Intermediate-conductance Ca2+-activated K+ channel, KCa3.1, as a novel therapeutic target for benign prostatic hyperplasia.
Recently, a new experimental stromal hyperplasia animal model corresponding to clinical benign prostatic hyperplasia (BPH) was established. The main objective of this study was to elucidate the roles of the intermediate-conductance Ca(2+)-activated K(+) channel (K(Ca)3.1) in the implanted urogenital sinus (UGS) of stromal hyperplasia BPH model rats. Using DNA microarray, real-time polymerase chain reaction, Western blot, and/or immunohistochemical analyses, we identified the expression of K(Ca)3.1 and its transcriptional regulators in implanted UGS of BPH model rats and prostate needle-biopsy samples and surgical prostate specimens of BPH patients. We also examined the in vivo effects of a K(Ca)3.1 blocker, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), on the proliferation index of implanted UGS by measurement of UGS weights and proliferating cell nuclear antigen immunostaining. K(Ca)3.1 genes and proteins were highly expressed in implanted UGS rather than in the normal host prostate. In the implanted UGS, the gene expressions of two transcriptional regulators of K(Ca)3.1, repressor element 1-silencing transcription factor and c-Jun, were significantly down- and up-regulated, and the regulations were correlated negatively or positively with K(Ca)3.1 expression, respectively. Positive signals of K(Ca)3.1 proteins were detected exclusively in stromal cells, whereas they were scarcely immunolocalized to basal cells of the epithelium in implanted UGS. In vivo treatment with TRAM-34 significantly suppressed the increase in implanted UGS weights compared with the decrease in stromal cell components. Moreover, significant levels of K(Ca)3.1 expression were observed in human BPH samples. K(Ca)3.1 blockers may be a novel treatment option for patients suffering from BPH.


Gold(III) complexes of pyridyl- and isoquinolylamido ligands: structural, spectroscopic, and biological studies of a new class of dual topoisomerase I and II inhibitors.
The structures, spectroscopy, and cytotoxicity of four novel nominally square-planar gold(III) chelates 1-4 with the general formula cis-AuCl2(X), where the ligand X is an anionic bidentate pyridyl- or isoquinolylamido chelating agent, are described. The Au-N(amido), Au-N(pyridyl), and Au-N(isoquinolyl) distances are 2.002(9)-2.016(3), 2.01(1)-2.037(3), and 2.037(3) Å, respectively. Density functional theory simulations afforded accurate gold(III) coordination geometries for 1-4 (bond distances and angles to within 5% of the X-ray values), while accurate transition energies were limited to those calculated in the UV spectral region. The complexes had variable stability in dimethyl sulfoxide: compound 3 (relatively rigid) was indefinitely stable, compounds 1 and 2 (conformationally flexible) slowly demetalated over 30 days, and 4 (extensively aromatic) formed an insoluble precipitate after 10 days (72 h in an aqueous buffer). The isoquinolylamido derivative 4 was sufficiently cytotoxic in the NCI-60 screen to undergo full five-dose testing. Notably low GI50 (1.8, 2.3, and 3.2 μM) and IC50 (4.0, 9.8, and 15 μM) values were recorded for the OVCAR-3, IGROV1, and SW-620 cell lines, respectively. Hierarchical cluster analysis employing the National Cancer Institute (NCI) data for known anticancer drugs and 4 revealed that compound 4 is mechanistically identical with the topoisomerase IIα (Top2) poison zorubicin and statistically similar to the topoisomerase IB (Top1) poisons camptothecin and 9-methoxycamptothecin. The Top2-catalyzed decatenation reaction of kinetoplast DNA was studied as a function of the concentration of 4: the compound acts as an interfacial poison of Top2 at low concentrations (<1 μM) and a catalytic inhibitor of the enzyme above 5 μM. Gel mobility shift assays (plasmid DNA substrate) showed that the catalytic inhibition of Top2 likely correlates with DNA binding by 4 at concentrations >5 μM. Compound 4 is also a catalytic inhibitor of Top1 at higher concentrations, consistent with DNA binding by the complex.


Association Between Helicobacter pylori cagA, babA2 Virulence Factors and Gastric Mucosal Interleukin-33 mRNA Expression and Clinical Outcomes in Dyspeptic Patients.
Helicobacter pylori (H. pylori) infection has been reported in more than half of the world human population. It is associated with gastric inflammation and noticeable infiltration of the immune cells to the stomach mucosa by several cytokines secretion. IL-1β, IL-18 have been shown to contribute to H. pylori induced gastritis, but the details of inflammation and association of virulence factors remain unclear. IL-1 cytokine family has a new additional cytokine, Interleukin-33 (IL-33), which is contemplated to have an important role for host defense against microorganisms. H. pylori virulence factors important in gastritis risk are the cag pathogenicity island (cag-PAI) and babA. This study evaluated IL-33 mucosal mRNA expression levels in infected and uninfected patients and its relationship with bacterial virulence factors cagA, babA2 and type of gastritis. Total RNA was extracted from gastric biopsies of 79 H. pylori-infected patients and 51 H. pylori-negative patients. Mucosal IL-33 mRNA expression levels in gastric biopsies were assessed using real-time PCR. Existence of virulence factors were detected by PCR. IL-33 mRNA expression was significantly higher in biopsies of H. pylori-infected patients compared to H. pylori-uninfected patients (P<0.0001). Also there was a direct relationship between virulence factor bab-A2 and enhancement in IL-33 mRNA expression. Furthermore, IL-33 mRNA expression level was significantly lower in chronic gastritis patients compared with patients with active gastritis (P<0.001). IL-33 may play a crucial role in the inflammatory response and induction of the chronic gastritis and severity of inflammatory changes in the gastric mucosa.


Prophylactic and therapeutic efficacy of immunoglobulin G antibodies to Pseudomonas aeruginosa lipopolysaccharide against murine experimental corneal infection.
To evaluate the efficacy of lipopolysaccharide (LPS)-specific antibodies administered prophylactically or therapeutically to protect against corneal challenge with Pseudomonas aeruginosa. The prophylactic efficacy of active immunization with purified P. aeruginosa LPS was evaluated in a murine corneal-scratch model of P. aeruginosa keratitis. The same model was used to evaluate both the prophylactic and the therapeutic efficacy of systemic passive transfer of variable region-identical, isotype-switched, LPS-specific, murine immunoglobulin M (IgM) and immunoglobulin G (IgG) monoclonal antibodies (mAbs). The mAbs were injected intraperitoneally at various times either before or after corneal challenge and the corneal response was monitored macroscopically. In addition, immune rabbit sera were used to evaluate the efficacy of treatment. Active immunization with homologous, but not heterologous, LPS before challenge reduced the severity of corneal disease and protected challenged mice against permanent corneal damage. Passive transfer of the LPS-specific IgM mAb 1F6 before challenge did not prevent corneal damage at any dose tested and had no effect on the course of disease. However, results of dose-response studies of the passive transfer of a variable region-identical IgG2b mAb, 2H3, before challenge indicated a 50% protective dose of 11.8 micrograms. When mAb 2H3 was administered at a dose of 50 micrograms before challenge and the challenge inoculum was increased, all mice were protected from corneal damage up to a challenge inoculum of 2.2 x 10(8) CFU/eye. When given 2 or 4 hours after corneal challenge with P. aeruginosa strain 6294 (which invades corneal epithelial cells during infection) but not when given at 8 or 24 hours, 50 micrograms of mAb 2H3 conferred significant protection (P < 0.05). The maximal interval after challenge during which this antibody could be administered and still protect 50% of mice was calculated by probit analysis to be 9.4 hours. Administration of homologous LPS-specific rabbit antiserum to mice at various times after challenge with P. aeruginosa strain 6206 (which is cytotoxic to corneal epithelial cells and does not remain in these cells during infection) resulted in significant protection when administered 4 or 8 hours after infection. Although probit analysis could not be performed with the available data, 50% of mice were completely protected when the antiserum was given up to 24 hours after challenge. In an experimental model of P. aeruginosa keratitis, systematically delivered IgG antibodies directed against the O-side-chain antigens of P. aeruginosa, LPS conferred protection against severe corneal damage when administered both prophylactically and therapeutically.


[The epidemic situation with malaria in Uzbekistan].
In the past five years (1994-1998), 223 cases of imported malaria were recorded in the Republic (Table 1), 190 of which were from countries in the Commonwealth of Independent States (CIS) and 33 from other countries. It is noteworthy that the number of cases imported from Tadjikistan--a country that borders eight of the Republic's 12 regions (oblasts)--has increased each year (12 in 1994, 69 in 1998). Some 25% of the population of our Republic live in the 67 cities and regions bordering Tadjikistan, Turkmenistan, Kazakhstan, Kyrgyzstan and Afghanistan. 35.5% of the cases of imported malaria have been registered in Surkhandarin region, which borders Afghanistan and Tadjikistan. Seventy-four (imported) cases of malaria were registered in the Republic in 1998, of which 17 (23%) were children under 14 years of age. Cases were registered in eight regions of the Republic and in the city of Tashkent. Thirty-six patients were detected in Surkhandarin region. Malaria was imported mainly from Tajikistan (69 cases) and Azerbaijan (two cases), as well as from Afghanistan (two cases) and India (one case). The infectious agent of vivax malaria was identified in 94.6% of cases, while in four cases it was found to be that of falciparum malaria. Three cases of falciparum malaria were registered for the first time in Surkhandarin region (imported from Tadjikistan) and one in the city of Tashkent (imported from Afghanistan). A large proportion of malaria cases (53, or 71.6%) were detected in the period from June to September, which is the time of high risk of infection. In the first six months of 1999, 15 cases of imported tertian malaria were recorded in the country as a whole, with six in Tashkent and Surkhandarin region, two in Fergana region and one in Samarkand region. Importation occurred mainly from Tajikistan (12 cases), with Azerbaijan, Kazakhstan and Afghanistan each accounting for one case. In order to prevent the spread of the infection from neighbouring malarious countries, steps are being taken to make medical personnel more alert to this threat, with the aims of ensuring prompt detection of people suspected of having malaria, improving the quality of laboratory diagnosis and treatment, and strengthening vector control.


