Multicenter, double-blind, multiple-dose, parallel-groups efficacy and safety trial of azelastine, chlorpheniramine, and placebo in the treatment of spring allergic rhinitis.
Azelastine, a novel antiallergic medication, was compared with chlorpheniramine maleate and placebo for efficacy and safety in the treatment of spring allergic rhinitis in a multicenter, double-blind, multiple-dose, parallel-groups study. One hundred fifty-five subjects participated. Subjects ranged in age from 18 to 60 years of age and had at least a 2-year history of spring allergic rhinitis, confirmed by positive skin test to spring aeroallergens. Medications were given four times daily; the azelastine groups received 0.5, 1.0, or 2.0 mg in the morning and evening with placebo in the early and late afternoon; the chlorpheniramine group received 4.0 mg four times daily. Daily subject symptom cards were completed during a screening period to assess pretreatment symptoms and during a 4-week treatment period while subjects received study medications. Individual symptoms, total symptoms, and major symptoms were compared to determine efficacy of medication. Elicited, volunteered, and observed adverse experiences were recorded for each subject and compared among groups. Vital signs, body weights, serum chemistry values, complete blood cell counts, urine studies, and electrocardiograms were obtained for each subject and compared among groups. Symptoms relief in the group receiving the highest concentration of azelastine (2.0 mg twice daily) was statistically greater than in the placebo group during all weeks of the study. Lower doses of azelastine were statistically more effective than placebo only during portions of the first 3 weeks of the study. In contrast, although the chlorpheniramine group did have fewer symptoms than the placebo group during the study, the difference never reached statistical significance during any week of the study. There were no serious side effects in any of the treatment groups. Drowsiness and altered taste perception were increased significantly over placebo only in the high-dose azelastine group. Azelastine appears to be a safe, efficacious medication for seasonal allergic rhinitis.


Patients' relatives and psychiatric doctors: letter writing in the York Retreat, 1875-1910.
This article investigates the practice of letter writing from family and friends of patients to doctors at the York Retreat asylum at the end of the nineteenth and beginning of the twentieth century. During this time, letter writing was an important part of asylum practice and a collection of incoming and outgoing letters remain in the Retreat archive. Using mainly incoming correspondence, this article will show how families and friends remained significantly involved in asylum life and patient care. It will investigate the practice of family letter writing, asking questions such as who wrote to the Retreat, how often and why. It will also look at what types of relationships families and friends constructed with doctors, proposing that they regarded them in a variety of ways, ranging from seeing them as employees to treating them as confidants.


Mechanisms and Intermediates in the True Liquid Crystal Templating Synthesis of Mesoporous Silica Materials.
Mesoporous silica materials (MSMs) produced by true liquid crystal templating (TLCT) are often considered as direct inverted replicas of the initial lyotropic liquid crystal (LLC) phase. However, the predictive design of tailor-made MSMs requires the full knowledge of the TLCT process, which is still incomplete. Here, we tackle this issue by monitoring the structural evolution during the templating process by small-angle X-ray scattering, showing that after the addition of the silica source the reaction mixture is first isotropic and then an intermediary liquid crystal phase appears, which is the key to the success of the templating process, namely the formation of ordered MSMs. We analyze the structure and the formation dynamics of this intermediary phase and present a simple theoretical model, which allows us to connect the structural parameters of the initial LLC and the MSM. These results provide an enhanced understanding of the TLCT process and are an important step toward the predictable synthesis of new MSMs in the future.


Intractable diarrhea of infancy with facial dysmorphism, trichorrhexis nodosa, and cirrhosis.
A 3-year-old girl had severe intractable diarrhea with trichorrhexis nodosa and cirrhosis. This patient was referred to the pediatric dermatology clinic for lifelong brittle hair. The brittle hair microscopically demonstrated trichorrhexis nodosa. The girl also had facial dysmorphism, with a prominent forehead and cheeks, broad flat nose, and hypertelorism. She had a history of severe intractable diarrhea since 2 weeks of age and failure to thrive requiring lifelong total parenteral nutrition (TPN). Hepatomegaly was noted and prompted liver biopsy which demonstrated cirrhosis. Mental retardation and developmental delay was also found upon examination. This child may be included in the syndrome of intractable infant diarrhea, an entity known in the gastroenterology literature but yet not reported in the dermatologic literature. Dermatologists should be aware of this syndrome in which trichorrhexis nodosa is commonly seen.


HLA-DR-DQ alleles and HLA-DP alleles are independently associated with susceptibility to different stages of post-schistosomal hepatic fibrosis in the Chinese population.
Abstract: Evaluation of human leukocyte antigen (HLA) class I and class II genes was performed on patients from China with Schistosomiasis japonica. Patients were categorized as grade 0 (n=44), grade I (n=81), grade II (n=99), or grade III (n=6) based on increasing severity of hepatic fibrosis due to repeated Schistosoma japonicum infections. These results show that the HLA-DRB1*1101-DQA1*0501-DQB1*0301 (Pc<0.02) and HLA-DRB1*1501-DRB5*0101 (Pc<0.02) haplotypes are associated with protection and susceptibility to grade I fibrosis, respectively, and that the HLA-DPA1*0103 -DPB1*0201 haplotype (Pc<0.02) is associated with protection from both grade II and III severe fibrosis. There was no association between HLA-B DNA haplotypes and the disease. These findings indicate that the HLA-class II molecules play a role in preventing or promoting fibrotic liver change after deposition with Schistosome eggs. Moreover, a tendency was observed within the HLA class II genes for the HLA-DR-DQ alleles to be associated with protection against early changes in liver fibrosis, whereas HLA-DP alleles were associated with protection from the late phase of fibrosis or severe hepatosplenic schistosomiasis.


Kinetic effects of simultaneous inhibition by substrate and product.
The starting point for the present investigations was the finding that increasing influent concentrations from 10 to 380 mmol/L glucose decreased the attainable growth rate of an acidogenic population in continuous culture from 0.52 to 0.05 h(-1) To account for this phenomenon, a new kinetic model is developed that combines substrate and product inhibition. Both effects are connected through the product yield, giving rise to a complex dependency of the growth rate on the substrate concentration. As a main feature, the maximum attainable growth rate decreases almost hyperbolically above some optimal substrate concentration in the influent. Furthermore, under certain conditions the kinetic model predicts the existence of three steady states: a high-conversion and a low-conversion state that are both stable and a metastable intermediate state. The latter states from the multiple-steady-state region are to be avoided, and eventual transitions to these states may have important consequences for the stability and the operation of such reaction systems. Substrate as well as product inhibition is reported for Propionibacterium freundenreichii and recently could be demonstrated for the above-mentioned acidogenic population. The proposed model allows optimization of anaerobic wastewater treatment processes and is applicable also to other fermentations.


Acute abdomen in pregnancy: a retrospective study of pregnant patients hospitalised for abdominal pain.
Abdominal emergencies occur in pregnant women with the rate of 1:500635 pregnancies. Such conditions usually develop from full health and worsen rapidly. Symptoms are often similar to those in physiological pregnancy (abdominal pain, vomiting, constipation). The diagnostic process is thus difficult and both the mother and her child are at risk. Our aim was to evaluate the frequency of abdominal emergencies in the Department of Surgery, University Hospital in Pilsen and to consider their impact on pregnancy and on the newborn. We acquired a set of patients by retrograde collection of data. We searched for pregnant patients suspected of developing an abdominal emergency admitted to the Department of Surgery, Faculty of Medicine, Pilsen between 2004 and 2015. We evaluated a number of clinical signs to statistically describe the set. The set included 121 patients; 42 of the patients underwent a surgical procedure and 79 received conservative treatment. 38 patients underwent appendectomy; 6 appendixes were with no pathologies. McBurneys incision was an approach of choice in most cases. The most frequent symptom was pain in the right lower abdominal quadrant. The foetus has been lost in none of the cases. Acute appendicitis was the most frequent abdominal emergency in our set and also the most frequent reason for surgical intervention. The most specific sign was pain in the right lower abdominal quadrant. No impact of appendicitis or appendectomy on the health of the newborn has been observed. Even though abdominal emergencies in pregnancy are relatively rare, the results of the department are very good.


Reciprocal interactions among Cobll1, PACSIN2, and SH3BP1 regulate drug resistance in chronic myeloid leukemia.
Cobll1 affects blast crisis (BC) progression and tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML). PACSIN2, a novel Cobll1 binding protein, activates TKI-induced apoptosis in K562 cells, and this activation is suppressed by Cobll1 through the interaction between PACSIN2 and Cobll1. PACSIN2 also binds and inhibits SH3BP1 which activates the downstream Rac1 pathway and induces TKI resistance. PACSIN2 competitively interacts with Cobll1 or SH3BP1 with a higher affinity for Cobll1. Cobll1 preferentially binds to PACSIN2, releasing SH3BP1 to promote the SH3BP1/Rac1 pathway and suppress TKI-mediated apoptosis and eventually leading to TKI resistance. Similar interactions among Cobll1, PACSIN2, and SH3BP1 control hematopoiesis during vertebrate embryogenesis. Clinical analysis showed that most patients with CML have Cobll1 and SH3BP1 expression at the BC phase and BC patients with Cobll1 and SH3BP1 expression showed severe progression with a higher blast percentage than those without any Cobll1, PACSIN2, or SH3BP1 expression. Our study details the molecular mechanism of the Cobll1/PACSIN2/SH3BP1 pathway in regulating drug resistance and BC progression in CML.


Polymeric alkenoxy amino acid surfactants: IV. effects of hydrophobic chain length and degree of polymerization of molecular micelles on chiral separation of beta-blockers.
Four alkenoxy leucine-based surfactants with C8-C11 chains containing a terminal double bond, and one C11 chain surfactant with a terminal triple bond are synthesized and characterized in monomeric and polymeric forms. These polymeric pseudophases are then utilized to study the influence of chain length and DP for the enantioseparations of seven beta-blockers in MEKC. Variations in chain length and concentration of polymeric surfactants showed significant effects on the chiral resolution (Rs) and efficiency (N). A relatively large elution range combined with the highest polarity and aggregation number (A) but the lowest retention time, partial specific volume, and optical rotation generated with C8-polymeric surfactant results in simultaneous enantioseparation of all seven beta-blockers with higher N and R(s). In particular, highly hydrophobic beta-blockers are better resolved with shorter hydrocarbon chain even at higher surfactant concentration, which is unachievable with longer chain surfactant. On the other hand, polymer derived from C11-triple bond provided smaller A value compared to C11-double bond surfactant. However, chiral Rs of hydrophobic beta-blockers are still achievable with the C11-triple bond surfactant with enhanced N and shorter analysis time. In addition, effect of polymerization concentration is evaluated by polymerizing all five surfactants at five times their respective CMCs and 100 mM equivalent monomer concentrations. Polymerization of shorter chain (C8 and C9) double-bonded surfactants at five times their respective CMCs results in higher A values with better chiral Rs and N compared to the same two surfactants polymerized at 100 mM.


