Selecting appropriate endpoints for assessing treatment effects in comparative clinical studies for COVID-19.
To evaluate the efficacy and safety of a new treatment for COVID-19 vs. standard care, certain key endpoints are related to the duration of a specific event, such as hospitalization, ICU stay, or receipt of supplemental oxygen. However, since patients may die in the hospital during study follow-up, using, for example, the duration of hospitalization to assess treatment efficacy can be misleading. If the treatment tends to prolong patients' survival compared with standard care, patients in the new treatment group may spend more time in hospital. This can lead to a "survival bias" issue, where a treatment that is effective for preventing death appears to prolong an undesirable outcome. On the other hand, by using hospital-free survival time as the endpoint, we can circumvent the survival bias issue. In this article, we use reconstructed data from a recent, large clinical trial for COVID-19 to illustrate the advantages of this approach. For the analysis of ICU stay or oxygen usage, where the initiating event is potentially an outcome of treatment, standard survival analysis techniques may not be appropriate. We also discuss issues with analyzing the durations of such events.


Immunochemotherapy of transplantable Moloney leukemia with cyclophosphamide and allogeneic spleen lymphocytes and reversal of graft-versus-host disease with alloantiserum.
Histoincompatible (H-2) spleen cells from C57BL/6 mice that were sensitized with Moloney sarcoma virus caused fatal graft-versus-host disease in BALB/c mice when the cells were used in conjunction with an immunosuppressive, chemotherapeutic dose of cyclophosphamide to treat transplantable Moloney virus-induced leukemia. When antiserum against the donor spleen cells was administered 2 days after immunochemotherapy, graft-versus-host disease was prevented, but no immunotherapeutic effect was observed. When the antiserum was delayed for 3 days or more, lethal graft-versus-host disease occurred. Substitution of Moloney sarcoma virus-sensitized BALB/c X C57BL/6 F1 (hereafter called CB6F1) spleen cells for C57BL/6 cells, in conjunction with cyclophosphamide, "cured" 70% of the treated mice (accumulated value of two experiments). When anti-CB6F1 serum (alloantiserum) was administered 2 days after immunochemotherapy, the immunotherapeutic effect was abolished. Alloantiserum was not able to reverse the immunotherapeutic effect 3 days postgrafting or later, and there resulted a high percentage of long-term survivors. About two-thirds of the cured mice had positive donor-specific gamma-globulin titer 8 weeks postgrafting.


Through-the-Glass Portable Radiography of Patients in Isolation Units: Experience During the COVID-19 Pandemic.
OBJECTIVE. To reduce staff exposure to infection and maintain operational efficiency, we have developed a protocol to image patients using portable chest radiography through the glass of an isolation room. This technique is safe and easy to implement. Images are of comparable quality to standard portable radiographs. CONCLUSION. This protocol, used routinely by our department during the COVID-19 pandemic, can be applied to any situation in which the patient is placed in isolation.


Effects of prolonged physical exercise and fasting upon plasma testosterone level in rats.
Prolonged physical exercise and fasting in male rats were studied to determine the effect of these two treatments on plasma testosterone level. Blood and tissue samples were drawn after 1 h, 3 h, 5 h, and 7 h treadmill running, and after 24 h, 48 h, and 72 h of fasting. Both treatments resulted in a significant fall in plasma testosterone, plasma luteinizing hormone (LH), plasma Insulin (IRI) and in liver and muscle glycogen stores. In the course of these two treatments the injection of a supra maximal dose of Human Chorionic Gonadotropin (HCG) produced a rise in plasma testosterone similar to that in control rats. This indicates that the decrease of plasma LH may be responsible for the decrease in plasma testosterone, which is time-related with the decrease in glycogen stores. The possible metabolic role of the decrease in plasma testosterone is discussed.


Effect of complete pathological response related factors after neoadjuvant chemotherapy on skin-sparing mastectomy and breast reconstruction.
Immediate breast reconstruction after skin-sparing mastectomy in patients undergoing neoadjuvant chemotherapy is still controversial. The objective of this study is to determine factors related with axillary downstaging and complete pathological response (CPR), and how CPR influences the decision to perform bilateral mastectomy with immediate reduction. A retrospective analysis of breast cancer patients who had undergone neoadjuvant chemotherapy and bilateral mastectomy with immediate reduction between 2000-2018 was performed. Two groups were compared:1) CPR and 2) non-CPR. Descriptive and comparative statistical analyses are provided. 69 patients; 26 (37.68%) reached CPR and 43 (62.32%) non-CPR. Median follow-up of 45.3 months (IQR: 23.0-94.0). Age under 35 (p <.001), small size tumor at diagnosis (p=.006) and subtype HER2 (p <.001) were associated with higher rates of CPR in bivariate analysis. Axillary negativization rate was 80% in group 1 and 59.3% in group 2, and lymphadenectomy rates were similar (73.1% and 83.72%). CPR after neoadjuvant chemotherapy did not influence the decision to perform bilateral mastectomy with immediate reduction.


Methods of freezing cord blood hematopoietic stem cells.
Cord blood (CB) is a valuable source of hematopoietic stem cells (HSCs). Extended storage of CB is possible provided that validated cryopreservation procedures are used. The study objective was to determine optimal methods of CB cryopreservation. In the study we 1) compared the effect of two-step cryopreservation and controlled-rate freezing method on the postthaw quality of CB (Study A) and 2) evaluated the postthaw quality of HSC fractions isolated from CB with various methods and frozen with controlled-rate freezing method (Study B). The same cryoprotectant mixture was used for 20 CB units (Study A) and 122 CB units (Study B). In Study A, 13.79 × 10(8) and 13.29 × 10(8) initial white blood cell (WBC) counts decreased to 6.38 × 10(8) and 6.02 × 10(8) after thaw for the two methods, respectively. The mononuclear cell (MNC) counts decreased from 5.90 × 10(8) to 3.71 × 10(8) and from 5.64 × 10(8) to 3.47 × 10(8) dependent on the method. MNC viability decreased from 99.0% to 97.4% for the former and from 98.5% to 97.2% for the latter method. The differences were insignificant. In Study B, postthaw WBC recovery in HSC fractions was 74.4% to 103.5%, MNC recovery 106.4% to 118.5%, CD34+ cell recovery 102.5% to 150.2%, and MNC viability 94.1% to 97.4%. Neither the cryopreservation procedure nor the freezing of isolated HSCs affected product quality, which may indicate that various freezing methods can be used for cell banking provided the they follow recommendations of good manufacturing practice and Directive 2004/33/EC.


Contribution of high-content imaging technologies to the development of anti-infective drugs.
Originally developed to study fundamental aspects of cellular biology, high-content imaging (HCI) was rapidly adapted to study host-pathogen interactions at the cellular level and adopted as a technology of choice to unravel disease biology. HCI platforms allow for the visualization and quantification of discrete phenotypes that cannot be captured using classical screening approaches. A key advantage of high-content screening technologies lies in the possibility to develop and interrogate physiologically significant, predictive ex vivo disease models that reproduce complex conditions relevant for infection. Here we review and discuss recent advances in HCI technologies and chemical biology approaches that are contributing to an increased understanding of the intricate host-pathogen interrelationship on the cellular level, and which will foster the development of novel therapeutic approaches for the treatment of human bacterial and protozoan infections. © 2016 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC.


Novel activity of Rhodobacter sphaeroides spheroidene monooxygenase CrtA expressed in Escherichia coli.
The spheroidene monooxygenase CrtA of Rhodobacter sphaeroides introduces a keto group and/or hydroxy group at the ends of nonnative substrates in Escherichia coli, resulting in the production of novel oxocarotenoids. The heme-containing CrtA is not a P450 enzyme but a new type of oxygenase.


Correction: Contribution of the Cpx envelope stress system to metabolism and virulence regulation in Salmonella enterica serovar Typhimurium.
[This corrects the article DOI: 10.1371/journal.pone.0211584.].


Factors associated with healthcare utilisation during first year after cancer diagnose-a population-based study.
Improved cancer treatments and models of care (such as early palliative care) has developed during recent years. Aspects of healthcare utilisation-unplanned care have been used for evaluation of coordination and quality. The aim was to explore factors associated with cancer healthcare utilisation, during the first year after a cancer diagnosis. Population-based registry and patient-reported data, (The European Organisation of Research and Treatment of Cancer (EORTC), QLQ- C30 questionnaire and study-specific questions) were collected. Descriptive statistics and multivariate regression models were performed. The sample consists of 1718 patients (haematological, gynaecological, upper gastrointestinal and head and neck cancers). Living alone were associated with unplanned hospital admissions (OR 1.35; 95% CI [1.15, 1.59], p < 0.001). Patients with specialised palliative home care had a higher likelihood of unplanned hospital admissions, (OR 4.35; 95% CI [3.22-5.91], p < 0.001) and re-admissions within 30 days, (OR, 5.8; 95% CI [4.12-8.19], p < 0.001). Sociodemographic and clinical factors, such as living alone and disease stage, is associated with healthcare utilisation. Patients with specialised palliative home care report lower levels of HRQoL and higher levels of unplanned care, and our findings stresses the importance of a holistic view when planning care.


Associations between grip strength change and axial postmenopausal bone loss--a 10-year population-based follow-up study.
The aim of the present study was to investigate the associations between grip strength change and postmenopausal bone loss. The study population, 622 peri- and postmenopausal women, was a random sample of the OSTPRE-study cohort (n=13,100) in Kuopio, Finland. Bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN) was measured with dual X-ray absorptiometry and grip strength with a pneumatic squeeze dynamometer at baseline in 1989-1991, at the 5-year follow-up in 1994-1997 and at the 10-year follow-up in 1999-2001. Women were divided into three groups according to the change in age-grouped grip strength quartile they belonged to in each measurement (n in 5-year/10-year follow-up): "decreased" (n=150/n=140), "maintained" (n=314/n=320) and "improved" (n=158/n=162). Women within the improved group had significantly lower bone loss at both FN and LS in comparison to the other two groups after 10 years of follow-up (P<0.01). Furthermore, in HRT non-users (n=305) the difference between the improved group and maintained group was only modest (P=0.04). In contrast, in HRT users (n=310) the mean annual BMD change among the improved group was positive (bone gain 0.11%/year) and differed significantly in comparison to modest bone loss in the decreased and maintained groups in both LS and FN (P<0.01). The linear trend between grip strength quartile change and LS/FN bone loss was significant in HRT users (P<0.001) in contrast to HRT non-users (P=NS) in the linear regression model. Any of these differences were not affected by adjustments for age, weight, height and other potential confounders. In conclusion, the present study suggests that improvement in age-grouped grip strength quartile is strongly associated with axial bone loss among postmenopausal women. This effect seemed to interact positively with estrogen repletion status. These results encourage performing further clinical studies on associations between muscle strength changes and bone loss.