Cytotoxic effects of Chartergellus communis wasp venom peptide against melanoma cells.
Cancer is a huge public health problem being one of the main causes of death globally. Specifically, melanoma is one of the most threatening cancer types due to the metastatic capacity, treatment resistance and mortality rates. It is evident the urgent need for research on new agents with pharmacological potential for cancer treatment, in order to develop new cancer therapeutic strategies and overcome drug resistance. The present work investigated the anti-tumoral potential of Chartergellus-CP1 peptide, isolated from Chartergellus communis wasp venom on human melanoma cell lines with different pigmentation degrees, namely the amelanotic cell line A375 and pigmented cell line MNT-1. Chartergellus-CP1 induced selective cytotoxicity to melanoma cell lines when compared to the lower induced cytotoxicity towards to nontumorigenic keratinocytes. Chartergellus-CP1 peptide induced apoptosis in both melanoma cell lines, cell cycle impairment in amelanotic A375 cells and intracellular ROS increase in pigmented MNT-1 cells. The amelanotic A375 cell line showed higher sensitivity to the peptide than the pigmented cell line MNT-1. From our knowledge, this is the first study reporting the cytotoxic effects of Chartergellus-CP1 on melanoma cells.


Trypsin activation pathway of rotavirus infectivity.
The infectivity of rotaviruses is increased by and most probably is dependent on trypsin treatment of the virus. This proteolytic treatment specifically cleaves VP4, the protein that forms the spikes on the surface of the virions, to polypeptides VP5 and VP8. This cleavage has been reported to occur in rotavirus SA114fM at two conserved, closely spaced arginine residues located at VP4 amino acids 241 and 247. In this work, we have characterized the VP4 cleavage products of rotavirus SA114S generated by in vitro treatment of the virus with increasing concentrations of trypsin and with proteases AspN and alpha-chymotrypsin. The VP8 and VP5 polypeptides were analyzed by gel electrophoresis and by Western blotting (immunoblotting) with antibodies raised to synthetic peptides that mimic the terminal regions of VP4 generated by the trypsin cleavage. It was shown that in addition to arginine residues 241 and 247, VP4 is cleaved at arginine residue 231. These three sites were found to have different susceptibilities to trypsin, Arg-241 > Arg-231 > Arg-247, with the enhancement of infectivity correlating with cleavage at Arg-247 rather than at Arg-231 or Arg-241. Proteases AspN and alpha-chymotrypsin cleaved VP4 at Asp-242 and Tyr-246, respectively, with no significant enhancement of infectivity, although this enhancement could be achieved by further treatment of the virus with trypsin. The VP4 end products of trypsin treatment were a homogeneous VP8 polypeptide comprising VP4 amino acids 1 to 231 and a heterogeneous VP5, which is formed by two polypeptide species (present at a ratio of approximately 1:5) as a result of cleavage at either Arg-241 or Arg-247. A pathway for the trypsin activation of rotavirus infectivity is proposed.


Aortosternal Venous Compression: A Review of Two Cases.
Aortosternal venous compression (AVC) is a rare venous compression syndrome that involves brachiocephalic venous compression due to its positioning between the sternum and the aorta. One of the features of AVC involves compression of the left innominate vein with variability in luminal caliber on inspiration and expiration. Imaging modalities such as computed tomography (CT) examination can aid in initial diagnosis; however, venography can be utilized for confirmatory diagnosis due to its higher specificity during the inspiratory and expiratory phases. Through findings demonstrated during venography, we herein present two cases of confirmed AVC secondary to an aberrant right subclavian artery. Characteristic imaging features in the diagnosis of AVC and its etiology are discussed.


Therapeutic guidelines for prescribing antibiotics in neonates should be evidence-based: a French national survey.
This survey aims to describe and analyse the dosage regimens of antibiotics in French neonatal intensive care units (NICUs). Senior doctors from 56 French NICUs were contacted by telephone and/or email to provide their local guidelines for antibiotic therapy. 44 (79%) NICUs agreed to participate in this survey. In total, 444 dosage regimens were identified in French NICUs for 41 antibiotics. The number of different dosage regimens varied from 1 to 32 per drug (mean 9, SD 7.8). 37% of intravenous dosage regimens used a unique mg/kg dose from preterm to full-term neonates. Doses and/or dosing intervals varied significantly for 12 antibiotics (amikacin, gentamicin, netilmicin, tobramycin, vancomycin administered as continuous infusion, ceftazidime, cloxacillin, oxacillin, penicillin G, imipenem/cilastatin, clindamycin and metronidazole). Among these antibiotics, 6 were used in more than 70% of local guidelines and had significant variations in (1) maintenance daily doses for amikacin, imipenem/cilastatin, ceftazidime and metronidazole; (2) loading doses for continuous infusion of vancomycin; and (3) dosing intervals for gentamicin and amikacin. A considerable inter-centre variability of dosage regimens of antibiotics exists in French NICUs. Developmental pharmacokinetic-pharmacodynamic studies are essential for the evaluation of antibiotics in order to establish evidence-based dosage regimens for effective and safe administration in neonates.


miR-21 in ischemia/reperfusion injury: a double-edged sword?
MicroRNAs (miRNAs or miRs) are endogenous, small RNA molecules that suppress expression of targeted mRNA. miR-21, one of the most extensively studied miRNAs, is importantly involved in divergent pathophysiological processes relating to ischemia/reperfusion (I/R) injury, such as inflammation and angiogenesis. The role of miR-21 in renal I/R is complex, with both protective and pathological pathways being regulated by miR-21. Preconditioning-induced upregulation of miR-21 contributes to the protection against subsequent renal I/R injury through the targeting of genes such as the proapoptotic gene programmed cell death 4 and interactions between miR-21 and hypoxia-inducible factor. Conversely, long-term elevation of miR-21 may be detrimental to the organ by promoting the development of renal interstitial fibrosis following I/R injury. miR-21 is importantly involved in several pathophysiological processes related to I/R injury including inflammation and angiogenesis as well as the biology of stem cells that could be used to treat I/R injury; however, the effect of miR-21 on these processes in renal I/R injury remains to be studied.


Toxic shock: clinical presentation and management. II.
The management of toxic shock syndrome poses a challenge to clinicians because the syndrome has only been recently recognized and new complications are still being described. This report describes the major complications which arose in our case and highlights a severe bleeding disorder which was the cause of the patient's death. The bleeding disorder was characterized by normal in vitro coagulation screens, normal platelet aggregation tests, but prolonged skin bleeding time. It was not improved by haemodialysis, platelet transfusion or steroid therapy. We conclude that in cases with severe toxaemia, despite early recognition and appropriate treatment, there is still no effective method of preventing complications. Current avenues for investigation include plasmapheresis, the administration of fresh frozen plasma, and the development of a specific anti-toxin.


Metastatic penile squamous cell carcinoma to the retroperitoneum in a man with human papillomavirus type 45.
Squamous cell carcinoma of the penis is a rare cancer associated with smoking, genital warts, lack of neonatal circumcision, and human papillomavirus types 16 and 18. Metastasis of this condition is even rarer, occurring primarily in the lungs or liver. The current report describes a case of penile squamous cell carcinoma in an uncircumcised 63-year-old man who smoked cigarettes and who had genital warts and human papillomavirus type 45. Metastasis occurred in the abdominal cavity.


Clinical Guideline Highlights for the Hospitalist: The GOLD and NICE Guidelines for the Management of COPD.
Chronic obstructive pulmonary disease in over 16s: Diagnosis and management1 RELEASE DATE: December 5, 2018 with update July 2019 PRIOR VERSION(S): NICE guideline CG101 June 2010, 2004 FUNDING SOURCE: Department of Health and Social Care, United Kingdom TARGET POPULATION: Patients age 16 and older with Chronic Obstructive Pulmonary Disease (COPD) GUIDELINE TITLE: Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (2019 Report)2 RELEASE DATE: November 14, 2018 PRIOR VERSION(S): 2017, 2016, 2015, 2014, 2013, 2008, 2001 FUNDING SOURCE: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) TARGET POPULATION: Adults with Chronic Obstructive Pulmonary Disease (COPD).


Ultrasound-Assisted Extraction of Total Saponins from Aralia taibaiensis: Process Optimization, Phytochemical Characterization, and Mechanism of α-Glucosidase Inhibition.
Aralia taibaiensis, a medicinal food plant, and total saponins from its root bark extract inhibit α-glucosidase activity, which is associated with type 2 diabetes; however, the inhibitory mechanism is unknown. Furthermore, a green extraction technique superior to conventional hot reflux extraction (HRE) is needed for the rapid and easy extraction of A. taibaiensis total saponins (TSAT) to exploit and utilize this resource. Our aim was to develop a green extraction method for obtaining TSAT and to investigate the mechanism by which TSAT inhibits α-glucosidase. In this study, the ultrasound-assisted extraction (UAE) process was optimized using a Box-Behnken design, and the extraction mechanism was investigated using scanning electron microscopy (SEM). High-performance liquid chromatography (HPLC) was used for qualitative and quantitative analyses of TSAT. In vitro glycosylation assays, enzyme kinetics, fluorescence spectroscopy measurements, atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FT-IR) and molecular docking techniques were used to investigate the mechanism by which the A. taibaiensis active ingredients inhibit α-glucosidase. The optimal parameters for the extraction yield were obtained as an ethanol concentration of 73%, ultrasound time of 34 min, ultrasound temperature of 61 °C and solid-liquid ratio of 16 g/mL, which were better than HRE. The SEM analysis showed that UAE effectively disrupted plant cells, thus increasing the TSAT yield. In vitro α-glucosidase inhibition experiments showed that both TSAT and its active ingredient, araloside A, inhibited α-glucosidase activity by binding to α-glucosidase, thereby changing the conformation and microenvironment of α-glucosidase to subsequently inhibit enzyme activity. The optimal extraction conditions identified here established a basis for future scale-up of ultrasound extraction parameters with the potential for obtaining maximum yields. In vitro enzyme inhibition experiments investigated the mechanism of the TSAT interaction with α-glucosidase and further explored whether araloside A may be the main contributor to the good inhibition of α-glucosidase activity by TSAT.