Acid-free, aminoborane-mediated Ugi-type reaction leading to general utilization of secondary amines.
A variety of secondary amines have become utilized in the Ugi reaction by using aminoborane 1 as an iminium ion generator. Aldehydes, secondary amines, and isocyanides are coupled in the presence of 1 at room temperature, giving the corresponding alpha-amino amides in good yields. The nonacidic reaction conditions are beneficial for unique chemoselectivity, where the aldimine functionality is left intact in the present Ugi-type reaction.


Structural neuroimaging phenotypes and associated molecular and genomic underpinnings in autism: a review.
Autism has been associated with differences in the developmental trajectories of multiple neuroanatomical features, including cortical thickness, surface area, cortical volume, measures of gyrification, and the gray-white matter tissue contrast. These neuroimaging features have been proposed as intermediate phenotypes on the gradient from genomic variation to behavioral symptoms. Hence, examining what these proxy markers represent, i.e., disentangling their associated molecular and genomic underpinnings, could provide crucial insights into the etiology and pathophysiology of autism. In line with this, an increasing number of studies are exploring the association between neuroanatomical, cellular/molecular, and (epi)genetic variation in autism, both indirectly and directly in vivo and across age. In this review, we aim to summarize the existing literature in autism (and neurotypicals) to chart a putative pathway from (i) imaging-derived neuroanatomical cortical phenotypes to (ii) underlying (neuropathological) biological processes, and (iii) associated genomic variation.


10-formyltetrahydrofolate dehydrogenase requires a 4'-phosphopantetheine prosthetic group for catalysis.
10-Formyltetrahydrofolate dehydrogenase (FDH) consists of two independent catalytic domains, N- and C-terminal, connected by a 100-amino acid residue linker (intermediate domain). Our previous studies on structural organization and enzymatic properties of rat FDH suggest that the overall enzyme reaction, i.e. NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO(2), consists of two steps: (i) hydrolytic cleavage of the formyl group in the N-terminal catalytic domain, followed by (ii) NADP(+)-dependent oxidation of the formyl group to CO(2) in the C-terminal aldehyde dehydrogenase domain. In this mechanism, it was not clear how the formyl group is transferred between the two catalytic domains after the first step. This study demonstrates that the intermediate domain functions similarly to an acyl carrier protein. A 4'-phosphopantetheine swinging arm bound through a phosphoester bond to Ser(354) of the intermediate domain transfers the formyl group between the catalytic domains of FDH. Thus, our study defines the intermediate domain of FDH as a novel carrier protein and provides the previously lacking component of the FDH catalytic mechanism.


Improvement of Salt Tolerance Using Wild Rice Genes.
Salt stress causes significant reductions in rice production worldwide; thus, improving salt tolerance is a promising approach to meet the increasing food demand. Wild rice germplasm is considered a valuable genetic resource for improving rice cultivars. However, information regarding the improvement of salt tolerance in cultivated rice using wild rice genes is limited. In this study, we identified a salt-tolerant line Dongxiang/Ningjing 15 (DJ15) under salt-stress field conditions from the population of a salt tolerant Dongxiang wild rice × a cultivated rice variety Ningjing16 (NJ16). Genomic resequencing analysis of NJ16, DJ15 and Dongxiang wild rice revealed that the introgressed genomic fragments were unevenly distributed over the 12 chromosomes (Chr.) and mainly identified on Chr. 6, 7, 10, and 11. Using quantitative trait locus (QTL) mapping, we found 9 QTL for salt tolerance (qST) at the seedling stage located on Chr. 1, 3, 4, 5, 6, 8, and 10. In addition, sequence variant analysis within the QTL regions demonstrated that SKC1/HKT8/HKT1;5 and HAK6 transporters along with numerous transcriptional factors were the candidate genes for the salt tolerant QTL. The DJ15/Koshihikari recombinant inbred lines that contained both qST1.2 and qST6, two QTL with the highest effect for salt tolerance, were more tolerant than the parental lines under salt-stress field conditions. Furthermore, the qST6 near-isogenic lines with IR29 background were more tolerant than IR29, indicating that qST1.2 and qST6 could improve salt tolerance in rice. Overall, our study indicates that wild rice genes could markedly improve the salt tolerance of cultivated rice.


Mek1/Mre4 is a master regulator of meiotic recombination in budding yeast.
Sexually reproducing organisms create gametes with half the somatic cell chromosome number so that fusion of gametes at fertilization does not change the ploidy of the cell. This reduction in chromosome number occurs by the specialized cell division of meiosis in which two rounds of chromosome segregation follow a single round of chromosome duplication. Meiotic crossovers formed between the non-sister chromatids of homologous chromosomes, combined with sister chromatid cohesion, physically connect homologs, thereby allowing proper segregation at the first meiotic division. Meiotic recombination is initiated by programmed double strand breaks (DSBs) whose repair is highly regulated such that (1) there is a bias for recombination with homologs rather than sister chromatids, (2) crossovers are distributed throughout the genome by a process called interference, (3) crossover homeostasis regulates the balance between crossover and non-crossover repair to maintain a critical number of crossovers and (4) each pair of homologs receives at least one crossover. It was previously known that the imposition of interhomolog bias in budding yeast requires meiosis-specific modifications to the DNA damage response and the local activation of the meiosis-specific Mek1/Mre4 (hereafter Mek1) kinase at DSBs. However, because inactivation of Mek1 results in intersister, rather than interhomolog DSB repair, whether Mek1 had a role in interhomolog pathway choice was unknown. A recent study by Chen et al. (2015) reveals that Mek1 indirectly regulates the crossover/non-crossover decision between homologs as well as genetic interference. It does this by enabling phosphorylation of Zip1, the meiosis-specific transverse filament protein of the synaptonemal complex (SC), by the conserved cell cycle kinase, Cdc7-Dbf4 (DDK). These results suggest that Mek1 is a "master regulator" of meiotic recombination in budding yeast.


Enantiomeric NMR discrimination of carboxylic acids using actinomycin D as a chiral solvating agent.
Actinomycin D (Act-D) is a biologically important polypeptide antibiotic clinically used to treat several malignant tumors. Herein, we extended its hitherto-unexplored application as an applicable chiral solvating agent (CSA) for the rapid enantiomeric determination of different chiral carboxylic acids in deuterated chloroform by 1H NMR spectroscopy. Notable enantiodiscrimination with well-splitting α-H or α-CH3 resonance signals of the enantiomers of carboxylic acids were achieved without significant interference from Act-D. To check its applicability for the determination of enantiomeric excess (ee) values, various mandelic acid (MA) samples were determined and compared with the observed ones, resulting in an excellent linear relationship. To our knowledge, this is the first example of using a natural antibiotic compound as a CSA to achieve chiral recognition for carboxylic acids.


Acute myelofibrosis in a patient with diffuse large cell non Hodgkin's lymphoma and renal cancer.
Relapse after anthracycline based combination chemotherapy is frequently seen in patients with aggressive non Hodgkin's Lymphomas (NHL), whereas complications such as secondary leukemia or solid tumor rarely occur. We report a patient with diffuse large cell (DLC) NHL and concurrent renal cancer, who developed acute myelofibrosis (AMF) later in the course of her disease. This 60-year-old female patient presented with pancytopenia and a right sided renal mass. Diagnostic work up revealed severe bone marrow infiltration by DLC NHL and renal cancer T1N0M0G2. Cytogenetic and molecular evaluation of bone marow cells showed three distinct clones, (a normal 46XX karyotype, a ringed chromosome 7 and a third clone with an enlarged chromosome 2 as well as several fragments). The patient underwent nephrectomy and eventually received 6 cycles of CHOP 14 chemotherapy. Anemia persisted followed by severe granulocytopenia and thrombocytopenia 6 weeks later. Repeated bone marrow biopsy showed absence of lymphoma and/or cancer metastasis, but massive myelofibrosis with an increased number of atypical megakaryocytes. Considering the short clinical course and the absence of hepatosplenomegaly AMF was diagnosed. The concurrence of three distinctneoplasms within a short period of time as well as the complex cytogenetic aberrations found in her bone marrow cells reflect a strong individual susceptibility to malignant disease in this patient.


Hepatitis C virus NS5A disrupts STAT1 phosphorylation and suppresses type I interferon signaling.
Responses to alpha interferon (IFN-α)-based treatment are dependent on both host and viral factors and vary markedly among patients infected with different hepatitis C virus (HCV) genotypes (GTs). Patients infected with GT3 viruses consistently respond better to IFN treatment than do patients infected with GT1 viruses. The mechanisms underlying this difference are not well understood. In this study, we sought to determine the effects of HCV NS5A proteins from different genotypes on IFN signaling. We found that the overexpression of either GT1 or GT3 NS5A proteins significantly inhibited IFN-induced IFN-stimulated response element (ISRE) signaling, phosphorylated STAT1 (P-STAT1) levels, and IFN-stimulated gene (ISG) expression compared to controls. GT1 NS5A protein expression exhibited stronger inhibitory effects on IFN signaling than did GT3 NS5A protein expression. Furthermore, GT1 NS5A bound to STAT1 with a higher affinity than did GT3 NS5A. Domain mapping revealed that the C-terminal region of NS5A conferred these inhibitory effects on IFN signaling. The overexpression of HCV NS5A increased HCV replication levels in JFH1-infected cells through the further reduction of levels of P-STAT1, ISRE signaling, and downstream ISG responses. We demonstrated that the overexpression of GT1 NS5A proteins resulted in less IFN responsiveness than did the expression of GT3 NS5A proteins through stronger binding to STAT1. We confirmed that GT1 NS5A proteins exerted stronger IFN signaling inhibition than did GT3 NS5A proteins in an infectious recombinant JFH1 virus. The potent antiviral NS5A inhibitor BMS-790052 did not block NS5A-mediated IFN signaling suppression in an overexpression model, suggesting that NS5A's contributions to replication are independent of its subversive action on IFN. We propose a model in which the binding of the C-terminal region of NS5A to STAT1 leads to decreased levels of P-STAT1, ISRE signaling, and ISG transcription and, ultimately, to preferential GT1 resistance to IFN treatment.


