resulted in a significant IPdR dose-dependent tumor growth delay, with the maximum radiosensitization using > or =500 mg/kg/d. IPdR doses of 500 and 1000 mg/kg/d resulted in transient 5-15% body weight loss during treatment. In U87 human glioblastoma s.c. xenografts, p.o. IPdR given q.d. x 14 days and RT given 2 Gy/d x 4 days (days 11-14 of IPdR treatment) results in a significant tumor growth delay in an IPdR dose-dependent pattern. The use of p.o. IPdR plus RT holds promise for Phase I/II testing in patients with high-grade gliomas.


Traumatic hemorrhage of the thyroid as a work-related injury: a case report and review of the literature.
Traumatic hemorrhage of the thyroid gland resulting from blunt injury to the neck is a very rare event. Particular neck positions can expose the thyroid to trauma, especially in motor vehicle collisions, falls, direct blows, or sport activities. Preexisting conditions such as goiters, adenomas, and cysts can increase the risk of bleeding, reducing the force required to rupture the gland and make the thyroid more prone to injury. The authors report the case of a 53-year-old man who was involved in a fire while working on maintenance of a liquid petroleum gas (LPG)-powered car. He subsequently presented to the emergency department with painful swelling of his right anterior neck with a palpable mass. CT scan showed a right thyroid hemorrhagic cyst. The worker reported that he had jumped into the car trunk to extinguish the fire and covered the gas tank nozzle with his own body to prevent dispersal of the accelerant. In this case, the medico-legal evaluation was useful to delineate between natural and traumatic causes of the injury. Medico-legal assessment is key in understanding the dynamics involved in work-related events to identify any legal responsibilities of the worker or the employer.


Enhanced Cellular Transduction of Nanoparticles Resistant to Rapidly Forming Plasma Protein Coronas.
Nanoparticles (NPs) are increasingly being developed as biomedical platforms for drug/nucleic acid delivery and imaging. However, in biological fluids, NPs interact with a wide range of proteins that form a coating known as protein corona. Coronae can critically influence self-interaction and binding of other molecules, which can affect toxicity, promote cell activation, and inhibit general or specific cellular uptake. Glycosaminoglycan (GAG)-binding enhanced transduction (GET) is developed to efficiently deliver a variety of cargoes intracellularly; employing GAG-binding peptides, which promote cell targeting, and cell penetrating peptides (CPPs) which enhance endocytotic cell internalization. Herein, it is demonstrated that GET peptide coatings can mediate sustained intracellular transduction of magnetic NPs (MNPs), even in the presence of serum or plasma. NP colloidal stability, physicochemical properties, toxicity and cellular uptake are investigated. Using label-free snapshot proteomics, time-resolved profiles of human plasma coronas formed on functionalized GET-MNPs demonstrate that coronae quickly form (<1 min), with their composition relatively stable but evolving. Importantly GET-MNPs present a subtly different corona composition to MNPs alone, consistent with GAG-binding activities. Understanding how NPs interact with biological systems and can retain enhanced intracellular transduction will facilitate novel drug delivery approaches for cell-type specific targeting of new nanomaterials.


Simultaneous bilateral tubal pregnancy after in vitro fertilization and embryo transfer.
Ectopic pregnancies are known to occur with increased frequency after in vitro fertilization (IVF) and related techniques. We present a case of bilateral tubal pregnancy following IVF and embryo transfer (ET). A 27-year-old woman was referred to our IVF clinic because of primary infertility, and underwent three cycles of IVF-intracytoplasmic sperm injection treatment. In her third cycle, 32 days after ET, she suffered from pelvic pain and vaginal bleeding. Transvaginal ultrasonography revealed bilateral tubal ectopic pregnancy with fluid in the pouch of Douglas but no intrauterine gestational sac. One of the embryos had fetal heart motion. Laparoscopic bilateral salpingostomy was performed immediately. The postoperative course was uneventful. Pathologic examination also identified chorionic villi and placental tissue in both tubes, and an Arias-Stella reaction without villi in the endometrium. The diagnosis of ectopic or heterotopic pregnancy should always be considered in patients undergoing IVF-ET because of its increased incidence with this technique compared with natural conception. Although the incidence of bilateral tubal pregnancy is not high, sonographers and surgeons should examine both adnexa when diagnosing an ectopic pregnancy, especially in IVF-ET patients. Early diagnosis is essential for the prevention of significant maternal morbidity and mortality.