Reclamation of agro-wastewater polluted with thirteen pesticides by solar photocatalysis to reuse in irrigation of greenhouse lettuce grown.
In Mediterranean countries, reuse of reclaimed water is essential for crop irrigation. The occurrence of pesticides in agro-wastewater may represent a risk for human health and environment owing to their release in soil and translocation to plants. The novelty of this work relies on the reuse of reclaimed agro-wastewater polluted with thirteen pesticides for lettuce irrigation. Removing of pesticide residues in agro-wastewater was carried out using natural sunlight and TiO2/Na2S2O8 in a pilot facility located in Murcia (SE of Spain). The studied pesticides were azoxystrobin, boscalid, chlorpropham, flutolanil, flutriafol, isoxaben, methoxyfenozide, myclobutanil, napropamide, prochloraz, propamocarb, propyzamide and triadimenol, which are commonly used in southeast Spain to treat lettuces grown. Different heterogeneous and homogeneous processes were studied and compared. Previously, the optimization of the process for the selection of the best catalytic system was performed at lab-scale. TiO2+ S2O82- was selected due to the greater effectiveness, achieving almost complete disappearance after about 400 kJ m-2 of cumulative UVA exposure. No significant differences were observed in quality parameters of lettuce grown using treated and non-treated agro-wastewater.


Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells.
To examine the impact of tumors on the immune system, we compared global gene expression profiles of peripheral blood T cells from previously untreated patients with B cell chronic lymphocytic leukemia (CLL) with those from age-matched healthy donors. Although the cells analyzed were not part of the malignant clone, analysis revealed differentially expressed genes, mainly involved in cell differentiation in CD4 cells and defects in cytoskeleton formation, vesicle trafficking, and cytotoxicity in CD8 cells of the CLL patients. In coculture experiments using CLL cells and T cells from healthy allogeneic donors, similar defects developed in both CD4 and CD8 cells. These changes were induced only with direct contact and were not cytokine mediated. Identification of the specific pathways perturbed in the T cells of cancer-bearing patients will allow us to assess steps to repair these defects, which will likely be required to enhance antitumor immunity.


[Comparative physiological characteristics of the neuronal impulse activity of the midbrain auditory centers in amphibians and mammals].
Comparative studies have been made on the neuronal activity of the midbrain auditory centers of the frog, guinea pig, rat and cat during the effect of sonic signals of various frequency, duration and intensity. It was shown that with the higher taxonomic position of the animal, the range of activating frequencies also increases, together with the increase in the sharpness of frequency tuning of the neurones and the increase in absolute sensitivity of the latter in the band of frequencies of the best sound perception. Minimal latency values for midbrain neuronal reactions decrease, whereas their distribution range becomes more narrow. The depth of temporal summation increases, while the decrease is observed in the duration time of summation in those neurones which are sensitive to transient phenomena in sonic signals. Possible reasons are discussed which account for the differences in time-frequency properties of the auditory system among vertebrates.


Intermediate Markers and Molecular Genetics of Lung Carcinogenesis.
BACKGROUND: Various options are available for the local control of cancer in the breast - mastectomy, conservation therapy, and mastectomy with reconstruction. METHODS: To evaluate the benefits and drawbacks of the available management options, the authors combine their extensive experience with a review of the literature on outcomes from these approaches. RESULTS: Conservation therapy provides survival outcomes similar to those from mastectomy. Differences in local recurrence rates can be minimized by close adherence to guidelines for patient selection, operative approach, and radiation technique. CONCLUSIONS: The role of the physician in selecting a local therapy for breast cancer has changed from one of informing the patient of the treatment to assessing the presence of medical contraindications to any of the treatments, educating the patients on each treatment approach, providing access to multidisciplinary consultation, and allowing the patient to choose an appropriate treatment approach.


The emerging role and therapeutic implications of bacterial and parasitic deubiquitinating enzymes.
Deubiquitinating enzymes (DUBs) are emerging as key factors for the infection of human cells by pathogens such as bacteria and parasites. In this review, we discuss the most recent studies on the role of deubiquitinase activity in exploiting and manipulating ubiquitin (Ub)-dependent host processes during infection. The studies discussed here highlight the importance of DUB host-pathogen research and underscore the therapeutic potential of inhibiting pathogen-specific DUB activity to prevent infectious diseases.


[Endovascular technique in aortic aneurysm. A promising alternative to open surgery].
The article consists in a presentation of endovascular surgery for abdominal aortic aneurysm repair in 23 cases. Two cases required conversion to open surgery, but the procedure could be completed in the remaining 21 cases, with a current duration of follow-up of up to 30 months. There was early leakage in one case, and late leakage in five cases. Late conversion has been necessary in three instances, and supplementary endovascular measures have been required in a further two instances. All complications have occurred in those cases operated during the first half of the study period. Modification of the endoprosthesis used and increasing skill have reduced both operation time and the complication rate. Intensive care is no longer required, and the median duration of hospitalisation is three days. Follow-up with magnetic resonance imaging has yielded new and important information.


Breastfeeding media coverage and beliefs during the COVID-19 pandemic in Mexico: implications for breastfeeding equity.
Because breastfeeding offers short- and long- term health benefits to mothers and children, breastfeeding promotion and support is a public health priority. Evidence shows that SARS-CoV-2 is not likely to be transmitted via breastmilk. Moreover, antibodies against SARS-CoV-2 are thought to be contained in breastmilk of mothers with history of COVID-19 infection or vaccination. WHO recommends direct breastfeeding as the preferred infant feeding option during the COVID-19 pandemic, even among women with COVID-19; but conflicting practices have been adopted, which could widen existing inequities in breastfeeding. This study aims to describe how information about breastfeeding was communicated in Mexican media during the pandemic and assess Mexican adults' beliefs regarding breastfeeding among mothers infected with COVID-19. We conducted a retrospective content analysis of media coverage on breastfeeding in Mexico between March 1 and September 24, 2020, excluding advertisements. For the content analysis, we performed both a sentiment analysis and an analysis based on strengths, weaknesses, opportunities, and threats (SWOT) for breastfeeding promotion. Additionally, we conducted a descriptive analysis of nationally representative data on adults' beliefs about breastfeeding from the July 2020 round of the ENCOVID-19 survey in Mexico and stratified the results by gender, age, and socioeconomic status. A total of 1014 publications on breastfeeding were identified on the internet and television and in newspapers and magazines. Most information was published during World Breastfeeding Week, celebrated in August. The sentiment analysis showed that 57.2% of all information was classified as positive. The SWOT analysis indicated that most information focused on current actions, messages, policies, or programs that enable breastfeeding (i.e., strengths) or those not currently in place but that may enable breastfeeding (i.e., opportunities) for breastfeeding promotion. However, ENCOVID-19 survey results showed that 67.3% of adults living in households with children under 3 years of age believe that mothers with COVID-19 should not breastfeed, and 19.8% do not know whether these mothers should breastfeed. These beliefs showed differences both by gender and by socioeconomic status. While the Mexican government endorsed the recommendation on breastfeeding during the COVID-19 pandemic, communication was sporadic, inconstant and unequal across types of media. There was a widespread notion that mothers with COVID-19 should not breastfeed and due to differences on beliefs by socioeconomic status, health inequities could be exacerbated by increasing the risk of poorer breastfeeding practices and preventing vulnerable groups from reaping the short and long-term benefits of breastfeeding.


One-Decade-Spanning transgenerational effects of historic radiation dose in wild populations of bank voles exposed to radioactive contamination following the chernobyl nuclear disaster.
The concept of historic radiation doses associated with accidental radioactive releases and their role in leading to radiation-induced non-targeted effects on affected wild animals are currently being evaluated. Previous research studying Fukushima butterfly, Chernobyl bird and fruit fly populations shows that the effects are transgenerational, underlined by the principles of genomic instability, and varied from one species to another. To further expand on the responses of and their sensitivity in different taxonomically distinct groups, the present study sought to reconstruct historic radiation doses and delineate their effects on bank voles (Clethrionomys glareolus) found within a 400-km radius of the Chernobyl Nuclear Power Plant meltdown site. Historic dose reconstruction from the whole-body dose rates for the bank vole samples for their parental generation at the time of radioactive release was performed. Relationships between the historic doses and cytogenetic aberrations and embryonic lethality were examined via graphical presentations. Results suggest that genomic instability develops at the historic dose range of 20-51 mGy while a radioadaptive response develops at the historic dose range of 51-356 mGy. The Linear No-Threshold (LNT) relationship was absent at historic doses of lower than 356 mGy at all generations. However, LNT was apparent when the very high historic dose of 10.28 Gy in one sampling year was factored into the dose response curve for the bank vole generation 21-22. It is worth being reminded that natural mutation accumulation and other environmental stressors outside the realm of dose effects could contribute to the observed effects in a multiple-stressor environment. Nevertheless, the consistent development of genomic instability and radio-adaptive response across generations and sampling sites unearths the utmost fundamental radiobiological principle of transgenerational non-targeted effects. As a result, it calls for better attention and regulation from global governing bodies of environmental health protection.


Deaths Attributable to Diabetes in the United States: Comparison of Data Sources and Estimation Approaches.
The goal of this research was to identify the fraction of deaths attributable to diabetes in the United States. We estimated population attributable fractions (PAF) for cohorts aged 30-84 who were surveyed in the National Health Interview Survey (NHIS) between 1997 and 2009 (N = 282,322) and in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2010 (N = 21,814). Cohort members were followed prospectively for mortality through 2011. We identified diabetes status using self-reported diagnoses in both NHIS and NHANES and using HbA1c in NHANES. Hazard ratios associated with diabetes were estimated using Cox model adjusted for age, sex, race/ethnicity, educational attainment, and smoking status. We found a high degree of consistency between data sets and definitions of diabetes in the hazard ratios, estimates of diabetes prevalence, and estimates of the proportion of deaths attributable to diabetes. The proportion of deaths attributable to diabetes was estimated to be 11.5% using self-reports in NHIS, 11.7% using self-reports in NHANES, and 11.8% using HbA1c in NHANES. Among the sub-groups that we examined, the PAF was highest among obese persons at 19.4%. The proportion of deaths in which diabetes was assigned as the underlying cause of death (3.3-3.7%) severely understated the contribution of diabetes to mortality in the United States. Diabetes may represent a more prominent factor in American mortality than is commonly appreciated, reinforcing the need for robust population-level interventions aimed at diabetes prevention and care.


Clinical and histologic comparative study of subepithelial connective tissue graft and extracellular matrix membrane. A preliminary split-mouth study in humans.
The purpose of this randomized, controlled, split-mouth study was to compare the behavior of the extracellular matrix membrane (EMM) with autogenous subepithelial connective tissue graft (SCTG) when used as a biologic barrier in the covering of immediate implant placement after modified edentulous ridge expansion. A total of five patients between 40 and 59 years of age (three men, two women) were selected for this study and randomly assigned to one of two groups: EMM (test) or SCTG (control). Treatments were randomly assigned at the same surgical appointment. A total of 29 screw-shaped titanium implants were inserted. Clinical examinations and prophylaxis were performed in recall sessions at 2, 4, and 16 weeks postsurgery. A soft tissue biopsy was performed at both sides 4 months postsurgery. This study indicates that both procedures were effective and predictable in barrier membrane coverage after bone expansion and immediate implant placement. The use of EMM may be a valid alternative to SCTG as a biologic barrier in bone expansion procedures. The use of EMM eliminates the need for the palatal donor site and, as such, provides a less invasive solution.