Bronchoscopic administration of bovine natural surfactant in ARDS and septic shock: impact on gas exchange and haemodynamics.
The aim of the present study was to investigate the feasibility and efficacy of bronchoscopic surfactant administration in a noncontrolled multicentre study in five university centres. A total number of 27 patients, suffering from severe acute respiratory distress syndrome (mean+/-SEM lung injury score: 3.15+/-0.06) and septic shock (Acute Physiology and Chronic Health Evaluation (APACHE) II score at study entry 33.2+/-1.3, lactate 4.3+/-0.6 mmol x L(-1)) were studied. The patients were ventilated with a mean tidal volume of 11.0+/-0.5 mL x kg(-1) body weight (bw), either volume or pressure controlled, with 16.3+/-2.8 cmH2O positive end-expiratory pressure, for an average of 3.5+/-0.3 days at study entry. A natural bovine surfactant extract (300 mg x kg(-1) bw Alveofact; mean total volume 378 mL) was delivered in divided doses to each segment of the lungs via flexible bronchoscope within approximately 45 min. No untoward effects on gas exchange, lung mechanics and haemodynamics were noted during the procedure of surfactant administration. Within 12 h the oxygen tension in arterial blood/inspiratory oxygen fraction increased from a mean of 109+/-8 mmHg to 210+/-20 mmHg (p<0.001). In seven patients, in whom gas exchange again deteriorated with further progression of the disease, a second surfactant dose of 200 mg x kg(-1) was administered 18-24 h after the first application, again improving arterial oxygenation. A total of 15 patients survived the 28-day study period (mortality rate 44.4%, compared to a calculated risk of death for the given APACHE II scores of 74.0+/-3.5%), with all causes of death being nonrespiratory. The bronchoscopic application of a high dose of natural surfactant in patients with severe acute respiratory distress syndrome and septic shock is both feasible and safe, resulting in a pronounced improvement in gas exchange.


Low Vision Referral Patterns in Intermediate Age-Related Macular Degeneration.
Sparse data exist regarding low vision (LV) services referral patterns. We retrospectively examined our institution's intermediate age-related macular degeneration (iAMD) patients to determine factors influencing referral. We compared visual acuity (VA) and Visual Function Questionnaire (VFQ-25) composite and subscale scores for referred and non-referred iAMD patients. VA was collected at time of referral or most recent visit, and VFQ-25 was taken upon enrollment into the registry. Thirty-six (15.5%) of the 232 iAMD patients were referred to LV. Referred patients were more likely to have older age, worse VA in both eyes, and lower VFQ-25 scores. Univariate analysis of VFQ-25 subscales demonstrated worse scores in general vision, near, distance, mental health, role limitations, dependency, and driving. Multivariable analysis revealed lower scores in general health, general vision, and driving. Forty-eight percent of non-referred patients had VA or VFQ-25 composite scores at least as poor as the median for referred patients. Two-thirds of patients who were not referred had no discernable obstacle to referral. Our institution refers patients with worse objective and functioning vision, but more patients may benefit from referral. Future studies should identify metrics to prompt referral and evaluate this approach.


What Makes Intentional Unidirectional Peer Support for Homeless People Work? An Exploratory Analysis Based on Clients' and Peer Workers' Perceptions.
Homeless people are increasingly supported by peer workers in one-on-one mentorship relations called intentional unidirectional peer support (IUPS). Insight is therefore needed into the application and outcome of IUPS for this vulnerable population. This study examined the outcomes, critical elements, and working mechanisms of IUPS within homeless services from the perspective of both clients receiving IUPS and peer workers providing IUPS. Semi-structured face-to-face interviews were held with ten homeless clients and ten peer workers. According to participants, IUPS enhances clients' self-image, advances their personal growth, and results in better engagement with needed services. Rapport and empathy, a trustworthy and empowering relationship, as well as support, guidance, and mediation are what makes IUPS work according to the participants. The inclusion of both perspectives has led to a deeper understanding of what makes IUPS work for homeless people. Implications for practice are discussed.


Current trends in gingival recession coverage--part I: the tunnel connective tissue graft.
The recession of the gingiva is increasingly becoming a more prominent condition in the oral health of many patients and should be treated at its earliest detection. The multifactorial etiology, decision modality, and current trends followed in the treatment of gingival recession are discussed in this presentation. The correction of Class I and II gingival recessions are presented as a means of minimizing surgical trauma and achieving predictable aesthetic results. Part II of this discussion will present alternative techniques in treating gingival recession.


Cocaine inhibits muscarinic cholinergic receptors in heart and brain.
(-)-Cocaine inhibits M2 muscarinic cholinergic binding measured with [3H]quinuclidinyl benzilate in heart and brain with a Ki of 18.8 microM. The cyclic nucleotide 5'-guanylylimidodiphosphate does not shift the competition curve, suggesting that (-)-cocaine is an antagonist. (-)-Cocaine also reverses the methacholine-induced inhibition of guinea pig atrial contractions at a similar concentration. Although (+)-cocaine is about 8-fold more potent than (-)-cocaine, (+)-cocaine is not present in extracts of the coca plant. Of the many compounds tested, only (-)-cocaine and lidocaine have a higher affinity at M2 muscarinic receptors than at M1 receptors; other compounds such as (+)-cocaine, norcocaine, procaine and dimethocaine are equipotent at the M1 and M2 subtypes. These results indicate that cocaine can act as an antimuscarinic agent, particularly at higher, toxic doses.


Case Report and Literature Review of a Pathologic Mandibular Fracture from Metastatic Esophageal Adenocarcinoma.
Distant metastasis to the jaws, including the maxilla or mandible, is very rare. Although the mandible is the preferred sight of these rare metastases, it is extremely rare for oral cavity malignancies to present as pathological mandibular fractures. Here, we present a case of esophageal adenocarcinoma metastasizing to the mandible, and the first reported case presenting with a pathological mandibular fracture secondary to esophageal adenocarcinoma. We also review the 9 other reported cases of metastatic esophageal adenocarcinoma to either the maxilla or mandible.


Contingency management interventions: effects on treatment outcome during methadone detoxification.
We examined the effectiveness of a contingency management program in preventing relapse to illicit opiate use and increasing treatment retention during outpatient methadone detoxification treatment. Twenty male opiate addicts were randomly assigned to an experimental or control group. Following a 3-week methadone stabilization period, men in both groups received identical gradual methadone dose reductions during Weeks 4 through 9 and were maintained on placebo during Weeks 10 through 13. Beginning in Week 4, control patients received $5.00 for providing a specimen twice weekly. Experimental patients received $10.00 and a take home methadone dose for each opiate-free urine specimen but forfeited the incentives and participated in more intensive clinic procedures when specimens were opiate positive. The contingency management procedure slowed the rate of relapse to illicit opiate use. Experimental patients provided significantly more opiate-free urines during the methadone dose reduction in Weeks 4 through 9 than control patients, although the difference between groups was no longer significant during placebo administration in Weeks 10 through 13. In addition, the contingency management program improved treatment retention and reduced symptom complaints during the detoxification. The usefulness and limitations of contingency management procedures for outpatient methadone detoxification are discussed.


Relationship between skin phototype and MED in Korean, brown skin.
The Fitzpatrick skin classification has been a useful method to categorize cutaneous sensitivity to ultraviolet radiation (UVR), although it was based originally on responses in white skin. Because the relevance of this phototype in brown skin is in question, we investigated skin phototypes of university students by a self-reporting questionnaire and measured their MEDs in Korean, brown skin. After studying our explanation of the definition of Fitzpatrick skin types, 707 Korean university students answered the questionnaire. We then measured UVB MEDs in 156 randomly selected male students. The order of frequency of skin type was type III (55.0%), IV (29.0%), and V (12.3%) by the questionnaire, with the sun sensitive categories (types I and II) reported only for 3.7%. There was no significant difference in MEDs between types IV and V, and the mean MED of each skin type did not show a monotonic increase with increasing skin type. Subjects with MEDs of 70-90 mJ/cm2 (corresponding to the MED of skin type V, as proposed by Pathak & Fitzpatrick) represented about half or more of the subjects in all categories, even types II and III. Subjects with MEDs lower than 60 mJ/cm2 were more prevalent in types II and III compared with types IV and V. We suggest that there is at best a weak relationship between the skin types, by the Fitzpatrick method, and MEDs in Korean, brown skin.


Low-Temperature Catalytic Graphitization to Enhance Na-Ion Transportation in Carbon Electrodes.
Sodium-ion batteries (SIBs) are now emerging as a low-cost alternative to the current lithium-ion batteries, but their performance is limited by the sluggish transportation of large Na ions in electrodes. Expanded graphite has been employed in enhancing the transport kinetics. However, high-performance graphite should be synthesized at high temperatures when using traditional methods, which inevitably increases the total cost of material production. To tackle the kinetic issue for SIBs, we develop a three-dimensional network of graphene during catalytic graphitization in carbon electrodes at a temperature as low as 450 °C by using Prussian blue as a precursor. Furthermore, a strategy is proposed to enhance the transport ability of the Na-ion in the network by controlling the diffusion distance of the Fe cluster and the distance between Prussian blue particles, leading to optimized performance with both excellent high-rate performance (167 mAh g-1 at 1.0 A g-1) and high charging capacity (390 mAh g-1 at 0.05 A g-1). The results provide insights into the engineering of ionic transport properties through low-temperature catalytic graphitization in electrodes for SIBs and help design high-performance and low-cost electrodes for large-scale energy storage systems.


