Estrogenic effect on swelling and monocytic receptor expression in an arthritic temporomandibular joint model.
Clinical presentation of temporomandibular joint (TMJ) disorders are more common in women and changes in the female hormone estrogen affect the level of swelling, pro-inflammatory cytokine release and pain in animal models of TMJ arthritis. Estrogen also modulates the expression of the CD16 receptor in vitro. This alters pro-inflammatory cytokine release in monocytes/macrophages when auto-antigens and arthritic factors bind the CD16 receptor. This study investigated the effects of various levels of estrogen on the intensity of inflammation and CD16 expression in a TMJ arthritic animal model. The experiments included rats that were intact or ovariectomized (OVX), eliminating the major source of estrogen output. A portion of the OVX animals had estrogen replaced with 17-beta estradiol (E2) using Alzet pumps. In OVX animals E2 levels were administered for 10 days to create an artificial estrus cycle or to simulate pregnancy. Following E2 treatment the rats were given an intra-articular TMJ injection of saline or complete Freund's adjuvant (CFA). CFA injection significantly increased TMJ swelling, stress induced chromodacryorrhea and attenuated food intake, thus indicating the adjuvant induced TMJ pain/inflammation. Removing endogenous E2 through OVX reduced CFA induced TMJ inflammation, whereas CFA increased the number of TMJ monocytes expressing the CD14 receptor equally in all groups irrespective of plasma E2 levels. Paradoxically, higher levels of E2 reduced the number of TNF-alpha positive, CD16+ and double labeled CD14+/CD16+ cells. The findings indicate that reduced plasma E2 levels attenuated CFA induced TMJ inflammation, whereas increasing E2 levels enhanced TMJ swelling in a dose dependent manner. Estrogenic group differences in CFA induced swelling were independent of TMJ CD14+, CD14+/CD16+ or CD16+ cell numbers suggesting E2 action on the CFA immune response primarily excluded CD16 receptor action.


[Kristeller's procedure--Expressio fetus, its genesis and contemporary application].
The aim of the article is to introduce the original version of Kristeller's procedure - Expressio fetus. The author of the procedure, Samuel Kristeller, was bom in 1820 in Ksiaz Wielkopolski. He worked as a physician in Gniezno, then in Berlin. He is known as the creator of the described procedure - pushing out the foetus. He had also specified the meaning of the cervical plug (Kristeller's plug), and modified obstetrical forceps. He died in Berlin in 1900. In 1867, Kristeller published a study in which he described a procedure, of which he was the author, of pushing out the foetus (manual assistance), its technique, conditions and recommendations for its application. The main idea of the procedure meant strengthening uterine contractions during labour by massaging the uterus and pressing it many times shortly, towards the long axis of the birth canal. Nowadays this procedure has become warped in its form; there remains also the controversy whether or not to use external force directed on the uterine fundus during labour, due to the risk of intrauterine foetal anoxia and other complications.


Effect of casein diet on gonadotropin releasing hormone antagonist induced changes in adrenal gonadal functions in male rats.
Adult male rats received daily injections (sc) of gonadotropin releasing hormone antagonist (0.2 mg/kg(-1) x day(-1)) for 21 days when they were sacrificed on day 22, adrenal weight, adrenal A5-3beta (delta 5-3beta) hydroxysteroid dehydrogenase (Delta5-3beta-HSD) activity and serum level of corticosterone were increased significantly while testicular 17beta (17beta) hydroxysteroid dehydrogenase (17beta-HSD) activity and serum level of testosterone and spermatogenesis were decreased in the rats fed on 5% casein diet. GnRH antagonist treated rats fed on 20% casein diet, resulted significant decrease in adrenal weight, serum corticosterone and adrenal A5-3beta-HSD activity while testicular 17beta-HSD activity serum testosterone levels and the weights of sex organs were increased with respect to anti GnRH treated rats fed on 5% casein diet. But the GnRH antagonist treated rats fed on 20% casein diet showed decreased spermatogenesis quantitatively and sperm count appeared similar to anti GnRH treated rats fed on 5% casein diet. These results indicate that high casein diet protects adrenocortical activity and stimulates testosterone synthesis without effecting spermatogenic arrest in GnRH antagonist treated rats. It may be concluded that GnRH antagonist in presence of high milk protein diet may be considered to be a suitable antihormone in the development of an ideal male contraceptive.


Exploring high-efficiency electrocatalysts of metal-doped two-dimensional C4N for oxygen reduction, oxygen evolution, and hydrogen evolution reactions by first-principles screening.
A single-atom catalyst is a landmark finding in the catalysis field and due to its excellent catalytic efficiency and maximum atom utilization, it is widely applied in the hydrogen evolution reaction (HER), oxygen reduction reaction (ORR), and oxygen evolution reaction (OER). Herein, 3d, 4d, and 5d single transition metal atom supported C4N catalysts (TM-C4N) are explored using density functional theory methods. First, seven thermodynamically stable TM-C4N (TM = Sc, Ti, V, Mn, Cu, Y, and Ag) are identified. Next, the calculated ΔG*H values reveal that all screened TM-C4N materials exhibit considerable catalytic performance for the HER. Besides, the ORR and OER activities of all screened TM-C4N materials are inferior to those of Pt(111) and Ru-/IrO2(110). Considering that the binding strength of *OH limits the catalytic performance of most TM-C4N, high-valent metal complexes (TM-OH-C4N) are further studied. Owing to the modification of OH, the binding strength of reaction species on most TM-OH-C4N is weakened, thereby improving the performance of the ORR and OER. In particular for Cu-OH-C4N, the overpotentials for the ORR and OER (0.61 and 0.48 V, respectively) are closest to those of Pt(111) and Ru-/IrO2(110), manifesting that it exhibits good bifunctional catalytic activity. Additionally, the variation trend of ΔE*OH on TM-C4N and TM-OH-C4N can be appropriately described by the intrinsic descriptor φ.


Phosphoinositide 3-Kinase-Dependent Signalling Pathways in Cutaneous Squamous Cell Carcinomas.
Cutaneous squamous cell carcinoma (cSCC) derives from keratinocytes in the epidermis and accounts for 15-20% of all cutaneous malignancies. Although it is usually curable by surgery, 5% of these tumours metastasise leading to poor prognosis mostly because of a lack of therapies and validated biomarkers. As the incidence rate is rising worldwide it has become increasingly important to better understand the mechanisms involved in cSCC development and progression in order to develop therapeutic strategies. Here we discuss some of the evidence indicating that activation of phosphoinositide 3-kinases (PI3Ks)-dependent signalling pathways (in particular the PI3Ks targets Akt and mTOR) has a key role in cSCC. We further discuss available data suggesting that inhibition of these pathways can be beneficial to counteract the disease. With the growing number of different inhibitors currently available, it would be important to further investigate the specific contribution of distinct components of the PI3Ks/Akt/mTOR pathways in order to identify the most promising molecular targets and the best strategy to inhibit cSCC.


Endothelial-derived angiocrine factors as instructors of embryonic development.
Blood vessels are well-known to play roles in organ development and repair, primarily owing to their fundamental function in delivering oxygen and nutrients to tissues to promote their growth and homeostasis. Endothelial cells however are not merely passive conduits for carrying blood. There is now evidence that endothelial cells of the vasculature actively regulate tissue-specific development, morphogenesis and organ function, as well as playing roles in disease and cancer. Angiocrine factors are growth factors, cytokines, signaling molecules or other regulators produced directly from endothelial cells to instruct a diverse range of signaling outcomes in the cellular microenvironment, and are critical mediators of the vascular control of organ function. The roles of angiocrine signaling are only beginning to be uncovered in diverse fields such as homeostasis, regeneration, organogenesis, stem-cell maintenance, cell differentiation and tumour growth. While in some cases the specific angiocrine factor involved in these processes has been identified, in many cases the molecular identity of the angiocrine factor(s) remain to be discovered, even though the importance of angiocrine signaling has been implicated. In this review, we will specifically focus on roles for endothelial-derived angiocrine signaling in instructing tissue morphogenesis and organogenesis during embryonic and perinatal development.


Migration of Strongyloides venezuelensis in rats after oral inoculation of free-living infective larvae.
Strongyloides venezuelensis (SVZ) infection was chronologically monitored in 85 Sprague-Dawley rats (SDR), which were orally inoculated with approximately 1,000 infective larvae. In order to describe the characteristics of migrating larvae (MLS) in various visceral organs (the liver, lung, cardiac blood, and small intestine), 5 SDR were sacrificed at 20 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 16 hr, 48 hr, 72 hr, 96 hr, 120 hr, 144 hr, 168 hr and 192 hr post inoculation (PI). MLS were recovered from the liver and blood 20 and 45 min PI and measured 788 +/- 26 microm and 846 +/- 40 microm in length, respectively. MLS were first observed in the lung tissue 45 min PI and measured 925 +/- 38 microm on the average. In the trachea, MLS measuring 849 +/- 75 microm appeared 3 to 96 hrs PI. Adult worms (AWS) measuring 1,926 +/- 521 microm to 2,956 +/- 159 microm in length were observed in the small intestine from 120 hr PI. The worms appeared to mature more than 168 hr PI and attained the average maximum length of 2,420 +/- 532 microm. At 3 hr PI focal hyperemic and necrotic lesions were evidently observed in the liver and lung, together with eosinophilic infiltration in the stomach, liver, and lung. The parasites were histologically detectable in the lung tissues but were very difficult to find in the liver and the epithelial layer of small intestine. These data demonstrate that SVZ parasites take 20 min to reach the liver via the stomach and only three hours to reach the trachea through the same route. The development from eggs to adults takes 168 hr in the SDR model.


Nanoporous Microneedle Arrays Effectively Induce Antibody Responses against Diphtheria and Tetanus Toxoid.
The skin is immunologically very potent because of the high number of antigen-presenting cells in the dermis and epidermis, and is therefore considered to be very suitable for vaccination. However, the skin's physical barrier, the stratum corneum, prevents foreign substances, including vaccines, from entering the skin. Microneedles, which are needle-like structures with dimensions in the micrometer range, form a relatively new approach to circumvent the stratum corneum, allowing for minimally invasive and pain-free vaccination. In this study, we tested ceramic nanoporous microneedle arrays (npMNAs), representing a novel microneedle-based drug delivery technology, for their ability to deliver the subunit vaccines diphtheria toxoid (DT) and tetanus toxoid (TT) intradermally. First, the piercing ability of the ceramic (alumina) npMNAs, which contained over 100 microneedles per array, a length of 475 µm, and an average pore size of 80 nm, was evaluated in mouse skin. Then, the hydrodynamic diameters of DT and TT and the loading of DT, TT, and imiquimod into, and subsequent release from the npMNAs were assessed in vitro. It was shown that DT and TT were successfully loaded into the tips of the ceramic nanoporous microneedles, and by using near-infrared fluorescently labeled antigens, we found that DT and TT were released following piercing of the antigen-loaded npMNAs into ex vivo murine skin. Finally, the application of DT- and TT-loaded npMNAs onto mouse skin in vivo led to the induction of antigen-specific antibodies, with titers similar to those obtained upon subcutaneous immunization with a similar dose. In conclusion, we show for the first time, the potential of npMNAs for intradermal (ID) immunization with subunit vaccines, which opens possibilities for future ID vaccination designs.