Splenic platelet-sequestration following routine blood transfusion is reduced by filtered/washed blood products.
The mean fall in the platelet count following 23 routine transfusions of 3-5 units packed cells for anaemia was 32.5%. This was significantly reduced to 12.5% in 15 similar transfusions through a 40 microns microaggregate filter (P less than 0.01) and to 4.6% following five transfusions through a polyester fibre filter (P less than 0.005). In 10 transfusions with frozen or polyester fibre filtered, washed red cells, the decrease in platelet count was 4.2% (P less than 0.001). A study of 111In-oxine labelled autologous platelets in nine patients indicated that the fall in platelet count was due to increased splenic sequestration. Since thrombocytopenia following routine transfusion is reduced by procedures which filter the packed cells, the decrease in platelets is probably caused by their adherence to infused microaggregate debris causing their premature removal from the circulation. Patients with preexisting thrombocytopenia who receive red cell transfusions for anaemia, should therefore receive blood products depleted of microaggregate debris in order to avoid exacerbation of thrombocytopenia and haemorrhagic complications.


Up-regulation of M3-muscarinic receptors in labial salivary gland acini in primary Sjögren's syndrome.
M3-muscarinic receptors (M3R) mediate parasympathetic cholinergic neurotransmission to salivary and lacrimal glands, and autoantibodies to these receptors have been implicated in sicca symptoms and autonomic dysfunction in Sjögren's syndrome. We have investigated the expression of M3R in paraffin-embedded labial salivary glands (LSG) from seven patients with primary Sjögren's syndrome (pSS) and five healthy controls using high-resolution confocal microscopy and an affinity-purified goat polyclonal antibody raised against the COOH-terminal sequence of the human M3R. Immunolocalization of M3R was similar in control and pSS glands, with punctate staining of M3R in the basal membrane of acinar cells and in the luminal and abluminal membrane of myoepithelial cells. Bright, granular M3R staining was also detected in the cytoplasm and membranes of all intercalated and striated ducts, and infiltrating lymphocytes in pSS. All immunoreactivity was specifically blocked by the immunizing peptide. An increase in M3R expression specifically in acini in pSS was demonstrated by a 30% increase in receptor number per cluster and a 68% increase in the number of clusters in the membrane. This up-regulation is consistent with inhibition of parasympathetic neurotransmission, possibly by antagonistic autoantibodies to M3R. The up-regulation, rather than down-regulation, of M3R in acini of pSS LSG can explain the effectiveness of muscarinic agonists in treating sicca symptoms in pSS.


Hepatic encephalopathy and altered cimetidine kinetics.
Cimetidine kinetics were followed in 16 cirrhotic patients after a single IV 300-mg dose. The patients were grouped according to a history of portal systemic encephalopathy (PSE). There were no differences among the groups in volume of distribution, biologic t 1/2, or distributional clearance. In cirrhotic patients with no history of PSE, cimetidine kinetics and metabolism were the same as in healthy subjects. Patients with a history of PSE (n = 8) had lower cimetidine total body clearance than cirrhotic patients without a history of PSE and healthy subjects. Cirrhotic patients with a history of PSE also had decreased formation of cimetidine sulfoxide (as judged by differences in the sulfoxide serum concentration-time AUC). Because of the 40% decrease in total clearance, dosage in cirrhotic patients with a history of PSE should be reduced to minimize the risk of CNS side effects associated with cimetidine.


Production and validation of a polyclonal serum against bovine FSH receptor.
In ovarian granulosa cells, follicle-stimulating hormone (FSH) regulates the proliferation and differentiation events required for follicular growth and oocyte maturation. FSH actions are mediated exclusively through the FSH receptor (FSHR). In cattle, the FSHR gene expression pattern during folliculogenesis and the implications of this receptor in reproductive disorders have been extensively studied. However, the limited availability of specific antibodies against bovine FSHR has restricted FSHR protein analysis. In the present study, we developed an anti-FSHR polyclonal serum by using a 14-kDa peptide conjugated to maltose binding protein. The antiserum obtained was characterized by western blot of protein extracts from bovine follicles, BGC-1 cells and primary cultures of granulosa cells stimulated with testosterone. Also, the blocking effect of serum on estradiol secretion and cell viability after gonadotropin stimulus was characterized in a functional in vitro assay. A 76-kDa protein, consistent with the predicted molecular size of full-length FSHR, was detected in ovarian tissue. Besides, two immunoreactive bands of 60-kDa and 30-kDa (only in cultured cells) were detected. These bands would be related to some of the isoforms of the receptor. Therefore, immunohistochemical assays allowed detecting FSHR in the cytoplasm of granulosa cells and an increase in its expression as follicles progressed from primordial to large preantral follicles. These results suggest that the anti-FSHR serum here developed has good reactivity and specificity against the native FSHR. Therefore, this antiserum may serve as a valuable tool for future studies of the biological function of FSHR in physiological conditions as well as of the molecular mechanism and functional involvement of FSHR in reproductive disorders.


Distinctive iron requirement of tryptophan 5-monooxygenase: TPH1 requires dissociable ferrous iron.
A peripheral type of tryptophan 5-monooxygenase (EC 220.127.116.11), TPH1, is very unstable in vitro, but the inactivation was reversible and full reactivation occurs upon anaerobic incubation with a high concentration of dithiothreitol (DTT, 15 mM). In this study, distinctive iron requirement of TPH1 was revealed through analysis of the enzyme's inactivation and activation by DTT. For this purpose, all the glasswares, plastics, Sephadex G-25 gels, and reagents including protein solutions had been treated with metal chelators, and apo-TPH was prepared by treatment with EDTA. Apo-TPH thus prepared exclusively required free Fe2+ for its catalytic activity; 10(-8) M was enough under the strict absence of Fe3+ but 10(-12) M was too low. No other metal ions including Fe3+ were effective. It appeared that Fe3+ bound to the enzyme with a higher affinity than Fe2+, resulting in the inactivation. Ascorbate, a non-thiol reducing agent, did not substitute DTT in the activation of TPH1, but enhanced the Fe2+-dependent activity of apo-TPH as effectively as DTT. Thus, the DTT-activation was essentially substituted by preparation of apo-TPH by the EDTA treatment and the assay of apo-TPH in the presence of Fe2+ and ascorbate. The activation of TPH1 by incubation with DTT was accompanied by exposure of 9 sulfhydryls out of the total 10 cysteine residues, but the cleavage of disulfide bonds seemed not to be crucial, even if it occurred. The effect of DTT was substituted by some other sulfhydryls whose structure was analogous to that of commonly used metal chelators. Based on these observations, the following dual roles of DTT are proposed: (1) in the activation of TPH, DTT removes inappropriate bound iron (Fe3+) as a chelator, keeping Fe3+ away from the enzyme's binding site which needs to bind Fe2+ for the catalytic activity, and (2) in both the activation and reaction processes, DTT prevents oxidation of Fe2+ to Fe3+ as a reducing agent.


Spring alloplasty in the treatment of fractures of the thoracic and lumbar spines. A correlation of the results of treatment with the mechanism of injury.
We describe 270 patients with spinal injuries who were treated by spring alloplasty between 1971 and 1985. The radiological results were compared with the mechanism of injury. The best outcome was obtained in patients with a spinal dislocation or flexion fracture. The technique is also recommended in compression fractures with wedging of the vertebral body, where there is a smaller proportion of good radiological results, but a gratifying improvement in neurological and functional outcome. The method is only cautiously advocated in cases of facet joint fracture and is generally contraindicated in massive compression fractures.


Synergistic down-regulation of telomerase by all-trans retinoic acid and antisense oligonucleotide in oral squamous cell carcinoma cell line (Tca8113).
Human telomerase, activated in about 90% of cancers, is mainly composed of hTR, hTERT and TP1. The exposed RNA template of hTR is an ideal target for antisense oligonucleotides (As-ODN); while recent findings indicate all-trans retinoid acid (ATRA) could effectively inhibit the expression of catalytic subunit-hTERT. The aim of this study was to investigate the effect of ATRA and As-ODN in oral squamous cell carcinoma and whether telomerase activity could be synergistically inhibited by them and thus therapeutically exploited in the future. As-ODN-hTR was transfected into human tongue squamous cell carcinoma cell line (Tca8113) with or without ATRA. Telomerase activity was examined by PCR-Elisa; viability was compared with growth curve; apoptotic rate was analyzed by Annexin V/PI double staining and hTERT expression was tested with western blot. Tca8113 cells displayed significant growth inhibition during the 9-day exposure to ATRA/As-ODN, especially to a combination of As-ODN-hTR and 5muM ATRA, correlating with the inhibition of telomerase expression. The relative telomerase activity was inhibited during treated with As-ODN-hTR alone, ATRA alone, or a combination of them. While without ATRA, the effect of As-ODN would disappear at 96h after transfection. As-ODN-hTR alone or combined with ATRA also significantly increase the apoptotic rate. Our findings provided direct evidence, in oral squamous cell carcinoma, As-ODN-hTR and ATRA could synergistically inhibit telomerase activity and telomerase protein in human tongue squamous cell carcinoma cells, which correlated with the induction of growth arrest.


Prehypertension and cardiovascular morbidity.
The Seventh Report of the Joint National Commission (JNC 7) on High Blood Pressure established prehypertension (120 to 139 mm Hg systolic or 80 to 89 mm Hg diastolic) as a new risk category. We aim to determine the risk of major cardiovascular events associated with blood pressure in the prehypertensive range in a longitudinal, population-based cohort. Analyses were conducted on participants in the National Health and Nutrition Examination Survey I (1971-1975) observed for 18 years for major cardiovascular disease events. Cox proportional hazard ratios were calculated to assess relative risk of cardiovascular disease, including stroke, myocardial infarction, and heart failure, in participants with prehypertension and normal blood pressure (<120/80 mm Hg). Prehypertension was associated with increased risk for cardiovascular disease (1.79 [95% confidence interval (CI) 1.40-2.24]) in unadjusted analysis. After adjustment for cardiovascular risk factors, the relationship of prehypertension to cardiovascular disease was diminished but persisted (1.32 [95% CI 1.05-1.65]). Ninety-three percent of prehypertensive individuals had at least 1 cardiovascular risk factor. Low prehypertension (120-129/80-84 mm Hg) was associated with increased cardiovascular disease in unadjusted analyses (1.56 [95% CI 1.23-1.98]) but was not statistically significant in adjusted analyses (1.24 [95% CI 0.96-1.59]). High-normal blood pressure (130-139/85-89 mm Hg) remained a predictor of cardiovascular disease in unadjusted (2.13 [95% CI 1.64-2.76]) and adjusted (1.42 [95% CI 1.09-1.84]) analyses. In a longitudinal, population-based, US cohort, prehypertension was associated with increased risk of major cardiovascular events independently of other cardiovascular risk factors. These findings, along with the presence of cardiovascular risk factors in the majority of participant sample with prehypertension, support recommendations for physicians to actively target lifestyle modifications and multiple risk reduction in their prehypertensive patients.