Multi-analyte capillary immunosensor for the determination of hormones in human serum samples.
In this work we present the development of a multi-analyte immunosensor for the determination of follitropin, human chorionic gonadotropin and prolactin in human serum. The immunosensor is based on plastic capillaries. According to the methodology, discrete areas of the internal capillary surface are coated with different antibodies, which are highly specific for each one of the analytes to be determined. The sample that will be analyzed along with a mixture of analyte-specific biotinylated antibodies is introduced into the capillary. The coated and the detection antibodies react with different epitopes of the analytes in the sample to form a 'sandwich'. The detection is based on reaction of the immobilized biotinylated antibody with streptavidin labeled with R-phycoerythrin. The fluorescent areas formed were quantified by scanning the capillary with a light beam of appropriate wavelength. A light sensor placed at the end of the capillary detects the emitted photons, that are trapped and waveguided into the capillary walls. The multi-analyte immunosensor assays were characterized by high specificity and short analysis time. In addition, the results obtained by the multi-analyte optical capillary immunosensor were comparable to those obtained by immunofluorimetric assays performed in microtitration wells. Potential applications of the proposed immunosensor include determination of several analyte panels in a broad spectrum of disciplines such as endocrinology, hematology, and oncology.


[Analysis of a group of HIV positive women who gave birth in the Czech Republic].
An analysis of HIV positive women who gave birth between 1st January 1985 to 31st December 2006 in the Czech Republic. A retrospective descriptive analysis. Teaching Hospital Bulovka, 1st Faculty of Medicine, Charles University, Prague. The study included HIV positive women that gave birth between 1st January 1985 to 31st December 2006 at Bulovka hospital. The group of 62 HIV positive women (including 7 secundiparae) gave birth to 71 new-borns (twice twins). The deliveries were performed by C-section. We interrupted breast-feeding by all these women. All new-borns were born alive, no one had Apgar score less than 7 at five minutes. No congenital disorders were found. Three new-borns were transfered to Intensive care unit for new-born babies, two due to dysmaturity and one due to abstinence syndrome. 3 new-borns out of total 71 new-borns were HIV positive (4.2%). Routine prenatal screening for HIV and high-quality cooperation between obstetricians and infection control doctors are the basic condition of low rate of vertical trasmission HIV infection in the Czech Republic.


Impacts of Medicaid Expansion on Health Insurance and Coverage Transitions among Women with or at Risk for HIV in the United States.
As employment, financial status, and residential location change, people can gain, lose, or switch health insurance coverage, which may affect care access and health. Among Women's Interagency HIV Study participants with HIV and participants at risk for HIV attending semiannual visits at 10 U.S. sites, we examined whether the prevalence of coverage types and rates of coverage changes differed by HIV status and Medicaid expansion in their states of residence. Geocoded addresses were merged with dates of Medicaid expansion to indicate, at each visit, whether women lived in Medicaid expansion states. Age-adjusted rate ratios (RRs) and rate differences of self-reported insurance changes were estimated by Poisson regression. From 2008 to 2018, 3,341 women (67% Black, 71% with HIV) contributed 43,329 visits at aged less than 65 years (27% under Medicaid expansion). Women with and women without HIV differed in their proportions of visits at which no coverage (14% vs. 19%; p < .001) and Medicaid enrollment (61% vs. 51%; p < .001) were reported. Women in Medicaid expansion states reported no coverage and Medicaid enrollment at 4% and 69% of visits, respectively, compared with 20% and 53% of visits for those in nonexpansion states. Women with HIV had a lower rate of losing coverage than those without HIV (RR, 0.81; 95% confidence interval [CI], 0.70 to 0.95). Compared with nonexpansion, Medicaid expansion was associated with lower coverage loss (RR, 0.62; 95% CI, 0.53 to 0.72) and greater coverage gain (RR, 2.32; 95% CI, 2.02 to 2.67), with no differences by HIV status. Both women with HIV and women at high risk for HIV in Medicaid expansion states had lower coverage loss and greater coverage gain; therefore, Medicaid expansion throughout the United States should be expected to stabilize insurance for women and improve downstream health outcomes.