Neural correlates to flight-related density-dependent phase characteristics in locusts.
Locust phase polymorphism is an extreme example of behavioral plasticity; in response to changes in population density, locusts dramatically alter their behavior. These changes in behavior facilitate the appearance of various morphological and physiological phase characteristics. One of the principal behavioral changes is the more intense flight behavior and improved flight performance of gregarious locusts compared to solitary ones. Surprisingly, the neurophysiological basis of the behavioral phase characteristics has received little attention. Here we present density-dependent differences in flight-related sensory and central neural elements in the desert locust. Using techniques already established for gregarious locusts, we compared the response of locusts of both phases to controlled wind stimuli. Gregarious locusts demonstrated a lower threshold for wind-induced flight initiation. Wind-induced spiking activity in the locust tritocerebral commissure giants (TCG, a pair of identified interneurons that relay input from head hair receptors to thoracic motor centers) was found to be weaker in solitary locusts compared to gregarious ones. The solitary locusts' TCG also demonstrated much stronger spike frequency adaptation in response to wind stimuli. Although the number of forehead wind sensitive hairs was found to be larger in solitary locusts, the stimuli conveyed to their flight motor centers were weaker. The tritocerebral commissure dwarf (TCD) is an inhibitory flight-related interneuron in the locust that responds to light stimuli. An increase in TCD spontaneous activity in dark conditions was significantly stronger in gregarious locusts than in solitary ones. Thus, phase-dependent differences in the activity of flight-related interneurons reflect behavioral phase characteristics.


Quality of survival the 1st year with glioblastoma: a longitudinal study of patient-reported quality of life.
By exploring longitudinal patient-reported health-related quality of life (HRQoL), the authors sought to assess the quality of survival for patients in the 1st year after diagnosis of glioblastoma. Thirty unselected patients ≥ 18 years who underwent primary surgery for glioblastoma in the period 2011-2013 were included. Using the generic HRQoL questionnaire EQ-5D 3L, baseline HRQoL was assessed before surgery and at postoperative follow-up after 1, 2, 4, 6, 8, 10, and 12 months. There was an apparent correlation between deterioration in HRQoL scores and tumor progression. Patients with permanent deterioration in HRQoL early after surgery represented a subgroup with rapid progression and short survival. Both positive and negative changes in HRQoL were more often seen after surgery than after radio- or chemotherapy. Patients with gross-total resection (GTR) reported better and more stable HRQoL. In a multivariable analysis preoperative cognitive symptoms (p = 0.02), preoperative functional status (p = 0.03), and GTR (p = 0.01) were independent predictors of quality of survival (area under the curve for EQ-5D 3L index values). The results indicate that progression-free survival is not only a surrogate marker for survival, but also for quality of survival. Quality of survival seems to be associated with GTR, which adds further support for opting for extensive resections in glioblastoma patients with good preoperative functional levels.


Direct metallic amalgam alternative: a research update.
Discussions between two group leaders at the National Institute of Standards and Technology (NIST) led to the suggestion that a mercury-free, silver-based material could be used for dental direct-filling applications. This concept brought about a new approach that, nonetheless, is still based on powder technology such as amalgams. The resulting material also retains the tin and silver components of conventional amalgams. The condensation of a loose powder mixture into a cohesive solid relies, however, on cold-welding across atomically clean silver-silver interfaces after a mild acid treatment of the surfaces. The National Institute of Dental Research (NIDR) and American Dental Association Health Foundation (ADAHF) became involved in the research in 1992, and ADAHF scientists continue to collaborate with NIST metallurgists and electrochemists toward the further development of this promising new technology.


No effect of the oral neutral endopeptidase inhibitor candoxatril, on bronchomotor tone and histamine reactivity in asthma.
Neutral endopeptidase (NEP) is found in many tissues in man, including the lung. Metabolism by NEP is one of the main mechanisms for the clearance of atrial natriuretic peptide (ANP), a hormone that causes bronchodilation and reduces nonspecific bronchial reactivity in man. Candoxatril, an oral NEP inhibitor has been shown to elevate circulating ANP levels. We have sought to determine whether the administration of candoxatril will alter bronchomotor tone (forced expiratory volume in one second (FEV1)) and histamine reactivity. Ten male asthmatic patients with stable asthma were enrolled (mean (SD) age 32 (10) yrs; FEV1 92 (11)% predicted) in a randomized, double-blind, placebo-controlled study. On each study day, after baseline spirometry, patients received 200 mg of candoxatril or placebo. Spirometry was repeated at half hourly intervals. After 2 h a histamine inhalation test was performed. There was no significant difference in FEV1 values at baseline or at 2 h post-dosing between active and placebo study days, with mean (SEM) FEV1 at baseline and 2 h of 3.71 (0.29) l and 3.85 (0.29) l on the placebo day, and 3.89 (0.27) l and 4.05 (0.82) l on the active day, respectively. The geometric mean (range) provocative concentration of histamine producing a 20% fall in FEV1 (PC20) on the placebo day and active day did not differ significantly, being 1.17 (0.25-25.8) and 0.93 (0.13-32) mg.ml-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Eating away from home in Canada: impact on dietary intake.
Public health measures related to the COVID-19 pandemic have upended the way Canadians eat and shop for food. Since the pandemic began, many Canadians have reported consuming food away from home (FAFH) less often. FAFH tends to be less healthful than food prepared at home. Little is known about patterns of Canadians' FAFH consumption before the pandemic. This study used 2015 national-level nutrition data, the most recent available, to characterize patterns of FAFH consumption and selected markers of dietary intake. National-level food intake data came from the first 24-hour dietary recall provided by 20,475 respondents aged 1 or older to the 2015 Canadian Community Health Survey-Nutrition. Mean daily intakes of selected food subgroups and nutrients, adjusted for total energy intake, were compared between those who had consumed any food in a restaurant on the previous day and those who had not. Estimates were generated overall and for eight age and sex groups. In 2015, overall, 21.8% of Canadians had consumed FAFH in a restaurant on the previous day. Eating out was most common among males aged 19 to 54 (27.7%) and least common among young children aged 1 to 5 (8.4%). Compared with Canadians who had not eaten out on the previous day, those who had eaten out had consumed, on that day, fewer servings of whole fruit; whole grains; dark green and orange vegetables; other vegetables (excluding potatoes); milk and fortified soy-based beverages; and legumes, nuts and seeds, on average. Those who had eaten out had consumed, on average, less fibre and total sugar, and more total fat, saturated fat and sodium on that day. There were few differences for meat and poultry, fish and seafood, and protein intake. On the day that Canadians ate out in a restaurant, their dietary intake was generally less favourable than that of Canadians who did not eat out. If Canadians continue to eat at home more and to consume less FAFH, as early pandemic-period reports suggest, then results can be used to gauge the potential dietary implications of these shifts.


Extraction, Isolation, Screening, and Preliminary Characterization of Polysaccharides with Anti-Oxidant Activities from Oudemansiella raphanipies.
Response surface methodology (RSM) was used to find the optimal extraction process of Oudemansiella raphanipies polysaccharides (ORPs). The results showed that the optimal extraction parameters were an alkali concentration of 0.02 mol/L, a ratio of material to liquid of 1:112.7 g/mL, an extraction temperature of 66.0 °C, and an extraction time of 4.0 h. Under the optimal conditions, the yield of ORPs was raised to 16.2 ± 0.1%. The antioxidant activities of ORPs-I~V were determined and compared, and ORPs-V was further purified by chromatography, with an average molecular weight (Mw) of 18.86 kDa. The structure of ORPs-V was determined by Fourier transform-infrared spectroscopy (FT-IR), monosaccharide analysis, and nuclear magnetic resonance (NMR) spectroscopy. The ORPs-V comprised fucose, rhamnose, arabinose, glucose, galactose, mannose, xylose, fructose, galacturonic acid, and glucuronic acid at a ratio of 1.73:1.20:1.13:2.87:8.71:2.89:1.42:0.81. Compared to other ORPs, ORPs-V showed the strongest antioxidant activities (ABTS radical cation, hydroxyl radical and DPPH scavenging activities, and reducing power), and were able to significantly increase the activities of superoxide dismutase, catalase, lactate dehydrogenase, and glutathione peroxidase. However, they reduced the malondialdehyde content in mice fed a high-fat diet. These results indicate that ORPs-V may be good anti-oxidant agents to be applied in functional foods.


Bronchial sensitivity and bronchial reactivity in children with cough variant asthma.
Cough variant asthma (CVA) is diagnosed in some children with chronic cough who do not have wheezing. However, the precise mechanism of CVA in children is unclear. To evaluate the physiologic differences in the airways of children with classic asthma and CVA, the methacholine dose-response curves of respiratory resistance (Rrs) were studied. CVA was diagnosed in 31 children with chronic cough (age range, 5 to 14 years; 19 boys and 12 girls; mean age, 8.5 years) on the basis of methacholine inhalation challenge using an oscillation method. For comparison, the study included 86 age-matched children with classic asthma (age range, 5 to 15 years; 42 boys and 44 girls; mean age, 9.5 years), 25 age-matched children with cough (age range, 5 to 15 years; 17 boys and 8 girls; mean age, 8.8 years), and 23 age-matched control subjects (8 boys and 15 girls; mean age, 9.2 years). Consecutive doses of methacholine were doubled until a 200% increase in Rrs from baseline was reached. The cumulative dose of methacholine at the inflection point of Rrs was considered to represent the bronchial sensitivity to inhaled methacholine (minimum dose of methacholine [Dmin]). The slope of the methacholine dose-response curve (SRrs), which was considered to represent bronchial reactivity, was measured from the increasing Rrs curve. The values of Dmin in classic asthma patients and in CVA patients were significantly lower than those for cough patients and control subjects. There was no significant difference in the values of Dmin between the classic asthma and CVA patients. The value of SRrs in CVA patients was significantly lower than that in classic asthma patients, cough patients, and control subjects (p < 0.05, p < 0.01, and p < 0.01, respectively). There was no significant difference in the value of SRrs between classic asthma patients, cough patients, and control subjects. These data show that bronchial reactivity in the children with CVA was significantly lower than that in the children with classic asthma, and this specificity has an effect on prolonged cough without wheezing in children with CVA.