Postnatal development and GABA allosteric modulation of benzodiazepine receptor binding in the vitamin B-6 deficient rat brain.
We have measured the postnatal development and GABA modulation of benzodiazepine receptors in neuronal membranes from vitamin B-6 deficient and normal rats. In rats fed vitamin B-6 adequate and deficient diets there were age-dependent changes in [3H]flunitrazepam binding site affinity and in the number of binding sites. Vitamin B-6 deficiency produced a significant reduction in the potency of GABA to enhance [3H]flunitrazepam binding to cortical membranes prepared from 14 day old rats. These results suggests an uncoupling of the GABAa/benzodiazepine receptor at a developmental period when the animals are most susceptible to spontaneous seizures.


Intra-procedural imaging of the left atrium and pulmonary veins with rotational angiography: a comparison of anatomy obtained by pre-procedural cardiac computed tomography and trans-thoracic echocardiography.
This study evaluated the feasibility and accuracy of three-dimensional rotational angiography (3DRA) to determine the anatomy of the left atrium (LA) and pulmonary veins (PVs) compared with cardiac computed tomography (CCT) and trans-thoracic echocardiography (TTE). One hundred two patients (56.1 ± 9.9 years, 86 males) with an indication for atrial fibrillation ablation were prospectively enrolled. Intra-procedural 3DRA was performed with power injected contrast medium (20 cc/s for 4 s, 240°) in the LA. 3DRA images of the LA and PVs were assessed qualitatively and then compared quantitatively. LA volume measured by 3DRA, CCT and TTE were compared. The majority of 3DRA acquisitions were optimal in delineating the right-side LA-PV (95 % for right superior PV and 96 % for right inferior PV) and left inferior PV anatomy (91 %), whereas it was optimal in only 63 % of left superior PV and 73 % of the LA appendage. The circumferences of PV ostia identified by 3DRA and CCT were correlated in four PVs (r = 0.57 for right superior PV, r = 0.67 for right inferior PV, r = 0.60 for left superior PV, and r = 0.52 for left inferior PV, p < 0.001). The mean LA volume measured by 3DRA (120 ± 32 mL) was greater than that found by CCT (109 ± 35 mL) or TTE (64 ± 23 mL), but the 3DRA LA volume measurements correlated well with those of CCT (r = 0.83, p < 0.001) and TTE (r = 0.69, p < 0.001). Intra-procedural 3DRA provided anatomical accuracy of LA and PVs comparable to those of CCT. However, optimal delineation of the left superior PV and LA appendage was limited. The LA volume determined by 3DRA was well correlated with those of CCT and TTE, despite different absolute values of each.


SOCS-1 protects against Chlamydia pneumoniae-induced lethal inflammation but hampers effective bacterial clearance.
Suppressor of cytokine signaling 1 (SOCS1) plays a major role in the inhibition of STAT1-mediated responses. STAT1-dependent responses are critical for resistance against infection with Chlamydia pneumoniae. We studied the regulation of expression of SOCS1 and SOCS3, and the role of SOCS1 during infection with C. pneumoniae in mice. Bone marrow-derived macrophages (BMM) and dendritic cells in vitro or lungs in vivo all showed enhanced STAT1-dependent SOCS1 mRNA accumulation after infection with C. pneumoniae. Infection-increased SOCS1 mRNA levels were dependent on IFN-alphabeta but not on IFN-gamma. T or B cells were not required for SOCS1 mRNA accumulation in vivo. Infection-induced STAT1-phosphorylation occurred more rapidly in SOCS1(-/-) BMM. In agreement, expression of IFN-gamma responsive genes, but not IL-1beta, IL-6, or TNF-alpha were relatively increased in C. pneumoniae-infected SOCS1(-/-) BMM. Surprisingly, C. pneumoniae infection-induced IFN-alpha, IFN-beta, and IFN-gamma expression in BMM were attenuated by SOCS1. C. pneumoniae infection of RAG1(-/-)/SOCS1(-/-) mice induced a rapid lethal inflammation, accompanied by diminished pulmonary bacterial load and increased levels of iNOS and IDO but not IL-1beta, IL-6, or TNF-alpha mRNA. In summary, C. pneumoniae infection induces a STAT1, IFN-alphabeta-dependent and IFN-gamma independent SOCS1 mRNA accumulation. Presence of SOCS1 controls the infection-induced lethal inflammatory disease but impairs the bacterial control.


National Drug Information Sharing in the Thailand Health Care Supply Chain.
The paper explores the problems of health care supply chain in Thailand. A national drug information database is designed and presented to facilitate drug information sharing. Literatures are analysed in order to develop the information needed by stakeholders in health care supply chain. Expert interviews are conducted to verify the necessity of all of the attributes. A conceptual network of web-based services is designed. The study purposes the use of a national drug information database containing drug information needed by all players and enabling nationwide information exchanges in a standard electronic format. Due to fragmented data and information and lack of data standard problems, the study purposes the information sharing system by constructing a national drug information database. The database contains information needed by all players in health care supply chain. A conceptual network of web-based services is presented to facilitate drug information sharing among health care supply chain members as well nationwide implementation.


Physician Satisfaction With Lactation Resources Following an Intervention to Improve Lactation Accommodations.
Physicians who attempt to continue breastfeeding after returning from childbearing leave identify numerous obstacles at work, which may affect job satisfaction, retention, and the diversity of the physician workforce. To study the association between improved lactation accommodation support and physician satisfaction. This cohort study compared the physician experience before and after a July 2020 intervention to improve physician lactation accommodation support at a large, urban, academic health system. The satisfaction of physicians returning from childbearing leave between July 1, 2018, and June 30, 2020 (preintervention), was compared with that of physicians returning from leave between July 1, 2020, and November 30, 2021 (postintervention). Initial data analysis was performed on February 22, 2022, with additional tests for interaction performed on May 18, 2023. The intervention included creating functional lactation spaces, redesigning communication regarding lactation resources, establishing physician-specific lactation policies, and developing a program to reimburse faculty for time spent expressing breastmilk in the ambulatory setting. The main outcomes were (1) space improvements, use, and costs of the lactation accommodation program and (2) an ad hoc survey of physicians' reported experience with lactation accommodation support before and after the intervention. Survey data were collected using a 5-point Likert scale to assess physician perceptions of institutional support. Responses collected during the preintervention period were compared with those collected during the postintervention period using unpaired t tests. In this study, 70 clinical faculty (mean [SD] age, 34.4 [2.9] years) took childbearing leave in the preintervention period compared with 52 (mean [SD] age, 34.8 [2.7] years) in the postintervention period. Fifty-eight physicians (83%) completed the preintervention survey and 48 completed the postintervention survey. When comparing the pre- and postintervention periods, faculty reported improvements in finding time in their clinical schedule to devote to pumping (mean [SD] response, 2.5 [1.3] vs 3.6 [1.5]; P < .001), initiatives to address the impact of lactation time on productivity (mean [SD] response, 2.0 [1.0] vs 3.0 [1.5]; P = .001), and a culture supportive of lactation (mean [SD] response, 2.8 [1.4] vs 3.4 [1.3]; P = .047). Forty childbearing faculty took advantage of lactation time reimbursement and were reimbursed a total of $242 744.37. Faculty whose return to work overlapped with the entire year of the study received financial support for lactation for a mean (SD) of 8.9 (0.2) months, with an average reimbursement of $9125.78. The findings of this cohort study suggest that a multifaceted intervention to combat common challenges in lactation support in academic medical centers yielded improvements in faculty perceptions of institutional support for pumping breastmilk, addressing the impact of lactation time on productivity, and providing a culture supportive of lactation. These findings support the adoption of interventions to improve physician lactation accommodations.


Linear analysis of the nasal septum in patients treated with surgically assisted rapid maxillary expansion.
Surgically assisted rapid maxillary expansion is a widely used surgical procedure for resolving transverse maxillary occlusal changes in patients with bone maturity. However, few studies about the postoperative morphologic alterations in the nasal cavity in its inferior portion and the nasal septum positioning exist. The linear nasal septum measurements of 26 adult patients treated with surgically assisted rapid maxillary expansion from 2009 to 2013 were assessed through a retrospective analysis of cone-beam computed tomographies, in Digital Imaging and Communications in Medicine files, through the Dolphin Imaging program (Dolphin Imaging and Management Solutions, Chatsworth, Calif), aimed to identify significant changes during 3 time periods of the treatment: preoperative, immediately after the palatal expansion device locking (immediate postoperative), and 6-months postoperative (late postoperative). The analyses were performed in the inferior third of the nasal septum, from 4 equidistant points in anteroposterior position and height, using fixed cranial references for lateral measures of displacement. No significant difference was found between preoperative, immediate postoperative, and late postoperative measurements in the 4 fixed nasal septum measurements, applying the analysis of variance test with a significance level of 5%. Comparing the surgical times alone, we found no statistically significant difference between the right and left sides applying the Student t test, which also showed symmetry in the nasal septum. The measurements of the nasal septum did not change in the different surgical times throughout their inferior extension, and they remained symmetrical throughout patients' follow-up period.


Incidental finding of bilateral renal and adrenal anastomosing hemangiomas: A rare case report.
Anastomosing hemangiomas are rare variants of vascular tumors found in adrenal, hepatic, and gastrointestinal tissue. Frequently, renal anastomosing hemangiomas are misdiagnosed on computed tomography (CT) as kidney cancers, resulting in unnecessary workups and detrimental treatments. We present a rare case of bilateral renal and adrenal anastomosing hemangioma found incidentally on renal biopsy. Patient is a 39 year-old African American male on hemodialysis with a history of end-stage renal disease secondary to lupus who presented with acute pericarditis and worsening renal insufficiency.


Benzalkonium chloride toxicity to the human cornea.
A 36-year-old woman fitted with a soft contact lens after an uneventful extracapsular cataract extraction was wearing her aphakic lens successfully until she switched her lens-soaking solution to an isotonic solution of boric acid, potassium chloride, and sodium carbonate preserved with benzalkonium chloride and edetic acid. After three days her eye became inflamed and vision decreased. No endothelial damage was apparent and the anterior chamber showed 2+ cell and flare reaction. Three weeks after removal of the lens and fitting with an aphakic lens visual acuity was 6/9 (20/30). Study of the preservative by a semiquantitative dilution method together with the clinical evidence in this case proved the cytotoxic effect of benzolkonium chloride when used to sterilize soft contact lenses.