Effect and mechanism of propranolol on promoting osteogenic differentiation and early implant osseointegration.
The present study aimed to investigate the effect of β‑receptor blocker propranolol on early osseointegration of pure titanium implants and the underlying molecular regulatory mechanisms. An implant osseointegration model using the tibial metaphysis of New Zealand rabbits was established. The rabbits were divided into control and low‑, medium‑ and high‑dose propranolol groups. The formation of implant osseointegration was detected by X‑ray scanning. Mesenchymal stem cells (MSCs) and osteoblasts (OBs) were isolated and cultured in vitro, isoproterenol was supplemented to simulate sympathetic action and propranolol was subsequently administrated. The effect of propranolol on cell proliferation and osteogenic differentiation were assessed by EdU, flow cytometry, alizarin red staining and alkaline phosphatase (ALP) detection. The expression levels of bone morphogenetic protein (BMP)2, RUNX family transcription factor (RunX)2, collagen (COL)‑1, osteocalcin (OCN) and β2‑adrenergic receptor (AR) were detected by immunofluorescence, reverse transcription‑quantitative PCR and western blot assay. Propranolol effectively promoted implant osseointegration in vivo, facilitated proliferation of OBs, inhibited proliferation of MSCs and enhanced osteogenic differentiation of OBs and MSCs. The calcium content and ALP activity of cells treated with propranolol were markedly higher than in the control group. Propranolol also elevated mRNA and protein expression levels of BMP2, RunX2, COL‑1 and OCN in tissue and cells, and decreased the expression of β2‑AR. The present study demonstrated that the β‑receptor blocker propranolol promoted osteogenic differentiation of OBs and MSCs and enhanced implant osseointegration. The present study provided a novel insight into the application and regulatory mechanisms of propranolol.


Prevention and Control of Coal and Gas Outburst by Directional Hydraulic Fracturing through Seams and Its Application.
The regionalized pressure relief, permeability enhancement, and outburst prevention of "three high and one low" coal seams with high gas, high ground stress, high outburst risk, and low permeability have become important problems to be solved urgently in realizing the sustainable development of coal mines. In this study, a combination of theoretical research, RFPA2D-Flow numerical simulation, and field test was used to study the initiation mechanism and propagation law of directional hydraulic fracturing fractures through the seam. The results show that fracture initiation depends on the axial and radial horizontal stress of the fracture hole, the physical and mechanical properties of coal and rock, and the inside of the weakest layer. Single-hole hydraulic fracturing can achieve a pressure relief radius of 7-8 m, but there is a stress concentration zone outside, which is not conducive to regional pressure relief and permeability enhancement. Directional hydraulic fracturing with multiple holes produces an approximate cylindrical compression and crushing ring and a penetrating fracture surface along the center line of the pressure crack hole and the directional hole, which better eliminates the phenomenon of stress concentration in nondirectional hydraulic fracturing. The technology was applied to the 2238 auxiliary roadway of Chengzhuang Mine of Jinmei Group, and the field implementation results showed that field implementation results showed that directional hydraulic fracturing through the seam reduced the gas content in the coal seam to a great extent, and the coal seam gas content was reduced by about 42.3%, indicating that the technology can effectively reduce the risk of coal and gas outbursts.


Changes in soluble proteins in cervical mucus during midcycle in normally menstruating women.
Albumin, IgG and complement C3c were analyzed by immunonephelometry in cervical mucus collected daily at midcycle. There was a statistically significant difference in the amount of mucus recovered on the day of the luteinizing hormone (LH) surge and on the following day. Several nadirs in protein concentration could be visualized in 8 out of 14 subjects, whereas in 6 subjects, no such changes in concentration were found. In terms of soluble protein concentrations and amounts there were no differences between cycle days. For changes in soluble protein concentrations and amounts, no systematic time relation to the LH peak could be found.


Does non-malignant hypertension cause renal insufficiency? Evidence-based perspective.
While it is clear that malignant hypertension damages the kidneys, the question of whether non-malignant hypertension actually causes renal insufficiency remains controversial. A recent meta-analysis of 10 randomized controlled trials of antihypertensive drug therapy showed that patients randomized to antihypertensive therapy (or more-intensive therapy) did not show a significant reduction in their risk of developing renal dysfunction (relative risk, 0.97; 95% confidence interval, 0.78-1.21; P=0.77). A review of the totality of the evidence shows that there is relatively weak support for the thesis that non-malignant hypertension itself is an important de-novo cause (initiator) of renal insufficiency (as opposed to being a promoter of existing renal disease, which is a well established fact). Failure to evaluate the possibility that pre-existing renal disease could explain any observed association between elevated blood pressure and subsequent loss of renal function is an important limitation of published studies.


Paroxysmal tonic upgaze: a reappraisal of outcome.
Paroxysmal tonic upgaze (PTU) of childhood is a distinctive neuro-ophthalmological syndrome of unknown etiology and pathogenesis that is characterized by episodes of sustained upward deviation of the eyes, often with incomplete downward saccades on attempted downgaze. It is generally regarded as having a benign outcome. We observed 16 children with PTU, from 10 months to 11 years from onset (mean, 5.4 years), to study the natural history and possible etiology. Five cases were from two unrelated families. Onset of PTU occurred either during or after an intercurrent infection or vaccination in 5 children. No antecedent was identifiable in the rest. PTU had completely resolved in 10 children (62%) (mean age at offset, 2.5 years), whereas 2 children intermittently manifest a modified form of the disorder. At follow-up, 11 children (69%) had developmental delay, intellectual disability, or language delay and 9 (56%) had ocular motility problems other than PTU. Only 3 children (19%) had normal development and neurological findings. PTU is a heterogeneous syndrome with respect to associations and outcome and may simply be an age-dependent manifestation of a variety of disorders affecting corticomesencephalic control of vertical eye movement. This disorder may be an early sign of more widespread neurological dysfunction.


Prepontine cisternal routine for intrathecal targeted drug delivery in craniofacial cancer pain treatment: technical note.
Intrathecal targeted drug delivery provides effective relief for cancer-related pain. However, its validation in management of craniofacial pain remains much less widely practiced, mainly due to the localized diffusion of analgesic agent with current approach. Here, we report our experience of prepontine cisternal routine for placement and implantation of intrathecal targeted drug delivery in two cases of cancer-related craniofacial pain. Lumbar cannulation was applied and the intrathecal catheter tip was positioned at the prepontine cistern under fluoroscopic guidance during the surgical implantation. Postoperative imaging confirmed that the catheter tip was successfully placed in the prepontine cisternal space. Satisfactory control of pain was achieved after intrathecal therapy, with significant reduction of background and breakthrough cancer pain. None obvious complications were observed in this study. Thus, our novel intrathecal routine may provide an alternative option for craniofacial pain caused by tumor, who were insufficiently treated by oral analgesic agents.


[The care of stillborn babies and their family].
Practices around the care of stillborn babies have evolved considerably over the last 15 years. Perinatal bereavement care requires a team approach to support the parents experiencing this ordeal. The place of rituals is important as is the personalisation of the care. The humanity which surrounds such moments constitutes the foundation on which the future equilibrium of these bereaved families will be based.


Contrasting sirtuin and poly(ADP-ribose)polymerase activities of selected 2,4,6-trisubstituted benzimidazoles.
Both sirtuin and poly(ADP-ribose)polymerase (PARP) family of enzymes utilize NAD+ as co-substrate. Inhibitors of sirtuins and PARPs are important tools in drug discovery as they are reported to be linked to multiple diseases such as cancer. New potent sirtuin inhibitors (2,4,6-trisubstituted benzimidazole) were discovered from reported PARP inhibitor scaffold. Interestingly, the synthesized compounds have contrasting sirtuin and PARP-1 inhibitory activities. We showed that modification on benzimidazoles may alter their selectivity toward sirtuin or PARP-1 enzymes. This offers an opportunity for further discovery and development of new promising sirtuin inhibitors. Molecular docking studies were carried out to aid the rationalization of these observations. Preliminary antiproliferative studies of selected compounds against nasopharyngeal cancer cells also showed relatively promising results.


pH-Dependent Effects of L-Cysteine on Mercury Dissolution of α-HgS and β-HgS.
Mercury sulfide is an insoluble inorganic mercury compound, and it is the main chemical form in traditional oral mercury-containing medicines. Hg2+ has a high affinity for thiols, and small molecule thiols in the gastrointestinal tract may promote mercury dissolution of mercury sulfide by binding to Hg2+. L-cysteine is the only amino acid that possesses a reducing sulfhydryl group (-SH), out of the 20 amino acids. This study investigates the effect of L-cysteine on mercury dissolution of mercury sulfide at pHs ranging from 1.2 to 7.2. The results showed that L-cysteine had different pH-dependent effects on the mercury dissolution of α-HgS and β-HgS. For α-HgS, the dissolved mercury concentration increased from 5.47 ± 0.97 ng/mL to 12.49 ± 0.54 ng/mL when the pH rose from 1.2 to 4.2, and decreased to 3.37 ± 0.70 ng/mL at pH 6.0 and then increased to 9.36 ± 0.79 ng/mL at pH 7.2. For β-HgS, the dissolved mercury concentration increased from 151.09 ± 2.25 ng/mL to 2346.71 ± 62.62 ng/mL when the pH increased from 1.2 to 7.2. In conclusion, L-Cys was distinctly enhanced upon mercury dissolution of α-HgS and β-HgS with increasing pH. These results may contribute to our understanding of the mercury absorption mechanism of traditional oral mercury-containing medicines.


The role of mitochondrial and plasma membrane nucleoside transporters in drug toxicity.
Many anticancer and antiviral drugs are nucleoside analogues, which interfere with nucleotide metabolism and DNA replication to produce pharmacological effects. Clinical efficacy and toxicity of nucleoside drugs are closely associated with nucleoside transporters because they mediate the transport of nucleoside drugs across biological membranes. Two families of human nucleoside transporters (equilibrative nucleoside transporters and concentrative nucleoside transporters) have been extensively studied for several decades. They are widely distributed, from the plasma membrane to membranes of organelles such as mitochondria, and the distribution differs in different tissues. In addition, they have different specificities to nucleoside drugs. The characteristics of equilibrative and concentrative nucleoside transporters affect the therapeutic outcomes achieved with anticancer and antiviral nucleoside drugs. In this review, an overview of the role of mitochondrial and plasma membrane nucleoside transporters in nucleoside drug toxicity is provided. Rational design and therapeutic application of nucleoside analogues are also discussed.