Prevalence of posttraumatic stress disorder among adolescents in school and its impact on their well-being: a cross-sectional study.
anyone can develop posttraumatic stress disorder (PTSD) following a traumatic event; this disorder can develop comorbid PTSD disorders such as anxiety and depression, which could seriously interfere with the daily life of the adolescent who was to be the subject of our study by evaluating the prevalence of PTSD in public schools and also evaluating the impact of this disorder. the survey was carried out during the period from March to June 2017. Participants were selected for a cross-sectional survey. Standardized questionnaires (life events checklist, CPTS-RI, STAIY and CDI) were used. The independent variables were investigated using binary logistic regression analyzes which were performed to investigate factors associated with PTSD. the number of students was 982 adolescents with an age of 12 to 17 years (14.98 ± 1.49) and the participation rate was 88.69% (n = 871). A high prevalence of PTSD was found with 19.3% (n = 168). The factors independently associated with PTSD included being a girl (adjusted odds ratio (AOR) =2.113, 95% C.I =1.015-4.399, p=0.046), having a middle school level (AOR =5.765, 95% C.I =2.262-14.692, p<0.0001), sleep interrupted (AOR =0.142, 95% C.I =0.027-0.745, p=0.021), guilt (AOR =27.378, 95% C.I =6.835-109.663, p<0.0001), difficulties of memory (AOR =0.157, 95% C.I = 0.071-0.346, p<0.0001), and difficulties of concentration (AOR =0.041, 95% C.I = 0.004-0.392, p=0.006). Among adolescents in school with PTSD, anxiety had 79.1% (n = 133) and depression had 51.1% (n = 86). the prevalence of PTSD and comorbid anxiety and depression was high among educated students. Factors associated with PTSD included being in college, being a girl, and having guilt. It is necessary to adapt suitable treatments immediately after a traumatic event or during the disease.


New Cytotoxic Seco-Type Triterpene and Labdane-Type Diterpenes from Nuxia oppositifolia.
Chromatographic purification of the n-hexane and dichloromethane extracts of Nuxia oppositifolia aerial parts, growing in Saudi Arabia, resulted in the isolation and characterization of three new labdane-type diterpene acids, 2β-acetoxy-labda-7-en-15-oic acid (1), 2β-acetoxy-7-oxolabda-8-en-15-oic acid (2), 2β-acetoxy-6-oxolabda-7-en-15-oic acid (3), and one new seco-triterpene, 3,4-seco olean-12-en-3,30 dioic acid (4), together with 10 known lupane, oleanane and ursane-type triterpenes, as well as the common phytosterols, β-sitosterol and stigmasterol (5-16). Their structures have been assigned on the basis of different spectroscopic techniques including 1D and 2D NMR. Moreover, 13 of the isolated compounds were tested on the human cancer cell lines HeLa (cervical), A549 (lung) and MDA (breast), and most of the compounds showed potent cytotoxic activities in vitro.


Medial rectus recession is as effective as lateral rectus resection in divergence paralysis esotropia.
To propose medial rectus (MR) recession to be equally as effective as lateral rectus (LR) resection, which has heretofore been the preferred treatment for divergence paralysis esotropia (DPE). We examined a 17-year surgical experience comparing LR resection with MR recession in adults with DPE, defined as symptomatic distance esotropia (ET) at least double the asymptomatic ET of 10 or less prism diopters() at near. Twenty-four patients with DPE underwent surgery. Six patients underwent bilateral LR resection and 2 underwent unilateral LR resection (group L), while 13 underwent bilateral MR recession and 3 underwent unilateral MR recession,with the target angle double the distance ET (group M). One of 8 patients in group L and 15 of 16 patients in group M underwent intra operative adjustable surgery under topical anesthesia. Mean (SD) preoperative central gaze ET measured 15.0 (7.7) Δ at distance and 4.1 (3.4) Δ at near in group L, but 10.4 (6.8) Δ at distance and 0.6 (1.7) Δ at near in group M (P=.15; distance, 0.003, near). Postoperatively, no patient in either group had symptomatic diplopia or convergence insufficiency in follow-up from 8.5 to 40 months. Twice the usual surgical dose of MR recession per prism diopter was required to achieve correction of the distance deviation in DPE as compared with that recommended for ET generally and also for LR resection in the same condition. Recession of the MR provides binocular single vision in DPE without convergence insufficiency at near, and it is convenient for intraoperative adjustment under topical anesthesia.


Pitfalls in diagnosing a case of extranodal NK/T-cell lymphoma with CD20 aberrant expression and IGH gene rearrangement.
Extranodal NK/T-cell lymphoma (ENKTL) is a subtype of non-Hodgkin lymphoma mainly derived from NK cells and, uncommonly, T-cells. A diagnostic challenge is presented when an atypical phenotype and gene rearrangement are encountered. Herein, we report a case of ENKTL with CD20 expression and IGH gene rearrangement, which is extremely rare. A 57-year-old female patient was seen in 2021 due to a nodule on her left leg and simultaneously impaired eyesight for 6 months. Skin biopsy and immunohistochemistry were performed. The lymphoid cells were positive for CD3, CD56, granzyme B, and TIA-1, partially positive for CD2, and mildly positive for CD20. In situ hybridization for Epstein-Barr virus was positive. Molecular studies revealed immunoglobulin heavy chain (IGH) gene rearrangement, while no T-cell receptor gene rearrangement was detected. The positron emission tomography scan showed that the lymphoma affected bilateral adrenal glands, pelvic cavity, peritoneal cavity, small intestine, skin, and subcutis of the bilateral lower extremities of the patient. Her disease progressed despite eight cycles of chemotherapy and radiation therapy. The importance of this case lies in the atypical phenotype and IGH gene rearrangements, necessitating comprehensive interpretation of clinicopathological data.


Expression of the Na+/Ca2+ exchanger emerges in hepatic stellate cells after activation in association with liver fibrosis.
Activation of hepatic stellate (Ito) cells is a final common pathway of liver fibrosis. The findings presented in this paper indicate that expression of Na+/Ca2+ exchanger (NCX) emerges in rat hepatic stellate cells after activation in vitro during primary culture or in vivo in response to intoxication with CCl4. NCX mRNA became detectable by Northern blot analysis in cultured stellate cells on day 3, as was alpha-smooth muscle actin, an indicator not only of smooth muscle differentiation but also of stellate cell activation. Western blot analysis showed expression of the exchanger protein in the activated stellate cells. Functional expression of the exchanger, monitored by Ni2+-sensitive, verapamil-insensitive intracellular free Ca2+ increases in response to reduction of extracellular Na+ concentration, became sizable by using Fura-2 in stellate cells by 7 days in culture. Furthermore, increased expression of the exchanger mRNA was found predominantly in stellate cells freshly isolated from the CCl4 model rat of hepatic fibrosis. Thus, it is concluded that NCX expression is closely associated with activation of hepatic stellate cells in vitro and in vivo. Because, even at the whole liver level, increased expression of NCX mRNA became observable after induction of liver fibrosis, it is suggested that NCX expression serves a useful diagnostic marker of liver fibrosis or cirrhosis.


Vesicular stomatitis forecasting based on Google Trends.
Vesicular stomatitis (VS) is an important viral disease of livestock. The main feature of VS is irregular blisters that occur on the lips, tongue, oral mucosa, hoof crown and nipple. Humans can also be infected with vesicular stomatitis and develop meningitis. This study analyses 2014 American VS outbreaks in order to accurately predict vesicular stomatitis outbreak trends. American VS outbreaks data were collected from OIE. The data for VS keywords were obtained by inputting 24 disease-related keywords into Google Trends. After calculating the Pearson and Spearman correlation coefficients, it was found that there was a relationship between outbreaks and keywords derived from Google Trends. Finally, the predicted model was constructed based on qualitative classification and quantitative regression. For the regression model, the Pearson correlation coefficients between the predicted outbreaks and actual outbreaks are 0.953 and 0.948, respectively. For the qualitative classification model, we constructed five classification predictive models and chose the best classification predictive model as the result. The results showed, SN (sensitivity), SP (specificity) and ACC (prediction accuracy) values of the best classification predictive model are 78.52%,72.5% and 77.14%, respectively. This study applied Google search data to construct a qualitative classification model and a quantitative regression model. The results show that the method is effective and that these two models obtain more accurate forecast.


[Clinical experiences with the use of a new antibiotic in inflammatory diseases of surgical interest].
Therapeutic and prophylactic management of 23 adults with inflammation of surgical interest using a new antibiotic, cefalexin sodium (Glaxo). 1.5-6 g/day were administered either i.m. (2 cases) or i.v. (21 cases) for 4 to 13 days. Examinations carried out before and after treatment showed that no damage was caused to the liver, kidney or haematopoietic apparatus. The clinical pharmacokinetic data made it clear that high serum levels were reached and renal elimination of the drug was almost complete. Cepoven displayed a high therapeutic capacity in nearly all cases. Both general and local tolerance were excellent.


Detection of self-reactive CD8⁺ T cells with an anergic phenotype in healthy individuals.
Immunological tolerance to self requires naturally occurring regulatory T (Treg) cells. Yet how they stably control autoimmune T cells remains obscure. Here, we show that Treg cells can render self-reactive human CD8(+) T cells anergic (i.e., hypoproliferative and cytokine hypoproducing upon antigen restimulation) in vitro, likely by controlling the costimulatory function of antigen-presenting cells. Anergic T cells were naïve in phenotype, lower than activated T cells in T cell receptor affinity for cognate antigen, and expressed several coinhibitory molecules, including cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Using these criteria, we detected in healthy individuals anergic T cells reactive with a skin antigen targeted in the autoimmune disease vitiligo. Collectively, our results suggest that Treg cell-mediated induction of anergy in autoimmune T cells is important for maintaining self-tolerance.