Effects of exposure to per- and polyfluoroalkyl substances on vaccine antibodies: A systematic review and meta-analysis based on epidemiological studies.
Vaccines are essential for children to defend against infection. Per- and polyfluoroalkyl substances (PFAS) are emerging contaminants with the characteristics of persistence and bioaccumulation. PFAS exposure can affect the function of the nervous, endocrine, and immune system of animals and humans. We aimed to conduct a systematic review and meta-analysis of the epidemiological studies investigating potential relationships between PFAS exposure and vaccine antibody levels, and assessed whether PFAS would affect vaccine response in healthy children. A literature search was conducted in PubMed, Web of Science, and Scopus databases up to February 2022. We chose studies that measured serum vaccines antibodies and PFAS concentrations of the participants. Essential information, including mean difference of percentage change, regression coefficient, odds ratio, Spearman correlation coefficient, and 95% confidence intervals, were extracted from the selected studies to conduct descriptive analysis and meta-analysis where appropriate. The qualities of these studies were evaluated as well. Finally, nine epidemiological studies about children met our inclusion criteria. A high degree of heterogeneity is observed in terms of breastfeeding time, confounder control, and detection method. Exposure to perfluorooctanoic acid and perfluorohexane sulfonic acid is negatively associated with tetanus antibody level in children without heterogeneity by Cochran's Q test (p = 0.26; p = 0.55), and exposure to perfluorohexane sulfonate is negatively associated with tetanus antibody level but with heterogeneity (p = 0.04). This comprehensive review suggests that PFAS can have adverse health effects on children by hindering the production of vaccine antibodies. There are some consistent and negative associations between children exposure to certain PFAS and tetanus antibody level. The association of the other four vaccines (measles, rubella, mumps, and influenza) with PFAS remains uncertain, because very few studies are available. Further studies are needed to validate the possible associations.


Treatment selection for stage IIIA Hodgkin's disease patients.
Two treatment policies for the therapy of patients with Stage IIIA Hodgkin's disease are compared. From 1969-1976, 49 newly diagnosed and pathologically staged IIIA patients received total nodal irradiation (TNI) alone (no liver irradiation). Although actuarial survival was 80% at 5 years and 68% at 10 years, actuarial freedom from relapse was only 38% at 5 years. Accordingly, a new treatment policy was instituted in 1976. Patients with either CS IIIA disease, multiple splenic nodules, IIIA with a large mediastinal mass or III2, received combined modality therapy (combination chemotherapy and irradiation). All others received TNI. Thirty-six patients have been treated under the new program. The actuarial survival is 90% at 5 years and the relapse-free survival is 87%, suggesting the superiority of this approach.


Experimental ecology of Dryas octopetala ecotypes : IV. Fitness response to reciprocal transplanting in ecotypes with differing plasticity.
Growth, survival and reproduction of adult plants from three reciprocally-transplanted populations of Dryas octopetala were followed over a seven year period, from 1979 to 1986. The two most different ecotypes, from snowbed and fellfield environments, were strongly selected against in extreme foreign environments via differential growth, survival, and reproduction. The more phenotypically-plastic ecotype from the snowbed experienced rapid, early mortality on the fellfield, prior to morphological adjustment, but no mortality in the last five years of the experiment. The less plastic fellfield ecotype showed no mortality for the first three years followed by a steady decline in numbers for the next four years. The ecotypic difference in plasticity may account for the contrasting mortality patterns. A population of plants with intermediate morphology was intermediate in fitness in extreme environments, but showed no superiority in its home site, suggesting that it is not a locally-adapted population. Natural selection maintains genetic differences between snowbed and fellfield populations in the face of gene flow. However, based on the response of intermediates, there appear to be limits to the degree to which selection can fine-tune adaptation along environmental gradients.


Scaling up, characterization of levan and its inhibitory role in carcinogenesis initiation stage'.
Honey isolate Bacillus subtilis M was cultivated in shake flasks and in 16-l bioreactor cultures to investigate cell growth, bio-metabolites production kinetics and bioprocess scalability. The respective maximal levan and levansucrase productions of 59.5 g/l and 74.1 U/ml were achieved in bioreactor cultures under pH controlled condition (pH=7.0) after only 24 h. Crude levan (levE) was isolated, characterized and fractionated into F1, F2, and F3 with different molecular weight (21.8, 13.118, 9.53 kDa). (1)H NMR and (13)C NMR spectroscopy proved that LevE and their fractions were mainly β-(2, 6)-linked levan-type polysaccharide. The cancer chemo-preventive activity indicated that the levE and its fraction 3 were promising inhibitors of cytochrome P-450 1A activity, inducers of glutathione-S-transferase activity in Murine hepatomaHepa1c1c7cells and possessed highest radical scavenging affinity to both ROO and OH. They inhibited the induced-DNA fragmentation. None of the tested samples triggered apoptosis or necrosis in splenocytes, except F2.


Study of the structure of arrestin (S-antigen) from bovine photoreceptors by FTIR spectroscopy.
Fourier transform-infrared spectroscopy has been used for the study of the secondary structure of arrestin from bovine retina rod cells. Spectra have been obtained in H2O and in D2O media. Resolution enhancement of the amide I secondary structure-sensitive overlapped component bands has been achieved by means of Fourier self-deconvolution and Fourier derivation. In order to obtain a quantitative estimation of the proportion of amino acid residues involved in each type of secondary structure, bands at the resolved frequencies have been curve-fitted to the deconvolved amide I contour by means of a least-squares best-fitting iterative program. The analysis of the results suggests that the secondary structure of arrestin comprises 56-63% of extended strands, 12-19% of turns and bends, 15% of alpha-helices and 10% of undefined and irregular segments.


Converting a motor to an anchor.
Myosin VI can move along actin filaments to serve as a transport motor. It is also thought to anchor vesicles or proteins to actin. How these two diverse activities, which require very different modes of interaction with actin, are mediated is not understood. Using single molecule observations, Altman et al. (2004 [this issue of Cell]) demonstrate that load applied to myosin VI can convert this motor from a transporter to an anchor.


Cooling vest improves surgeons' thermal comfort without affecting cognitive performance: a randomised cross-over trial.
Surgeons become uncomfortable while performing surgery because heat transfer and evaporative cooling are restricted by insulating surgical gowns. Consequently, perceptions of thermal discomfort during surgery may impair cognitive performance. We, therefore, aimed to evaluate surgeons' thermal comfort, cognitive performance, core and mean skin temperatures, perceptions of sweat-soaked clothing, fatigue and exertion with and without a CoolSource cooling vest (Cardinal Health, Dublin, Ohio, USA). Thirty orthopaedic surgeons participated in a randomised cross-over trial, each performing four total-joint arthroplasties with randomisation to one of four treatment sequences. The effects of cooling versus no cooling were measured using a repeated-measures linear model accounting for within-subject correlations. The cooling vest improved thermal comfort by a mean (95% CI) of -2.1 (-2.7 to -1.6) points on a 0-10 scale, p<0.001, with no evidence of treatment-by-period interaction (p=0.94). In contrast, cooling had no perceptible effect on cognition, with an estimated mean difference (95% CI) in Cleveland Clinic Cognitive Battery (C3B) Processing Speed Test score of 0.03 (95% CI -2.44 to 2.51), p=0.98, or in C3B Visual Memory Test score with difference of 0.88 (95% CI -2.25 to 4.01), p=0.57. Core temperature was not lower with the cooling vest, with mean difference (95% CI) of -0.13 (-0.33°C to 0.07°C), p=0.19, while mean skin temperature was lower, with mean difference of -0.23 (95% CI -0.40°C to -0.06°C) lower, p=0.011. The cooling vest significantly reduced surgeons' perceptions of sweat-soaked clothing, fatigue and exertion. A cooling vest worn during surgery lowered core and skin temperatures, improved thermal comfort, and decreased perceptions of sweating and fatigue, but did not improve cognition. Thermal discomfort during major orthopaedic surgery is thus largely preventable, but cooling does not affect cognition. NCT04511208.


Macrophage responsiveness to therapeutic ultrasound.
Macrophages are a source of many important growth factors which can act as wound mediators during tissue repair. The aim of this work was to find out if levels of ultrasound which accelerate repair could stimulate the release of fibroblast mitogenic factors from an established macrophage-like cell line (U937). The U937 cells were exposed in vitro to continuous ultrasound at a space average, temporal average intensity of 0.5 W/cm2 at either 0.75 MHz or 3.0 MHz, for 5 min. The macrophage-conditioned medium was removed either 30 min or 12 h after exposure, and placed on 3T3 fibroblast cultures. Fibroblast proliferation (defined here as increase in cell number) was assessed over a 5-day period. The results showed that 0.75 MHz ultrasound appeared to be effective in liberating preformed fibroblast affecting substances from the U937 cells, possibly by producing permeability changes, whereas 3.0 MHz ultrasound appeared to stimulate the cell's ability to synthesize and secrete fibroblast mitogenic factors.


Risk factors associated with skeletal-related events following discontinuation of denosumab treatment among patients with bone metastases from solid tumors: A real-world machine learning approach.
Clinical practice guidelines recommend the use of bone-targeting agents for preventing skeletal-related events (SREs) among patients with bone metastases from solid tumors. The anti-RANKL monoclonal antibody denosumab is approved for the prevention of SREs in patients with bone metastases from solid tumors. However, real-world data are lacking on the impact of individual risk factors for SREs, specifically in the context of denosumab discontinuation. We aim to identify risk factors associated with SRE incidence following denosumab discontinuation using a machine learning approach to help profile patients at a higher risk of developing SREs following discontinuation of denosumab treatment. Using the Optum PanTher Electronic Health Record repository, patients diagnosed with incident bone metastases from primary solid tumors between January 1, 2007, and September 1, 2019, were evaluated for inclusion in the study. Eligible patients received ≥ 2 consecutive 120 mg denosumab doses on a 4-week (± 14 days) schedule with a minimum follow-up of ≥ 1 year after the last denosumab dose, or an SRE occurring between days 84 and 365 after denosumab discontinuation. Extreme gradient boosting was used to develop an SRE risk prediction model evaluated on a test dataset. Multiple variables associated with patient demographics, comorbidities, laboratory values, treatments, and denosumab exposures were examined as potential factors for SRE risk using Shapley Additive Explanations (SHAP). Univariate analyses on risk factors with the highest importance from pooled and tumor-specific models were also conducted. A total of 1,414 adult cancer patients (breast: 40%, prostate: 30%, lung: 13%, other: 17%) were eligible, of whom 1,133 (80%) were assigned to model training and 281 (20%) to model evaluation. The median age at inclusion was 67 (range, 19-89) years with a median duration of denosumab treatment of 253 (range, 88-2,726) days; 490 (35%) patients experienced ≥ 1 SRE 83 days after denosumab discontinuation. Meaningful model performance was evaluated by an area under the receiver operating curve score of 77% and an F1 score of 62%; model precision was 60%, with 63% sensitivity and 78% specificity. SHAP identified several significant factors for the tumor-agnostic and tumor-specific models that predicted an increased SRE risk following denosumab discontinuation, including prior SREs, shorter denosumab treatment duration, ≥ 4 clinic visits per month with at least one hospitalization (all-cause) event from the baseline period up to discontinuation of denosumab, younger age at bone metastasis, shorter time to denosumab initiation from bone metastasis, and prostate cancer. This analysis showed a higher cumulative number of SREs, prior SREs relative to denosumab initiation, a higher number of hospital visits, and a shorter denosumab treatment duration as significant factors that are associated with an increased SRE risk after discontinuation of denosumab, in both the tumor-agnostic and tumor-specific models. Our machine learning approach to SRE risk factor identification reinforces treatment guidance on the persistent use of denosumab and has the potential to help clinicians better assess a patient's need to continue denosumab treatment and improve patient outcomes.