Induction of high mobility group box-1 in dorsal root ganglion contributes to pain hypersensitivity after peripheral nerve injury.
Pro-inflammatory cytokine high mobility group box-1 (HMGB-1) is involved in inflammation in the central nervous system, but less is known about its biological effects in the peripheral nervous system. In the present study, the role of HMGB-1 in the primary afferent nerve was investigated in the context of the pathophysiology of peripheral nerve injury-induced pain hypersensitivity. Real-time PCR confirmed an increase in HMGB-1 mRNA expression in the dorsal root ganglion (DRG) and spinal nerve at 1 day after spinal nerve ligation (SNL). Induction of HMGB-1 mRNA was observed in both injured L5 and uninjured L4. Immunohistochemistry for HMGB-1 revealed that SNL-induced HMGB-1 expression in the primary afferent neurons and satellite glial cells (SGCs) in the DRG, and in Schwann cells in the spinal nerve. Up-regulation of HMGB-1 was associated with translocation of its signal from the nucleus to the cytoplasm. Injection of HMGB-1 into the sciatic nerve produces transient behavioural hyperalgesia. Neutralizing antibody against HMGB-1 successfully alleviated the mechanical allodynia observed after SNL treatment. Receptor for advanced glycation end products (RAGE), one of the major receptors for HMGB-1, was expressed in the primary afferent neurons and SGCs in the DRG, as well as in Schwann cells in the spinal nerve. These results indicate that HMGB-1 is synthesized and secreted into the DRG and spinal nerve, and contributes to the development of neuropathic pain after nerve injury. Blocking HMGB-1/RAGE signalling might thus be a promising therapeutic strategy for the management of neuropathic pain.


Rapid, one-pot procedure to synthesise 103Pd:Pd@Au nanoparticles en route for radiosensitisation and radiotherapeutic applications.
The radioisotope palladium (103Pd), encapsulated in millimetre-size seed implants, is widely used in prostate cancer brachytherapy. Gold nanoparticles (Au NPs) distributed in the vicinity of 103Pd radioactive implants, strongly enhance the therapeutic dose of radioactive implants (radiosensitisation effect). A new strategy under development to replace millimetre-size implants, consist in injecting radioactive NPs in the affected tissues. The development of 103Pd@Au NPs distributed in the diseased tissue, could increase the uniformity of treatment (compared with massive seeds), while enhancing the radiotherapeutic dose to the cancer cells (through Au-mediated radiosensitisation effect). To achieve this goal, it is necessary to develop a rapid, efficient, one-pot and easy-to-automatise procedure, allowing the synthesis of core-shell Pd@Au NPs. The novel synthesis route proposed here enables the production of Pd@Au NPs in not more than 4 h, in aqueous media, with minimal manipulations, and relying on biocompatible and non-toxic molecules. This rapid multi-step process consists of the preparation of ultra-small Pd NPs by chemical reduction of an aqueous solution of H2PdCl4 supplemented with ascorbic acid (AA) as reducing agent and 2,3-meso-dimercaptosuccinic acid (DMSA) as a capping agent. Pd conversion yields close to 87% were found, indicating the efficiency of the reaction process. Then Pd NPs were used as seeds for the growth of a gold shell (Pd@Au), followed by grafting with polyethylene glycol (PEG) to ensure colloidal stability. Pd@Au-PEG (TEM: 20.2 ± 12.1 nm) formed very stable colloids in saline solution as well as in cell culture medium. The physico-chemical properties of the particles were characterised by FTIR, XPS, and UV-vis. spectroscopies. The viability of PC3 human prostate cancer cells was not affected after a 24 h incubation cycle with Pd@Au-PEG NPs to concentrations up to 4.22 mM Au. Finally, suspensions of Pd@Au-PEG NPs measured in computed tomography (CT) are found to attenuate X-rays more efficiently than commercial Au NPs CT contrast media. A proof-of-concept was performed to demonstrate the possibility synthesise radioactive 103Pd:Pd@Au-PEG NPs. This study reveals the possibility to synthesise Pd@Au NPs rapidly (including radioactive 103Pd:Pd@Au-PEG NPs), and following a methodology that respects all the strict requirements underlying the production of NPs for radiotherapeutic use (rapidity, reaction yield, colloidal stability, NPs concentration, purification).


Spectroscopic characterization of recombinant pea cytosolic ascorbate peroxidase: similarities and differences with cytochrome c peroxidase.
Recombinant pea cytosolic ascorbate peroxidase (APX) has been characterized by resonance Raman (RR) and electronic absorption spectroscopies. The ferric and ferrous forms together with the complexes with fluoride and imidazole have been studied and compared with the corresponding spectra of cytochrome c peroxidase (CCP). Ferric APX at neutral pH is a mixture of 6- and 5-coordinate high-spin and 6-c low-spin hemes, the latter two species being dominant. The results suggest that the low-spin form derives from a water/hydroxo ligand bound to the heme iron and not from a strong internal ligand as observed in CCP at alkaline pH. Two Fe-Im stretching modes are identified, as in CCP, but the RR frequencies confirm a weaker His163-Asp208 hydrogen bond than in CCP, as suggested on the basis of the X-ray structure [Patterson, W. R., and Poulos, T. L. (1995) Biochemistry 34, 4331-4341]. The data show that CCP and APX have markedly different orientations of the vinyl substituents on the heme chromophore resulting from different steric constraints exerted by the protein matrix.


Coccolithogenesis In Scyphosphaera apsteinii (Prymnesiophyceae).
Coccolithophores are the most significant producers of marine biogenic calcite, although the intracellular calcification process is poorly understood. In the case of Scyphosphaera apsteinii Lohmann 1902, flat ovoid muroliths and bulky, vase-shaped lopadoliths with a range of intermediate morphologies may be produced by a single cell. This polymorphic species is within the Zygodiscales, a group that remains understudied with respect to ultrastructure and coccolith ontogeny. We therefore undertook an analysis of cell ultrastructure, morphology, and coccolithogenesis. The cell ultrastructure showed many typical haptophyte features, with calcification following a similar pattern to that described for other heterococcolith bearing species including Emiliania huxleyi. Of particular significance was the reticular body role in governing fine-scale morphology, specifically the central pore formation of the coccolith. Our observations also highlighted the essential role of the inter- and intracrystalline organic matrix in growth and arrangement of the coccolith calcite. S. apsteinii secreted mature coccoliths that attached to the plasma membrane via fibrillar material. Time-lapse light microscopy demonstrated secretion of lopadoliths occurred base first before being actively repositioned at the cell surface. Significantly, growth irradiance influenced the coccosphere composition with fewer lopadoliths being formed relative to muroliths at higher light intensities. Overall, our observations support dynamic metabolic (i.e., in response to growth irradiance), sensory and cytoskeletal control over the morphology and secretion of polymorphic heterococcoliths. With a basic understanding of calcification established, S. apsteinii could be a valuable model to further study coccolithophore calcification and cell physiological responses to ocean acidification.


A novel Tmem119-tdTomato reporter mouse model for studying microglia in the central nervous system.
Microglia are resident immune cells of the central nervous system (CNS). The exact role of microglia in CNS disorders is not clear due to lack of tools to discriminate between microglia and infiltrating myeloid cells. Here, we present a novel reporter mouse model targeting a microglia-specific marker, TMEM119, for studying microglia in health and disease. By placing a reporter cassette (GSG-3xFlag-P2A-tdTomato) between the coding sequence of exon 2 and 3'UTR of the Tmem119 gene using CRISPR/Cas9 technology, we generated a Tmem119-tdTomato knock-in mouse strain. Gene expression assay showed no difference of endogenous Tmem119 in the CNS of Tmem119tdTomato/+ relative to wild-type mice. The cells expressing tdTomato were recognized by immunofluorescence staining using commercially available anti-TMEM119 antibodies. Additionally, immunofluorescence and flow cytometry techniques revealed that tdTomato+ cells are detected throughout the CNS, but not in peripheral tissues of Tmem119tdTomato/+ mice. Aging does not influence TMEM119 expression as tdTomato+ cells were detectable in the CNS of older mice (300 and 540 days old). Further immunofluorescence characterization shows that tdTomato+ cells colocalize with Iba1+ cells in the brain, but not with neurons, astrocytes or oligodendrocytes. Moreover, flow cytometry analysis of brain tissues of adult mice demonstrates that the majority of microglia CD45loCD11b+ cells (96.3%) are tdTomato-positive; and a minority of infiltrating CD45hiCD11b+ myeloid cells (5.3%) are also tdTomato-positive, which we further characterized and found that tdTomato expression is in part of choroid plexus macrophages but not in meningeal and perivascular macrophages. Functionally, using an acute injury model, we measured time-lapse activation of tdTomato-labeled microglia by transcranial two-photon microscopy in live Tmem119tdTomato/+ mice. Taken together, the Tmem119-tdTomato reporter mouse model is a valuable tool to specifically study the role of microglia in health and disease.


How thiamine diphosphate is activated in enzymes.
The controversial question of how thiamine diphosphate, the biologically active form of vitamin B1, is activated in different enzymes has been addressed. Activation of the coenzyme was studied by measuring thermodynamics and kinetics of deprotonation at the carbon in the 2-position (C2) of thiamine diphosphate in the enzymes pyruvate decarboxylase and transketolase by use of nuclear magnetic resonance spectroscopy, proton/deuterium exchange, coenzyme analogs, and site-specific mutant enzymes. Interaction of a glutamate with the nitrogen in the 1'-position in the pyrimidine ring activated the 4'-amino group to act as an efficient proton acceptor for the C2 proton. The protein component accelerated the deprotonation of the C2 atom by several orders of magnitude, beyond the rate of the overall enzyme reaction. Therefore, the earlier proposed concerted mechanism or stabilization of a C2 carbanion can be excluded.