An Improved Natural Transformation Protocol for the Cyanobacterium Synechocystis sp. PCC 6803.
The naturally transformable cyanobacterium Synechocystis sp. PCC 6803 is a widely used chassis strain for the photosynthetic production of chemicals. However, Synechocystis possesses multiple genome copies per cell which means that segregating mutations across all genome copies can be time-consuming. Here we use flow cytometry in combination with DNA staining to investigate the effect of phosphate deprivation on the genome copy number of the glucose-tolerant GT-P sub-strain of Synechocystis 6803. Like the PCC 6803 wild type strain, the ploidy of GT-P cells grown in BG-11 medium is growth phase dependent with an average genome copy number of 6.05 ± 0.27 in early growth (OD740 = 0.1) decreasing to 2.49 ± 0.11 in late stationary phase (OD740 = 7). We show that a 10-fold reduction in the initial phosphate concentration of the BG-11 growth medium reduces the average genome copy number of GT-P cells from 4.51 ± 0.20 to 2.94 ± 0.13 and increases the proportion of monoploid cells from 0 to 6% after 7 days of growth. In addition, we also show that the DnaA protein, which unusually for bacteria is not required for DNA replication in Synechocystis, plays a role in restoring polyploidy upon subsequent phosphate supplementation. Based on these observations, we have developed an alternative natural transformation protocol involving phosphate depletion that decreases the time required to obtain fully segregated mutants.


Characterization and sequence-specific binding to mouse mammary tumor virus DNA of purified activated human glucocorticoid receptor.
Activated glucocorticoid receptor (GR) from the human cell line HeLa S3 was purified by differential chromatography on DNA-cellulose followed by DEAE-Sepharose chromatography to 50-60% homogeneity according to sodium dodecyl sulfate gel electrophoresis and densitometric scanning of silver-stained gels. These gels routinely demonstrated a main band of Mr 94,000 (94K band) and two minor bands of Mr 79,000 (79K band) and 39,000 (39K band), respectively. Photoaffinity labeling indicated that the hormone was bound to the 94K and 79K components. In some preparations, a 72K band was observed. Further characterization of the purified receptor by gel permeation chromatography on Sephadex G-200 revealed a receptor complex with a Stokes radius of 5.8 nm. The sedimentation coefficient of the purified receptor was 4.4 Sw. In analogy to the rat hepatic GR, limited proteolysis of the purified GR with trypsin or alpha-chymotrypsin led to degradation of the 94K and 79K components and appearance of 28K and 39K fragments, respectively. In addition, no difference in the protease digestion pattern using Staphylococcus aureus V8 protease was observed. Immunoblotting using a monoclonal antibody raised against the 94K GR from rat liver demonstrated cross-reactivity with the human 94K and 79K proteins from HeLa S3 cells, indicating similar antigenic characteristics between rat and human GR. In our study, five out of nine tested monoclonal antibodies against the rat liver GR cross-reacted with human GR. DNase I and exonuclease III protection experiments demonstrated binding of the purified human GR to specific GR binding regions in mouse mammary tumor virus DNA.(ABSTRACT TRUNCATED AT 250 WORDS)


Arabidopsis myosin XI mutant is defective in organelle movement and polar auxin transport.
Myosins are eukaryotic molecular motors moving along actin filaments. Only a small set of myosin classes is present in plants, in which myosins have been found to play a role in cytoplasmic streaming and chloroplast movement. Whereas most studies have been done on green algae, more recent data suggest a role of higher plant myosin at the postcytokinetic cell wall. Here we characterize a loss-of-function mutation for a myosin of plant-specific class XI and demonstrate myosin functions during plant development in Arabidopsis. T-DNA insertion in MYA2 caused pleiotropic effects, including flower sterility and dwarf growth. Elongation of epidermal cells, such as in hypocotyls and anther filaments, was reduced by up to 50% of normal length. This effect on anther filaments is responsible for flower sterility. In the meristems of root tips, it was evident that cell division was delayed and that cell plates were mislocated. Like zwichel, a kinesin-related mutation causing two-branched trichomes, the mya2 knockout causes branching defects, but here the trichomes remained unbranched. Growth was also impaired in pollen tubes and root hairs, cells that are highly dependent on vesicle transport. A failure in vesicle flow could be directly confirmed, because cytoplasmic streaming of vesicles and, more so, of large endoplasmic reticulum-based organelles was slowed. The defect in vesicle trafficking was accompanied by failures in basipetal auxin transport, measured in stem segments of inflorescences. This result strongly suggests a causal link between auxin-dependent processes and the distribution of vesicles and membrane-bound molecules by plant myosin.


Comparison between turnaround time and cost of herpes simplex virus testing by cell culture and polymerase chain reaction from genital swabs.
Clinical diagnosis of genital herpes simplex virus (HSV) (GH) infection is insensitive and non-specific and requires laboratory confirmation. In this study we compared viral culture and the amplification of HSV DNA by polymerase chain reaction (PCR) with respect to turnaround time and cost. We compared 182 swabs submitted to our laboratory between March and May 2005, which were tested using MRC-5 cell culture, with 168 genital swabs submitted during the same months in 2006, and were tested by PCR. We concluded that PCR testing in our laboratory has significantly improved the turnaround time, with 68.4% of tests having been reported in less than 24 hours. This in turn significantly improved the service provided for the diagnosis of genital herpes without additional costs.


[Synthesis and biological activity of 1-(4-alkyloxy)benzyl-1,2,3,4-tetrahydroisoquinolines and related compounds].
In an attempt to search for novel cardiovascular drugs which might act on calcium or potassium channels, on the basis of the previous study of our group, 15 1-(4-alkyloxy)benzyl-1,2,3,4-tetrahydroisoquinolines derivatives were designed and synthesized among which 10 were not reported previously in the literature. Preliminary pharmacological studies showed that most of these compounds exhibited relaxation of rat thoria aorta in vitro. Compound III9 exhibited potent inhibiting action on low KCl(20 mmol.L-1)-induced contraction of rat aorta, and significant protective effect on experimental arrhythmia in rats.


Sample Size for Joint Testing of Indirect Effects.
This paper presents methods to calculate sample size for evaluating mediation by joint testing of both links in an indirect pathway from exposure to mediator to outcome. Calculations rely on simulations of the underlying data structure, with testing of the two links performed under the simplifying assumption that the two test statistics are asymptotically independent. Simulations show that the proposed methods are accurate. Continuous and binary exposures and mediators, as well as continuous, binary, count, and survival outcomes are accommodated, along with over-dispersion of count outcomes, design effects, and confounding of the exposure-mediator and mediator-outcome relationships. An illustrative example is provided, and a documented R program implementing the calculations is available online.


Association Between Hospital Case Volume of Sepsis, Adherence to Evidence-Based Processes of Care and Patient Outcomes.
We sought to explore potential mechanisms underlying hospital sepsis case volume-mortality associations by investigating implementation of evidence-based processes of care. Retrospective cohort study. We determined associations of sepsis case volume with three evidence-based processes of care (lactate measurement during first hospital day, norepinephrine as first vasopressor, and avoidance of starch-based colloids) and assessed their role in mediation of case volume-mortality associations. Enhanced administrative data (Premier, Charlotte, NC) from 534 U.S. hospitals. A total of 287,914 adult patients with sepsis present at admission between July 2010 and December 2012 of whom 58,045 received a vasopressor for septic shock during the first 2 days of hospitalization. None. Among patients with sepsis, 1.9% received starch, and among patients with septic shock, 68.3% had lactate measured and 64% received norepinephrine as initial vasopressor. Patients at hospitals with the highest case volume were more likely to have lactate measured (adjusted odds ratio quartile 4 vs quartile 1, 2.8; 95% CI, 2.1-3.7) and receive norepinephrine as initial vasopressor (adjusted odds ratio quartile 4 vs quartile 1, 2.1; 95% CI, 1.6-2.7). Case volume was not associated with avoidance of starch products (adjusted odds ratio quartile 4 vs quartile 1, 0.73; 95% CI, 0.45-1.2). Adherence to evidence-based care was associated with lower hospital mortality (adjusted odds ratio, 0.81; 95% CI, 0.70-0.94) but did not strongly mediate case volume-mortality associations (point estimate change ≤ 2%). In a large cohort of U.S. patients with sepsis, select evidence-based processes of care were more likely implemented at high-volume hospitals but did not strongly mediate case volume-mortality associations. Considering processes and case volume when regionalizing sepsis care may maximize patient outcomes.


Nociceptin Receptors in Alcohol Use Disorders: A Positron Emission Tomography Study Using [11C]NOP-1A.
The neuropeptide transmitter nociceptin, which binds to the nociceptin/orphanin FQ peptide (NOP) receptor, is a core component of the brain's antistress system. Nociceptin exerts its antistress effect by counteracting the functions of corticotropin-releasing factor, the primary stress-mediating neuropeptide in the brain. Basic investigations support a role for medications that target nociceptin receptors in the treatment of alcohol use disorders. Thus, it is of high interest to measure the in vivo status of NOP receptors in individuals with alcohol use disorders. Here, we used [11C]NOP-1A and positron emission tomography to measure the in vivo binding to NOP receptors in 15 alcohol-dependent humans as identified by DSM-IV and 15 healthy control subjects matched for age, sex, and smoking status. Alcohol-dependent individuals with no comorbid psychiatric, medical, or drug abuse disorders were scanned following 2 weeks of outpatient monitored abstinence (confirmed with three times per week urine alcohol metabolite testing). [11C]NOP-1A distribution volume in regions of interest (including the amygdala, hippocampus, and midbrain, striatal, and prefrontal cortical subdivisions) was measured with kinetic analysis using the arterial input function. Regional [11C]NOP-1A distribution volume in alcohol dependence was not significantly different compared with healthy control subjects. No relationship between [11C]NOP-1A distribution volume and other clinical measures (including duration and severity of alcohol abuse, craving, and anxiety or depressive symptoms) were significant after correction for the multiple hypotheses tested. The results of this study do not support alterations in the binding to NOP receptors in alcohol dependence. However, this finding does not necessarily rule out alterations in nociceptin transmission in alcohol dependence.


Fourier Collocation Approach With Mesh Refinement Method for Simulating Transit-Time Ultrasonic Flowmeters Under Multiphase Flow Conditions.
A numerical model for transit-time ultrasonic flowmeters operating under multiphase flow conditions previously presented by us is extended by mesh refinement and grid point redistribution. The method solves modified first-order stress-velocity equations of elastodynamics with additional terms to account for the effect of the background flow. Spatial derivatives are calculated by a Fourier collocation scheme allowing the use of the fast Fourier transform, while the time integration is realized by the explicit third-order Runge-Kutta finite-difference scheme. The method is compared against analytical solutions and experimental measurements to verify the benefit of using mapped grids. Additionally, a study of clamp-on and in-line ultrasonic flowmeters operating under multiphase flow conditions is carried out.