Mesoscopic bar magnet based on ε-Fe2O3 hard ferrite.
Ferrite magnets have a long history. They are used in motors, magnetic fluids, drug delivery systems, etc. Herein we report a mesoscopic ferrite bar magnet based on rod-shaped ε-Fe2O3 with a large coercive field (>25 kOe). The ε-Fe2O3-based bar magnet is a single crystal with a single magnetic domain along the longitudinal direction. A wide frequency range spectroscopic study shows that the crystallographic a-axis of ε-Fe2O3, which corresponds to the longitudinal direction of the bar magnet, plays an important role in linear and non-linear magneto-optical transitions, phonon modes, and the magnon (Kittel mode). Due to its multiferroic property, a magnetic-responsive non-linear optical sheet is manufactured as an application using an ε-Fe2O3-based bar magnet, resin, and polyethylene terephthalate. Furthermore, from the viewpoint of the large coercive field property, we demonstrate that a mesoscopic ε-Fe2O3 bar magnet can be used as a magnetic force microscopy probe.


Development of a mathematical model for propagation of ultrasonic waves in thick-walled cylinders in the presence of a thermal gradient - Case of axial scanning.
Investigation of variations in ultrasonic wave velocity and travel path in the presence of thermal gradient is essential for accurate ultrasonic testing of engineering components which are subjected to high temperatures. In this paper, a mathematical model is developed for calculation of the wave velocity and travel path in thick-walled hollow cylinders that are subjected to thermal gradients during axial scanning. The cylinder is assumed to be homogeneous, isotropic, and made from Structural steel. The independent variables are incidence angle, cylinder outer radius, and temperature of the cylinder's inner surface. The results obtained from the theoretical model indicate that the wave velocity and travel path are highly sensitive to inner-surface temperature of the cylinder. Moreover, at incidence angles much lower than critical angles (especially at low temperatures), the wave velocity is almost independent of the incidence angle and the travel path is very close to a straight line. However, as the incidence angle approaches one of the critical angles, the wave travel path considerably deviates from a straight line. An experimental setup was designed and built in-house for measuring the longitudinal wave velocity in a steel hollow cylinder in the presence of a thermal gradient. The preliminary experimental results were found to be in good agreement with theoretical results.


Variation in foliar δ13C in Hawaiian Metrosideros polymorpha: a case of internal resistance?
Sun leaves of Metrosideros polymorpha were collected in 51 sites on 9 lava flows that represented gradients of elevation, precipitation, substrate age, and substrate texture on Mauna Loa volcano, Hawai'i. Leaf mass per unit leaf area increased with increasing elevation on all flows, while foliar nitrogen concentration decreased with increasing elevation and increased with increasing substrate age. Foliar δ13C became less negative with increasing elevation on the wet east-side lava flows, but not the dry northwest-side flows; it did not reflect patterns of precipitation or presumed water availability. δ13C was very strongly correlated with leaf mass per area across all of the sites. Limited gas-exchange information suggested that calculated ci/ca did not decrease with elevation in association with less-negative δ13C, and photosynthesis per unit of nitrogen was significantly reduced in high-elevation plants. These results are consistent with a substantial internal resistance to CO2 diffusion in the thick Metrosideros polymorpha leaves in high elevation sites.


De Novo Lipogenesis as a Source of Second Messengers in Adipocytes.
Obesity is a major risk factor for type 2 diabetes. Although adipose tissue allows storage of excess calories in periods of overnutrition, in obesity, adipose tissue metabolism becomes dysregulated and can promote metabolic diseases. This review discusses recent advances in understandings how adipocyte metabolism impacts metabolic homeostasis. The ability of adipocytes to synthesize lipids from glucose is a marker of metabolic fitness, e.g., low de novo lipogenesis (DNL) in adipocytes correlates with insulin resistance in obesity. Adipocyte DNL may promote synthesis of special "insulin sensitizing" signaling lipids that act hormonally. However, each metabolic intermediate in the DNL pathway (i.e., citrate, acetyl-CoA, malonyl-CoA, and palmitate) also has second messenger functions. Mounting evidence suggests these signaling functions may also be important for maintaining healthy adipocytes. While adipocyte DNL contributes to lipid storage, lipid precursors may have additional second messenger functions critical for maintaining adipocyte health, and thus systemic metabolic homeostasis.


An Exploratory Investigation of Parental Incarceration, Emotional Independence, and Adult Children's Criminal Activity.
Although research suggests that parental incarceration is associated with intergenerational continuity in crime, the mechanisms underlying this association remain unclear. Using multi-population structural equation modeling and data from the Toledo Adolescent Relationships Study (n = 1207), the current study explored specific experiences associated with labeling as well as internalizing labels, including experiencing corporal punishment during childhood, criminal arrests during adolescence, and identifying as a troublemaker/partier in young adulthood (measured with reflected appraisals), as potential mechanisms linking parental incarceration and young adults' offending. We assessed whether this association differed by young adults' level of emotional independence, that is, freedom from the need for parental approval. We found that parental incarceration indirectly influenced criminal activity particularly through identifying as a troublemaker/partier during young adulthood but only for those who sought parental approval. Overall, we concluded that high emotional independence, or not seeking parental approval, may be a protective factor that facilitates intergenerational discontinuities in crime.


Vascular dysfunction induced by hypochlorite is improved by the selective phosphodiesterase-5-inhibitor vardenafil.
Reactive oxygen species, such as hypochlorite induce oxidative stress, which impairs nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signalling and leads to vascular dysfunction. It has been proposed, that elevated cGMP-levels may contribute to an effective cytoprotection against oxidative stress. We investigated the effects of vardenafil, a selective inhibitor of the cGMP-degrading phosphodiesterase-5 enzyme on vascular dysfunction induced by hypochlorite. In organ bath experiments for isometric tension, we investigated the endothelium-dependent and endothelium-independent vasorelaxation of isolated rat aortic rings using cumulative concentrations of acetylcholine and sodium nitroprusside (SNP). Vascular dysfunction was induced by exposing rings to hypochlorite (100-400 µM). In the treatment groups, rats were pretreated with vardenafil (30 and 300 µg/kg i.v.). Immunohistochemical analysis was performed for the oxidative stress markers nitrotyrosine, poly(ADP-ribose) and for apoptosis inducing factor (AIF). Exposure to hypochlorite resulted in a marked impairment of acetylcholine-induced endothelium-dependent vasorelaxation of aortic rings. Pretreatment with vardenafil led to improved endothelial function as reflected by the higher maximal vasorelaxation (Rmax) to acetylcholine. Regarding endothelium-independent vasorelaxation, hypochlorite exposure led to a left-shift of SNP concentration-response curves in the vardenafil groups without any alterations of the Rmax. In the hypochlorite groups immunohistochemical analysis showed enhanced poly(ADP-ribose)-formation and nuclear translocation of AIF, which were prevented by vardenafil-pretreatment. Our results support the view that cytoprotective effects of PDE-5-inhibitors on the endothelium may underlie the improved endothelial function, however, a slight sensitisation of vascular smooth muscle to NO was also confirmed. PDE-5-inhibition may represent a potential therapy approach for treating vascular dysfunction induced by oxidative stress.


Antiviral effects of foscarnet and ganciclovir therapy on human immunodeficiency virus p24 antigen in patients with AIDS and cytomegalovirus retinitis. Studies of Ocular Complications of AIDS Research Group in collaboration with AIDS Clinical Trials Group.
To examine whether the prolonged survival seen in patients treated with foscarnet compared with those treated with ganciclovir was due to a direct effect on human immunodeficiency virus (HIV) replication, HIV p24 antigen was measured. Of 71 receiving foscarnet, 54% were p24 antigen-positive at enrollment (vs. 44% of 79 receiving ganciclovir). By immune complex-dissociated (ICD) p24 antigen analysis, 87% and 78%, respectively, were positive. After 1 month of treatment, there was a significant decline in standard (mean decline, 10.1 pg/mL) and ICD (mean, 39.6 pg/mL) p24 antigen in both groups (P = .0001). Mortality was greater in those who were ICD p24 antigen-positive than in those -negative at baseline (P = .03) and in subjects with an increase in ICD p24 antigen than in those with a decline (P = .09). Thus, each drug had a suppressive effect on circulating p24 antigen, which was predictive of improved survival. The inhibitory effect on CMV replication may have a beneficial effect on limiting HIV replication.


Expression of the RAC1, RHOA and CXCR4 proteins and their interaction as risk factors for infiltration to the nipple areola complex in operable breast carcinoma.
Nipple areola complex (NAC) infiltration in operable breast carcinoma (OBC) is associated with local recurrence. NAC infiltration in OBC suggests that RAC1, RHOA and CXCR4 proteins are risk factors for migration and infiltration of OBC to NAC. This study aims to analyze the expression and interactions of these proteins as risk factors for NAC infiltration in OBC. This is an analytic observational cross-sectional study coupled with a categorical comparative study in each 40 subjects of OBC with and without NAC infiltration. The immunohistochemistry performed with a cut-off point based on the result of a receiver operating characteristics (ROC). RAC1, p < 0.001 with POR 5.76, 95% CI: 2.06-16.08; RHOA, p < 0.001 with POR 7.00, 95% CI: 2.28-21.53; and CXCR4, p = 0.001 with POR 6.33, 95% CI 2.06-19.49. There was an interaction between RAC1 and RHOA (p < 0.001 with POR 17.14, 95% CI: 3.07-125.66); between RAC1 and CXCR4 (p < 0.001 with POR 30.93, 95% CI 3.62-686.89); between RHOA and CXCR4 (p < 0.001 with POR 10.21, 95% CI 2.19-54.17); and between the RAC1, RHOA and CXCR4 proteins (p < 0.001 with POR = 23.69, 95% CI 2.51-544.86). We conclude that the expression of the RAC1, RHOA, and CXCR4 proteins and their interactions play a role as risk factors of NAC infiltration.