Reduction in prime volume attenuates the hyperdynamic response after cardiopulmonary bypass.
A hyperdynamic response to cardiopulmonary bypass is characteristically observed in the post-operative course. To determine the effect of prime volume on the hemodynamic response, a database study was performed on patients who underwent elective coronary artery bypass grafting with an extracorporeal circuit with either a large prime volume (2,350-mL prime, n = 20) or a small prime volume (1,400-mL prime, n = 20). Measurements were carried out at fixed time points before and after cardiopulmonary bypass (until 18 hours postoperatively) and include hematocrit, colloid oncotic pressure, fluid balance, and hemodynamic profile (mean of three measurements). The lower colloid oncotic pressure in the large prime group (16.2 +/- 0.6 mm Hg versus 19.1 +/- 1.1 mm Hg, p = 0.0002) was associated with a highly positive fluid balance (5.5 +/- 0.9 L versus 2.8 +/- 0.7 L, p = 0.0001). With the on-bypass hematocrit aimed at 22% to 23%, autologous blood was predonated by 16 patients in the small prime group but by none in the large prime group. Reinfusion of autologous blood resulted in a reduction in blood bank requirements (p = 0.03). Mean arterial pressure was 83 +/- 4 mm Hg for small prime versus 76 +/- 4 mm Hg for large prime (p = 0.01). Cardiac index was 2.9 +/- 0.2 L.min-1.m-2 for small prime versus 3.8 +/- 0.3 L.min-1.m-2 for large prime (p = 0.0001). Pulmonary vascular resistance index was 281 +/- 40 dyne.s.cm5.m-2 for small prime versus 188 +/- 22 dyne.s.cm5.m-2 for large prime (p = 0.0009). Oxygen delivery was 42 +/- 5 mL.min-1.m-2 for small prime versus 51 +/- 3 mL.min-1.m-2 for large prime (p = 0.004). Vasoactive medication was not different among groups. Reduction in prime volume attenuates the hyperdynamic response after cardiopulmonary bypass. Furthermore, an important reduction in blood bank products can be obtained with small prime volumes.


Plasma gonadotropins and androgens in surgically treated cryptorchid patients.
Plasma LH, FSH, and total 17betaOH androgen levels were measured in a group of 40 adult patients who underwent orchiopexy for either unilateral or bilateral cryptorchism during childhood. Gonadotropin abnormalities were found in 15 of 40 patients and thereby appeared to be a much more sensitive indicator of testicular malfunction than the androgens which were abnormal in only four patients. In the postpubertal phase, the estimation of gonadotropins and androgens appeared valuable, first, as an additional help in the prognosis of fertility, where combined raised levels of LH and FSH were found to indicate a poor prognosis; second, to detect in infertile patients gonadotropin deficiency which, if previously missed, can still be expected to respond to gonadotropin therapy; third, for the detection of the subclinically hypogonad group who may require follow-up, and finally for the detection of the low-androgen group who may require some form of hormonal therapy. As several patients in this study were found to have low gonadotropins, it is postulated that low levels of gonadotropin may play a role in the production of cryptorchism. The finding of high gonadotropin levels in another group may indicate a feedback mechanism sensitive to a damaged testis, but alternatively it is possible that there might be a primary resistance to the action of gonadotropins and it is postulated that such a resistance may be an additional factor of the causation of cryptorchism in some cases.