Transumbilical Laparoscopic-Assisted Appendectomy in the Treatment of Acute Uncomplicated Appendicitis in Children.
Transumbilical laparoscopic-assisted appendectomy (TULAA) is increasingly being performed worldwide. The authors report their experience in the treatment of acute uncomplicated appendicitis in children with TULAA. From January 2008 to December 2012 all types of acute appendicitis were divided, according to the clinical and ultrasonographic findings, into complicated (appendiceal mass/abscess, diffuse peritonitis) and uncomplicated. Complicated appendicitis was treated by open appendectomy (OA). All patients with the suspicion of uncomplicated appendicitis were offered TULAA by all surgeons of the team. Conversion to open or laparoscopic appendectomy (LA) was performed in case of impossibility to complete TULAA, depending on the choice of surgeon. The histopathologic examination of appendix was always performed. 444 children (252 males) with acute appendicitis were treated. The mean age was 9.2 years (range, 2 to 14 years). Primary OA was performed in 144 cases. In 300 patients a transumbilical laparoscopic-assisted approach was performed. TULAA was completed in 252 patients. Conversion to OA was performed in 45 patients and to LA in 3. Conversion was related to the impossibility to adequately expose the appendix in 47 patients and bleeding in 1. The mean operative time for TULAA was 42 minutes. Histopathologic examination of the appendix removed by TULAA showed a phlegmonous/gangrenous type in 92.8% of cases. Among the 252 TULAA there were 11 cases of umbilical wound infection. TULAA is a feasible and effective procedure for uncomplicated appendicitis in children. It combines the advantages of open and laparoscopic technique (low operative time, low complications rate, and excellent cosmetic results).


Studying flowers in 3D using photogrammetry.
Flowers are intricate and integrated three-dimensional (3D) structures predominantly studied in 2D due to the difficulty in quantitatively characterising their morphology in 3D. Given the recent development of analytical methods for high-dimensional data, the reconstruction of flower models in three dimensions represents the limiting factor to studying flowers in 3D. We developed a floral photogrammetry protocol to reconstruct 3D models of flowers based on images taken with a digital single-lens reflex camera, a turntable and a portable lightbox. We demonstrate that photogrammetry allows a rapid and accurate reconstruction of 3D models of flowers from 2D images. It can reconstruct all visible parts of flowers and has the advantage of keeping colour information. We illustrated its use by studying the shape and colour of 18 Gesneriaceae species. Photogrammetry is an affordable alternative to micro-computed tomography (micro-CT) that requires minimal investment and equipment, allowing it to be used directly in the field. It has the potential to stimulate research on the evolution and ecology of flowers by providing a simple way to access 3D morphological data from a variety of flower types.


Immediate-early gene expression in the barrel cortex.
Since their detection in the early 1980s immediate-early genes (most of them being inducible transcription factors) have been regarded as molecular keys to the orchestration of late-effector genes that ultimately would enable functional and structural adaptation of the brain to changing external and internal demands. This is called neuronal plasticity and it has been intensively studied in the somatosensory (barrel) cortex of rodents. This brain region is intimately involved in the processing and probably also the storage of tactile information, stemming from the large facial whiskers, necessary for object detection or spatial navigation in the environment. On the other hand, several of the inducible transcription factors have been found to function as neuronal activity markers providing a cellular resolution, thus, enabling the cell-type specific mapping of activated neuronal circuits. Some recent data on both topics in the rodent barrel cortex will be presented in this topical review.


Flexor hallucis longus transfer for repair of chronic achilles tendinopathy.
The flexor hallucis longus (FHL) tendon has been used to augment the repairs for chronic Achilles tendinopathy. Two common methods of FHL harvesting include a single incision (posterior) technique and a double incision (posterior and medial utility) technique. This cadaver study was designed to measure and compare the lengths of FHL tendon obtainable for reconstruction with each technique. Fourteen fresh-frozen cadaver lower limbs were utilized for FHL harvest. The tendon was first exposed through the single posterior-medial incision approach adjacent to the Achilles. A second medial utility midfoot incision was then made and the FHL was marked at the level of Henry's knot with a suture, to approximate the level of potential harvest via a two-incision technique. The FHL was then harvested and delivered into the posterior wound. Single incision technique graft length was then measured from the tip of the calcaneal tuber to the level of transection. The remaining in situ tendon was then also measured between its level of transection and the more distal suture placed at Henry's knot. These two lengths were then combined to determine the total potential tendon graft length obtainable using a double incision technique. The average length of the FHL tendon harvested through the single posterior incision technique measured 5.16 cm (range, 3.4-6.9 cm, SD = 1.29). The average total tendon graft length available using the double incision technique measured 8.09 cm (range, 5.1-11.1 cm, SD = 1.63). The difference between the lengths obtained from these two techniques was significant (p < .001). These results demonstrate approximate FHL graft lengths obtainable by using either a single or double incision harvest technique and show that a significantly longer graft can be obtained using a double incision technique. Further data need to be obtained, however, to support whether the extra surgery and graft length obtained from a double incision technique are of any benefit in improving the ultimate functional outcome of these repairs.


Ring-opening polymerization of prodrugs: a versatile approach to prepare well-defined drug-loaded nanoparticles.
The synthesis of polymer-drug conjugates from prodrug monomers consisting of a cyclic polymerizable group that is appended to a drug through a cleavable linker is achieved by organocatalyzed ring-opening polymerization. The monomers polymerize into well-defined polymer prodrugs that are designed to self-assemble into nanoparticles and release the drug in response to a physiologically relevant stimulus. This method is compatible with structurally diverse drugs and allows different drugs to be copolymerized with quantitative conversion of the monomers. The drug loading can be controlled by adjusting the monomer(s)/initiator feed ratio and drug release can be encoded into the polymer by the choice of linker. Initiating these monomers from a poly(ethylene glycol) macroinitiator results in amphiphilic diblock copolymers that spontaneously self-assemble into micelles with a long plasma circulation, which is useful for systemic therapy.


Hypertonicity triggers RhoA-dependent assembly of myosin-containing striated polygonal actin networks in endothelial cells.
Endothelial cells respond to mechanical stresses of the circulation with cytoskeletal rearrangements such as F-actin stress fiber alignment along the axis of fluid flow. Endothelial cells are exposed to hypertonic stress in the renal medulla or during mannitol treatment of cerebral edema. We report here that arterial endothelial cells exposed to hypertonic stress rearranged F-actin into novel actin-myosin II fibers with regular 0.5-microm striations, in which alpha-actinin colocalizes with actin. These striated fibers assembled over hours into three-dimensional, irregular, polygonal actin networks most prominent at the cell base, and occasionally surrounding the nucleus in a geodesic-like structure. Hypertonicity-induced assembly of striated polygonal actin networks was inhibited by cytochalasin D, blebbistatin, cell ATP depletion, and intracellular Ca(2+) chelation but did not require intact microtubules, regulatory volume increase, or de novo RNA or protein synthesis. Striated polygonal actin network assembly was insensitive to inhibitors of MAP kinases, tyrosine kinases, or phosphatidylinositol 3-kinase, but was prevented by C3 exotoxin, by the RhoA kinase inhibitor Y-27632, and by overexpressed dominant-negative RhoA. In contrast, overexpression of dominant-negative Rac or of dominant-negative cdc42 cDNAs did not prevent striated polygonal actin network assembly. The actin networks described here are novel in structure, as striated actin-myosin structures in nonmuscle cells, as a cellular response to hypertonicity, and as a cytoskeletal regulatory function of RhoA. Endothelial cells may use RhoA-dependent striated polygonal actin networks, possibly in concert with cytoskeletal load-bearing elements, as a contractile, tension-generating component of their defense against isotropic compressive forces.


Addiction to Tobacco Smoking and Vaping.
The tobacco epidemic has been one of the biggest public health threats, and smoking is one of the world's largest preventable causes of premature death. An estimated 15.4% of all deaths in the world are attributable to tobacco smoking. The present review aims to describe addiction to tobacco smoking and vaping. Tobacco and vaping devices contain nicotine, a highly addictive drug, which explains why smoking is so prevalent and persistent. Electronic cigarettes are a group of novel nicotine or tobacco products that have rapidly gained popularity in recent years. Electronic cigarette devices allow for the use of other drugs, including THC, while the lax regulation may allow for the introduction of toxic compounds that can lead to acute or subacute toxicity, such as the e-cigarette- or vaping-associated lung injury that has been linked to vitamin E acetate. In addition, regular vapers and heated tobacco devices emit toxins, although at lower concentrations than burned tobacco. However, more and more side effects have been identified. No new effective treatment for nicotine addiction has been developed recently, despite its huge adverse impact on overall health and other outcomes. As for the primary line of medications, the last one started in 2006, the varenicline, demonstrating a low interest in developing new medications against smoking, an unacceptable state of affairs, given the huge impact of smoking on morbidity and mortality.


Medicating the environment: assessing risks of pharmaceuticals to wildlife and ecosystems.
Global pharmaceutical consumption is rising with the growing and ageing human population and more intensive food production. Recent studies have revealed pharmaceutical residues in a wide range of ecosystems and organisms. Environmental concentrations are often low, but pharmaceuticals typically are designed to have biological effects at low doses, acting on physiological systems that can be evolutionarily conserved across taxa. This Theme Issue introduces the latest research investigating the risks of environmentally relevant concentrations of pharmaceuticals to vertebrate wildlife. We take a holistic, global view of environmental exposure to pharmaceuticals encompassing terrestrial, freshwater and marine ecosystems in high- and low-income countries. Based on both field and laboratory data, the evidence for and relevance of changes to physiology and behaviour, in addition to mortality and reproductive effects, are examined in terms of the population- and community-level consequences of pharmaceutical exposure on wildlife. Studies on uptake, trophic transfer and indirect effects of pharmaceuticals acting via food webs are presented. Given the logistical and ethical complexities of research in this area, several papers focus on techniques for prioritizing which compounds are most likely to harm wildlife and how modelling approaches can make predictions about the bioavailability, metabolism and toxicity of pharmaceuticals in non-target species. This Theme Issue aims to help clarify the uncertainties, highlight opportunities and inform ongoing scientific and policy debates on the impacts of pharmaceuticals in the environment.