Serum concentrations of laminin gamma2 fragments in patients with head and neck squamous cell carcinoma.
The laminin (LN) gamma2 chain expression has been linked to tumor invasion and prognosis. To provide a convenient clinical use, procedures that analyze LNgamma2 expression by using the serum and/or urine of patients should be developed. The serum concentrations of the N-terminal fragments of the LNgamma2 chain in 73 patients with head and neck squamous cell carcinomas were measured by immunoassay. The concentrations of the LNgamma2 fragments ranged between 14.5 and 324.2 ng/mL, and the normal upper limit was estimated to be 50 ng/mL. The LNgamma2 fragment concentrations increased according to the T classification. The amount of elevated LNgamma2 fragment concentrations decreased after the use of curative treatments. Three patients displayed a continuous increase of the concentrations and subsequently died of the diseases. The serum concentrations of the LNgamma2 fragments may prove useful in assessing the treatment results and clinical courses of patients with head and neck squamous cell carcinomas.


Topical pharmacotherapy for ocular surface squamous neoplasia: systematic review and meta-analysis.
Ocular surface squamous neoplasia (OSSN) has different treatment modalities. Although surgical excision has been the gold standard therapeutic option, topical pharmacotherapy agents such as 5-fluorouracil (5-FU), interferon alfa-2b (IFN) and mitomycin-C (MMC) are also commonly used. The protocol was registered (CRD42021224961). Comprehensive literature research was carried out to compare topical pharmacotherapy (5-FU or IFN or MMC) to surgical excision regarding clinical success (tumor resolution), recurrence and complications in patients undergoing treatment for OSSN. From 7859 records, 7 articles were included in the qualitative and 4 in the quantitative synthesis. The outcomes of surgical excision and topical pharmacotherapy were comparable in the included articles. There were no significant differences between surgical excision and topical pharmacotherapy regarding the clinical success [odds ratio (OR): 0.785; confidence interval (CI): 0.130-4.736, P = 0.792)] and tumor recurrence (OR: 0.746; CI: 0.213-2.609; P = 0.646). The most common side effect of the different therapeutic options was dry eye. The highest rate of dry eye symptoms was reported after surgical excision (in 59%). Topical pharmacotherapy with all the 3 agents is as effective and well-tolerable as surgical excision in terms of tumor resolution, recurrence rate and side effects in all OSSN patients suggesting similar long-term clinical benefits.


Developmental regulation of cognitive abilities: modified composition of a molecular switch turns on associative learning.
N-methyl-D-aspartate receptors (NMDARs) act as molecular coincidence detectors and allow for association or dissociation between pre- and postsynaptic neurons. NMDA receptors are central to remodeling of synaptic connections during postnatal development and associative learning abilities in adults. The ability to remodel neural networks is altered during postnatal development, possibly due to a change in the composition of NMDARs. That is, as forebrain systems (and cerebellum) develop, synaptic NR2B-containing NMDARs (NR2B-NMDARs) are replaced by NR2A-containing NMDARs (NR2A-NMDARs) and NR2B-NMDARs move to extrasynaptic sites. During the initial phase of the switch, synapses contain both NR2A- and NR2B-NMDARs and both long-term potentiation and long-term depression are enhanced. As NMDAR subunit expression decreases and NR2A-NMDARs come to predominate in the synapse, channel function and synaptic plasticity are reduced, and remodeling ability dissipates. The end result is a balance of plasticity and stability that is optimal for information processing and storage. Associative learning abilities involving different sensory modalities emerge sequentially, in accordance with synaptic maturation in related cortical and underlying brain structures. Thus, developmental alterations in NMDAR composition that occur at different ages in various brain structures may explain the protracted nature of the maturation of various associative learning abilities.


Stuck with pancytopenia in dengue fever: Evoke for hemophagocytic syndrome.
The hemophagocytic syndrome is an atypical and rare manifestation of dengue fever (DF). We describe a 15-year-old girl developing DF associated hemophagocytic syndrome who responded with supportive treatment.


When the fingers need to act faster than the arm: coordination between grip force and load force during oscillation of a hand-held object.
Using a precision grip, 12 participants horizontally oscillated a lightweight object at different movement frequencies (1.0, 1.5, and 2.0 Hz) under two types of elastic load. In the first (CENT), the center of oscillation coincided with the neutral position of the object in the elastic force field, leading to two peaks in load force (LF) per cycle of movement (2:1 frequency ratio). In the second (BACK and FRONT), the neutral elastic force position of the object was located outside the range of movement, thus leading to only one LF peak per cycle of movement (1:1 frequency ratio). Results showed that in BACK and FRONT the coupling between grip force (GF) and LF (as reflected by coefficients of correlations) remained strong for all movement frequencies. In contrast, this coupling decreased in CENT as movement frequency increased, with participants switching progressively from two to one GF modulation per cycle of movement. Specific evaluation of performance under conditions giving rise to comparable LF frequencies (CENT at 1.0 Hz vs. BACK/FRONT at 2.0 Hz) confirmed the effect of frequency ratio on GF-LF coupling. We conclude that the control of GF is more efficient when LF varies at the frequency of movement than when it varies at twice this frequency, especially when movement frequency is high. These results are interpreted in the context of coordination dynamics and forward modeling approach.


Elevated TRH levels in pyriform cortex after partial and fully generalized kindled seizures.
In a previous study we reported significant elevations of TRH in neocortex, hippocampus and combined amygdala/pyriform cortex in rats 48 h after the last of a series of stage 5 kindled seizures. In the present study, to determine whether the increases in TRH were proportional to the intensity of the convulsions, and the degree of development of the kindling process, we compared the effects of partially kindled (stage 2) vs fully kindled (stage 5) seizures. As a further refinement, we examined separately the TRH responses in the pyriform, cingulate and frontal cortices. The responses were especially marked in the pyriform cortex, where TRH increased 7-fold after stage 5 kindled convulsions, compared with 2-fold increases after stage 2-3 seizures. Increases were seen in other cortical regions, as well, but only after stage 5 seizures. These findings are consistent with reports suggesting that the increases in brain TRH occurring after convulsions are aftereffects of the seizures, possibly representing homeostatic anticonvulsant responses, and that the pyriform cortex is a site that is uniquely activated by convulsions.


Pharmacological manipulation of anxiety and male rat sexual behavior.
Several anxiolytic/anxiogenic treatments were evaluated on male rat sexual behavior. The anxiolytic drug diazepam (1.0 mg/kg) inhibited copulatory behavior as indicated by an increase in the number of mounts preceding ejaculation, prolongation of the ejaculation latency and the postejaculatory interval. These changes were not accompanied by alterations in motor coordination as tested on a treadmill apparatus. A lower dose of diazepam (0.5 mg/kg) did not affect the sexual behavior. The anxiogenic drug Zk 39106 (2 and 4 mg/kg) facilitated the copulatory behavior by reducing the number of intromissions preceding ejaculation. A higher dose of Zk 39106 (8 mg/kg) inhibited sexual behavior. The selective benzodiazepine antagonist, Ro 15-1788 (5 and 10 mg/kg), did not modify male sexual behavior, but effectively antagonized the effects of Zk 39106 and diazepam. The administration of Zk 39106 (2 mg/kg) reversed the inhibitory action of diazepam (1.0 mg/kg) on copulation; however, diazepam did not prevent the facilitory effect of Zk 39106. The data are discussed in terms of the possible relationship existing between anxiety and masculine sexual behavior.


Efficacy of ProTaper universal retreatment files in removing filling materials during root canal retreatment.
The aim of this study was to evaluate the efficacy of the ProTaper Universal System rotary retreatment system and of Profile 0.06 and hand instruments (K-file) in the removal of root filling materials. Forty-two extracted single-rooted anterior teeth were selected. The root canals were enlarged with nickel-titanium (NiTi) rotary files, filled with gutta-percha and sealer, and randomly divided into 3 experimental groups. The filling materials were removed with solvent in conjunction with one of the following devices and techniques: the ProTaper Universal System for retreatment, ProFile 0.06, and hand instruments (K-file). The roots were longitudinally sectioned, and the image of the root surface was photographed. The images were captured in JPEG format; the areas of the remaining filling materials and the time required for removing the gutta-percha and sealer were calculated by using the nonparametric one-way Kruskal-Wallis test and Tukey-Kramer tests, respectively. The group that showed better results for removing filling materials was the ProTaper Universal System for retreatment files, whereas the group of ProFile rotary instruments yielded better root canal cleanliness than the hand instruments, even though there was no statistically significant difference. The ProTaper Universal System for retreatment and ProFile rotary instruments worked significantly faster than the K-file. The ProTaper Universal System for retreatment files left cleaner root canal walls than the K-file hand instruments and the ProFile Rotary instruments, although none of the devices used guaranteed complete removal of the filling materials. The rotary NiTi system proved to be faster than hand instruments in removing root filling materials.


Serum Zinc Status and Its Association with Allergic Sensitization: The Fifth Korea National Health and Nutrition Examination Survey.
Zinc (Zn) is an essential trace element that plays important roles in the immune system. There is little known about the role of trace elements in allergic diseases, and previous reports have shown conflicting results. The aim of this study was to investigate the relationship between serum Zn levels and total or allergen-specific immunoglobulin E (IgE) levels. The initial candidates for this study were those who participated in the 5th Korean National Health and Nutrition Examination Survey 2010 (n = 8,958), and 1,867 adults who had serum total and allergen specific-IgE levels measured were included. Upon adjusting for covariates, mean total IgE, Dermatophagoides farinae and dog-specific IgE levels increased significantly as the Zn levels decrease from the highest to the lowest quartile (p = 0.009, 0.004, and < 0.001, respectively). The multiple logistic regression analyses showed significant negative linear correlations between serum Zn levels and total, D. farinae-, cockroach-, and dog-specific IgE levels (p-value for linear trend = 0.004, 0.006, 0.027, and < 0.001, respectively). This study demonstrated that total/allergen specific IgE and Zn levels are significantly inversely related.