The Impact of Language Discordance on Patients' Perception of a Clinical Encounter and Trust in Provider.
The impact of language discordance on care for Spanish-speaking patients with pelvic floor disorders is unknown. The aim of this study was to compare the impact of language concordance with the impact of language discordance on the patient experience and trust in their provider. This cross-sectional cohort study enrolled English- and Spanish-speaking patients during initial evaluation in a urogynecology clinic. English- and Spanish-speaking patients seen by native English- or Spanish-speaking providers were recruited to the language-concordant group. The language-discordant group included Spanish-speaking patients seen with a translator or by nonnative Spanish-speaking providers. Patients completed the Trust in Physician Scale and the Consumer Assessment of Healthcare Providers and Systems Clinician and Group Survey (CG-CAHPS). Patients and providers rated the provider's Spanish proficiency on a 10-point scale from 0 (low) to 10 (high). Symptom bother questionnaires were completed 4-6 months after enrollment. Eighty women were recruited, with 40 in each group. Mean age was 55.4 ± 12.9 years. The majority identified as White (75%) and Hispanic (77.5%). Trust in Physician Scale scores were similar between groups (46.2 ± 8.5 vs 44.4 ± 7.5, P > 0.05). The provider communication, provider rating, and recommendation domains of the CG-CAHPS did not differ between groups (all P > 0.05). Provider self-rating of Spanish proficiency was lower than patient ratings (7.5 ± 1.8 vs 9.8 ± 0.5, P < 0.001). There was no difference between groups in symptom bother at 4-6 months (all P > 0.05). Patient-provider language discordance does not affect patient trust in the provider or perception of the encounter as measured by the Trust in Physician Scale and CG-CAHPS questionnaires.


Syntheses of 6,7-Benzotropolones by a Sequence of Acylation (or α-Hydroxyalkylation/Oxidation), Ring-Closing Metathesis, and Hydrolysis/β-Elimination.
Starting from ortho-bromostyrenes, 12 6,7-benzotropolones were synthesized in 3 or 4 steps. Br/Li exchanges provided the respective ortho-lithiostyrenes. The latter were acylated by a Weinreb amide, if unhindered, or hydroxyalkylated by an aldehyde, if hindered (an oxidation ensuing thereafter). Acetonide-containing benzannulated nonatrienones resulted. Ring-closing olefin metatheses converted them into acetonide-containing benzocycloheptadienones. Treatment with aq. HCl caused hydrolyses followed by β-elimination reactions giving 6,7-benzotropolones.


Semaphorin3A released from human dental pulp cells inhibits the increase in interleukin-6 and CXC chemokine ligand 10 production induced by tumor necrosis factor-α through suppression of nuclear factor-κB activation.
Human dental pulp cells (HDPCs) play an important role in pulpitis. Semaphorin3A (Sema3A), which is an axon guidance molecule, is a member of the secretory semaphorin family. Recently, Sema3A has been reported to be an osteoprotective factor and to be involved in the immune response. However, the role of Sema3A in dental pulp inflammation remains unknown. The aim of this study was to reveal the existence of Sema3A in human dental pulp tissue and the effect of Sema3A which is released from tumor necrosis factor (TNF)-α-stimulated HDPCs on production of proinflammatory cytokines, such as interleukin (IL)-6 and CXC chemokine ligand 10 (CXCL10), from HDPCs stimulated with TNF-α. Sema3A was detected in inflamed pulp as compared to normal pulp. HDPCs expressed Neuropilin-1(Nrp1) which is Sema3A receptor. TNF-α increased the levels of IL-6 and CXCL10 in HDPCs in time-dependent manner. Sema3A inhibited production of these two cytokines from TNF-α-stimulated HDPCs. TNF-α induced soluble Sema3A production from HDPCs. Moreover, antibody-based neutralization of Sema3A further promoted production of IL-6 and CXCL10 from TNF-α-stimulated HDPCs. Sema3A inhibited nuclear factor (NF)-κB P65 phosphorylation and inhibitor κBα degradation in TNF-α-stimulated HDPCs. These results indicated that Sema3A is induced in human dental pulp, and TNF-α acts on HDPCs to produce Sema3A, which partially inhibits the increase in IL-6 and CXCL10 production induced by TNF-α, and that the inhibition leads to suppression of NF-κB activation. Therefore, it is suggested that Sema3A may regulate inflammation in dental pulp and be novel antiinflammatory target molecule for pulpitis.