Lack of type XVIII collagen results in anterior ocular defects.
Mice lacking type XVIII collagen have defects in the posterior part of the eye, including delayed regression of the hyaloid vasculature and poor outgrowth of the retinal vessels. We report here that these mice also have a fragile iris and develop atrophy of the ciliary body. The irises of Col18a1-/- mice can be seen to adhere to the lens and cornea. After the pupils begin to function, the double layer of epithelial cells separates at the apical cell contacts, leading to defoliation of its posterior pigment epithelial cell layer, and extracellular material begins to accumulate in the basement membrane zones of the iris. In contrast to the iris epithelia, where no clear signs of cellular atrophy were detected, the lack of type XVIII collagen resulted in atrophy of the pigmented epithelial cells of the ciliary body, and there were also ultrastructural abnormalities in the basement membrane zones. These changes did not lead to chronically elevated intraocular pressures, however. Our results indicate that type XVIII collagen is needed for the integrity of the epithelial basement membranes of the iris and the ciliary body and that its gene should therefore be taken into account as a new potential cause of anterior segment disorders in the eye.


The clinical utility of blood pressure load in hypertension.
The variability of blood pressure and its consequences suggests that ambulatory blood pressure (ABP) data should be analyzed not only by mean ambulatory blood pressure (MABP), but also by looking at blood pressure load (BPL, the percentage of measurements > 140/90 mm Hg while awake and > 120/80 while asleep). In one study, several hypertensive patients whose ambulatory diastolic blood pressure was < 90 mm Hg had a diastolic load near 50%. Studies have reported strong correlations between BPL and indices of target-organ changes such as left ventricular mass index (LVMI). It was necessary to lower office blood pressure to < 85 mm Hg to reduce BPL to a normal range of 15 to 20%. To further investigate the usefulness of BPL in the study of hypertension, more longitudinal studies of cardiovascular disease and blood pressure variability are needed.


Pathways of tumour cell killing by activated macrophages: both tumour cell membrane and nucleus can be the primary target.
Plasma membrane and nucleus can be primary targets of tumour cell killing by activated macrophages (AMø). Necrotic-type cytotoxicity with loss of membrane integrity and cytoplasmic swelling was expressed by AMø from normal and from perforin-deficient mice, indicating that perforin was not involved. Incubation with AMø consistently triggered the release of thymidine from prelabelled targets, whereas chromatin condensation and small DNA fragments were only occasionally detected. It is shown by means of Pulsed-Field Gel Electrophoresis that DNA degradation in target cells is a slowly progressing process that may stop at any time, indicating that nuclear-type killing doesnot necessarily lead to the formation of low molecular weight fragments. Neither Fas nor the p55 tumour necrosis factor receptor appear to be involved in signalling nuclear-type killing. Accordingly, AMø do mediate membrane- and nuclear-type killing but the mechanisms differ from those identified in T cell cytotoxicity.


Effect of converting enzyme inhibitors on hypertensive large arteries in humans.
As demonstrated in hypertensive humans on the basis of non-invasive Doppler methods, converting enzyme inhibitors (CEI) dilate not only small arteries but also large arteries, particularly in the brachial and the carotid circulations. The dilating effect of CEI on large arteries is associated with an enhancement of systemic and brachial arterial compliance, implying a particular action of the drug on arterial smooth muscle. Converting enzyme inhibitors are thus able to reverse the reduced arterial compliance observed in patients with essential hypertension.


Comparison of induction of labour regimes for termination of pregnancy, with and without mifepristone, from 20 to 41 weeks gestation.
To investigate the efficacy of mifepristone for induction of labour in pregnancies at 20-41 weeks' gestation, by comparing the outcomes of length of labour and duration of admission in women with and without mifepristone pretreatment. In this retrospective cohort study, all women who underwent a medical termination of a singleton pregnancy between 20 and 41 weeks gestation for either a fetal abnormality or fetal death in utero between 1 January, 2009 and 1 January, 2014 were identified. Women who went into spontaneous labour, required a primary surgical delivery or had a multiple pregnancy were not included. The total number of women included in the study was 147: 63 in the mifepristone treatment and 84 in the no mifepristone treatment. In the group of women induced after mifepristone pre-treatment there was a 38% reduction in the median duration of labour, with 2.5 h in the group treated with mifepristone versus 4.0 h in women induced without (P = 0.001). We also found a 50% reduction in the number of days admitted to hospital with the length of admission being 1 day versus 2 days (P = 0.005). This study supports the hypothesis that in pregnancies greater than 20 weeks, the duration of labour and length of admission are reduced when induction of labour for termination of pregnancy is preceded by treatment with mifepristone.


Anti-inflammatory effects and anti-oxidant capacity of Myrathius arboreus (Cecropiaceae) in experimental models.
Inflammation is involved in various diseases; search for safe treatments is warranted. Anti-inflammatory effects of ethanol extract of Myrathius arboreus (EEMa) were studied in carrageenan-induced model, formaldehyde sub-acute-induced model, and in 48 h lipopolysaccharide-induced air pouch model of inflammation. EEMa membrane-stabilizing activities and anti-oxidant capacity were determined in vitro. In the carrageenan model EEMa (125, 250, or 500 mg/kg), indomethacin (5 mg/kg), or vehicle 3 mL/kg was administered orally in rats (n=5). After 1 h, 0.1 mL of 1% carrageenan was injected into the right hind paw of rats. Change in edema sizes was measured for 3 h with plethysmometer. One-tenth milliliter (0.1 mL) of 2.5% formaldehyde was injected into the rat paw on the first day and the third day to induce sub-acute inflammation; changes in the edema sizes were determined, and percentages of inhibitions were calculated. Anti-inflammatory effects of EEMa were further examined in lipopolysaccharide (LPS)-induced air-pouch based on leukocytes count, volume of exudates, levels of malondialdehyde, glutathione, superoxide dismutase, nitric oxides, and tumor necrosis factor released into the inflammatory fluids. EEMa-free radicals scavenging activities were studied in DPPH and reducing power tests. Membrane-stabilizing activities of EEMa were evaluated in the red blood cell lysis induced by thermal and hypotonic solution. EEMa (250, 500 mg/kg) produced significant (p<0.001; p<0.05) inhibition of inflammation when compared with vehicle. Also, EEMa (250, 500, or 1000 μg/mL) significantly stabilized membrane and produced free radical scavenging activities. M. arboreus possesses anti-inflammatory and the anti-oxidant properties that might benefit translational medicine.


Association between genetic polymorphisms and angiotensin-converting enzyme inhibitor-induced cough: a systematic review and meta-analysis.
Genetic polymorphisms may influence the incidence of angiotensin-converting enzyme (ACE) inhibitor-induced cough. This study aims to investigate this association. Ten electronic databases and PharmGKB were systematically searched. Pooled odds ratio values and their 95% CI were used to assess the association, using the random-effects model. A total of 26 studies were included in the review, 17 of them were included from two separated meta-analysis (ACE I/D or BDKRB2-58T/C). Significant association was found between ACE I/D I carriers (ACE gene insertion) and ACE inhibitor-induced cough, showing racial and age differences. This study demonstrated that ACE I/D but not BDKRB2-58T/C polymorphism could be a predictor for the risk of ACE inhibitor-induced cough, especially in east Asians and the aged.


Deep sound-field denoiser: optically-measured sound-field denoising using deep neural network.
This paper proposes a deep sound-field denoiser, a deep neural network (DNN) based denoising of optically measured sound-field images. Sound-field imaging using optical methods has gained considerable attention due to its ability to achieve high-spatial-resolution imaging of acoustic phenomena that conventional acoustic sensors cannot accomplish. However, the optically measured sound-field images are often heavily contaminated by noise because of the low sensitivity of optical interferometric measurements to airborne sound. Here, we propose a DNN-based sound-field denoising method. Time-varying sound-field image sequences are decomposed into harmonic complex-amplitude images by using a time-directional Fourier transform. The complex images are converted into two-channel images consisting of real and imaginary parts and denoised by a nonlinear-activation-free network. The network is trained on a sound-field dataset obtained from numerical acoustic simulations with randomized parameters. We compared the method with conventional ones, such as image filters, a spatiotemporal filter, and other DNN architectures, on numerical and experimental data. The experimental data were measured by parallel phase-shifting interferometry and holographic speckle interferometry. The proposed deep sound-field denoiser significantly outperformed the conventional methods on both the numerical and experimental data. Code is available on GitHub (https://github.com/nttcslab/deep-sound-field-denoiser).


Different-shaped micro-objects driven by active particle aggregations.
The dynamics of passive micro-objects in an active bath has been receiving much attention. However, the influence of the shapes of micro-objects remains unclear. Here, we use 2D simulation to investigate the interaction between active Brownian particles and different-shaped passive micro-objects. We show that active particles accumulate around micro-objects and self-assemble into living aggregations at a high active velocity and high volume fraction. The shapes of micro-objects affect the distributions of the aggregations. In turn, the different distribution of aggregations influences the motion of micro-objects and induces abnormal diffusive behaviors. We further demonstrate that polar distributed aggregations at a high active velocity and the inhibition of the active bath at a low active velocity induce the counterintuitive anisotropic enhanced diffusion of rods, and the steric interaction between active particles induces the reverse translation-rotation coupled diffusion of chevrons.


A novel fabrication method for titania resistive switching device.
The titania showing reversible resistive switching are attractive for today's semiconductor technology in nonvolatile random-access memories. A novel fabrication method for titania resistive switching device with vertical structure is proposed. First, the Pt electrode was fabricated the bottom using conventional photolithography and chemical etching technique. Next, the titania thin films with the thickness about 50 nm was deposited on the bottom electrode by electron beam evaporation (EBE). Then, the trench of photoresist for electrode deposit was etched with mild chemical process to preserve the original structure of titania layer. After that, the platinum was deposited in the trench of photoresist using ion sputter. A final lift-off process to define the Pt top electrodes was performed with acetone in an ultrasonic bath to remove the resist. The resistive bistability was observed in this device. The on-threshold voltage is +1.5 V and the off-threshold voltage is -0.6 V. The resistance ratio between the two stable states of the device including Al electrode is approximately 1 x 10(3), the state is nonvolatile and the retention-time test performed over an hour in sweeping mode measurement. The results indicate the forming and rupture of conductive channel relate to the defects and distributing of oxygen vacancy. This method is low-cost, high-yielding, and easy to implement, which is applicable to the fabrication of nonvolatile memories.