Unveiling the therapeutic potential of exogenous β-hydroxybutyrate for chronic colitis in rats: novel insights on autophagy, apoptosis, and pyroptosis.
Ulcerative colitis (UC) is a chronic relapsing inflammatory disease of the colorectal area that demonstrates a dramatically increasing incidence worldwide. This study provides novel insights into the capacity of the exogenous β-hydroxybutyrate and ketogenic diet (KD) consumption to alleviate dextran sodium sulfate (DSS)-induced UC in rats. Remarkably, both interventions attenuated disease activity and colon weight-to-length ratio, and improved macro and microstructures of the damaged colon. Importantly, both β-hydroxybutyrate and KD curbed the DSS-induced aberrant NLRP3 inflammasome activation as observed in mRNA and protein expression analysis. Additionally, inhibition of the NLRP3/NGSDMD-mediated pyroptosis was detected in response to both regimens. In parallel, these modalities attenuated caspase-1 and its associated consequences of IL-1β and IL-18 overproduction. They also mitigated apoptosis as indicated by the inactivation of caspase-3. The anti-inflammatory effects of BHB and KD were confirmed by the reported decline in the levels of inflammatory markers including MPO, NFκB, IL-6, and TNF-α. Moreover, these interventions exhibited antioxidative properties by reducing ROS production and improving antioxidative enzymes. Their effectiveness in mitigating UC was also evident in the renovation of normal intestinal epithelial barrier function, as shown by correcting the discrepancies in the levels of tight junction proteins ZO-1, OCLN, and CLDN5. Furthermore, their effects on the intestinal microbiota homeostasis were investigated. In terms of autophagy, exogenous β-hydroxybutyrate upregulated BECN-1 and downregulated p62, which may account for its superiority over KD in attenuating colonic damage. In conclusion, this study provides experimental evidence supporting the potential therapeutic use of β-hydroxybutyrate or β-hydroxybutyrate-boosting regimens in UC.


Bladder training versus combination of propiverine with bladder training for female urinary frequency. A prospective, randomized, comparative study.
Among lower urinary tract symptoms, urinary frequency is one of the prevalent symptoms in the female population. The objective of this study was to evaluate the effect of bladder training with or without pharmacotherapy in women with only a frequency symptom. Patients were randomized to either bladder training alone (n = 23) or propiverine combined with bladder training (n = 25). All patients were treated during 3 months. At baseline, daytime frequency was higher in the combination therapy group than in the bladder training group (p = 0.031). No difference in other characteristics was observed in the two groups. After treatment, there was no significant difference of functional bladder capacity and average voided volume between the two groups but daytime frequency was higher in the combination therapy group than in the bladder training group (p = 0.013). However, the changes of daytime frequency, functional bladder capacity and average voided volume were not significantly different in the groups. Of total patients, 15 (65.2%) in the bladder training group and 21 (84.0%) in the combination therapy group were rated as responders (defined as improved or much improved) (p = 0.133). Both bladder training with or without pharmacotherapy may improve the subjective and objective frequency symptom in women with only a frequency symptom. However, we could not find that there was more symptomatic improvement when anticholinergics combined with bladder training were compared with bladder training alone.


Surface labelling of senescent chick fibroblasts by lactoperoxidase-catalysed iodination.
Cell surface of chick fibroblasts were labelled by a short treatment with 125I in presence of lactoperoxidase. A glycoprotein (220,000 molec. wt) was iodinated and was present in a more exposed position or in greater amounts at the surface of old phase III cells compared to young phase II cells. The findings extend our previous observations on cell surface modifications in in vitro senescing fibroblasts.


Concurrent administration of thyroxine and donepezil induces plastic changes in the prefrontal cortex of adult hypothyroid rats.
The aim of the present study was to observe the effects of the concurrent administration of thyroxine (T4) and an acetylcholinesterase (AChE) inhibitor, donepezil (DON), on the hypothyroidism‑induced ultrastructural changes of the prefrontal cortex (PFC) in adult rats. The acetylcholine (ACh) content and AChE activity was assessed, as well as the expressions of synaptotagmin‑1 (syt‑1) and SNAP‑25 were analyzed in the rats. Adding 0.05% propylthiouracil to rats' drinking water induced a hypothyroid rat model. The animals were treated with T4 and DON administered separately or in combination from the fifth week. Transmission electron microscope analysis revealed that hypothyroidism induced marked ultrastructural changes, including the neurons, the synapses and the myelin sheath in the PFC. T4 or DON treatment improved the morphologic features of the PFC, and the performance of the T4 combined DON group was the closest to the control group. Moreover, hypothyroidism significantly decreased the content of ACh (29.8%) and activity of AChE (27.8%), which were restored to control values by T4 admi-nistration. In addition, DON treatment restored ACh content to normal. At the protein level, hypothyroidism increased the levels of syt‑1 and SNAP‑25 in the PFC, both of which were not restored to control values following T4 administration, while concurrent administration of T4 and DON was able to induce this effect. These results suggested that adult‑onset hypothyroidism induce morphological, biochemical and molecular alterations in the PFC, combined administration of T4 and DON induce plastic changes in the PFC, different from that of the standard T4 therapy, and that the DON treatment may facilitate the recovery of synaptic protein impairments induced by hypothyroidism.


Passive Shimming of MRI Static Magnetic Field Using Regularization of Truncated Singular Value Decomposition.
To develop a new shimming calculation method, which can calculate iron piece placements rapidly to make the magnetic field homogeneous at intended homogeneity and then to make the shimming working time short. The shimming calculation yields magnetic moment (MM) distribution, which is calculated by the truncated singular value decomposition (SVD) from the measured magnetic field. The MM distribution is described by a superposition of eigenmodes obtained by SVD of a response matrix from the moment distributions to magnetic fields at the field of view (FOV). The homogeneity is regulated by a truncation number of the superposed eigenmodes. The magnetic moments are converted into iron volumes with the assumption of saturated magnetization and the iron pieces are placed according to the calculation results. Since the SVD calculation can be done in advance, the computational time at the shimming site is short. Trial applications on a 0.5T magnetic resonance imaging (MRI) magnet were done using the new shimming calculation method, which was proved to work well. However, since the iron piece volumes had tolerances, the work was repeated until enough homogeneity was obtained. As a result, an intended homogeneity of 8.9 ppm (peak-to-peak) on 40 cm diameter spherical surface was successfully obtained from measured homogeneity of 543 ppm with short computational and working time. The test shimming work showed that the developed shimming calculation method with truncated SVD regularization is applicable to the shimming work on the MRI magnets.


Ovarian hyperstimulation syndrome as an etiology of obstructive uropathy.
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of controlled ovarian hyperstimulation (COH) protocols performed in women undergoing assisted reproductive technologies. Overstimulation of the ovaries results in the overproduction of vasoactive cytokines and mediators by the ovaries, thereby causing a generalized capillary leak and acute shift of protein-rich fluid from the intravascular compartment into the third space. This may lead to the development of ascites, pleural effusions, pericardial effusion, anasarca, intravascular volume depletion, hemoconcentration, oliguria, hypoalbuminemia and hypoproteinemia, electrolyte imbalances, acute renal failure, abdominal compartment syndrome, thromboembolic events, and adult respiratory distress syndrome. The only effective treatment available is prevention of the syndrome from developing by individualizing the stimulation protocol, especially in high-risk patients. Once the syndrome develops, the management is mainly supportive. Oliguria and some degree of acute renal failure commonly develop in patients with moderate to severe OHSS and are usually due to prerenal causes. Acute renal failure (ARF) secondary to obstructive uropathy is rare. Here we report a case of severe, life-threatening OHSS resulting in ARF secondary to obstructive uropathy.


Antinociceptive, anti-inflammatory and acute toxicity effects of Zhumeria majdae extracts in mice and rats.
Antinociceptive and anti-inflammatory effects and acute toxicity of aqueous infusion and ethanolic maceration extracts of the aerial parts of Zhumeria majdae were studied in mice and rats. Antinociceptive activity was determined using hot-plate and writhing tests. The effect of the extracts against acute inflammation was studied by acetic acid increased vascular permeability and xylene-induced ear edema in mice. The activity of the extracts against chronic inflammation was assessed using the cotton pellet test in rats. LD50 values of the infusion and maceration extracts were 3.09 g/kg body wt., and 3.94 g/kg body wt., respectively. Phytochemical screening of the extracts indicated the presence of flavonoids and tannins. In the hot-plate test, the intraperitoneal injection of both extracts showed significant and dose-dependent antinociceptive activity in mice. Naloxone, an opioid antagonist, on pretreatment inhibited the antinociceptive activity of the extracts. The extracts exhibited antinociceptive activity against acetic acid-induced writhing, which was partially blocked by naloxone. Both extracts showed significant effect against acute inflammation induced by acetic acid in mice. In the chronic inflammation test, efficacy of the extracts was similar to that of baclofen and dexamethasone in rats. It is concluded that the aqueous infusion and ethanolic maceration extract of the aerial parts of Zhumeria majdae have antinociceptive effects and this may be mediated by opioid receptors. The extracts also showed anti-inflammatory effects against acute and chronic inflammation.


Syntheses and biological activities of octahydro-1H-cyclopenta[d]pyrimidine derivatives.
Various nitromethylene derivatives were synthesized regioselectively. Compounds 8a-f were obtained by the reaction of 1-((5-chloropyridin-2-yl)methyl)-2-(nitromethylene)-octahydro-1H-cyclopenta[d]-pyrimidine (3) with primary amines and formaldehyde. The synthesized compounds were identified by 1H NMR, HRMS (EI), and IR, and preliminary bioassays indicated that most of them showed moderate insecticidal activities against Aphis craccivora. The relationship between hydrophobicity and biological activity was also discussed.


Performance of Trichogramma japonicum under field conditions as a function of the factitious host species used for mass rearing.
Different factitious hosts were used to mass rear Trichogramma japonicum Ashmead in different parts of the globe because thorough details were lacking in both the laboratory and the field. The objective of this study was to compare, parasitoid, T. japonicum reared in different factitious hosts. Three commonly used factitious host eggs, Corcyra cephalonica (Stainton), Ephestia kuehniella Zeller and Sitotroga cerealella Olivier were tested under laboratory conditions and then in the field over a yellow stem borer, Scirpophaga incertulus (Walker) of rice. The highest parasitism by T. japonicum was observed on E. kuehniella eggs. The parasitoid's highest emergence (88.99%) was observed on S. cerealella eggs at 24 h exposure, whereas at 48 h it was on E. kuehniella eggs (94.66%). Trichogramma japonicum females that emerged from E. kuehniella eggs were significantly long-lived. The days of oviposition by hosts and the host species were significant individually, but not their interaction. Higher proportions of flying T. japonicum were observed when reared on E. kuehniella and C. cephalonica eggs. Field results showed that T. japonicum mass-reared on E. kuehniella showed higher parasitism of its natural host, S. incertulus eggs. Hence, by considering these biological characteristics and field results, E. kuehniella could be leveraged for the mass rearing of quality parasitoids of T. japonicum in India, the Asian continent and beyond.