Transoropharyngeal closed reduction for traumatic atlantoaxial dislocation: a novel technique for fast and precise reduction.
The aim of this study is to introduce a new technique for the rapid and accurate reduction of traumatic atlantoaxial dislocation (TAAD) and to investigate its radiological and clinical outcomes. The clinical outcomes of 18 patients who were diagnosed with acute TAAD and underwent rapid transoropharyngeal closed reduction in our hospital were retrospectively analyzed from January 2015 to December 2020. Following general anaesthesia, all patients were immediately treated with oropharyngeal reduction under somatosensory evoked potential monitoring. The Japanese Orthopedic Association score, neck disability index and visual analog scale score for neck pain were used to evaluate clinical efficacy. Atlantodental distance, posterior atlantodental interval, and the clivus-canal angle were used to assess reduction and spinal cord compression. The mean follow-up time was 23.3 months, with a range of 13-38 months. No neurovascular injury occurred during the operations. For all patients, the closed reduction method through the oropharynx under general anaesthesia was successful, and the success rate of reduction was 100%. All patients recovered uneventfully with marked improvement in clinical outcomes and imaging parameters (P < 0.01). Two patients developed mild postoperative dysphagia. One patient developed postoperative fever and pulmonary infection. Rapid trans-oropharyngeal closed reduction can safely, effectively, and rapidly reduce acute TAAD. This method provides a new strategy for treatment of the condition.


Oxytetracycline-induced oxidative liver damage by disturbed mitochondrial dynamics and impaired enzyme antioxidants in largemouth bass (Micropterus salmoides).
Oxytetracycline (OTC), a commonly used tetracycline antibiotic in aquaculture, has been found to cause significant damage to the liver of largemouth bass (Micropterus salmoides). This study revealed that OTC can lead to severe histopathological damage, structural changes at the cellular level, and increased levels of reactive oxygen species (ROS) in M. salmoides. Meanwhile, OTC impairs the activities of antioxidant enzyme (such as T-SOD, CAT, GST, GR) by suppressing the activation of MAPK/Nrf2 pathway. OTC disrupts mitochondrial dynamics and mitophagy through via PINK1/Parkin pathway. The accumulation of damaged mitochondria, combined with the inhibition of the antioxidant enzyme system, contributes to elevated ROS levels and oxidative liver damage in M. salmoides. Further investigations demonstrated that an enzyme-treated soy protein (ETSP) dietary supplement can help maintain mitochondrial dynamic balance by inhibiting the PINK1/Parkin pathway and activate the MAPK/Nrf2 pathway to counteract oxidative damage. In summary, these findings highlight that exposure to OTC disrupts mitochondrial dynamics and inhibits the antioxidant enzyme system, ultimately exacerbating oxidative liver damage in M. salmoides. We propose the use of a dietary supplement as a preventive measure against OTC-related side effects, providing valuable insights into the mechanisms of antibiotic toxicity in aquatic environments.