Comparison of two different scleral fixation techniques of posterior chamber Carlevale lens.
To investigate the surgical outcomes of 2 different scleral fixation techniques of the new single-piece foldable acrylic Carlevale lens (Soleko) and to compare our results with previous reports of the literature.A retrospective, non-randomized comparative study involving 2 series of patients who underwent 2 different scleral fixation techniques of Carlevale lens was performed. Minimum follow-up of 3 months was requested for inclusion in the study. All the patients underwent a standard ophthalmologic examination including best correct visual acuity, measurement of intraocular pressure, anterior segment, and fundus examination. In the first technique (group 1), plugs were externalized through a 23 gauge sclerotomy and placed within 2 scleral pockets. In the second technique (group 2), plugs were externalized through a 25-gauge sclerotomy and covered by 2 scleral flaps. For an estimation of the refractive prediction error, the postoperative spherical equivalent of objective refraction was calculated (IOL Master 750, Carl Zeiss Meditec AG, Jena, Germany). Spectral domain optical coherence tomography (Spectralis HRA+OCT2, Heidelberg Engineering, Heidelberg, Germany) of anterior segment was used to check plugs positioning postoperatively.Twenty-three eyes in group 1 and 9 eyes in group 2 were included. Preoperative diagnosis was aphakia, dislocated posterior chamber intra ocular lens, dislocated lens, anisometropia, Uveitis-Glaucoma-Hyphema syndrome, perforating trauma with dislocated intra ocular lens, and open globe injury with dislocated intra ocular lens. Respectively, in groups 1 and 2, refractive spherical equivalent prediction error was -0,31 ± 0,74 D and -0,27 ± 0,80 D, and postoperative best-corrected visual acuity was 0,42 ± 0,31 logMAR and 0,47 ± 0,45 logMAR. In group 1, 1 eye developed cystoid macular edema, 1 eye vitreous haemorrhage, and 3 eyes showed plugs located outside the scleral pockets under the conjunctiva. Rupture of 1 of the 2 tips of the plug was observed in 1 patient of group 1 during the externalization.Carlevale lens is a scleral fixated intra ocular lens specifically designed for posterior chamber implantation that could be successfully managed without any significant difference between the 2 surgical techniques, and appears approachable for anterior and posterior segment surgeons. A 25-gauge sclerotomy should be preferred with the aim of a sutureless surgery regardless the technique employed.


Use of gemtuzumab ozogamicin in the treatment of pediatric relapsed/ refractory Acute Myeloid Leukemia.
Gemtuzumab ozogamicin (GO, MylotargTM) is an antibody-targeted chemotherapy agent that has been studied in acute myeloid leukemia (AML) at first relapse in adults. There is limited experience in pediatric patients. We report six patients with refractory/relapsed CD33+AML who were treated with GO on compassionate-use basis. One patient attained remission. One patient is still alive following hematopoietic stem cell transplantation (HSCT), and one patient died in remission. Two patients were refractory and three patients had a response with <5% blasts in the bone marrow. Fever and chills, hypotension and hypoxia were observed as side effects. Three patients developed veno-occlusive disease (VOD) of the liver. Two of these three patients had persistence of VOD at the time of their deaths. One patient treated postSCT had bone marrow response without VOD. GO should be used cautiously in chemotherapy-refractory AML pediatric patients due to the high incidence of VOD.


Papillary-cystic neoplasm of the pancreas. Report of two cases and review of the literature.
Two cases of papillary-cystic neoplasm of the pancreas are reported in women aged 22 and 23 years. The patient in the first case presented with acute abdominal pain and hemoperitoneum. This form of presentation has not been previously reported. This type of pancreatic tumor is very rare, exclusively affecting young women, and has a good prognosis despite its various histologic features, which suggest a malignant appearance. The authors consider this neoplasm as having an acinar origin because in the cells of one of the patients we observed ultrastructurally the presence of abundant rough endoplasmatic reticulum with formation of annulate lamellae and a few prezymogen granules.


Biophysical profile scoring in the management of the diabetic pregnancy.
Biophysical profile scoring was the principal technique of antepartum fetal surveillance in 238 well-controlled diabetic pregnancies. Fifty insulin-dependent diabetics had twice-weekly testing, and 188 gestational diabetics had weekly testing. Intervention was not pursued unless there were maternal or fetal complications. There were no stillbirths and three neonatal deaths, all resulting from congenital anomalies, giving a corrected perinatal mortality rate of 0. The incidence of abnormal biophysical profile scores, eight of 238 (3.3%) overall, was low, with no significant difference between types of diabetics. In those with an abnormal score, intervention was mandated; the cesarean section rate was 50% and the rate of intensive care nursery admissions was high. Of the 230 fetuses with a normal biophysical profile score, 200 (87%) were delivered at term with minimal maternal or neonatal morbidity. Amniocentesis for phospholipid profile was performed in only 33 cases (13.9%). Hyaline membrane disease was confined to five premature neonates (incidence 2.1%). We conclude that antepartum fetal surveillance using the biophysical profile score permits safe expectant management in the diabetic pregnancy, yielding significant clinical advantages to both mother and fetus.


Repair of root resorption 2 to 16 weeks after the application of continuous forces on maxillary first molars in rats: a 2- and 3-dimensional quantitative evaluation.
Root resorption is a side effect of orthodontic treatment that occurs with the removal of hyalinized tissue. Studies have shown that a reparative process in the periodontium begins when the applied orthodontic force is discontinued or reduced below a certain level. However, quantitative 3-dimensional evaluation of root resorption repair has not been done. The aim of this study was to quantitatively assess the 2- and 3-dimensional changes of root resorption craters after 2 weeks of continuous mesially applied orthodontic forces of 50 g on rat molars and 2- to 16-week retention periods. We used 60 male Wistar rats (10 weeks old). Nickel-titanium closed-coil springs were used to apply 50-g mesial forces for 2 weeks to move the maxillary left first molars. The rats were randomly allocated to 6 groups. Those in the zero-week retention group were killed after force application. In the remaining 5 groups, the interdental spaces between the maxillary first and second molars were filled with resin to retain the molars. The molars were extracted after periods of retention from 2 and 16 weeks. The maxillary right molars were used as the controls. Mesial and distal roots (distobuccal and distopalatal) were examined by using scanning electron and 3-dimensional scanning laser microscopes. The surface area, depth, volume, and roughness of the root resorption craters were measured. The area, depth, and volume of the craters decreased gradually and showed similar trends over the retention time, approaching a plateau at the 12th week. After 16 weeks of retention, the volumes of the resorption craters of the distobuccal and distopalatal roots reached recovery peaks of 69.5% and 66.7%, respectively. Small pits on the mesial roots showed recovery of 62.5% at the 12th week. The healing patterns in distal roots with severe resorption and mesial roots with shallow resorption had no significant differences. The resorption and repair processes during the early stages of retention are balanced, and most of the reparative process occurs after 4 weeks of passive retention after the application of orthodontic force. Frequent orthodontic reactivations should be avoided to allow recovery and repair of root surface damage.


Clinical use of dimethyl fumarate in multiple sclerosis treatment: an update to include China, using a modified Delphi method.
Dimethyl fumarate (DMF) is a widely used oral disease-modifying therapy for multiple sclerosis (MS). Its efficacy and safety profiles are supported by over a decade of experience. Differences exist between Asia and Europe/United States in the prevalence and characteristics of MS; most data for DMF are derived from populations outside Asia. DMF was recently (2021) approved for use in China. The objectives of this review were to evaluate the evidence for DMF's profile, to provide an update to healthcare providers on current knowledge surrounding its use and to assess the relevance of existing data to use in China. This study used a modified Delphi method based on the insights of a scientific Steering Committee (SC), with a structured literature review conducted to assess the data of DMF. The literature review covered all papers in English (from 01 January 2011 to 21 February 2022) that include 'dimethyl fumarate' and 'multiple sclerosis', and their MeSH terms, on PubMed, supplemented by EMBASE and Citeline searches. Papers were categorized by topic and assessed for relevance and quality, before being used to formulate statements summarizing the literature on each subject. SC members voted on/revised statements, requiring ⩾80% agreement and ⩽10% disagreement for inclusion. Statements not reaching this level were discussed further until agreement was reached or until there was agreement to remove the statement. A total of 1030 papers were retrieved and used to formulate the statements and evidence summaries considered by the SC members. A total of 45 statements were agreed by the SC members. The findings support the positive efficacy and safety profile of DMF in treating patients with MS. Limited Chinese patient data are an ongoing consideration; however, based on current evidence, the statements are considered applicable to both the global and Chinese populations. DMF is a valuable addition to address unmet MS treatment needs in China. Registration: Not applicable.


Systematically ranking the tightness of membrane association for peripheral membrane proteins (PMPs).
Large-scale quantitative evaluation of the tightness of membrane association for nontransmembrane proteins is important for identifying true peripheral membrane proteins with functional significance. Herein, we simultaneously ranked more than 1000 proteins of the photosynthetic model organism Synechocystis sp. PCC 6803 for their relative tightness of membrane association using a proteomic approach. Using multiple precisely ranked and experimentally verified peripheral subunits of photosynthetic protein complexes as the landmarks, we found that proteins involved in two-component signal transduction systems and transporters are overall tightly associated with the membranes, whereas the associations of ribosomal proteins are much weaker. Moreover, we found that hypothetical proteins containing the same domains generally have similar tightness. This work provided a global view of the structural organization of the membrane proteome with respect to divergent functions, and built the foundation for future investigation of the dynamic membrane proteome reorganization in response to different environmental or internal stimuli.


[Usefulness of computerized tomography and bronchoscopy in patients with hemoptysis. Analysis of 482 cases].
We have examined the computed chest tomography (CT) and bronchoscopy utility in diagnosis and accurately identifying the sites of pulmonary bleeding in patients with hemoptysis. We prospectively reviewed the etiology and the site of bleeding of 482 patients with hemoptysis who had undergone bronchoscopy and CT when we suspected a carcinoma, bronchiectasis or the type of bleeding. We analyzed the age, sex, history of tobacco, bleeding, chest radiography, chest computed tomography and bronchoscopy. 62 years (DS 13.6), 84.4% males, 80% smokers and a volume of bleeding of 42.5 ml/day (DS 89) for 15 days (DS 25). Lung cancer was identified in 43%, bronchiectasis in 20%, chronic obstructive lung disease in 14%, pneumonia 8% and an unknown etiology in only 3%. Bronchoscopy located the site of bleeding in 77% and CT in 83%. When we examine only the lung carcinomas, the chest radiography was normal in 11% and the bronchoscopy was diagnostic in 87%, including 6 cases with a normal CT. Simultaneously chest CT or radiography and bronchoscopy detected all the lung cancers. When the chest radiography was inespecific (32%), CT was diagnostic in 43% and bronchoscopy in 14% (p < 0.001) or localized the site of bleeding in 52% with the CT or 23% with the bronchoscopy (< 0.001). We concluded that bronchoscopy and CT were useful and complementary in etiologic diagnosis and to localize the site of bleeding in patients with hemoptysis. The bronchoscopy was preferable in patients with a lung cancer and the CT when we studied all the etiologies or the patients without a lung cancer, especially when the radiography was normal. When we simultaneously used a CT or a radiography and the bronchoscopy, all the lung cancers were detected.