Loss of responsiveness to transforming growth factor beta induces malignant transformation of nontumorigenic rat prostate epithelial cells.
Transforming growth factor (TGF)-betas are multifunctional growth factors, the properties of which include the potent inhibition of epithelial cell growth. Expression patterns of TGF-betas and TGF-beta receptors in the normal prostate indicate that these growth regulators play key roles in prostatic development and proliferative homeostasis. Importantly, TGF-beta receptor levels are frequently diminished in malignant human prostate tissue. To test the hypothesis that loss of TGF-beta responsiveness is causally involved in the tumorigenic process, we have used retroviral transduction to introduce a dominant-negative mutant type II TGF-beta receptor (DNR) into the premalignant rat prostatic epithelial cell line, NRP-152. High-level expression of the DNR abolished the ability of TGF-beta to inhibit cell growth, to promote cell differentiation, and to induce apoptosis, and it partially blocked the induction of extracellular matrix gene expression. When injected into nude mice, NRP-152-DNR cells formed carcinomas at 13 of 34 sites, compared with 0 of 30 sites for parental and control cells (P = 0.0001). We conclude that the type II TGF-beta receptor is an important tumor suppressor in the prostate, and furthermore, that loss of TGF-beta responsiveness can contribute early in the tumorigenic process by causing the malignant transformation of preneoplastic cells.


Calcium-induced long-term potentiation in the hippocampal slice: characterization of the time course and conditions.
A transient increase in extracellular calcium concentration causes a long-lasting enhancement of radiatum fibers evoked excitatory postsynaptic potential and population spike responses of CA1 pyramidal neurons which resembles long-term potentiation (LTP). The duration of this potentiation is much longer than described previously and is probably limited by the survival of the preparation itself (greater than 8 hr). Therefore, Ca-induced LTP can be used for the investigation of a postulated late phase of LTP. Ca effects were activity-independent, since the subsequently evoked responses were facilitated even when the presynaptic fibers were not concurrently stimulated during or immediately after superfusion with the high Ca medium. In contrast, if too frequent testing of the synaptic input was done during the high Ca pulse, a short lasting depression instead of potentiation was observed. A lower extracellular magnesium concentration in the standard medium (1.3 instead of 2.0 mM MgSO4) prevents the potentiation of the EPSP at least for the first few hours. Presumably, both tetanus- and Ca-induced LTP share some common mechanisms, since an additional tetanization after Ca induction was not followed by an additional LTP. Compared to the potentiation following tetanization, the Ca-induced LTP was, however, not accompanied by a potentiation of the EPSP/spike ratio within the range of the population spike threshold intensity.


Planar tetracoordinate carbons with a double bond in CAl3E clusters.
The potential energy surfaces of a series of clusters with the formula CAl3E (E = P, As, Sb, Bi) are systematically explored using density functional theory and high level ab initio calculations. The global minimum structure of these clusters contains a planar tetracoordinate carbon atom. The presence of a C=E double bond is supported by the Wiberg bond indices, the adaptive natural density partitioning analysis, and the magnetic response. Our results show that these planar tetracoordinate carbon clusters are both thermodynamically and kinetically viable species in the gas phase.


Nuclear envelope breakdown in mammalian cells involves stepwise lamina disassembly and microtubule-drive deformation of the nuclear membrane.
We have studied nuclear envelope disassembly in mammalian cells by morphological methods. The first signs of nuclear lamina depolymerization become evident in early prophase as A-type lamins start dissociating from the nuclear lamina and diffuse into the nucleoplasm. While B-type lamins are still associated with the inner nuclear membrane, two symmetrical indentations develop on antidiametric sites of the nuclear envelope. These indentations accommodate the sister centrosomes and associated astral microtubules. At mid- to late prophase, elongating microtubules apparently push on the nuclear surface and eventually penetrate the nucleus. At this point the nuclear envelope becomes freely permeable to large ligands, as indicated by experiments with digitonin-treated cells and by the massive release of solubilized A-type lamins into the cytoplasm. At the prophase/prometaphase transition, the B-type lamina is fragmented, but 'islands' of lamin B polymer can still be discerned on the tips of congressing chromosomes. Finally, at metaphase, the lamin B polymer breaks down into small pieces, which tend to concentrate in the area of the mitotic spindle. Nuclear envelope breakdown is not prevented when the microtubules are depolymerized by nocodazole; however, the mode of nuclear lamina fragmentation in the absence of microtubules is markedly different from the normal one and involves multiple raffles and gaps, which develop rapidly along the entire surface of the nuclear envelope. These data suggest that nuclear envelope disassembly is a stepwise process in which the microtubules play an important part.


Xenobiotic effects in the ovary: temporary versus permanent infertility.
Damage caused by xenobiotic compounds to the ovaries is a subject of concern because of their critical role in reproduction. Female mammals are born with a finite number of germ cells (oocytes) encased in primordial follicles. Xenobiotic-induced damage to primordial follicles can result in early ovarian failure (premature menopause). Alternatively, damage affecting larger growing follicles can prevent ovulation, thereby causing infertility during childbearing years. This review summarizes information from animal studies and human observations about xenobiotic compound classes known to target the ovary to potentially cause reversible infertility (amenorrhea) as well as early ovarian failure. Toxicological evidence supporting ovotoxicity mechanisms from some of these compounds is presented. The reader will gain an appreciation of how exposures to certain widespread environmental chemicals are of concern as regards impacting a woman's reproductive capabilities and life span. Three emerging areas of mechanistic targeting of the ovary by these chemicals are identified. These areas relate to the type of cell death, effects on follicular development and the importance of ovarian metabolism. In each case, the potential translational relevance of these areas to toxicological as well as physiological insight is highlighted. A recommendation to expand upon these three areas is made.


Impact of spirometry on the management of chronic obstructive airway disease.
A simple spirometer was tested in an outpatient family practice to determine whether its use increased detection of chronic obstructive airway disease (COAD) in patients at risk, more accurately identified patients with reversible bronchospasm, and helped to make the most of their bronchodilator therapy. Three (17 percent) of 18 patients at risk, previously unlabeled, were found to have COAD. Of 28 patients with a previous COAD diagnosis, 5 (18 percent) had the diagnosis deleted, and 5 who had previously been classified as "reversible" were reclassified as having "irreversible" bronchospasm (P less than .025). Of 46 patients studied, bronchodilator therapy was changed in 18 (39 percent); 12 of these improved symptomatically according to a subjective score (P less than .02). A few patients demonstrated a significant improvement in 1-second forced expiratory volume.


Effect of nicotinamide and urea on the solubility of riboflavin in various solvents.
Hydrotropy is a solubilization process whereby addition of large amounts of a second solute results in an increase in the aqueous solubility of another solute. Past investigations have focused on the potential interaction of the hydrotropic agent with the solubilized solute. Conversely, this study proposes that at least some hydrotropic agents exert their solubilizing effect predominately by interacting with the solvent. To that end, the effect of two hydrotropic agents, nicotinamide and urea, on riboflavin solubility in aqueous and nonaqueous systems was examined. The term "solutropy" is introduced to describe solubilization by addition of large amounts of a second solute in any solvent. The nonaqueous solvents used included methanol, N-methylformamide, dimethyl sulfoxide, and acetone. In water, methanol, and N-methylformamide, riboflavin solubility was found to increase with increasing nicotinamide concentration; however, riboflavin solubility decreased with increasing nicotinamide concentration in dimethyl sulfoxide and acetone, thus establishing the solvent-dependent nature of solutropy. An examination of solvent properties revealed that the solvent's ability to be both a proton donor and acceptor is important mechanistically, while dielectric constant and polarity are not. The same solvent-dependency was observed with urea, although urea is a poorer solutrope than nicotinamide. This study proposes that some solutropic agents act by changing the nature of the solvent, specifically by altering the solvent's ability to participate in structure formation via intermolecular hydrogen bonding.


Primary care of adults with mental retardation living in the community.
An increased number of adults with mental retardation are living in the community and seeking health care from family physicians. When mentally retarded patients are enrolled in a medical practice, guardianship status should be determined, but these patients should be involved in their own care to as great an extent possible. Since a verbal history may be difficult to obtain, a systematic, thorough physical examination is important. Certain Illnesses, such as hepatitis B, recurrent aspiration syndrome, leukemia and atlantoaxial instability, are much more common in adults with Down syndrome then in adults with mental retardation from other causes. Seizures and mental illness are equally common in all mentally retarded adults. The behavior management and pharmacologic therapy of patients with mental retardation are best handled in close association with caregivers, as well as psychiatrists and neurologists who are familiar with the special needs of this population.


Surfaces of rod photoreceptor disk membranes: light-activated enzymes.
The light-activated GTP-binding protein (GBP) in toad rod outer segments has been located on the cytoplasmic surface (CS) of rod disk membranes by correlating biochemical results with images of quick-frozen, freeze-fractured, and deep-etched rod outer segments. This has been accomplished by selectively removing and replacing the 8-12-nm particles that are found on the CS of disk membranes, exactly in parallel with the GBP. In contrast, the large particles are not correlated with another major disk enzyme, the light-activated cGMP phosphodiesterase. We have been unable to visualize this protein. The surface density of large particles, one particle per eleven rhodopsins in isolated rod outer segments and one particle per nine rhodopsins in intact retina, correlates well with previous biochemical estimates of GBP numbers based on enzyme activity. After the identification of the large particles, we tested the effects of light on the density of particles on the surface of disk membranes in intact retinas. Retinas quick-frozen at various intervals after a bright flash of light show a modest increase (approximately 30%) in particle density by 10 s after the flash but no increase before 1 s. The number of particles on the disk membrane returns to dark levels between 1 and 10 min after the flash. The 1-s latency in the change of particle binding would appear to rule out this process as a mechanism for initiating phototransduction in the rod.