Characterization of the dose-concentration-dependent hemodynamic effects of nifedipine in heart failure.
The hemodynamic effects of increasing oral doses of nifedipine (10 to 30 mg) were studied in 12 patients who had low output heart failure. With each set of hemodynamics, serum concentrations of nifedipine were measured to determine the concentration/response relationships. Eleven of twelve patients responded acutely to nifedipine, defined as a reduction in systemic vascular resistance (SVR), and an augmentation in cardiac index (CI) and stroke volume index (SVI). The differential dose effects (X +/- SD) for SVR and SVI for baseline (N = 11), 10 mg (N = 10), 20 mg (N = 3) and 30 mg (N = 4) were: 1913 +/- 486, 1102 +/- 221, 1128 +/- 166, 803 +/- 176 and 17.9 +/- 4.8, 23.8 +/- 4.5, 31 +/- 0.42, 33 +/- 3.5, respectively. All nifedipine doses reduced SVR and increased CI and SVI compared with baseline (P less than .001). The increase in CI and SVI was significantly correlated to the mg/kg dose of nifedipine (r = 0.79; P less than .001). Nifedipine administration resulted in no significant change in central venous pressure, pulmonary capillary wedge pressure, or pulmonary vascular resistance. No relationship could be demonstrated between serum concentrations of nifedipine and any hemodynamic effect. Conclusions drawn were: (1) the afterload reduction effects of nifedipine are acutely efficacious in a large portion of patients with heart failure and this activity supercedes the negative inotropic effects of the drug at doses between 10 and 30 mg; (2) the magnitude of the hemodynamic effects are dose dependent.(ABSTRACT TRUNCATED AT 250 WORDS)


The effects of four different suture materials on penile tissue of rats.
Several types of suture materials are being used for the correction of penile curvature and this study was designed to compare histopathological changes on penile tissue among different suture materials. A total of 30 male Sprague-Dawley rats were divided into five groups and right cavernosal body was sutured with 5/0 sutures (ETB: polyethylene terephthalate; PRL: polypropylene; VCR: polyglactine; and PDS: polydioxanone). An identical needle (3/8-13 mm cutting) was passed through the cavernosal bodies in the sham group (SHAM). After 3 weeks, all rats were killed and penile tissues were examined to assess the level (0-3) of inflammation, granuloma formation and fibrosis. There was a statistically significant difference among five groups regarding inflammation, granuloma formation and fibrosis levels (P<0.01 for all). The histological changes in the PRL group were not different from the SHAM group. Although the levels of granulation and fibrosis in the PDS group were also similar to the SHAM group, inflammation level was significantly higher. The inflammation, granulation and fibrosis levels were the highest in the ETB group. VCR caused similar levels of granulation and fibrosis to ETB. In conclusion, PRL suture is associated with the least histopathological change in the penile tissue. PDS can theoretically be a reasonable alternative to PRL as it causes similar levels of granulation and fibrosis.


Advanced type 1 diabetes is associated with ASIC alterations in mouse lower thoracic dorsal root ganglia neurons.
Acid-sensing ion channels (ASICs) from dorsal root ganglia (DRG) neurons are proton sensors during ischemia and inflammation. Little is known about their role in type 1 diabetes (T1D). Our study was focused on ASICs alterations determined by advanced T1D status. Primary neuronal cultures were obtained from lower (T9-T12) thoracic DRG neurons from Balb/c and TCR-HA(+/-)/Ins-HA(+/-) diabetic male mice (16 weeks of age). Patch-clamp recordings indicate a change in the number of small DRG neurons presenting different ASIC-type currents. Multiple molecular sites of ASICs are distinctly affected in T1D, probably due to particular steric constraints for glycans accessibility to the active site: (i) ASIC1 current inactivates faster, while ASIC2 is slower; (ii) PcTx1 partly reverts diabetes effects against ASIC1- and ASIC2-inactivations; (iii) APETx2 maintains unaltered potency against ASIC3 current amplitude, but slows ASIC3 inactivation. Immunofluorescence indicates opposite regulation of different ASIC transcripts while qRT-PCR shows that ASIC mRNA ranking (ASIC2 > ASIC1 > ASIC3) remains unaltered. In conclusion, our study has identified biochemical and biophysical ASIC changes in lower thoracic DRG neurons due to advanced T1D. As hypoalgesia is present in advanced T1D, ASICs alterations might be the cause or the consequence of diabetic insensate neuropathy.