The current and future status of inotropes in heart failure management.
Heart failure (HF) is a complex syndrome with a wide range of presentations and acuity, ranging from outpatient care to inpatient management due to acute decompensated HF, cardiogenic shock or advanced HF. Frequently, the etiology of a patient's decompensation is diminished cardiac output and peripheral hypoperfusion. Consequently, there is a need for use of inotropes, agents that increase cardiac contractility, optimize hemodynamics and ensure adequate perfusion. Inotropes are divided into 3 major classes: beta agonists, phosphodiesterase III inhibitors and calcium sensitizers. Additionally, as data from prospective studies accumulates, novel agents are emerging, including omecamtiv mecarbil and istaroxime. The aim of this review is to summarize current data on the optimal use of inotropes and to provide an expert opinion regarding their current and future use in the management of HF. The use of inotropes has long been linked to worsening mortality, tachyarrhythmias, increased myocardial oxygen consumption and ischemia. Therefore, individualized and evidence-based treatment plans for patients who require inotropic support are necessary. Also, better quality data on the use of existing inotropes is imperative, while the development of newer and safer agents will lead to more effective management of patients with HF in the future.


The African swine fever virus proteins p54 and p30 are involved in two distinct steps of virus attachment and both contribute to the antibody-mediated protective immune response.
The nature of the initial interactions of African swine fever (ASF) virus with target cells is only partially known, and to date only the ASF virus protein p12 has been identified as a viral attachment protein. More recently, antibodies to viral proteins p54 and p30 have been shown to neutralize the virus, inhibiting virus binding and internalization, respectively. Therefore, we investigated the role of these proteins in the receptor-mediated ASF virus endocytosis in swine macrophages, the natural host cells. Proteins p54 and p30, released from ASF virus particles after treatment of virions with a nonionic detergent, bound to virus-sensitive alveolar pig macrophages. Binding of these proteins was found to be specifically inhibited by neutralizing antibodies obtained from a convalescent pig or from pigs immunized with recombinant p54 or p30 proteins. The baculovirus-expressed proteins p54 and p30 retained the same biological properties as the viral proteins, since they also bound specifically to these cells, and their binding was equally inhibited by neutralizing antibodies. Binding of 35S-labeled recombinant p54 and p30 proteins to macrophages was specifically competed by an excess of unlabeled p54 and p30, respectively. However, cross-binding inhibition was not observed, suggesting the existence of two different saturable binding sites for these proteins in the susceptible cells. In addition, protein p54 blocked the specific binding of virus particles to the macrophage, while protein p30 blocked virus internalization. Both proteins independently prevented virus infection and in a dose-dependent manner, suggesting that binding interactions mediated by both proteins are necessary to give rise to a productive infection. The relevance of blockade of virus-cell interactions mediated by p54 and p30 in the protective immune response against ASF virus was then investigated. Immunization of pigs with either recombinant p54 or p30 proteins induced neutralizing antibodies which, as expected, inhibited virus attachment or internalization, respectively. However, immunized pigs were not protected against lethal infection and the disease course was not modified in these animals. In contrast, immunization with a combination of p54 and p30 proteins simultaneously stimulated both virus neutralizing mechanisms and modified drastically the disease course, rendering a variable degree of protection ranging from a delay in the onset of the disease to complete protection against virus infection. In conclusion, the above results strongly suggest that proteins p54 and p30 mediate specific interactions between ASF virus and cellular receptors and that simultaneous interference with these two interactions has a complementary effect in antibody-mediated protection.


Pigment gallstones of the common bile duct in infancy.
Ten infants of less than 6 months of age presented with cholestatic jaundice and gallstones. Jaundice occurred after a lag period, and sepsis was present in three children. Ultrasound examination showed dilatation of intrahepatic and extrahepatic bile ducts in eight patients and detected cholelithiasis in three. Percutaneous transhepatic cholangiography and/or surgery allowed separation of the patients into two groups: (i) six children with lithiasis in the distal common bile duct, and (ii) four children with lithiasis associated with bile duct perforation at the junction between the cystic and common bile ducts with gallstones probably secondary to bile stasis and infection. Surgical treatment was confined to removal of calculi and drainage in eight children; biliary reconstructive surgery was necessary in the other two who had serious biliary duct lesions. No recurrence was observed after 1 to 7 years. The pigmentary nature of cholelithiasis was established by stone morphology in all cases, and by bile and stone analysis in several cases.


The case for utilizing more strict quantitative Doppler echocardiographic criterions for diagnosis of subclinical rheumatic carditis.
Our aim was to perform a comparative, quantitative and qualitative, analysis of valvar echocardiographic findings in patients with acute rheumatic fever, with or without clinical manifestations of carditis, as compared to healthy controls. We analyzed cross-sectional Doppler echocardiographic images of 31 patients with acute rheumatic fever diagnosed according to the Jones criterions as modified in 1992. Of 31 patients, 22 presented with clinical carditis, while 9 had subclinical carditis. The patients, and a control group of 20 healthy individuals, underwent cardiac examination and echocardiographic assessment, assessing quantitative and qualitative findings of mitral and aortic valvar abnormalities. The leaflets of the mitral valve were statistically thicker in those with clinical and subclinical carditis when compared to controls (p less than 0.001). We observed a greater frequency of mitral variance, convergence of mitral flow, and aortic regurgitation for those with clinical and subclinical carditis when compared to controls (p less than 0.001, p less than 0.001 and p equal to 0.003, respectively). Patients with clinical and subclinical carditis had more quantitative and qualitative changes in the parameters than did the controls. Echocardiography is a sensitive method to detect valvar abnormalities in patients with acute rheumatic fever and carditis. Additionally, by using regular standardized criterions, abnormalities that lead to a diagnosis of subclinical carditis are found in those patients with acute rheumatic fever in the apparent absence of cardiac involvement.


Effects of switching to aripiprazole from current atypical antipsychotics on subsyndromal symptoms and tolerability in patients with bipolar disorder.
We evaluated the effectiveness of aripiprazole among bipolar patients who had switched to this medication as a result of difficulty maintaining on their prestudy atypical antipsychotics (AAPs) because of subsyndromal mood symptoms or intolerance. This study included 77 bipolar patients who were in syndromal remission with an AAP as monotherapy or with an AAP combined with a mood stabilizer(s) who needed to switch from their present AAP because of subsyndromal symptoms or intolerance. At 24 weeks after switching to aripiprazole, the remission rates on the Montgomery-Åsberg Depression Rating Scale (MADRS) and on both the MADRS and the Young Mania Rating Scale were increased significantly in the full sample and in the inefficacy subgroup. In the inefficacy subgroup, the MADRS score change was significant during the 24 weeks of study. Total cholesterol and prolactin decreased significantly after switching to aripiprazole. The proportion of patients who had abnormal values for central obesity and hypercholesterolemia decreased significantly from baseline to week 24. These findings suggest that a change from the current AAP to aripiprazole was associated with improvement in subsyndromal mood symptoms and several lipid/metabolic or safety profile parameters in patients with bipolar disorder with tolerability concerns or subsyndromal mood symptoms.


[RNA transduction by phage MS2 noninfectious virions].
Two fragments (1.9 and 1.8 kb) including, respectively, "structural" genes (A, B, and lysis polypeptide) and "replicase" gene, were obtained by reverse transcription PCR on the template of bacteriophage MS2 genome RNA. The fragments contained a common sequence which allowed the assembly of the entire functional genome sDNA. 1.8 kb fragment was subjected to two independent modifications: 1) so that the replicase gene could be replaced by other sequences no more than 1.5 kb in size and 2) it was inserted (on an artifician Tn-like structure) into E. coli chromosome. A system for replication of MS2-like corpuscles was thus created, containing a "shortened" genome and having extra genes. For extra genes, aminoglycoside-3'-phosphotransferase (kanamycin resistance) or a sequence of antiviral genetic program directed against hepatitis C virus were used.


[Malignant peritoneal mesothelioma].
Public attention has recently been devoted worldwide to malignant mesotheliomas and their relation to exposure to industrial materials, especially asbestos and its products. The more common form of the disease is the pleural type, while the peritoneal variant is rare, with an estimated incidence of less than 1:1,000,000 new cases per year. In contrast to the pleural type, the relationship of malignant peritoneal mesothelioma to exposure to asbestos is unclear. The differential diagnosis, based on clinical appearance and imaging techniques, is broad and the diagnosis is inconclusive, so that the diagnosis must be confirmed by histologic examination. Treatment is a combination of surgery, chemotherapy and irradiation. Contrary to occasional reports, the malignancy is fatal, death occurring within a few months of diagnosis. We present a 65-year-old man in whom malignant peritoneal mesothelioma was diagnosed. The presenting symptoms were a large abdominal mass involving the colon, and ascites. He died 5 months after the diagnosis was made.


A survey of 1000 consecutive epidural catheter placements performed by inexperienced anesthesia trainees.
Education is the core activity of academic anaesthesia departments. One of the main difficulties appears to be the development of realistic high-quality 'training' practices that are safe for patients. The aim of this study was to determine the incidence of complications occurring after epidural catheter placement by inexperienced anaesthesia trainees and their possible relationship with the experience of the operator. In a period covering 16 months, we performed a survey of 1,000 consecutive epidural placements performed by inexperienced anaesthesia residents under the direction of staff members in Padoa University Hospital, Italy. Neurological and cardiovascular complications as well as side effects were assessed and analyzed in terms of the experience levels of the trainees. Complications during epidural catheter placement included dural puncture (2.2%), epidural vascular damage (1.7%), and paresthesias (0.9%). Postoperative complications and side effects comprised local bleeding at the catheter insertion point (0.7%), catheter malfunction (0.4%), cardiovascular side effects (2.0%) and persistent postoperative paresthesias not caused by local anaesthetic infusion (1.7%). One patient suffered a transient radiculopathy. The overall incidence of complications was similar for each experience level examined. Epidural catheterization performed under supervision by inexperienced anaesthesia residents is not associated with a significantly greater number of complications than reported in the literature. Moreover, at the early stage of training, we could not demonstrate any correlation between the experience of the operator and the incidence of complications incidence.