Anabolic steroids and growth hormone.
Athletes are generally well educated regarding substances that they may use as ergogenic aids. This includes anabolic steroids and growth hormone. Fortunately, the abuse of growth hormone is limited by its cost and the fact that anabolic steroids are simply more enticing to the athlete. There are, however, significant potential adverse effects regarding its use that can be best understood by studying known growth hormone excess, as demonstrated in the acromegalic syndrome. Many athletes are unfamiliar with this syndrome and education of the potential consequences of growth hormone excess is important in counseling athletes considering its use. While athletes contemplating the use of anabolic steroids may correctly perceive their risks for significant physiologic effects to be small if they use the steroids for brief periods of time, many of these same athletes are unaware of the potential for habituation to the use of anabolic steroids. The result may be incessant use of steroids by an athlete who previously considered only short-term use. As we see athletes taking anabolic steroids for more prolonged periods, we are likely to see more severe medical consequences. Those who eventually do discontinue the steroids are dismayed to find that the improvements made with the steroids generally disappear and they have little to show for hours or even years of intense training beyond the psychological scars inherent with steroid use. Counseling of these athletes should focus on the potential adverse psychological consequences of anabolic steroid use and the significant risk for habituation.


Administration of beta-glycolipids overcomes an unfavorable nutritional dependent host milieu: a role for a soy-free diet and natural ligands in intrahepatic CD8+ lymphocyte trapping and NKT cell redistribution.
Soy-based diets are a major source of sphingolipids and play a complicated role in various aspects of the immune system. Administration of beta-glycolipids, including beta-glucosylceramide (GC), beta-lactosylceramide (LC) and a 1:1 combination of GC and LC (IGL) were shown to exert immune-modulatory effects. To examine the effects of a soy-free diet, and several beta-glycolipids on concanavalin A (ConA)-induced hepatitis in the presence of an altered host glycolipid milieu. ConA hepatitis was induced in C57BL/6 mice that were fed a soy-free diet (glycolipid content 200 micromol/kg). Two hours prior to administration of ConA, animals were injected IP with GC, LC, IGL or PBS. Animals were sacrificed 6 h after ConA administration. Both a soy-free diet and administration of beta-glycolipids were associated with significant alterations in the distribution of NKT cells. Specifically, there was a decrease in intrahepatic and an increase in intrasplenic NKT lymphocytes. beta-glycolipids prevented the ConA-induced intrahepatic CD8 lymphocyte trapping, not seen in mice with only a soy-free diet. Both a soy-free diet and beta-glycolipids alleviated ConA-induced hepatitis by inhibiting IL10 secretion and increasing IL12 serum levels. The effect of IGL was clinically and immunological superior to that of either glycolipid alone. Both a soy-free diet and beta-glycolipids can overcome the unfavorable host milieu in the setting of ConA hepatitis. The host glycolipid milieu profoundly influenced the immune and clinical effects of various insults, and suggests that alteration of the glycolipid background of the host can serve as a novel therapeutic tool.


High-performance dye-sensitized solar cells based on solvent-free electrolytes produced from eutectic melts.
Low-cost excitonic solar cells based on organic optoelectronic materials are receiving an ever-increasing amount of attention as potential alternatives to traditional inorganic photovoltaic devices. In this rapidly developing field, the dye-sensitized solar cell (DSC) has achieved so far the highest validated efficiency of 11.1% (ref. 2) and remarkable stability. However, the cells with the best performance use volatile solvents in their electrolytes, which may be prohibitive for outdoor solar panels in view of the need for robust encapsulation. Solvent-free room-temperature ionic liquids have been pursued as an attractive solution to this dilemma, and device efficiencies of over 7% were achieved by using some low-viscosity formulations containing 1-ethyl-3-methylimidazolium thiocyanate, selenocyanate, tricyanomethide or tetracyanoborate. Unfortunately, apart from tetracyanoborate, all of these low-viscosity melts proved to be unstable under prolonged thermal stress and light soaking. Here, we introduce the concept of using eutectic melts to produce solvent-free liquid redox electrolytes. Using a ternary melt in conjunction with a nanocrystalline titania film and the amphiphilic heteroleptic ruthenium complex Z907Na (ref. 10) as a sensitizer, we reach excellent stability and an unprecedented efficiency of 8.2% under air-mass 1.5 global illumination. Our results are of importance to realize large-scale outdoor applications of mesoscopic DSCs.


A systematic review of qualitative studies on adjusting after stroke: lessons for the study of resilience.
To synthesize qualitative studies on adjusting after stroke, from stroke survivors' and carers' perspectives, and to outline their potential contribution to an understanding of resilience. A systematic review of qualitative studies in peer reviewed journals from 1990 to 2011 was undertaken. Findings from selected studies were summarized and synthesized and then considered alongside studies of resilience. Forty studies were identified as suitable. These suggested that the impact of stroke was felt on many dimensions of experience, and that the boundaries between these were permeable. Nor was stroke as an adverse "event" temporally bounded. Adjustment was often marked by setbacks and new challenges over time. Participants identified personal characteristics as key, but also employed practical and mental strategies in their efforts to adjust. Relationships and structural factors also influenced adjustment after stroke. The impacts of stroke and the processes of adjusting to it unfold over time. This presents a new challenge for resilience research. Processes of adjustment, like resilience, draw on personal, inter-personal and structural resources. But the reviewed studies point to the importance of an emic perspective on adversity, social support, and what constitutes a "good" outcome when researching resilience, and to a greater focus on embodiment. Implications for Rehabilitation Stroke is a sudden onset condition which for around a third of people has long-term consequences. Stroke can cause a variety of physical and cognitive impairments, some of which may not be obvious to an outsider. As well as physical functioning, stroke can have a profound effect on survivors' sense of self and on their relationships. Stroke survivors' accounts suggest that relationships (including relationships with health care professionals) and structural factors (such as access to health services, employment possibilities and welfare systems) mediate efforts to adjust after stroke. While there is considerable overlap between notions of adjustment and resilience, the experiences of stroke survivors suggest further issues that need to be addressed in order to gain a more comprehensive understanding of resilience.


COVID-19 Is an Independent Risk Factor for Acute Ischemic Stroke.
Coronavirus disease 2019 (COVID-19) is an active worldwide pandemic with diverse complications. Stroke as a presentation has not been strongly associated with COVID-19. The authors aimed to retrospectively review a link between COVID-19 and acute stroke. We conducted a retrospective case-control study of 41 cases and 82 control subjects matched by age, sex, and risk factors. Cases were patients who underwent stroke alert imaging with confirmed acute stroke on imaging between March 16 and April 5, 2020, at 6 hospitals across New York City. Control subjects were those who underwent stroke alertimaging during the same timeframe without imaging evidence of acute infarction. Data pertaining to diagnosis of COVID-19 infection, patient demographics, and risk factors were collected. A univariate analysis was performed to assess the covariate effect of risk factors and COVID-19 status on stroke imaging with positive findings. The mean age for cases and controls was 65.5 ± 15.3 years and 68.8 ± 13.2 years, respectively. Of patients with acute ischemic stroke, 46.3% had COVID-19 infection compared with 18.3% of controls (P = .001). After adjusting for age, sex, and risk factors, COVID-19 infection had a significant independent association with acute ischemic stroke compared with control subjects (OR, 3.9; 95% CI, 1.7-8.9; P = .001). We demonstrated that COVID-19 infection is significantly associated with imaging confirmation of acute ischemic stroke, and patients with COVID-19 should undergo more aggressive monitoring for stroke.


Steroid pretreatment improves graft recovery in a sheep orthotopic heart transplantation model.
Previous reports provide conflicting evidence concerning effects of steroids on recovery of cardiac function during procedures involving cardiopulmonary bypass. This study was designed to test the hypothesis that pretreatment of animals with steroids before heart transplantation improves graft hemodynamic function. Four groups of sheep were studied: CON, nonsteroid-treated nontransplanted controls (n = 8); CON-S, steroid-treated nontransplanted controls (n = 5); TX, nonsteroid-treated transplanted animals (n = 5); and TX-S, steroid-treated transplanted animals (n = 5). Steroid-treated animals were given methylprednisolone 30 mg/kg immediately before surgery. Procedures for harvest and orthotopic transplantation were similar to those used clinically. Contractile function, left ventricular diameter, and cardiac output of control and transplanted hearts were measured for 6 hours. A 2 x 2 factorial repeated measures analysis of variance was used to determine statistical significance (p < 0.05). Steroid pretreatment produced significantly higher function in controls and transplanted animals compared with nonsteroid-treated animals. On average over 6 hours, significant steroid effects were observed for left ventricular peak systolic pressure, mm Hg (CON, 85 +/- 2; CON-S, 98 +/- 3; TX, 74 +/- 3; TX-S, 91 +/- 2); global stroke work, mJoule x cm(-2) (CON, 4.69 +/- 0.21; CON-S, 5.88 +/- 0.32; TX, 2.27 +/- 0.17; TX-S, 4.23 +/- 0.16); and peak rate of pressure relaxation (-dP/dt(max)), mm Hg/msec (CON, 1.23 +/- 0.05; CON-S, 1.44 +/- 0.08; TX, 0.60 +/- 0.03; TX-S, 2.04 +/- 0.13). Steroid pretreatment produced more stable recovery for transplanted animals. All five TX-S animals could be removed from inotropic support and had stable function for 6 hours. In contrast, 1 of 5 TX animals could not be removed from inotropic support, and 1 of 5 TX hearts failed 3 hours after transplant. Arterial blood PO2 values were significantly higher in steroid-treated animals than in nonsteroid treated animals. Blood systemic lactate, which was elevated after transplantation, returned to control level by 6 hours in the steroid-treated group but not in the nonsteroid-treated group. Steroid pretreatment of heart donors and recipients improved systolic and diastolic function and hemodynamic stability after transplantation. In addition, steroid pretreatment improved pulmonary gas exchange of control and transplanted animals.


Inability of serum from abetalipoproteinemic subjects to stimulate proliferation of human smooth muscle cells and dermal fibroblasts in vitro.
Serum from two patients with abetalipoproteinemia, a rare disorder of lipid metabolism characterized by the absence of chylomicrons and very low density and low density lipoproteins, did not stimulate the proliferation and growth of human smooth muscle cells or dermal fibroblasts in vitro as effectively as normal serum. The growth-promoting activity of this serum was comparable to that observed for lipoprotein-deficient plasma from normolipidemic subjects. Although the mitogenic effect of abetalipoproteinemic serum was improved with supplementation of low density lipoproteins, it was still about half the activity achieved with normal serum. However, the growth-promoting activity of this serum was completely restored to normal levels after addition of a lysate of normal platelets. In contrast, the mitogenic activity of lipoprotein-deficient plasma remained unchanged after addition of a lysate from abetalipoproteinemic platelets, whereas a similar supplementation of normal platelets completely restored its growth-promoting activity to normal. Thus, the inability of abetalipoproteinemic serum to promote growth appears to be due both to a deficiency of a platelet-releasable growth factor(s) and to the absence of serum lipoproteins.