[Radiation exposure and 3 dimensional imaging options of SIREMOBIL Iso-C(3D) for planning surgical dental interventions].
Preoperative dental X-ray diagnostics of multimorbid, non compliant patients requiring dental surgery are often insufficient. The SIREMOBIL Iso-C(3D) has made intraoperative 3D imaging available, even for the facial skeleton. This modality was used intraoperatively in two patients referred for surgical dental treatment. Furthermore, radiation exposure of the SIREMOBIL Iso-C(3D), an orthopantomography and a complete dental status was compared. An Alderson-Rando phantom was exposed to ten cycles of the SIREMOBIL Iso-C(3D) using the fast mode (50 projections). In comparison 28 panoramic views of an Orthophos and 10 sets of 14 dental images using the Oralix DC with a quadrate mask were applied. Twenty-five anatomically defined TLD positions were analyzed. Furthermore, SIREMOBIL Iso-C(3D) was used in one patient by performing 100 projections and in a second patient by performing 50 projections. After DICOM-import in eFilm, axial, coronal, and sagittal reconstructions were evaluated by five examiners regarding defined criteria. The radiation exposure level of the SIREMOBIL Iso-C(3D) was lower than in the complete dental status and only slightly higher in comparison with the orthopantomography, although the system requires the highest number of single projections. Quantitative evaluation of the visualization and recognition of defined structures proved to be very good and good in most points. However, limitations of the system became obvious regarding apical processes. Because of the dosimetry results and the visualization of the relevant structures, in patients for whom preoperative images cannot sufficiently be performed, the intraoperative use of the SIREMOBIL Iso-C(3D) as a base examination is justified.


pLoc_bal-mGneg: Predict subcellular localization of Gram-negative bacterial proteins by quasi-balancing training dataset and general PseAAC.
One of the hottest topics in molecular cell biology is to determine the subcellular localization of proteins from various different organisms. This is because it is crucially important for both basic research and drug development. Recently, a predictor called "pLoc-mGneg" was developed for identifying the subcellular localization of Gram-negative bacterial proteins. Its performance is overwhelmingly better than that of the other predictors for the same purpose, particularly in dealing with multi-label systems in which some proteins, called "multiplex proteins", may simultaneously occur in two or more subcellular locations. Although it is indeed a very powerful predictor, more efforts are definitely needed to further improve it. This is because pLoc-mGneg was trained by an extremely skewed dataset in which some subset (subcellular location) was about 5 to 70 times the size of the other subsets. Accordingly, it cannot avoid the biased consequence caused by such an uneven training dataset. To alleviate such a consequence, we have developed a new and bias-reducing predictor called pLoc_bal-mGneg by quasi-balancing the training dataset. Cross-validation tests on exactly the same experiment-confirmed dataset have indicated that the proposed new predictor is remarkably superior to pLoc-mGneg, the existing state-of-the-art predictor in identifying the subcellular localization of Gram-negative bacterial proteins. To maximize the convenience for most experimental scientists, a user-friendly web-server for the new predictor has been established at http://www.jci-bioinfo.cn/pLoc_bal-mGneg/, by which users can easily get their desired results without the need to go through the detailed mathematics.