Inhibition of signaling through the B cell antigen receptor by the protooncogene product, c-Cbl, requires Syk tyrosine 317 and the c-Cbl phosphotyrosine-binding domain.
The Syk protein-tyrosine kinase couples the B cell Ag receptor (BCR) to intracellular biochemical pathways. Syk becomes phosphorylated on multiple tyrosine residues upon receptor cross-linking. Tyrosine 317 is a site of phosphorylation located within the linker region of Syk that separates the amino-terminal, tandem pair of SH2 domains from the carboxyl-terminal catalytic domain. The amino acid sequence surrounding phosphotyrosine 317 matches the consensus sequence for recognition by the phosphotyrosine-binding (PTB) domain of the protooncogene product, c-Cbl. The overexpression of c-Cbl in DT40 B cells inhibits Ag receptor-mediated activation of the NF-AT transcription factor. The ability of overexpressed c-Cbl to inhibit signaling requires both Syk tyrosine 317 and a functional c-Cbl PTB domain. Mutant forms of Syk lacking tyrosine 317 exhibit an enhanced ability to couple the BCR to pathways leading to the activation of both NF-AT and Elk-1. Coimmunoprecipitation experiments indicate that Syk phosphotyrosine 317 and the c-Cbl PTB domain enhance, but are not required for, all interactions between these two proteins. In unstimulated cells, c-Cbl and Syk can be isolated in a complex that also contains tubulin. A mutant form of Syk lacking tyrosine at position 317 exhibits an enhanced ability to interact with a diphosphopeptide modeled on the immunoreceptor tyrosine-based activation motif of the CD79a component of the Ag receptor. These studies indicate that c-Cbl may contribute to the regulation of BCR signaling by modulating the ability of Syk to associate with the BCR and couple the receptor to intracellular signaling pathways.


[Metabolism and kinetics of ampicillin elimination in cirrhosis. Therapeutical consequences (author's transl)].
In cirrhotic patients, the authors studied the modification of the pharmacokinetics of ampicillin in the plasma and in the ascitic fluid, as well as its concentration in the urine. The influence of the jaundice, the ascites and diuretics were studied. In cirrhosis, dilution and elimination of the antibiotic are modified, as is shown by the increase in T 1/2 alpha and T 1/2 beta. These anomalies seem to be due essentially to modifications in the distribution volume; the degree of hepatocellular insufficiency does not appear to be of importance. The ascites acts as an independent compartment, into which the antibiotic's passage is slight. The practical consequences are the following: less frequent injections, increasing of the fractionated doses, in situ injections of ampicillin in cases of infection of the ascitic liquid.


Dendritic cells and B cells cooperate in the generation of CD4(+)CD25(+)FOXP3(+) allogeneic T cells.
CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) play an essential role in immune tolerance, suppressing responses against self-antigens. Additionally, Treg play an important role in maintaining immunosuppression to alloantigens as well as to other antigens. It is well known that in the gut, a subset of dendritic cells produces retinoic acid (RA), which together with transforming growth factor (TGF-beta) is able to differentiate naïve T cells into Treg. The aim of this study was to establish the role of antigen-presenting cells (APC) in the differentiation of allogeneic Tregs under the effect of RA and TGF-beta. Splenic CD4(+)CD25(-) naïve T cells from C57BL/6 mice were co-cultured with splenic CD11c-enriched APC from Balb/c mice in the presence of TGF-beta, RA, and interleukin (IL-2). After 6 days of culture, cells were analyzed for the expression of Foxp3 by flow cytometry. Additionally, we investigated the role of B cells and dendritic cells (DCs) and their stimulatory capacity in the generation of Tregs. Our results showed that co-culture of naive T cells with the appropriate level of stimulation by APC in the presence of TGF-beta, RA, and IL-2 provided a new powerful approach to generate allogeneic Treg cells. We demonstrated that although B cells and DCs can generate Tregs by themselves, a mixure of both APC improved their capacity to efficiently generate Tregs. Also, we observed that although the addition of IL-2 to the cultures was not crucial to generate Tregs, it was required to optimize their expansion and cell survival.


Self-operated endovaginal telemonitoring: a prospective, clinical validation study.
To study the comparability of self-operated endovaginal telemonitoring (SOET) with conventional two-dimensional transvaginal sonography (2D-TVS) monitoring during assisted reproductive technology (ART) cycles. Single center, observational, single-blinded cohort study. University-affiliated in vitro fertilization center. A total of 60 women undergoing ART cycles. Explanation, training, and use of SOET system, and measurements of follicular and endometrial diameter with SOET and 2D-TVS. Correlation of the total number of follicles >10 mm measured by SOET versus conventional 2D-TVS. In 16 cases (26.7%) the images were judged unsuitable for analysis. In these excluded cases the body mass index (BMI) was statistically significantly higher (29.3 vs. 24.4 kg/m(2)). The total number of follicles >10 mm was highly similar comparing SOET with conventional 2D-TVS (r = 0.91). For the concordance of whether more than 19 follicles or more than 25 follicles >10 mm were present, we found agreement between the methods in 43 of 44 cases (κ = 0.88) and 43 of 44 cases (κ = 0.85), respectively. For concordance on predefined human chorionic gonadotropin administration criteria, agreement was found in 39 of 44 cases (κ = 0.734). The incidence of SOET videos not suitable for analysis seems to be associated with higher BMI. Otherwise, SOET showed good agreement with conventional 2D-TVS both for follicles and endometrium measurements. More importantly we also found good concordance regarding the cutoffs relevant for clinical decisions.


Fatigue Severity among Adults with Chronic Low Back Pain: Relations to Opioid Use and Hazardous Alcohol Use.
Chronic low back pain is the second leading cause of disability in the United States and is related to greater risk of opioid misuse. Research suggests that severe fatigue may be a relevant factor for better understanding the greater rates of opioid and misuse among adults with chronic low back pain. Therefore, the current study sought to examine differences in opioid misuse, risk for opioid use disorder, and hazardous alcohol use in two different groups: one group with clinically significant fatigue, and one group without clinically significant fatigue. Participants were recruited utilizing a validated online survey management system that yielded 1,681 adults (70.0% female, 81.1% White, M age = 44.5 years, SD = 11.88) with current mild to severe chronic low back pain. One-way analysis of covariance (ANCOVA) models were conducted to examine group differences. Among adults with chronic low back pain, those with clinically significant fatigue reported significantly greater opioid misuse and risk for opioid use disorder compared to those without clinically significant fatigue. These results were evident after controlling for pain severity and interference. The results for hazardous alcohol use were not significantly different between groups. Clinically significant fatigue is a distinguishing characteristic among adults with chronic low back pain in terms of opioid misuse and risk for opioid use disorder. Potential clinical implications of such findings suggest that it may be important for clinicians to assess fatigue levels to better manage opioid misuse potential among adults with chronic low back pain.


Molecular mechanism of CCDC106 regulating the p53-Mdm2/MdmX signaling axis.
The tumor suppressor p53 (p53) is regulated by murine double minute 2 (Mdm2) and its homologous MdmX in maintaining the basal level of p53. Overexpressed Mdm2/MdmX inhibits cellular p53 activity, which is highly relevant to cancer occurrence. Coiled-coil domain-containing protein 106 (CCDC106) has been identified as a p53-interacting partner. However, the molecular mechanism of the p53/Mdm2/MdmX/CCDC106 interactions is still elusive. Here, we show that CCDC106 functions as a signaling regulator of the p53-Mdm2/MdmX axis. We identified that CCDC106 directly interacts with the p53 transactivation domain by competing with Mdm2 and MdmX. CCDC106 overexpression downregulates the cellular level of p53 and Mdm2/MdmX, and decreased p53 reversibly downregulates the cellular level of CCDC106. Our work provides a molecular mechanism by which CCDC106 regulates the cellular levels of p53 and Mdm2/MdmX.


Reduction of adhesion formation after knee surgery in a rat model by botulinum toxin A.
Adhesion of the knee is a major concern after knee surgery, the treatment of which is difficult. Botulinum toxin A (BTX-A) injection is demonstrated as efficient in treating knee adhesion after surgery. However, the treatment outcomes and the mechanism of action are not yet determined. The aim of the present study was to examine the effects and molecular mechanism of a BTX-A treatment in preventing adhesion of the knee. Twenty-four Wistar rats were randomly divided into a BTX-A treatment group and a control group. BTX-A or saline was injected into the cavity of the knee in the BTX-A treatment or control group respectively. Gross and histopathological examinations of interleukin 1 (IL-1) and fibroblast growth factor (FGF) levels, as well as fibroblast cell numbers, were assessed in the knee intra-articular adhesions in each group 6 weeks after recovery from the surgery. Macroscopic observations showed a significant reduction in adhesion severity in the BTX-A treatment group compared with the control group. In addition, the levels of IL-1 and FGF were lower and the number of fibroblasts was smaller in the BTX-A treatment group compared with those in the control group. BTX-A prevented intra-articular adhesion of knee in the rats, which might be associated with reduced expressions of IL-1 and FGF.


Cue-induced reinstatement of alcohol-seeking behavior is associated with increased CaMKII T286 phosphorylation in the reward pathway of mice.
Cue-induced reinstatement of alcohol-seeking is a hallmark behavioral pathology of addiction. Evidence suggests that reinstatement (e.g., relapse), may be regulated by cell signaling systems that underlie neuroplasticity. A variety of plasticity events require activation of calcium calmodulin-dependent protein kinase II (CaMKII) in components of the reward pathway, such as the nucleus accumbens and amygdala. We sought to determine if cue-induced reinstatement of alcohol-seeking behavior is associated with changes in the activation state (e.g., phosphorylation) of CaMKII-T286. Male C57BL/6J mice (n=14) were trained to lever press on a fixed-ratio-4 schedule of sweetened alcohol (2% sucrose+9% EtOH) reinforcement. After 14-d of extinction (no cues or reinforcers), mice underwent a response-contingent reinstatement (n=7) vs. an additional day of extinction (n=7). Brains were removed immediately after the test and processed for evaluation of pCaMKII-T286 immunoreactivity (IR). Number of pCaMKII-T286 positive cells/mm2 was quantified from coronal brain sections using Bioquant Image Analysis software. Mice emitted significantly more responses on the alcohol vs. the inactive lever throughout the baseline phase with average alcohol intake of 1.1±0.03g/kg/1-h. During extinction, responses on the alcohol lever decreased to inactive lever levels by day 7. Significant cue-induced reinstatement of alcohol-seeking was observed during a single test with no effects on the inactive lever. Reinstatement was associated with increased pCaMKII-T286 IR specifically in amygdala (LA and BLA), nucleus accumbens (AcbSh), lateral septum, mediodorsal thalamus, and piriform cortex as compared to extinction control. Brain regions showing no change included the dorsal striatum, medial septum, cingulate cortex, habenula, paraventricular thalamus, and ventral hypothalamus. These results show response contingent cue-induced reinstatement of alcohol-seeking behavior is associated with selective increases in pCaMKII-T286 in specific reward- and memory-related brain regions of male C57BL/6J mice. Primary molecular mechanisms of associative learning and memory may regulate relapse in alcohol addiction.