Association between the detection of alcohol, illicit drugs and/or psychotropic medications/opioids in patients admitted due to trauma and trauma recidivism: A cohort study.
To quantify the association between the presence and type of drug detected and trauma recidivism in a cohort of patients admitted due to trauma. A cohort study was conducted based on data from a project where the presence of alcohol and other drugs (cannabis, cocaine, amphetamines, methamphetamines, tricyclic antidepressants, barbiturates, opiates and benzodiazepines) was analysed in 1,187 patients aged 16 to 70 years admitted due to trauma. The patients were followed for a period of between 10 to 52 months until June 2016. For this study, the recurrence of injuries from a sample of 929 patients from this cohort was analysed according to their consumption profile. Survival curves were estimated and adjusted Hazard Rate Ratios (aHRR) and adjusted incidence rate ratios (aIRR) were calculated. The incidence rate of TR was 10.94 cases per 100 patient-years in the group of patients negative for substances and 27.99 per 100 patient-years in positive patients. The survival curves show very significant differences in cumulative recurrence-free survival between the groups (Log Rank: p<0.001). Both the aHRR and the aIRR estimates show an increased risk of re-injury due to alcohol consumption (aIRR: 2.33 (1.72-3.15), p<0.001), cannabis use (aIRR: 1.87 (1.09-3.20), p = 0.022) and polydrug use (aIRR: 2.34 (1.80-3.04), p<0.001). The presence of alcohol and/or illicit drugs in these patients doubles the risk of trauma recidivism.


Psychology, immunology, and HIV.
The interdisciplinary field of psychoneuroimmunology (PNI), which aims to clarify the relationship between psychological factors and immunity, can also play a role in our understanding of individual susceptibility to, progression of immunologically mediated disease. Mechanisms proposed to account for the profoundly damaging effects of human immunodeficiency virus (HIV) on immune function do only partially explain the variability in individual rates of progression, suggesting, therefore, that other immunomodulatory factors are also involved. Studies have examined the proposal that the effects of stress and HIV may interact in some complex way, and psychological, physiological and virological evidence for the role of stress in HIV progression is discussed in detail. A critical review of HIV-specific research in PNI, which can be broadly divided into cross-sectional, longitudinal, and intervention studies, and studies of long-term survivors, reveals that the relationship between stress and HIV progression remains equivocal, because of limitations due to methodological difficulties and to our inadequate understanding of immunology and HIV. A model is proposed for the influence of psychosocial stress on progression in HIV disease, which takes account of some of these difficulties.


Military Burn Care and Burn Disasters.
Mass-casualty incidents can occur because of natural disasters; industrial accidents; or intentional attacks against civilian, police, or in case of combat, military forces. Depending on scale and type of incident, burn casualties often with a variety of concomitant injuries can be anticipated. The treatment of life-threatening traumatic injuries should take precedent but the stabilization, triage, and follow-on care of these patients will require local, state, and often regional coordination and support.


Graphene oxide enhanced fluorescence of conjugated polyelectrolytes with intramolecular charge transfer characteristics.
We herein find that graphene oxide (GO) can enhance the fluorescence signal of conjugated polyelectrolytes (CPEs) with charge transfer characteristics under certain conditions, which is due to a relative hydrophobic environment of CPEs upon complexation with GO.


[13-YEAR-OLD GIRL WITH PHEOCHROMOCYTOMA PRESENTING WITH SECONDARY NOCTURNAL ENURESIS].
Pheochromocytoma is a rare, catecholamine secreting tumor arising from chromaffin cells of the adrenal medulla and it is responsible for 0.5-2% of pediatric hypertension cases. We hereby present a case of a 13-year-old girl with obesity, excessive hypertension, prediabetes and secondary nocturnal enuresis, who was eventually diagnosed with pheochromocytoma. Most symptoms significantly improved after treating the tumor. We suggest that this diagnosis should be considered in pediatric patients presenting with similar symptoms.


Laser capture microdissection for biomedical research: towards high-throughput, multi-omics, and single-cell resolution.
Spatial omics technologies have become powerful methods to provide valuable insights into cells and tissues within a complex context, significantly enhancing our understanding of the intricate and multifaceted biological system. With an increasing focus on spatial heterogeneity, there is a growing need for unbiased, spatially resolved omics technologies. Laser capture microdissection (LCM) is a cutting-edge method for acquiring spatial information that can quickly collect regions of interest (ROIs) from heterogeneous tissues, with resolutions ranging from single cells to cell populations. Thus, LCM has been widely used for studying the cellular and molecular mechanisms of diseases. This review focuses on the differences among four types of commonly used LCM technologies and their applications in omics and disease research. Key attributes of application cases are also highlighted, such as throughput and spatial resolution. In addition, we comprehensively discuss the existing challenges and the great potential of LCM in biomedical research, disease diagnosis, and targeted therapy from the perspective of high-throughput, multi-omics, and single-cell resolution.


Ferritin mRNA is found on bound as well as on free polyribosomes in rat heart.
Free and endoplasmic reticulum-bound polyribosomes from rat heart were examined for their ferritin mRNA content. A procedure for separation and purification of the two ribosome populations that produced good yields of homogeneous mono- and polyribosomes with no contaminating ultrastructures and gave distinctive sedimentation profiles in 15-50% sucrose gradients was developed. 14C-labeled free and bound polyribosomes added to heart preparations indicated that only 3% of free and 5.5% of bound polyribosomes cross-contaminated the bound and free fractions, respectively. RNA from both polyribosome populations hybridized with [32P]cDNA for rat ferritin. The extent of hybridization with mRNA from endoplasmic reticulum (ER)-derived polyribosomes was much greater than what could be accounted for by cross-contamination with free polyribosomes. This indicates that heart ferritin is synthesized not only on free polyribosomes for internal use in iron storage but also on ER-bound polyribosomes, where it may be destined for secretion into the plasma.


New standardization method of tibial tubercle-posterior cruciate ligament distance according to patient size in patients with patellofemoral instability.
Large differences in tibial tubercle-posterior cruciate ligament (TT-PCL) distance were described in several reports between countries, suggesting that abnormal TT-PCL distance is variable due to individual patient size. This study aimed to clarify the relationship between TT-PCL distance and patient size, and to determine a method for describing individualized TT lateralization. We analyzed 41 patients with recurrent patellar dislocation (RPD) and 41 age-matched patients without patellar instability who underwent primary anterior cruciate ligament reconstruction (control). TT-PCL distance and tibia width (TW) were measured based on preoperative T2-weighted magnetic resonance imaging. Then, TT-PCL distance was standardized based on TW (TT-PCL ratio), and TT-PCL distance and ratio were compared between groups. Correlations were investigated among TT-PCL distance, TT-PCL ratio and each measurement (patient height, weight, TW). Strong positive correlations were observed between TW and patient height, and weak or moderate positive correlations were found between TT-PCL distance and each parameter. The mean TT-PCL distance was 21.2 and 20.6 mm (P = .39), while the mean TT-PCL ratio was 31.6% and 29.0% (P = .0093) in the RPD and control groups, respectively. The TT-PCL ratio was <34% in 39 of 41 knees (95.1%) in the control group. No correlation was indicated between the TT-PCL ratio and patient size. Our findings demonstrate that the TT-PCL ratio is not affected by patient size, although the TT-PCL distance is associated with knee size and patient height. The TT-PCL ratio could be an important index for identifying patients for whom distal realignment surgery should be considered.


[Hemorrhagic lumbar juxta facet cyst. A case report].
We report the case of a hemorrhagic lumbar juxta facet cyst (L2-L3), revealed by a chronic right lumbocruralgia, in a 77-year-old woman treated by anticoagulants for cardiac arrhythmia. Computerized tomography and magnetic resonance imaging suggested the diagnosis of benign tumor. During surgical removal of the whole lesion, a hemorrhagic synovial cyst was evoked. The operation dramatically relieved the symptoms. The diagnosis was confirmed by the histopathological analysis confronted with the clinical and the radiological findings. This uncommon observation allows the discussion of the pathogenic mechanism and of the differential diagnosis.


Paradoxical euthyroid hormone profile in a case of Graves' disease with cardiac failure.
Cardiac failure is an uncommon complication of juvenile hyperthyroidism. We describe an adolescent boy with Graves' disease who developed manifestations of heart failure while on antithyroid medications. There was no evidence of any underlying cardiac disease. He had paradoxical euthyroid hormone profile which rose to hyperthyroid range when the manifestations of the cardiac failure subsided. The case highlights several unusual features of Graves' disease.


Eye movements and stress during eye-tracking gaming performance in children with dyskinetic cerebral palsy.
This study aimed to explore eye movements and stress during eye-tracking gaming performance in children with dyskinetic cerebral palsy (CP) compared with typically developing children, and associations between eye-tracking performance, eye movements, stress, and participants' characteristics. This cohort study included 12 children with dyskinetic CP aged 5 to 12 years (mean age 8 years 7 months, standard deviation [SD] 2 years 3 months) and 23 typically developing children aged 5 to 13 years (mean age 9 years 0 months, SD 2 years 7 months). Participants played 10 eye-tracking games. Tobii X3-120 and Tobii Pro Lab were used to record and analyse eye movements. Stress was assessed through heart rate variability (HRV), recorded during rest, and eye-tracking performance using the Bittium Faros360° ECG Holter device. Eye-tracking performance was measured using gaming completion time. Fixation and saccade variables were used to quantify eye movements, and time- and frequency-domain variables to quantify HRV. Non-parametric statistics were used. Gaming completion time was significantly different (p < 0.001) between groups, and it was negatively correlated with experience (rs = -0.63, p = 0.029). No significant differences were found between groups in fixation and saccade variables. HRV significantly changed from rest to eye-tracking performance only in typically developing children and not in children with dyskinetic CP. Children with dyskinetic CP took longer to perform the 10 games, especially the inexperienced users, indicating the importance of the early provision of eye-tracking training opportunities. It seems that eye-tracking tasks are not a source of increased stress and effort in children with dyskinetic CP. Participants with dyskinetic cerebral palsy (CP) took twice as long to perform 10 eye-tracking games than typically developing peers. Participants with dyskinetic CP with previous eye-tracking experience performed the games faster. Fixation and saccade variables were not significantly different between children with and without dyskinetic CP. Heart rate variability showed no differences between rest and performance in participants with dyskinetic CP. Gross Motor Function Classification System, Manual Ability Classification System, and Viking Speech Scale levels were not correlated to the eye movements or stress variables.