Some Japanese mothers do not follow package instructions of infant formula: a web-based analytical cross-sectional study.
Not following the infant formula package instruction endangers infant health. Although infant formula misuse has been reported abroad, its incidence in Japan remains unknown. Furthermore, it is reasonable to assume that experience in childcare reduces the likelihood of making mistakes in using infant formula. This study aimed to examine the association between compliance with infant formula package instruction and childcare experience in Tokyo and surrounding prefectures in Japan. Using a web-based questionnaire, mothers with infants were analyzed cross-sectionally and surveyed regarding their infants' nutrition and formula preparation methods in August 2021. Compliance with the infant formula package was determined according to (a) using unlabeled infant formula, (b) preparing infant formula without reading package instructions, (c) giving formula to children ≥ 2 h after preparing, and (d) adding other ingredients to the formula bottle. The association between the misuse of infant formula and childcare experience was examined by grouping the participants by infant age (< 6 months and ≥ 6 months), and by comparing first-born child status with later-born. Of the 333 mothers with infants, 3 were excluded due to out-of-scope responses, and 330 were included in the analysis. The major sources of information on infant feeding methods among the participants were obstetric facilities (92.1%), internet (36.1%), and family (20.9%). The proportions of participants using infant formulas not labeled as "infant formula," such as follow-up milk, not preparing at prescribed concentrations, feeding infant formulas > 2 h after preparation, and adding additional ingredients to the bottle were 7.9%, 4.1%, 23.1%, and 15.9%, respectively, which suggest the misuse of infant formula. These four answers did not differ significantly between mothers of children aged < 6 months and ≥ 6 months or between those with first-born and later-born children. This study suggested that some Japanese mothers do not follow package instructions of infant formula in Japan. The misuse of infant formula may not be related to the length of time spent in childcare or the presence or absence of childcare experience. Providing appropriate information on the correct use of infant formula to all caregivers, regardless of their parenting experience, is required.


Functional MRI Techniques Suggesting that the Stress System Interacts with Three Large Scale Core Brain Networks to Help Coordinate the Adaptive Response: A Systematic Review.
Synthesis of functional MRI (fMRI) and functional connectivity (FC) analysis data on human stress system (SS) function, as it relates to the dynamic function of the Salience (SN), Default Mode (DMN) and Central Executive (CEN) networks. Systematic search of Medline, Scopus, Clinical Trials.gov, and Google Scholar databases of studies published prior to September 2022 resulted in 28 full-text articles included for qualitative synthesis. Acute stress changes the states of intra-/inter- neural network FCs and activities from those of resting, low arousal state in the SN, DMN and CEN, during which intra- and inter-network FCs and activities of all three networks are low. SS activation is positively linked to the activity of the SN and negatively to that of the DMN, while, in parallel, it is associated with an initial decrease and a subsequent increase of the intra- network FC and activity of the CEN. The FC between the DMN and the CEN increases, while those between the SN and the CEN decrease, allowing time for frontal lobe strategy input and "proper" CEN activity and task decision. SN activation is linked to sensory hypersensitivity, "impaired" memory, and a switch from serial to parallel processing, while trait mindfulness is associated with FC changes promoting CEN activity and producing a "task-ready state". SS activation is tightly connected to that of the SN, with stress hormones likely potentiating the intra-network FC of the latter, attenuating that of the DMN, and causing a biphasic suppression-to-activation response of the CEN, all adaptive changes favoring proper decisions and survival.


Free-Radical Carbocyanation of Cyclopropenes: Stereocontrolled Access to All-Carbon Quaternary Stereocenters in Acyclic Systems.
Free-radical carbocyanation of cyclopropenes offers straightforward access to tetrasubstituted cyclopropanes in satisfying yields with moderate diastereoselectivity. The incorporation of various functional groups on the cyclopropane ring allows a subsequent base-mediated ring-opening reaction leading to functionalized acyclic systems having an all-carbon quaternary stereocenter.


Long-term prognosis for reconstruction of arterial lesions due to arteriosclerosis.
Out of 769 patients with arterial diseases, reconstructive surgery was performed on 100 limbs of 79 patients for arteriosclerosis. The overall patency rate was 59 per cent over a period of 3 to 8 years. Long-term patency was influenced by the condition of the run-off arteries, the site of the operation, and the method of surgery. No relation was found between patency rate and hypertension, cardiac insufficiency, total serum cholesterol, diabetes mellitus, or age. The survival rate was 62 per cent at 5 years and 48 per cent at 7 years. These rates were significantly poor (p less than 0.001), compared with those in the normal population. Mortality was related to the degree of hypertension, with cardiac and renal failure being responsible for 72 per cent of deaths. Aggressive reconstruction may be indicated in cases with hypertension of stage 2 or below based on the WHO classification. However, especially in patients with associated diabetes mellitus close long-term observation of the cardiovascular system is necessary.