Quorum sensing and virulence regulation in Xanthomonas campestris.
It is now clear that cell-cell communication, often referred to as quorum sensing (QS), is the norm in the prokaryotic kingdom and this community-wide genetic regulatory mechanism has been adopted for regulation of many important biological functions. Since the 1980s, several types of QS signals have been identified, which are associated commonly with different types of QS mechanisms. Among them, the diffusible signal factor (DSF)-dependent QS system, originally discovered from bacterial pathogen Xanthomonas campestris pv. campestris, is a relatively new regulatory mechanism. The rapid research progress over the last few years has identified the chemical structure of the QS signal DSF, established the DSF regulon, and unveiled the general signaling pathways and mechanisms. Particular noteworthy are that DSF biosynthesis is modulated by a novel posttranslational autoinduction mechanism involving protein-protein interaction between the DSF synthase RpfF and the sensor RpfC, and that QS signal sensing is coupled to intracellular regulatory networks through a second messenger cyclic-di-GMP and a global regulator Clp. Genomic and genetic analyses show that the DSF QS-signaling pathway regulates diverse biological functions including virulence, biofilm dispersal, and ecological competence. Moreover, evidence is emerging that the DSF QS system is conserved in a range of plant and human bacterial pathogens.


Salt restriction in the treatment of hypertension.
Moderate salt restriction lowers blood pressure in many patients with essential hypertension. The effectiveness of the salt restriction in lowering blood pressure appears to be directly related to the severity of the blood pressure and suppression of the renin-angiotensin system. Patients with more severe hypertension, older patients or black patients will respond best. Salt restriction is additive to the effect of blood pressure lowering drugs particularly those that block the renin-angiotensin system such as beta-blockers and converting enzyme inhibitors. All patients with high blood pressure and, particularly those already on drug treatment, should be instructed on how to cut back their salt intake moderately. Most patients find it easy to reduce salt intake to around half of their present consumption.


Nasal responses to elevated temperature and Francisella noatunensis infection in Atlantic cod (Gadus morhua).
We report the histological and transcriptomic changes in the olfactory organ of Atlantic cod exposed to Francisella noatunensis. Experimental infection was performed at either 12 °C or 17 °C. Infected fish presented the classic gross pathologies of francisellosis. Nasal morpho-phenotypic parameters were not significantly affected by elevated temperature and infection, except for the number of mucus cells in the 12 °C group seven weeks after the challenge. A higher number of genes were altered through time in the group reared at 17 °C. At termination, the nasal transcriptome of infected fish in both groups was similar to the control. When both infected groups were compared, 754 DEGs were identified, many of which were involved in signalling, defence, transmembrane and enzymatic processes. In conclusion, the study reveals that elevated temperature could trigger responses in the olfactory organ of Atlantic cod and shape the nasal response to F. noatunensis infection.


Genetic factors in autoimmune thyroid disease analyzed by restriction fragment length polymorphisms of candidate genes.
Possible genetic effects on the development of autoimmune thyroid disease were studied by analysis of restriction fragment length polymorphisms (RFLPs) of candidate genes. Peripheral blood leukocyte DNA was obtained from 65 caucasian patients with Graves' disease, 63 caucasian patients with Hashimoto's thyroiditis, and 65 caucasian controls. RFLP analysis was carried out on genomic DNA, using probes for DR beta, DQ alpha, DQ beta, DP alpha, DP beta, T-cell receptor TCR alpha, and thyroid peroxidase. The methodology allowed HLA-DR and DQ typing and provided information on specific RFLP patterns related to T cell receptor (TCR)alpha, DP alpha and -beta, and -beta, and thyroid peroxidase. HLA-DR3 frequency was significantly increased in patients with Graves' disease, as reported previously by others, but neither DNA-derived subtype of DR3 was differentially increased. HLA-DQw2 was also present in increased frequency because of its linkage disequilibrium with HLA-DR3. It is uncertain whether the primary susceptibility is with DQ, DR, or another nearby locus. Susceptibility was not related in these studies to genetic loci recognized in these studies involving DQ alpha, DP, TCR, or thyroid peroxidase. A significant linkage disequilibrium between DR3 and a specific DX alpha RFLP was observed in Graves' disease, but is believed to be representative of a generalized linkage disequilibrium between DR3 and DX alpha, rather than a specific abnormality in Graves' disease. Previous studies indicating association with specific TCR RFLPs could not be reproduced. The relative risk for carriers of HLA-DR3 subtype A in this study was 7.37-fold. RFLP analysis offers the possibility of investigating linkage in a variety of candidate genes as well as established genetic relationships for potentially important subtypes. While the significant relationship with HLA-DR3/DQw2 was reconfirmed, the involvement of other genes or haplotypes could not be established.


Filter materials for metal removal from mine drainage--a review.
A large number of filter materials, organic and inorganic, for removal of heavy metals in mine drainage have been reviewed. Bark, chitin, chitosan, commercial ion exchangers, dairy manure compost, lignite, peat, rice husks, vegetal compost, and yeast are examples of organic materials, while bio-carbons, calcareous shale, dolomite, fly ash, limestone, olivine, steel slag materials and zeolites are examples of inorganic materials. The majority of these filter materials have been investigated in laboratory studies, based on various experimental set-ups (batch and/or column tests) and different conditions. A few materials, for instance steel slag materials, have also been subjects to field investigations under real-life conditions. The results from these investigations show that steel slag materials have the potential to remove heavy metals under different conditions. Ion exchange has been suggested as the major metal removal mechanisms not only for steel slag but also for lignite. Other suggested removal mechanisms have also been identified. Adsorption has been suggested important for activated carbon, precipitation for chitosan and sulphate reduction for olivine. General findings indicate that the results with regard to metal removal vary due to experimental set ups, composition of mine drainage and properties of filter materials and the discrepancies between studies renders normalisation of data difficult. However, the literature reveals that Fe, Zn, Pb, Hg and Al are removed to a large extent. Further investigations, especially under real-life conditions, are however necessary in order to find suitable filter materials for treatment of mine drainage.


[A comparative evaluation of the use of immunoturbidimetry in clinical practice].
A variant of immunoturbidimetry available for any clinical diagnostic laboratory has been developed. The data of measurements of immunoglobulins, albumin, alpha 2-macroglobulin and some other proteins of pregnancy in the blood serum and other biologic fluids, carried out by immunoturbidimetry, coincided with the findings of radial immunodiffusion and rocket immunoelectrophoresis, but immunoturbidimetry is more rapid and simple.


Psychometric evaluation of the Muscle Dysmorphic Disorder Inventory (MDDI) among cisgender gay men and cisgender lesbian women.
Despite increasing empirical interest in muscle dysmorphia (MD), a dearth of research has assessed this construct in sexual minority populations. In particular, the psychometric properties of one of the most widely used measures of MD symptoms-the Muscle Dysmorphic Disorder Inventory (MDDI)-have not been evaluated in sexual minority populations despite emerging evidence suggesting differential risk for MD symptoms across sexual orientation groups. In this study, we assessed the psychometric properties of the MDDI in a sample of 715 cisgender gay men and 404 cisgender lesbian women ages 18-50 years who participated in a large-scale national longitudinal cohort study of sexual and gender minority adults. The factor structure of the MDDI was examined in each sample using a two-step, split-sample exploratory and confirmatory factor analytic approach. Exploratory factor analysis supported a three-factor structure in both samples, which were confirmed by confirmatory factor analysis. Moreover, results supported the internal consistency reliability and convergent validity of the MDDI subscales in both samples. Cumulatively, these findings suggest that the MDDI is an appropriate measure of MD symptoms among cisgender gay men and cisgender lesbian women.


A novel, highly potent and selective phosphodiesterase-9 inhibitor for the treatment of sickle cell disease.
The most common treatment for patients with sickle cell disease (SCD) is the chemotherapeutic hydroxyurea, a therapy with pleiotropic effects, including increasing fetal hemoglobin (HbF) in red blood cells and reducing adhesion of white blood cells to the vascular endothelium. Hydroxyurea has been proposed to mediate these effects through a mechanism of increasing cellular cGMP levels. An alternative path to increasing cGMP levels in these cells is through the use of phosphodiesterase-9 inhibitors that selectively inhibit cGMP hydrolysis and increase cellular cGMP levels. We have developed a novel, potent and selective phosphodiesterase-9 inhibitor (IMR-687) specifically for the treatment of SCD. IMR-687 increased cGMP and HbF in erythroid K562 and UT-7 cells and increased the percentage of HbF positive erythroid cells generated in vitro using a two-phase liquid culture of CD34+ progenitors from sickle cell blood or bone marrow. Oral daily dosing of IMR-687 in the Townes transgenic mouse SCD model, increased HbF and reduced red blood cell sickling, immune cell activation and microvascular stasis. The IMR-687 reduction in red blood cell sickling and immune cell activation was greater than that seen with physiological doses of hydroxyurea. In contrast to other described phosphodiesterase-9 inhibitors, IMR-687 did not accumulate in the central nervous system, where it would inhibit phosphodiesterase-9 in neurons, or alter rodent behavior. IMR-687 was not genotoxic or myelotoxic and did not impact fertility or fetal development in rodents. These data suggest that IMR-687 may offer a safe and effective oral alternative for hydroxyurea in the treatment of SCD.


Positive Outcome Expectancy Mediates the Relationship Between Peer Influence and Internet Gaming Addiction Among Adolescents in Taiwan.
The present study examined the role of positive outcome expectancy in the relationship between peer/parental influence and Internet gaming addiction (IGA) among adolescents in Taiwan. Two thousand, one hundred and four junior high students completed the Chen Internet Addiction Scale for IGA, Parental Influence for IGA, peer influence for IGA, and Positive Outcome Expectancy of Internet Gaming Questionnaire. Results showed that the three types of peer influences (positive attitudes toward Internet gaming, frequency of Internet game use, and invitation to play) and positive outcome expectancy were significantly and positively correlated with IGA. Moreover, peer influence was also positively correlated with positive outcome expectancy. On the other hand, positive outcome expectancy and parental influences had a low correlation. Structural equation modeling analysis revealed that positive outcome expectancy did not mediate the relationship between either type of parental influences and IGA, and only the parent's invitation to play Internet games directly predicted IGA severity. However, peers' positive attitude or the frequency of peers' Internet game use positively predicted IGA and was fully mediated through positive outcome expectancy of Internet gaming. In addition, the frequency of peers' invitation to play Internet games directly and indirectly predicted IGA severity through a partial mediation of positive outcome expectancy of Internet gaming. The overall fit of the model was adequate and was able to explain 25.0 percent of the variance. The findings provide evidence in illuminating the role of peer influences and positive outcome expectancy of Internet gaming in the process of why adolescents may develop IGA.