Porphyrin-Based Brain Tumor-Targeting Agents: [64Cu]Cu-porphyrin and [64Cu]Cu-TDAP.
The aim of this study is to evaluate a radioactive metal complex platform for brain tumor targeting. Herein, we introduce a new porphyrin derivative, 5,10,15,20-(tetra-N,N-dimethyl-4-aminophenyl)porphyrin (TDAP), in which four N,N-dimethyl-4-p-phenylenediamine (DMPD) moieties are conjugated to the porphyrin labeled with the radiometal 64Cu. DMPD affected the pharmacokinetics of porphyrin in terms of retention time in vivo and tumor-targeting ability relative to those of unmodified porphyrin. [64Cu]Cu-TDAP showed stronger enhancement than [64Cu]Cu-porphyrin in U87MG glioblastoma cells, especially in the cytoplasm and nucleus, indicating its tumor-targeting properties and potential use as a therapeutic agent. In the subcutaneous and orthotopic models of brain-tumor-bearing mice, [64Cu]Cu-TDAP was clearly visualized in the tumor site via positron emission tomography imaging and showed a tumor-to-brain ratio as high as 13. [64Cu]Cu-TDAP deserves attention as a new diagnostic agent that is suitable for the early diagnosis and treatment of brain tumors.


Racial and ethnic differentials in overweight and obesity among 3-year-old children.
We estimated racial/ethnic differences in overweight and obesity in a national sample of 3-year-olds from urban, low-income families and assessed possible determinants of differences. Survey, in-home observation, and interview data were collected at birth, 1 year, and 3 years. We used logistic regression analyses and adjusted for a range of covariates in examining overweight and obesity differentials according to race/ethnicity. Thirty-five percent of the study children were overweight or obese. Hispanic children were twice as likely as either Black or White children to be overweight or obese. Although we controlled for a wide variety of characteristics, we were unable to explain either White-Hispanic or Black-Hispanic differences in overweight and obesity. However, birthweight, taking a bottle to bed, and mother's weight status were important predictors of children's overweight or obesity at age 3 years. Children's problems with overweight and obesity begin as early as age 3, and Hispanic children and those with obese mothers are especially at risk.


Aspartyl protease from Trichoderma harzianum CECT 2413: cloning and characterization.
A gene that encodes an extracellular aspartyl protease from Trichoderma harzianum CECT 2413, papA, has been isolated and characterized. Based on several conserved regions of other fungal acid proteases, primers were designed to amplify a probe that was used to isolate the papA gene from a genomic library of T. harzianum. papA was an intronless ORF which encoded a polypeptide of 404 aa, including a prepropeptide at the N-terminal region formed by one putative signal peptide, a second peptide which could be cleaved to activate the enzyme and the active protease of calculated 36.7 kDa and pI 4.35. Northern experiments indicated that papA gene was pH regulated, repressed by ammonium, glucose and glycerol, and induced by organic nitrogen sources. The promoter possessed potential AreA, PacC and MYC sites for nitrogen, pH and mycoparasitism regulation respectively, but lacked potential CreA sites for carbon regulation. IEF and zymograms indicated that PAPA was a pepstatin-sensitive aspartyl protease of pI 4.5. Transformants from T. harzianum CECT 2413 cultivated in yeast extract-supplemented medium overexpressed papA and had a fourfold increase in protease activity compared to the wild-type, while transformants that overexpressed the beta-1,6-glucanase gene bgn16.2 and papA had an additional 30% increase in beta-1,6-glucanase activity compared to bgn16.2 single transformants. Overexpression of both genes in ammonium-supplemented medium did not result in higher levels of PAPA and/or BGN16.2 proteins. These results indicated that both PAPA and beta-1,6-glucanase undergo proteolysis in ammonium-supplemented medium but PAPA is not responsible for beta-1,6-glucanase degradation.


Reflex testing to define action limits for community-based requests.
Critical values are required to be phoned 24/7. Other abnormal results fall short of the thresholds used to define critical values and may only be required to be phoned during the day. Community-based requestors prefer not to be contacted unless a result is critical and contacting them requires substantial staff resource. It is common practice to add tests to requests to expedite diagnosis or clarify the significance of a particular result using algorithms. We devised algorithms for reflex addition of tests which allowed the differentiation of significantly abnormal results as either critical values or those that only require day phoning. Algorithms identified 158 out of 309 tests as being critical (51%) over nine months. Reflex addition of serum bicarbonate identified 4% of serum glucose (24.9-37.9 mmol/L) as critical. Use of estimated glomerular filtration rate by reflex addition of serum creatinine identified 68% of serum lithium (1.49-1.99 mmol/L) as critical. Addition of serum potassium, calcium and magnesium identified 21% of serum digoxin (>2.49 nmol/L) as critical and addition of serum potassium and calcium to all samples with serum magnesium (<0.31 mmol/L) identified hypocalcaemia in all cases. The addition of serum creatinine and potassium as markers for rhabdomyolysis-induced acute renal failure did not help in the differentiation of serum creatine kinase>4999 μ/L. Use of reflex tests helped inform a phoning system based on the division of results into critical values and non-emergency abnormal values. This avoids disturbing requestors unnecessarily and conserves staff time at night.


Naevus lipomatosus cutaneous superficialis.
A young male presenting with cutaneous papules and plaques in a segmental distribution in the pelvic girdle area is reported. The clinical features were suggestive of naevus lipomatosus cutaneous superficialis, but diagnostic biopsy is essential to demonstrate the typical histopathological features and exclude important differential diagnoses such as segmental neurofibromatosis.


Tumor-secreted exosomal Wnt2B activates fibroblasts to promote cervical cancer progression.
The activation of stromal fibroblasts into cancer-associated fibroblasts (CAFs) has been suggested to promote primary tumor growth and progression; however, the mechanisms underlying the crosstalk between tumors and fibroblasts that drives stromal heterogeneity remain unknown. Here, we show that high Wnt2B levels were positively correlated with the number of CAFs in cervical cancer (CC). More importantly, Wnt2B was characteristically enriched in CC cell-secreted exosomes and transferred into fibroblasts to promote fibroblast activation via Wnt/β-catenin signaling, and inhibiting exosomal release or the Wnt/β-catenin signaling pathway diminished the activation induced by exosomal Wnt2B. Moreover, circulating exosomal Wnt2B also promoted CAF conversion in vitro and its expression was significantly higher in CC patients. In conclusion, our findings indicate that CC cell-derived Wnt2B can induce the activation of fibroblasts into CAFs, mainly via exosome-dependent secretion, thus providing directions for the development of diagnostic and therapeutic targets for CC progression.


[Endoscopic gastrocnemius recession as therapy for gastrocnemius equinus].
Endoscopic gastrocnemius recession is a new technique to treat gastrocnemius equinus. Smaller incisions and the ability to perform the technique in a supine position are purported advantages. This study was designed to evaluate the results and possible complications of this new technique. 47 patients undergoing 54 endoscopic gastrocnemius recessions were followed in a prospective study. Pre-operative criteria were a lack of ankle dorsiflexion with the knee extended to create a 90 degrees relationship of the foot to the leg in symptomatic patients. Pre- and postoperative ankle dorsiflexion were assessed, as were complications such as infection, nerve injury, haematoma, over-lengthening and poor cosmesis. Mean age of the patients was 49.4 years. Post-operative follow-up from the index procedure was 27 months (range: 12 - 62 months). Pre-operative dorsiflexion was - 8 +/- 4 degrees; post-operative this improved significantly to 7 +/- 4 degrees (p = 0.00001). Most patients had additional reconstructive procedures. There were no infections; six limbs had lateral foot or leg dysaesthesia, one haematoma, one over-lengthened gastrocnemius while six limbs has an unacceptable cosmesis (due to tenting of the skin). Two diabetic patients required additional Achilles tendon lengthening in subsequent surgery. Patients with pre-operative dorsiflexion of - 10 degrees or more had an untoward result, but this was not statistically significant (p = 0.13). Lateral foot dysaesthesia was observed more often in patients having a combined procedure with calcaneal osteotomy (p = 0.03). The endoscopic gastrocnemius recession procedure can significantly increase ankle dorsiflexion, but has potential complications including lateral dysaesthesia (11 %), and unacceptable cosmesis (11 %) as the most common. Modifications to the technique may be needed. Overall, the endoscopic technique appears promising in decreasing gastrocnemius contracture.


Association between TNF α gene polymorphisms and the risk of duodenal ulcer: a meta-analysis.
Epidemiological studies have evaluated the association between tumor necrosis factor α (TNF-α) single nucleotide polymorphisms (SNPs) and duodenal ulcer (DU), but the results remain inconclusive. The aim of this study was to perform a meta-analysis to investigate a more authentic association between TNF-α SNPs and DU. We performed the meta-analysis by searching PubMed, Embase, and Web of Science databases from the first available year to Sep. 5, 2012. Additionally, checking reference lists from identified articles, reviews, and the abstracts presented at related scientific societies meetings were also performed. All case-control studies investigating the association between TNF-α SNPs and DU risk were included. The association was assessed by odds ratio (OR) with 95% confidence interval (CI). Publication bias was analyzed by Begg's funnel plot and Egger's regression test. A total of sixteen studies reporting TNF-α -308G/A, -1031T/C, -863C/A, -857C/T, and -238G/A polymorphism were included in our final meta-analysis. There was no statistically significant association between -308G/A polymorphism and DU in the overall study population, as well as subgroup analyses by ethnicity, study design, and H. pylori status. As for -1031T/C, -863C/A, -857C/T, and -238G/A, results of our meta-analyses showed no statistical evidence of significant association. Power calculation on the combined sample size showed that the statistical powers were all lower than 80% for all the meta-analyses. The data suggests that there is no statistical evidence of significant association between the studied TNF-α SNPs and DU. However, this conclusion should be interpreted with caution as low statistical powers were revealed by power calculations. In future, larger sample-size studies with homogeneous DU patients and well-matched controls are required.