Alcohol consumption and risk of benign proliferative epithelial disorders of the breast: a case-cohort study.
To study the association between alcohol consumption and risk of benign proliferative epithelial disorders (BPED) of the breast (conditions which are thought to have premalignant potential). Case-cohort study. The study was undertaken within the 56,537 women in the Canadian National Breast Screening Study (NBSS) who completed self-administered dietary questionnaires. (The NBSS is a randomized controlled trial of screening for breast cancer in women aged 40-59 years at recruitment.) The study subjects were the 657 women in the dietary cohort who were diagnosed with biopsy-confirmed incident BPED. For comparative purposes, a subcohort consisting of a random sample of 5681 women was selected from the full dietary cohort. After exclusions for various reasons, the analyses were based on 557 cases and 5028 non-cases. When compared to non-drinkers, rate ratios (95% CI) for those consuming > 0 and < or =10 g of ethanol day(-1), >10 and < or =20 g day(-1), >20 and < or =30 g day(-1) and >30 g day(-1) were 0.35 (0.27-0.45), 0.26 (0.18-0.39), 0.29 (0.18-0.48), and 0.23 (0.13-0.40), respectively (the associated P value for the trend was 0.089). Similar findings were obtained from analyses conducted separately in the screened and control arms of the NBSS, in premenopausal and postmenopausal women, and for non-atypical and atypical forms of BPED, and there was little difference between the results for screen-detected and interval-detected BPED. Alcohol consumption was associated with a non-dose-dependent reduction in risk of BPED.


Advanced glycation end products impair the migration, adhesion and secretion potentials of late endothelial progenitor cells.
Endothelial progenitor cells (EPCs), especially late EPCs, play a critical role in endothelial maintenance and repair, and postnatal vasculogenesis. Advanced glycation end products (AGEs) have been shown to impair EPC functions, such as proliferation, migration and adhesion. However, their role in the regulation of the production of vasoactive substances in late EPCs is less well defined. Passages of 3~5 EPCs, namely late EPCs, were cultured with different concentrations (0~500 μg/ml) of AGEs, and the apoptosis, adhesion and migration were subsequently determined. The release of vasoactive substances, such as stromal cell-derived factor-1 (SDF-1), nitric oxide (NO), prostaglandin I2 (PGI2), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), and in addition the activity of superoxide dismutase (SOD), were evaluated by ELISA. At the same time, the gene and protein expressions of CXCR4 were assayed by real-time RT-PCR and western-blot. AGEs promoted late EPC apoptosis. Moreover, AGEs impaired late EPC migration and adhesion in a concentration-dependent manner. Accordingly, the production of SDF-1 was decreased by AGEs. Although the CXCR4 expressions of late EPCs were up-regulated for AGE concentrations of 50, 100 or 200 μg/ml, a marked decrease was observed for the higher concentration of 500 μg/ml. Furthermore, co-culturing with AGEs decreased the levels of NO, t-PA, PGI2, and the activity of SOD but up-regulated the production of PAI-1. Our data provide evidence that AGEs play an important role in impairing late EPC functions, which could contribute to the development of vascular diseases in diabetes.


Purification of C-reactive protein on DEAE-cellulose by a simple two-step procedure utilizing the calcium-dependency of the protein.
A simple procedure for isolating C-reactive protein is presented. The method consists of two chromatographic separations on diethylaminoethyl (DEAE)-cellulose columns and utilized the difference between the binding of C-reactive protein to DEAE in the presence and absence of calcium. Electrophoretically pure C-reactive protein can be recovered from serum or ascitic fluid with a yield of approx. 50--60% within one day.


[Congenital nasolacrimal duct obstruction : A real-life study from the first symptoms to the results of surgical treatment].
The optimal timing for surgery of congenital nasolacrimal duct obstruction (CNLDO) is controversially discussed . An aspect that has not yet been studied in this context is the path from first symptoms to the initial diagnosis and surgical treatment with respect to social factors and burden of suffering. The aim of this study was a real-life analysis of the entire course of the disease. Monocentric, retrospective study evaluating children with CNLDO (n = 147) who underwent surgery. The minimum follow-up was 3 months (26 ± 14 months). The patient information was collected by telephone using a questionnaire especially created for this purpose. The famelial suffering was measured on a scale of 1-5. Data were collected from 118 parents with a mean follow-up of 26 months. First symptoms occurred at a median age of 1 month. The diagnosis was confirmed through a pediatrician/ophthalmologist after a median of 6 months. An assignment to a referral center for surgical treatment was performed a median of 18 months after the first presentation. The average age of the patients at the time of surgery was 23 months. Surgery before the age of 13 months showed a 100% success rate. The average age of those who needed revision surgery was 27 months (±12 months). The familial suffering was measured as 4.1 points before surgery and 1.3 after surgery. This study is the first real-life study, which illustrates the path of CNLDO from the first symptoms to rehabilitation, including influential social factors. Early surgery significantly shortens the suffering of both patients and parents. Considering the low operative risks and excellent success rate of operative treatment, an early consultation at a surgical department is recommended.


Hippocampal c-Fos activation in normal and LPA₁-null mice after two object recognition tasks with different memory demands.
Normal and LPA₁-null mice, that have well reported hippocampal deficits, were assessed in an episodic-like what-when-where memory task or in a comparable task designed to test memory for familiar objects and locations by discriminating them from novels. Both genotypes performed the novelty recognition task but failed to learn the what-when-where task. However, normal mice showed what-when memory that was impaired in nulls. Each task elicited a different pattern of c-Fos expression. In normal mice, the what-when-where task induced more hippocampal c-Fos activation in the CA1 area than the novelty-based task, correlating with the what-when memory. LPA₁-null mice displayed a basal c-Fos hyperactivity in the hippocampus and in the medial prefrontal cortex, which was regulated differently by the two behavioural tasks employed. Both tasks were matched in exploratory behaviour and c-Fos activation in stress-related brain areas for both genotypes. This study shows that the what-when-where memory task differs from a comparable novelty-based task in both the learning demands and the neuronal correlates. Moreover, results also stress the role of the LPA₁ receptor in hippocampal functioning.


HLA-A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies in a population of 432 healthy unrelated individuals from Albania.
This paper reports the HLA-A, -B, -C, -DRB1 and -DQB1 allele and haplotype polymorphism in a population of 432 healthy individuals from Albania. First-field HLA genotyping was performed by polymerase chain reaction sequence-specific priming and/or oligonucleotide methods. The data were analyzed statistically using gene counting and Arlequin software packages. No deviation from Hardy Weinberg Equilibrium was detected at any of the loci studied. The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database and they can serve as a reference database for further HLA-based population genetics studies including the Albanian population.


Histologic findings in T-cell lymphoma infiltration of the optic nerve.
To report the clinical and histologic features of lymphomatous infiltration of the optic nerve by systemic T-cell non-Hodgkin's lymphoma (NHL). Interventional case report. A patient with peripheral T-cell NHL. A 39-year-old man with a diagnosis of peripheral T-cell NHL, stage IV, with CNS involvement and decreased vision was found to have lymphomatous infiltration of the optic nerves. Visual acuity. Despite treatment with chemotherapy and an optic nerve sheath fenestration, the patient lost vision in the right eye and subsequently underwent an optic nerve biopsy. The histopathology showed diffuse infiltration with a clonal population of lymphocytic cells that were CD3 positive and CD20 negative, consistent with T-cell NHL. Optic nerve infiltration from systemic B-cell lymphoma is rare and has been reported; we report an unusual case of bilateral optic nerve infiltration secondary to peripheral T-cell NHL.


Comprehensive analysis of the lncRNAs-related immune gene signatures and their correlation with immunotherapy in lung adenocarcinoma.
Long non-coding RNAs (lncRNAs)-related immune genes (lrRIGs) play a crucial role in the development and progression of lung adenocarcinoma (LUAD). However, reliable prognostic signatures based on lrRIGs have not yet been identified. We screened lrRIGs associated with the prognosis of LUAD using The Cancer Genome Atlas (TCGA) database and then established a novel prognostic nine-gene signature composed of CD79A, INHA, SHC3, LIFR, TNFRSF11A, GPI, F2RL1, SEMA7A and WFDC2 through bioinformatic approaches. A risk score derived from this gene signature was used to divide LUAD patients into the low- and high-risk groups. The latter was confirmed to have markedly worse overall survival (O.S.). A nomogram was developed using the risk score and other independent prognostic elements, demonstrating excellent performance in predicting the O.S. rate of LUAD patients. We observed that the infiltration of diverse immune cell subtypes and response to immunotherapy and chemotherapy significantly differed between the low- and high-risk groups. Overall, stratification based on this gene signature could be used to guide better therapeutic management and improve outcomes for LUAD patients.


Prevalence of cerebrotendinous xanthomatosis among patients diagnosed with early-onset idiopathic bilateral cataracts: final analysis.
Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder caused by pathologic variants in CYP27A1, a gene involved in bile acid synthesis. Impaired function in this gene leads to accumulation of plasma cholestanol (PC) in various tissues, often in early childhood, resulting in such clinical signs as infantile diarrhea, early-onset bilateral cataracts, and neurological deterioration. The current study aimed to identify cases of CTX in a population of patients with a greater CTX prevalence than the general population, to facilitate early diagnosis. Patients diagnosed with early-onset, apparently idiopathic, bilateral cataracts between the ages of 2 and 21 years were enrolled. Genetic testing of patients with elevated PC and urinary bile alcohol (UBA) levels was used to confirm CTX diagnosis and determine CTX prevalence. Of 426 patients who completed the study, 26 met genetic testing criteria (PC ≥ 0.4 mg/dL and positive UBA test), and 4 were confirmed to have CTX. Prevalence was found to be 0.9% in enrolled patients, and 15.4% in patients who met the criteria for genetic testing.


Evaluation of dynamic lung changes during coronavirus disease 2019 (COVID-19) by quantitative computed tomography.
This study aims to trace the dynamic lung changes of coronavirus disease 2019 (COVID-19) using computed tomography (CT) images by a quantitative method. In this retrospective study, 28 confirmed COVID-19 cases with 145 CT scans are collected. The lesions are detected automatically and the parameters including lesion volume (LeV/mL), lesion percentage to lung volume (LeV%), mean lesion density (MLeD/HU), low attenuation area lower than - 400HU (LAA-400%), and lesion weight (LM/mL*HU) are computed for quantification. The dynamic changes of lungs are traced from the day of initial symptoms to the day of discharge. The lesion distribution among the five lobes and the dynamic changes in each lobe are also analyzed. LeV%, MLeD, and LM reach peaks on days 9, 6 and 8, followed by a decrease trend in the next two weeks. LAA-400% (mostly the ground glass opacity) declines to the lowest on days 4-5, and then increases. The lesion is mostly seen in the bilateral lower lobes, followed by the left upper lobe, right upper lobe and right middle lobe (p < 0.05). The right middle lobe is the earliest one (on days 6-7), while the right lower lobe is the latest one (on days 9-10) that reaches to peak among the five lobes. Severity of COVID-19 increases from the day of initial symptoms, reaches to the peak around on day 8, and then decreases. Lesion is more commonly seen in the bilateral lower lobes.