Association between diuretic administration before diagnosis and incidence of acute kidney injury in patients with minimal change disease: A single-center observational study.
We examined the association between diuretic administration before the diagnosis of minimal change disease and the incidence of acute kidney injury. Moreover, we examined whether the use of diuretics affected the time to complete remission in adults with such disease.The present study was a single-center, retrospective, observational cohort study. We included 107 patients with biopsy-proven minimal change disease who were treated at a tertiary referral center in Japan between January 1, 2000 and March 31, 2019. All biopsy specimens were examined by a board-certified renal pathologist. The patients were considered to have minimal change disease when the kidney biopsy specimen had no glomerular lesions or only mild focal mesangial prominence (not exceeding 3 or 4 cells per segment) by light microscopy and/or foot process effacement by electron microscopy. Logistic regression and Kaplan-Meier curve analyses were performed, comparing the data of patients who received diuretics or not.The median age was 47 (28-66) years, 52% of patients were women, and the median proteinuria dosage was 8.3 (5.3-11.2) g/d. When minimal change disease was diagnosed, 27% of patients were taking diuretics. Within 30 days after the diagnosis, acute kidney injury occurred in 27% of patients. On multivariable logistic regression analysis, the use of diuretics was significantly associated with a higher risk of acute kidney injury. The use of diuretics was also associated with a longer time to complete remission.Diuretic administration can be associated with an elevated acute kidney injury risk and longer remission time in adult patients with newly diagnosed minimal change disease.


Inhibition of vascular endothelial growth factor (VEGF) does not affect early renal changes in a rat model of lean type 2 diabetes.
Type 2 diabetes is the most frequent cause of end-stage renal failure in many Western countries. Approximately 10-15 % of all type 2 diabetics are lean. Various growth factors and cytokines have been implicated in the pathophysiology of diabetic kidney disease, including vascular endothelial growth factor (VEGF). To elucidate a role for VEGF in the renal changes associated with type 2 diabetes, we examined the effect of a VEGF-antibody (ab) on early renal changes in the Goto-Kakizaki (GK) rat, a lean type 2 diabetes model. GK-rats were treated for 6 weeks with the VEGF-ab or with an isotype-matched irrelevant IgG. Wistar rats were used as non-diabetic controls. Placebo-treated GK-rats showed a pronounced increase in glomerular volume and urinary albumin excretion (UAE) and no change in the renal expression of endothelial nitric oxide synthase (eNOS) compared to placebo-treated non-diabetic controls. Kidney weight and creatinine clearance were no different between the groups. VEGF-ab treatment had no effect on glomerular volume, UAE, eNOS expression, body weight, blood glucose levels or food intake, but lowered serum insulin levels in non-diabetic and diabetic animals. We conclude that VEGF inhibition has minimal effects on early renal changes in GK-rats.


Physiological and Symptomatic Responses to Arm versus Leg Activities in People with Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis.
While the mechanisms underlying exercise limitations and symptoms during leg activities have been investigated in detail, knowledge of potential differences between leg and arm activities are not well understood and results from individual studies are contradictory. Thus, the aim of the present study was to synthesize physiological and symptomatic responses during activities involving the arms relative to activities involving the legs in people with Chronic Obstructive Pulmonary Disease (COPD). Any study with a cross-sectional comparison of acute physiological (cardiorespiratory, metabolic) and symptomatic responses to activities performed with the arms versus the legs were included. Studies were sub-grouped based on the type of activity performed (cycle ergometer, resistance exercises, or functional test/activities). Eighteen studies with 423 individuals with COPD were included. Leg cycle ergometer resulted in greater tidal volume (137 mL), minute ventilation (4.8 L/min), and oxygen consumption (164 mL/min) than arm cycle ergometer, while symptomatic responses were similar. Resistance exercises resulted in similar physiological and symptomatic responses irrespective of whether the legs or the arms were involved while studies on functional activities report different results depending on the type and intensity of the activity performed. With the exception of cycle ergometer activities, physiological and symptomatic responses do not seem to depend on whether the arms or the legs are used, but rather seem to be task and intensity dependent. These novel findings suggest, for example, that strategies used to increase exercise tolerance should not be dependent on whether the arms or the legs are used, but rather the intensity of specific activity performed.


The effects of parental retirement on adult children's health: Evidence from China.
Using representative data from China, we examine the causal effects of parental retirement on the health of adult children. To do so, we adopt a fuzzy regression discontinuity design and exploit the mandatory retirement ages in China as cut-off points. We find no evidence that parental retirement has significant effects on the mental health, healthcare utilization, or risky health behaviors of adult children. However, paternal retirement and maternal retirement have different effects on adult children's Self-reported health (SRH). Paternal retirement has a significantly negative effect only on the SRH of sons, while maternal retirement does not induce such effects. Potential mechanisms of intergenerational transfer through which parental retirement might affect adult children's health are also explored.


Mucosa-Associated Lymphoid Tissue Lymphoma of the Thyroid Gland: A Systematic Review of the Literature.
Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type of the thyroid gland is a rare indolent malignant disease encountered in approximately 0.5% of patients with Hashimoto thyroiditis (HT). The purpose of the present systematic review was to accumulate the current evidence in the field. We searched the Medline, Scopus, EMBASE, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials CENTRAL databases from inception to May 2018. Statistical analysis was performed with SPSS version 22.0. Fourteen case series and 20 case reports were finally included in the present systematic review. Analysis of the patient data included in the published case reports suggested that the age at diagnosis of MALT lymphoma does no differ among males and females (64 [52.5-73] vs. 67 [60.5-72] years, p = 0.442). HT was detected in 60% of patients, whereas coexisting carcinoma was evident in 17% of cases. The incidence of HT and thyroid cancer was comparable among males and females (p = 0.474 and p > 0.999, respectively). Among all patients included in the present systematic review there were two disease relapses and two deaths attributed to the disease. MALT lymphoma of the thyroid gland is a rare malignancy with an indolent course. The scarce data available in the literature preclude safe conclusions concerning the mode of treatment and follow-up of these patients. However, the combination of minimally invasive surgery and adjuvant therapy seems feasible. Moreover, an extended follow-up period is recommended.


Manual compass measurement and trigonometric determination of proptosis.
To determine the accuracy of manual compass measurement and trigonometric determination of proptosis (MCMATDP). This agreement study included 120 eyes without eye diseases or injury of 60 patients who visited the ophthalmic clinic of Peking University Shenzhen Hospital from February 2020 to June 2020. The absolute values of proptosis were measured by MCMATDP and computed tomography (CT). The differences between the two methods were shown by Bland-Altman plot. The cohort comprised 25 males and 35 females (average age 38.3 years). The absolute value of proptosis measured by CT was correlated with the MCMATDP. Further analysis showed that a 95% limit of agreement (LoA) was - 0.53 to 0.60 mm in the right eye and - 0.46 to 0.55 mm in the left eye between CT and MCMATDP. In addition, the 95% LoA was - 0.49 to 0.60 mm in both eyes between the two methods. All points were < 5% in Bland-Altman plots. Compared to CT, MCMATDP is rather consistent in proptosis measurement. The new method is feasible in clinical practice when measuring proptosis. With the development of non-contact intelligent measurement software and the continuous improvement in measurement accuracy, a non-invasive, simple, and inexpensive measurement mode is true based on the theory of MCMATDP.


Determination of cytokine protein levels in cervical mucus samples from young women by a multiplex immunoassay method and assessment of correlates.
Cytokines in cervical mucus are likely to play important roles in controlling pathogens. The cervical mucosal environment is complex, however, with many endogenous and exogenous factors that may affect cytokine levels. We used a multiplex, suspension-array-based immunoassay method to measure 10 proinflammatory (interleukin-1beta [IL-1beta], IL-6, and IL-8) and immunoregulatory (gamma interferon [IFN-gamma], IL-2, IL-4, IL-5, IL-10, IL-12, and IL-13) cytokines in cervical mucus specimens collected via ophthalmic sponge from 72 healthy, nonpregnant women and correlate their levels with biologic and behavioral covariates in a cross-sectional design. Proinflammatory and immunoregulatory cytokines were readily detected, although proinflammatory cytokines were present at markedly higher levels than were immunoregulatory cytokines. Among the covariates examined, the most striking finding was the significant (P < or = 0.05) association between depressed levels of the cytokines IFN-gamma, IL-1beta, IL-6, and IL-10 and cigarette smoking. Also, nonsignificant trends toward lower cytokine levels were found in the settings of incident and persistent human papillomavirus infection. The ready detection of proinflammatory cytokines may be reflective of the female genital tract as an anatomic site that is constantly exposed to immunogenic stimulation. Cigarette smoking appears to downregulate cytokine responses in the cervical mucosa, which may help explain the implicated role of tobacco use as a cofactor for cervical cancer development.


[Objective diagnosis of cardiac ischemic disease in pilots].
Reviewed was specifics of diagnostics of the cardiac ischemic disease (CID) in pilots. It was stated that pilots develop CID at an earlier age and incidence of the disease rises with the period of employment. Frequently, CID proceeds asymptomatically posing problems to diagnostics and a thread to flight safety. In this context, the medical flight cetification should largely rely on verifying the diagnostic methods, coronary angiography in the first place. Indications and contraindications to the clinical and flight certification applications have been determined and made the core of a rational plan for early CID detection in flying personnel.


Next Directions in Measurement of the Home Mathematics Environment: An International and Interdisciplinary Perspective.
This article synthesizes findings from an international virtual conference, funded by the National Science Foundation (NSF), focused on the home mathematics environment (HME). In light of inconsistencies and gaps in research investigating relations between the HME and children's outcomes, the purpose of the conference was to discuss actionable steps and considerations for future work. The conference was composed of international researchers with a wide range of expertise and backgrounds. Presentations and discussions during the conference centered broadly on the need to better operationalize and measure the HME as a construct - focusing on issues related to child, family, and community factors, country and cultural factors, and the cognitive and affective characteristics of caregivers and children. Results of the conference and a subsequent writing workshop include a synthesis of core questions and key considerations for the field of research on the HME. Findings highlight the need for the field at large to use multi-method measurement approaches to capture nuances in the HME, and to do so with increased international and interdisciplinary collaboration, open science practices, and communication among scholars.