The influence of insulin and glucagon on the interactions between glycolytic enzymes and cellular structure.
The influence of insulin and glucagon on the release of glycolytic enzyme activities and actin from cultured pig kidney cells treated with digitonin has been studied. Both insulin and glucagon reduced the release of all glycolytic enzymes except for phosphofructokinase, and concurrently reduced the release of actin. These data have been discussed in relation to their contribution to knowledge of the interactions between glycolytic enzymes and actin filaments of the cytoskeleton, and to the influence of hormones on these interactions.


Screening and treatments using telemedicine in retinopathy of prematurity.
Several studies have validated the role of telemedicine as a new powerful screening and diagnostic tool for retinal disorders, such as diabetic retinopathy and retinopathy of prematurity. With regard to retinopathy of prematurity, bedside examination with binocular indirect ophthalmoscopy has been the gold standard technique for screening, yet with several limitations. Herein, we review the current evidence that supports the role of telemedicine for the screening of infants with retinopathy of prematurity.


A patient-specific approach to assessing blood pressure management in patients with hypertension and coronary artery disease.
The objective was to improve the management of patients with hypertension (HTN) and coronary artery disease (CAD), utilizing a model which integrates 3 determinants of coronary blood flow (CBF)-CAD severity, diastolic blood pressure (DBP), and left ventricular (LV) mass. We validated non-parametric equations for CBF estimation in a consecutive patient sample (N = 81) with HTN and CAD. There was a highly significant correlation (r = .565; P < .01) between clinical DBP and estimated CBF. Greater LV mass and more severe CAD shifted the relationship towards less CBF at the same DBP. LV mass was more critical when DBP >70 mm Hg. Estimated changes in CBF at different DBP considering the severity of CAD and LV mass can be calculated. In summary, the severity of CAD from coronary CT or coronary angiography combined with LV mass from echocardiography permits clinicians to guide the extent of, or target for, DBP to avoid seriously compromising CBF.


Expression of Heat Shock Protein Genes in Different Developmental Stages and After Temperature Stress in the Maize Weevil (Coleoptera: Curculionidae).
The maize weevil, Sitophilus zeamais Motschulsky, is a major pest of rice and other postharvest grain stocks in tropical countries. Heating and cooling treatments have been adopted to control this pest. Because heat shock protein (hsp) genes respond to temperature stress, we examined the association of hsp genes with development and thermal stress in S. zeamais. The temperature response of the insect to heat and cold treatments was assessed at four developmental stages: egg, larva, pupa, and adult. LT50 values at high temperatures were similar among the four developmental stages, while adults were the most tolerant to low temperatures, and eggs, larvae, and pupae exhibited similar LT50 values. Expression levels of three hsps--Szhsp70, Szhsc70, and Szhsp90--fluctuated substantially throughout the four stages at a rearing temperature of 28°C. Heat shock and cold shock increased the expression of all three hsps, and the highest upregulation was observed at 40°C, although the intensity of upregulation varied among the three genes: strongly in Szhsp70, moderately in Szhsp90, and slightly in Szhsc70. Basal expression of the three hsps at 28°C and gene responses to heat and cold shock also varied significantly at the tissue level.


Factitious decompression sickness.
The diagnosis of decompression sickness is made largely by history; there are few physical findings and no radiographic or laboratory tests to support the diagnosis. We present three cases of factitious decompression sickness in which patients fabricated an appropriate history and underwent compression therapy. Due to the potential severity of decompression sickness and the relative safety of compression therapy, the initiation of therapy must not be delayed in a case of decompression sickness. Once therapy is begun, investigation into the particulars of a suspicious case can be made.


Teaching geriatrics using an innovative, individual-centered educational game: students and educators win. A proof-of-concept study.
Given the increasingly aging population, nearly every doctor will encounter elderly adults who present with multiple complex comorbidities that can challenge even experienced physicians. This may explain why many medical students do not have a positive attitude toward elderly adults and find the complexity of their problems overwhelming. It was hypothesized that a recently developed medical school geriatrics course, based on the game GeriatriX and designed specifically to address the complexities associated with decision-making in geriatrics, can have a positive effect on attitudes toward geriatrics and on perceived knowledge of geriatrics. The effects of this game-based course were evaluated as a proof of concept. The assessment was based on the Aging Semantic Differential (ASD) and a validated self-perceived knowledge scale of geriatric topics. The usability of (and satisfaction with) GeriatriX was also assessed using a 5-point Likert scale. After completion of the course, the ASD changed significantly in the geriatrics course group (n = 29; P = .02) but not in a control group that took a neuroscience course (n = 24; P = .30). Moreover, the geriatrics course group had a significant increase in self-perceived knowledge for 12 of the 18 topics (P = .002), whereas in the control group self-perceived knowledge increased significantly for one topic only (sensory impairment) (P = .04). Finally, the geriatrics students reported enjoying GeriatriX. This proof-of-concept study clearly supports the hypothesis that a 4-week course using a modern educational approach such as GeriatriX can improve students' self-perceived knowledge of geriatrics and their attitudes toward elderly adults.


Aldehyde Dehydrogenases 1A2 Expression and Distribution are Potentially Associated with Neuron Death in Spinal Cord of Tg(SOD1*G93A)1Gur Mice.
The pathogenesis of amyotrophic lateral sclerosis (ALS) has not been unclear yet, it might be associated with the abnormal expression and distribution of certain proteins. Aldehyde dehydrogenases 1A2 (ALDH1A2) was thought to be one of potential candidates. Therefore, in this study we observed and analyzed the alteration of the expression and distribution of ALDH1A2 in the spinal cord of wild-type (WT) and Tg(SOD1*G93A)1Gur mice. We compared the expression and distribution of ALDH1A2 in the different segments, anatomic regions and neural cells of spinal cord at the different stages of WT and Tg(SOD1*G93A)1Gur mice applied the methods of fluorescent immunohistochemistry and western blot. Results revealed that ALDH1A2 extensively expressed and distributed in the spinal cord of adult WT and Tg(SOD1*G93A)1Gur mice. The expression and distribution of ALDH1A2 in the white matter including the anterior, posterior and lateral funiculus were more than that in the gray matter including the central canal, the anterior and dorsal horn. ALDH1A2 majorly expressed and distributed in the astrocyte, microglial, oligodendrocyte and neuron cells. The ALDH1A2 expression significantly decreased and redistributed in some anatomic regions of spinal cord at the onset and progression stages of Tg(SOD1*G93A)1Gur mice. The expression decrease of ALDH1A2 followed with the increase of neuron cells death. This study suggested that the alteration of expression and distribution of ALDH1A2 was potentially associated with the pathogenesis of ALS.


Differential Effect of White-Matter Lesions and Covert Brain Infarcts on the Risk of Ischemic Stroke and Intracerebral Hemorrhage.
We examined the association of white-matter hyperintensity (WMH) volume and covert brain infarcts, which are the 2 major magnetic resonance imaging markers of covert cerebrovascular disease in older adults, with long-term risk of ischemic stroke and intracerebral hemorrhage (ICH) in the general population. Participants were 1731 individuals aged ≥65 years from the Three-City Dijon study. We studied the association of WMH volume and brain infarct, with incident ischemic stroke overall, and by subtype, and with incident ICH. High total, periventricular, and deep WMHs were associated with incident ICH. Extensive periventricular WMH volume was associated with increased risk of ischemic stroke (hazard ratio, 1.94; 95% confidence interval, 1.12-3.35), particularly cardioembolic stroke. Covert brain infarcts were associated with incident ICH but not with incident ischemic stroke or its subtypes. Although of ischemic nature, both WMH volume and covert brain infarcts portend a major risk of ICH. If confirmed in independent studies, these findings could have important implications for the clinical management of covert vascular brain lesions.


Offset analgesia is not affected by cold pressor induced analgesia.
Background and aims Offset analgesia (OA) is a pain modulating mechanism described as a disproportionately large decrease in pain intensity evoked by a minor decrease in stimulus intensity. Precise mechanisms of OA are still not elucidated and studies are needed to evaluate factors modulating OA. The aim of this study was to investigate OA before and during tonic cold pain (thought to induce descending inhibition), in a group of healthy volunteers. Methods A randomized, crossover study was performed in 17 healthy participants (8 males and 9 females). The OA paradigm lasted 35 s and was induced by the traditional method using thermal stimulation applied to the forearm. A constant control heat stimulus (CTL) paradigm was used as control to assess adaptation. Pain intensity was assessed continuously. For induction of tonic cold pain, the participants immersed their hand into 2°C water for 2 min. After 1 min and 25 s, the heat stimulation (OA or CTL paradigm) was repeated to assess the modulatory effect of the cold pressor test. Results It was possible to induce OA both before and during the cold pressor test. Tonic cold pain modulated the peak pain reported during both the OA (p=0.015) and CTL paradigms (p=0.001) reflecting endogenous pain modulation. However, the magnitude of OA was not modulated by tonic cold pain (p>0.05). Conclusions The offset analgesia magnitude was not modulated by simultaneously tonic cold pain, thought to reflect another endogenous pain modulation mechanism. Implications Neither offset analgesia magnitude nor adaptation were modulated by cold pressor induced endogenous analgesia. This could be explained by the fact, that offset analgesia was already at maximum in healthy participants. Hence, offset analgesia may not be a suitable assessment tool to investigate modulation induced by experimental methods or pharmacology in healthy participants.


Cross-reactive antibodies against Langat virus protect mice from lethal tick-borne encephalitis virus infection.
Naturally attenuated Langat virus (LGTV) and highly pathogenic tick-borne encephalitis virus (TBEV) share antigenically similar viral proteins and are grouped together in the same flavivirus serocomplex. In the early 1970s, this has encouraged the usage of LGTV as a potential live attenuated vaccine against tick-borne encephalitis (TBE) until cases of encephalitis were reported among vaccinees. Previously, we have shown in a mouse model that immunity induced against LGTV protects mice against lethal TBEV challenge infection. However, the immune correlates of this protection have not been studied. We used the strategy of adoptive transfer of either serum or T cells from LGTV infected mice into naïve recipient mice and challenged them with lethal dose of TBEV. We show that mouse infection with LGTV induced both cross-reactive antibodies and T cells against TBEV. To identify correlates of protection, Monitoring the disease progression in these mice for 16 days post infection, showed that serum from LGTV infected mice efficiently protected from developing severe disease. On the other hand, adoptive transfer of T cells from LGTV infected mice failed to provide protection. Histopathological investigation of infected brains suggested a possible role of microglia and T cells in inflammatory processes within the brain. Our data provide key information regarding the immune correlates of protection induced by LGTV infection of mice which may help design better vaccines against TBEV.